Adult Depression Clinical Practice Guideline

N ATIONAL C LINICAL P RACTICE G UIDELINE
Adult Depression
Clinical Practice Guideline
This guideline is informational only. It is not intended or designed as a substitute for the
reasonable exercise of independent clinical judgment by practitioners, considering each
patient’s needs on an individual basis.
Guideline recommendations apply to populations of patients. Clinical judgment is necessary
to design treatment plans for individual patients.
Approved by the
National Guideline Directors
February 2012
Table of Contents
Introduction................................................................................................................................... 1
Guideline Summary ...................................................................................................................... 5
Rationale Statements .................................................................................................................. 12
1. First-Line Treatment of Major Depressive Disorder (MDD) .............................................. 12
2. Hypericum (St. John’s Wort) for MDD............................................................................... 38
3. Antidepressants In Patients With MDD Expressing Suicidal Ideation, Intent, Or Plan ...... 44
4. Second-Line Treatment Of MDD ........................................................................................ 48
5. Length Of Treatment With Antidepressants In Patients With MDD................................... 63
6. Follow-Up For Patients In The Acute Phase of Treatment For MDD................................. 70
7. Follow-Up For Patients In The Continuation Phase of Treatment of MDD........................ 72
8. Follow-Up For Patients In Maintenance Phase of Treatment of MDD ............................... 74
9. Discontinuation of Antidepressants in Patients with MDD................................................. 75
10. Treatment Preferences For MDD In Different Ethnic Groups ............................................ 77
11. Patient Self-Management Strategies for Improving Symptoms of MDD............................ 80
12. Behavioral Health Education Classes For Adults With MDD............................................. 95
13. Antidepressants To Avoid During Pregnancy or Breastfeeding.......................................... 98
Appendix A: Criteria for Grading the Evidence ................................................................... 108
Appendix B: Supporting Documentation ............................................................................... 110
1. First-Line Treatment of Major Depressive Disorder (MDD) ............................................ 110
Problem Formulation 1 ......................................................................................................... 110
Search Strategy ..................................................................................................................... 111
Evidence Tables .................................................................................................................... 114
2. Hypericum (St. John’s Wort) For Treatment of MDD ...................................................... 196
Problem Formulation 2 ......................................................................................................... 196
Search Strategy ..................................................................................................................... 197
Evidence Tables .................................................................................................................... 200
3. Antidepressants In Patients With MDD Expressing Suicidal Ideation, Intent, or Plan..... 207
Problem Formulation 3 ......................................................................................................... 207
Search Strategy ..................................................................................................................... 208
Evidence Tables .................................................................................................................... 210
4. Second-Line Treatement of MDD ..................................................................................... 214
Problem Formulation 4 ......................................................................................................... 214
Search Strategy ..................................................................................................................... 215
Evidence Tables .................................................................................................................... 218
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5. Length of Treatment With Antidepressants In Patients With MDD.................................. 228
Problem Formulation 5 ......................................................................................................... 228
Search Strategy ..................................................................................................................... 229
Evidence Tables .................................................................................................................... 232
6. Follow-Up For Patients In The Acute Phase of Treatment For MDD............................... 239
Problem Formulation 6 ......................................................................................................... 239
Search Strategy ..................................................................................................................... 240
Evidence Table...................................................................................................................... 242
7. Follow-Up For Patients In The Continuation Phase of Treatment For MDD ................... 243
Problem Formulation 7 ......................................................................................................... 243
Search Strategy ..................................................................................................................... 244
Evidence Table...................................................................................................................... 246
8. Follow-Up For Patients In Maintenance Phase Treatment Of MDD ................................ 247
Problem Formulation 8 ......................................................................................................... 247
Search Strategy ..................................................................................................................... 248
Evidence Table...................................................................................................................... 249
9. Discontinuation of Antidepressants In Patients With MDD.............................................. 250
Problem Formulation 9 ......................................................................................................... 250
Search Strategy ..................................................................................................................... 251
Evidence Tables .................................................................................................................... 253
10. Treatment Preferences For MDD In Different Ethnic Groups .......................................... 255
Problem Formulation 10 ....................................................................................................... 255
Search Strategy ..................................................................................................................... 256
Evidence Table...................................................................................................................... 258
11. Patient Self-Management Strategies For Improving Symptoms of MDD......................... 259
Problem Formulation 11 ....................................................................................................... 259
Search Strategy ..................................................................................................................... 260
Evidence Tables .................................................................................................................... 262
12. Behavioral Health Education Classes For Adults With MDD........................................... 276
Problem Formulation 12 ....................................................................................................... 276
Search Strategy ..................................................................................................................... 277
Evidence Tables .................................................................................................................... 279
13. Antidepressants To Avoid During Pregnancy or Breastfeeding........................................ 283
Problem Formulation 13 ....................................................................................................... 283
Search Strategy ..................................................................................................................... 284
Evidence Tables .................................................................................................................... 285
References.................................................................................................................................. 298
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Introduction
Kaiser Permanente’s National Guideline Program
The National Guideline Program (NGP) supports the development of a core set of explicit,
scientifically-based clinical practice guidelines, practice resources, and evidence synopses to
assist Kaiser Permanente (KP) physicians, administrators, and other health care professionals in
determining the most effective medical practices.
This core set of evidence-based resources will:
 Create Programwide economies of scale,
 Support ongoing performance improvement activities,
 Consistently provide high quality resources for use in care delivery tools and systems, and
 Increase KP regions’ abilities to leverage clinical guidelines to improve clinical outcomes.
Clinical practice guidance, based on scientific evidence, is essential for providing high quality
care and continuously improving on it. Such guidance needs to be integrated into the electronic
medical record and other decision support tools to be accessible to clinicians at the point of care.
In addition, engaging our members in collaborative, shared decision-making conversations
regarding their personal preferences is an essential component of patient-centered quality care.
Furthermore, cost-effectiveness of various evidence-based interventions and resource limitations
are important considerations. This involves addressing health problems in ways that maximize
the health of the population given the available resources.
Who are the National Guideline Directors’?
The National Guideline Directors (NGD) are a group of experts and advocates of evidence-based
medicine who provide direction and oversight to the National Guideline Program (NGP). In this
role, the NGD selects and approves topics for evidence-based knowledge products, owns Kaiser
Permanente’s Common Methodology, and is responsible for quality assurance review. This
group is composed of representatives from the Care Management Institute (CMI) and all eight
regions.
What Is the Guideline Quality Committee?
The Guideline Quality (GQ) Committee is a subcommittee of the NGD consisting of a group of
evidence experts from various KP regions and CMI who review and approve all the National
Guidelines. This review ensures that the processes used to develop guideline content have
adhered to KP evidence-based methods and that the labels applied to clinical recommendations
therein are accurate (e.g., “evidence-based” or “consensus-based”).
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How Are Guidelines Developed?
Guidelines are developed with the use of an “evidence-based methodology” and involve a
systematic literature search, critical appraisal of the research design and statistical results of
relevant studies, and grading of the sufficiency (quantity, quality, consistency, and relevancy) of
the evidence for drawing conclusions. An evidence search includes literature published in peerreviewed scientific journals, existing evidence-based guidelines, consensus-based statements
from external professional societies and government health organizations, and clinical expert
opinion of KP regional specialty groups. For additional information on evidence grading, see
Table 1 in Appendix A.
To develop a or revise a guideline, CMI consultants work with a multidisciplinary Guideline
Development Team (GDT). Each GDT consists of a core group of physicians, representing
primary care and the specialties most affected by the guideline topic, and, as appropriate, other
content experts from disciplines such as pharmacy, nursing, and health education. The members
of a GDT are nominated by the respective National Guideline Directors to represent their
regions. The GDT reviews the appraisal of the evidence and develops or revises clinical
recommendations based on the current evidence. Each regional representative then presents the
draft guideline recommendations to key experts and champions in their regions for critical
review and support to improve the likelihood of implementation once the guideline is published.
How Often Are Guidelines Reviewed and Revised?
To keep current with changing medical practices, all guidelines are reviewed, and, if appropriate,
revised at least every two years. To develop the Adult Depression Guideline, released in
February 2010, a multidisciplinary, interregional GDT first met in November 2009 to define the
scope of the guideline. The Project Management Team then performed systematic reviews of the
medical literature on each of the clinical questions identified by the GDT, assembled the
evidence, and developed draft recommendations for review by the GDT. All of the
recommendations and supporting evidence were reviewed in depth by the GDT in a series of
meetings from November through January 2010. The GQ Committee reviewed and approved the
guidelines in February 2010. All recommendations included in the guideline were approved by
the NGD.
What Does It Mean for a Guideline to Be Evidence-Based?
Each clinical recommendation within a guideline is labeled as “evidence-based” or “consensusbased.” A recommendation is considered “evidence-based” if there has been a systematic review
of the evidence, the evidence is sufficient, and the recommendation is consistent with the
evidence. A recommendation can also be considered “evidence-based” if there is insufficient
evidence but either no particular intervention is recommended or options are recommended
without favoring one of the options over others. A recommendation is considered “consensusbased” if there has been a systematic review of the evidence, the evidence is insufficient to
support an evidence-based recommendation, and the GDT decides to make a consensus
recommendation.
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What Does It Mean for a Guideline to Be Approved and National?
A recommendation that is consistent with the above policies is labeled as “National Guideline
Directors Approved.” A recommendation that fails to satisfy those criteria is not approved and
will be noted as such. A National Guideline Directors Approved guideline for which at least 90%
of the recommendations are approved by at least six of the eight KP regions is a "National
Guideline." On the topics for which they exist, National Guidelines are the preferred evidence
source for KP HealthConnect content.
Contact information:
David Price, MD
Adult Depression Clinical Lead
Care Management Institute
E-mail: [email protected]
Devon McCabe, MA
Care Management Consultant
Care Management Institute
E-mail: [email protected]
Acknowledgments
The Kaiser Permanente (KP) Adult Depression Clinical Practice Guideline is the result of the
extensive clinical expertise, collaborative efforts, and outstanding personal contributions of
the following participants:
KP Adult Depression Guideline Project Management Team
David Price, MD
Devon McCabe, MA
Christy N. Pham, MPH
Erin G. Stone, MD, FACP
Tabitha Pousson
Clinical Lead
Project Manager
Lead Analyst
EBM Methodologist
Staff Assistant
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Care Management Institute
Care Management Institute
KP-Southern California
Care Management Institute
Care Management Institute
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KP Adult Depression Guideline Development Team
There were no conflict of interests for any member of the Guideline Development Team (GDT).
Jean E Milofsky MD – Regional Department Chair, Psychiatry
Kerri Gaughan, PharmD, BCPP – Clinical Pharmacy Specialist, Mental Health
David Price, MD – Director of Medical Education, CPMG;
CMI Depression Guideline & Education Lead;
Medical Director, KP National CME Program
Georgia
Sam W. Moss, MD, MS – Lead Physician, Adult Medicine;
Assistant to the Chief of Medicine for
Asthma/Depression
John Draeger, MD – Chief, Behavioral Health Service
Hawai’i
Samuel V Gadam – Geriatric psychiatrist
Mid-Atlantic States
Timothy M Sitts, MD – Psychiatrist
Northern California
Mason Turner, MD – Chief, Department of Psychiatry;
Assistant Director, Regional Mental Health
and Chemical Dependency
Joyce O. Arango, DrPH – Sr. Managerial Consultant, Northern California
Guidelines Director
John Guzman, PhD – Subchief, SSF Behavioral Medicine, Regional
Chair; Behavioral Medicine Subchiefs
Gabrielle Beaubrun, MD – Psychiatrist Assistant Chief of Psychiatry
Steve Olson, MD – Family Physician, Depression Champion;
Co-Manager Behavior Medicine Services
Northwest
Jonathan Ebbing, MD – Psychiatrist
Ohio
William S. Schwab, MD PhD AGSF – Chief of Geriatrics
Horia Craciun, MD – Psychiatrist
Larissa Elgudin, MD – Regional Chief of Behavioral Health Services,
Parma
Program Offices
Andrew Bertagnolli, PhD – Senior Consultant,
Behavioral Medicine & Pain Mgmt
Care Management Institute
Southern California Christy N. Pham, MPH – Consultant, Technology Assessment &
Guidelines Unit
Erin G. Stone, MD, FACP – Physician Lead,
Clinical Content and Decision Support
Debbie R Kubota, PharmD – Pharmacist Evidence Analyst & Strategist
Misha Askren, MD – Family Medicine
Mark Dreskin, MD – Regional Depression Co-Lead;
Physician in Charge;
Same Day Acute Medical Services
Kerri Gaughan, PharmD, BCPP – Clinical Pharmacy Specialist, Mental Health
Colorado
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Guideline Summary
This guideline is informational only. It is not intended or designed as a substitute for the
reasonable exercise of independent clinical judgment by practitioners, considering each
patient’s needs on an individual basis.
Guideline recommendations apply to populations of patients. Clinical judgment is necessary
to design treatment plans for individual patients.
1.
First-Line Treatment of Major Depressive Disorder (MDD)
1A
For patients with mild to moderate Major Depressive Disorder (MDD), use either
antidepressant medication or psychotherapy* as first-line treatment. Evidence-based: B
Given the lack of evidence on a clearly superior approach for mild to moderate MDD,
base treatment decisions on patient and clinician preference, potential side effects, and
cost. Consensus-based
For patients with severe or chronic MDD, combine antidepressant use and
psychotherapy* as first-line treatment. Evidence-based: B
If antidepressants are used, any class of antidepressant (SSRI, TCA, SNRI, NRI, or DA)
may be prescribed as first-line treatment of MDD. Evidence-based: B
Given the equivalence of therapeutic effect, base the choice of antidepressant on
patient’s prior response, patient and clinician preference, potential side effects, and cost.
Consensus-based
1B
1C
1D
1E
*
(Interpersonal Therapy, Cognitive Behavioral Therapy, or Problem-Solving Therapy)
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2.
Hypericum (St. John’s Wort) For Treatment of MDD
2A
The GDT makes no recommendation for or against providing hypericum
(St. John’s wort) in patients with mild to moderate Major Depression.
2B
There is fair evidence of effectiveness of hypericum in this population. However, due to
lack of consistency of preparation oversight and dosage across trials, and concerns about
lack of FDA oversight and consistency of hypericum preparations, the balance of
benefits, harms, and costs compared with other treatments cannot be determined.
Evidence-based: C*
The GDT recommends against providing hypericum (St. John’s wort) to patients with
severe Major Depression. Evidence-based
3.
Antidepressants In Patients With MDD Expressing Suicidal
Ideation, Intent, or Plan
3A
For patients with Major Depression expressing suicidal intent or plan, the GDT
recommends consultation with specialty behavioral health. Consensus-based
For patients with suicidal ideation or who have made previous suicide attempts, the GDT
recommends consultation or collaboration with a psychiatrist before prescribing TCAs or
venlafaxine. Consensus-based
3B
*
Please note that only recommendations approved since the adoption in 2006 of evidence grading will use letters
(A, B, C, etc.) to specify the grade of the evidence. Recommendations approved prior to 2006 will not include a
letter grade following the statement “evidence-based.” For additional information on evidence grading, see
Appendix A.
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4.
Second-Line Treatment of MDD
4A
For patients with MDD whose symptoms fail to remit after first-line treatment, the GDT
recommends an assessment of the adherence to the initial treatment regimen.
Consensus-based
For patients with MDD whose symptoms fail to remit after adherence to first-line
treatment, the GDT recommends that treatment options include:
4B
 Combining antidepressants and psychotherapy. Evidence-based
 Increasing the dose of the initial antidepressant. Consensus-based
 Switching to a different antidepressant of the same or different class.
Consensus-based
 Switching from psychotherapy to antidepressants or antidepressants to psychotherapy.
Consensus-based
 Combined pharmacologic treatment (monitoring for toxicity, side effects and drug
interactions) with SSRIs and:
4C
4D
4E
 low-dose TCAs, or
 bupropion, or
 buspirone, or
 mirtazepine, or
 lithium, or
 liothyronine (T3).
Consensus-based (all in this list)
The GDT makes no recommendation for or against providing folate or inositol to patients
whose MDD symptoms fail to remit after adhering to first-line treatment.
Evidence-based: I
The GDT makes no recommendation for or against providing atypical an antipsychotics
to primary care patients with (nonpsychotic, nonbipolar) MDD whose symptoms fail to
remit after adherence to first-line treatment.
There is fair evidence of short-term effectiveness for use of atypical antipsychotic agents
to augment antidepressants in patients with nonpsychotic, nonbipolar MDD who fail to
remit after initial treatment. However, due to lack of longer-term data, known
cardiometabolic risks of treatment with these medications, and lack of comparison data
against other strategies, the balance of benefits, harms and costs compared with other
treatments cannot be determined. Evidence-based: I
The GDT recommends against providing augmentation with pindolol for patients with
MDD whose symptoms fail to remit after adherence to first-line treatment.
Evidence-based
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5.
Length of Treatment With Antidepressants In Patients With MDD
Patients Who Achieve Symptom Remission
5A
The GDT recommends that patients with MDD who achieve symptom remission
with antidepressants should continue antidepressants at the same dose for at least an
additional six to 12 months. Evidence-based
Patients With One Lifetime Episode of MDD
5B
Based on patient and provider preference, the GDT recommends that a trial of
antidepressant discontinuation is optional for patients in their first lifetime episode
of MDD, who are being treated with antidepressants, achieve remission, and remain
asymptomatic for six to 12 months after acute phase treatment. Consensus-based
Patients With Two or More Lifetime Episodes of MDD
5C
The GDT recommends that patients with two or more lifetime episodes of MDD, who are
being treated with antidepressants and remain asymptomatic after acute phase treatment,
should be maintained on the medication and dose with which they achieved remission for
at least an additional 15 months to five years after acute phase treatment.
Consensus-based
Patients With Chronic MDD or MDD With Concurrent Dysthymia
5D
The GDT recommends that patients with chronic MDD (continual symptoms for
more than two years) or Double Depression (MDD and dysthymia) who improve with
antidepressants during acute phase treatment should continue antidepressants for at least
an additional 15 to 28 months after acute phase treatment. Evidence-based
6.
Follow-Up For Patients In The Acute Phase
(First Three Months) of Treatment For MDD
6
For patients who are starting treatment with antidepressants for Major Depression, the
GDT recommends that the minimum recommended follow-up frequency is one patient
contact* within the first month, and at least one additional patient contact four to eight
weeks after the first contact.
Assess for adherence, side effects, suicidal ideation, and patient response during both
these visits. Consensus-based
*
Follow-up contact may include in-person visits, phone calls or email between patient and clinician, or phone
calls/email between patient and a care manager. The use of email between patients and providers is relatively
new, and has not been a widely utilized means of communication to date. However, it is being increasingly
advocated as part of a patient-centered, more efficient (“less visit dependent”) model of care. At least one
member of the GDT uses this modality regularly and deems it effective for follow-up contacts.
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7.
Follow-Up For Patients In The Continuation Phase
(Months Four To 12) of Treatment For MDD
7
After achieving symptom remission, the GDT recommends at least one follow-up
contact* during the fifth or sixth month of treatment in patients with Major Depression.
Assess for continuing symptom remission and dosage/treatment adjustment during this
contact.
The GDT recommends additional patient follow-up to consider either continuing
treatment beyond the continuation phase, or attempting a trial of treatment
discontinuation. Consensus-based
8.
Follow-Up For Patients In The Maintenance Phase
(Beyond 12 Months) of Treatment For MDD
8A
For asymptomatic patients with Major Depression who are continuing on antidepressants
beyond 12 months, the GDT recommends at least one annual follow-up contact* is
recommended to assess for continuing symptom remission, the need for ongoing
treatment, and dosage/treatment adjustment. Consensus-based
The GDT recommends that additional follow-up for asymptomatic patients with Major
Depression who are continuing on antidepressants beyond 12 months should be based on
patient preference and response. Consensus-based
8B
9.
Discontinuation of Antidepressants In Patients With MDD
9A
Fluoxetine may be discontinued, without tapering, with a relatively low risk of adverse
effects. Evidence-based
The GDT recommends tapering other antidepressants (other SSRIs, TCAs, SNRIs, NRIs,
and DAs) over a two to four week period. Consensus-based
9B
10.
Treatment Preferences For MDD In Different Ethnic Groups
10
Because patient preferences for treatment may vary based on their ethnicity and culture,
the GDT recommends asking patients from different ethnic groups about treatment
preference when discussing treatment options for MDD. Evidence-based
*
Follow-up contact may include in-person visits, phone calls or email between patient and clinician, or phone
calls/email between patient and a care manager. The use of email between patients and providers is relatively
new, and has not been a widely utilized means of communication to date. However, it is being increasingly
advocated as part of a patient-centered, more efficient (“less visit dependent”) model of care. At least one
member of the GDT uses this modality regularly and deems it effective for follow-up contacts.
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11.
Patient Self-Management Strategies For Improving Symptoms of MDD
Exercise
11A Exercise is an adjunctive strategy (in addition to antidepressants or psychotherapy)
for treating MDD. Evidence-based :B
Internet Resources
11B Selected internet-based patient self-help materials may be used as an optional adjunct
strategy (in addition to antidepressants or psychotherapy) for treating MDD.
Consensus-based
Bibliotherapy
11C Selected bibliotherapy* may be used as an optional adjunct strategy (in addition to
antidepressants or psychotherapy) for treating MDD. Consensus-based
Befriending
11D Befriending† is an optional adjunct to antidepressants or psychotherapy for treating
MDD. Consensus-based
Patient-Initiated Combined Phone/Computer Programs
11E There is insufficient evidence for or against using patient-initiated combined
phone/computer programs in the treatment of MDD. Evidence-based: I
Light Therapy
11F There is insufficient evidence for or against using light therapy as a primary or
adjunctive treatment for nonseasonal forms of MDD. Evidence-based: I
Music Therapy
11G There is insufficient evidence for or against using music therapy in the treatment of
MDD. Evidence-based: I
Life Review Therapy
11H There is insufficient evidence for or against using life review therapy in the treatment of
MDD. Evidence-based: I
12.
Behavioral Health Education Classes For Adults With MDD
(Cognitive Behavioral Skills or Problem-Solving Classes)
12
For patients with mild to moderate MDD, the GDT recommends behavioral health
education classes as an adjunctive treatment option. However, these classes should not
be used in lieu of either antidepressant medication or psychotherapy. Evidence-based
*
Bibliotherapy: Advising people to read specific written material based on cognitive-behavioral approaches to
depression treatment.
†
Befriending: Consists of a designated befriender who meets the depressed person to talk and socialize with for
at least one hour per week.
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13.
Antidepressants To Avoid During Pregnancy or Breastfeeding
Pregnancy
13A Do not start paroxetine in women who are pregnant. Evidence-based: D
13B Use caution in starting other selective serotonin re-uptake inhibitors (SSRIs) in women
who are pregnant. Consensus-based
 Discuss risks to the mother and fetus of untreated maternal depression, as well as the
risk of fetal adverse effects from antidepressants.
13C If drug therapy is a consideration for treatment of maternal MDD during pregnancy
and/or breastfeeding, then:
 Individualize according to patient history and need for medication, and
 Discuss the benefits and harms of the various treatment options with the patient.
Consensus-based
13D If MDD is in remission and a woman becomes pregnant while taking antidepressants
during the continuation or maintenance phase of treatment, then:
 Discuss the risks to the mother and fetus of untreated maternal depression or
depression relapse after antidepressant discontinuation, as well as the risk of fetal
adverse effects from continuing antidepressants, and
 Monitor for first trimester fetal malformations if taking paroxetine.
Consult OB/GYN for considerations on fetal malformation screening.
Consensus-based
Breastfeeding
13E Do not start fluoxetine and/or citalopram in breastfeeding women in most circumstances.
If used, they should be used with caution, and only in patients who had good results with
these medications during pregnancy or a previous depression episode. Consensus-based.
13F In women taking antidepressants during pregnancy whose depression is in remission and
who desire to breastfeed:
 Discuss the risks to the mother and fetus of untreated maternal depression or
depression relapse after antidepressant discontinuation and the risk of adverse
effects in the nursing newborn of mothers continuing antidepressants, and
 Consider changing treatment for depression if the newborn shows potential
antidepressant-related adverse effects (withdrawal symptoms) during the first few
hours after birth.
Consensus-based
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Rationale Statements
1.
First-Line Treatment of Major Depressive Disorder (MDD)
1A
For patients with mild to moderate Major Depressive Disorder (MDD), use either
antidepressant medication or psychotherapy* as first-line treatment. Evidence-based: B
Given the lack of evidence on a clearly superior approach for mild to moderate MDD,
base treatment decisions on patient and clinician preference, potential side effects, and
cost. Consensus-based
For patients with severe or chronic MDD, combine antidepressant use and
psychotherapy* as first-line treatment. Evidence-based: B
If antidepressants are used, any class of antidepressant (SSRI, TCA, SNRI, NRI, or DA)
may be prescribed as first-line treatment of MDD. Evidence-based: B
Given the equivalence of therapeutic effect, base the choice of antidepressant on
patient’s prior response, patient and clinician preference, potential side effects, and cost.
Consensus-based
1B
1C
1D
1E
Evidence Grade†
Evidence for Recommendation 1A: Fair.
Evidence for Recommendation 1C, D: Good.
Rationale:
2010 Update
New evidence was found, the recommendation remains unchanged.
*
(Interpersonal Therapy, Cognitive Behavioral Therapy, or Problem-Solving Therapy)
†
The criteria for grading the strength of the evidence as either “good,” “fair,” or “insufficient” adheres to the KP
National Guideline Program’s “Policies and Procedures” documents entitled “Label and Language of
Recommendations” and “KP System for Grading the Strength of a Body of Evidence,” which are located in
Appendix A.
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Search Strategy
Some studies found and used in this guideline did not appear in PubMed search results due to the
way studies are indexed in PubMed. Casacalenda(1) study was indexed as a review article in
PubMed and did not show up in the search results due to the way PubMed indexing is done.
Another information source was the AHRQ Evidence report on the Treatment of DepressionNewer Pharmacotherapies.(2) See Appendix B for more information on the search strategy.
The GDT determined that a limited review of the clinical question focusing on first-line
medication treatment for MDD was most appropriate for the current 2010 update. Systematic
reviews and meta-analyses were included in the current update. Original studies that
demonstrated selective reporting using non-systematic searches or were industry-sponsored were
excluded.
Note: There is no universally used definition of mild, moderate, and severe Major Depression.
To determine severity, clinicians can use either the depression score from a standardized,
validated depression rating scale (such as the PHQ-9, Beck Depression Inventory, Zung
Depression Scale, and others that are often used in Major Depression studies) or use the
following commonly used clinical consensus rating system as a guide to determining symptom
severity.
Severity of Major Depression
SYMPTOM
SEVERITY
NUMBER OF MDD SYMPTOMS
(DSM-IV CRITERIA)
PATIENT FAMILY, SOCIAL,
OR OCCUPATIONAL IMPAIRMENT
Mild
5 to 6
Minor
Moderate
6 to 7
Moderate
Severe
8 to 9
Severe; including suicidal intention or plan
After reviewing this new evidence, the overall recommendation for first-line antidepressant
treatment remains unchanged. The included studies are summarized below (please refer to
Evidence Table 1.1 for study details). A limited review focusing on first-line medication choice
for treatment of MDD was conducted. Systematic reviews and meta-analyses were included.
Analyses using non-systematic searches and single antidepressant vs. placebo trials of
established (previously reviewed) antidepressants were excluded. Eighteen relevant systematic
reviews and meta-analyses were identified. Efficacy outcomes were measured by response rates,
defined as a reduction of 50% of baseline Hamilton Depression Rating Scale (HAM-D) or the
Montgomery-Asberg Depression Rating Scale (MADRS) or a score of ‘much improved’ on the
Clinical Global Impression score(CGI); and/or remission, defined frequently in studies by a
preset cut-point of
≤ 7 to 9 on the HAM-D score. Tolerability or acceptability was measured by overall dropout
rates, discontinuation rates due to adverse events, or rates of adverse events.
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Three studies (Mukai 2009,(3) Gartlehner 2008a,(4) Gartlehner 2008b(5)) compared the efficacy
and tolerability of different drug classes (e.g., TCA, SSRI, SNRI, other antidepressants) to each
other; nine studies (Cipriani 2009b,(6) Cipriani 2009c,(7) Cipriani 2009a,(8) Nakagawa 2009,(9)
Omori 2009,(10) Cipriani 2008,(11) Van den Broek 2009,(12) Weinmann 2008,(13) Watanabe
2008(14)) compared individual antidepressants to other antidepressants; and six studies (Arroll
2009,(15) Hansen 2008,(16) Barbui 2009,(17) Barbui 2008,(18) Deshauer 2008,(19) Nelson 2008(20))
evaluated antidepressants, individually or as a class, relative to placebo. The majority of the
studies focused on the 12 newer, second-generation antidepressants that included bupropion,
citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone,
paroxetine, sertraline, trazodone and venlafaxine.
Head-to-Head Comparisons of Antidepressants*
 Mukai et al. (2009)(21) reviewed 18 RCTs examining the efficacy of single- versus dualaction Antidepressants for the treatment of depression among patients ≥ 59 years. In this
narrative review, authors conducted a systematic search of published studies; however,
data were scarce and insufficient to conduct a meta-analysis of head-to-head comparisons.
In addition, publication bias assessment was not reported. Overall, limited data suggest that
dual-action agents such as TCAs and SNRIs do not appear to confer any additional efficacy
benefits over single-action agents such as SSRIs in the treatment of depression in the elderly.
Two trials found no significant difference in efficacy between TCAs vs. SSRIs; three studies
found no significant difference between venlafaxine vs. SSRIs; one study of duloxetine vs.
placebo (funding source not reported) found significant improvement in depression
(p < 0.001), pain (p < 0.001), and cognition (p = 0.013) in favor of duloxetine; and five
studies suggested no additional efficacy benefit for the SNRI venlafaxine compared with
SSRIs or TCAs.
 Gartlehner et al. (2008a)(4) conducted a meta-analysis of 203 studies (including head-tohead RCTs; observational studies; placebo trials; systematic reviews, meta-analyses, and
studies with pooled data) on the comparative benefits and harms of second-generation
antidepressants. Overall, no substantial differences in comparative efficacy and effectiveness
of second-generation antidepressants for treatment of MDD were detected; the evidence did
not support the choice of one second-generation antidepressant over another. Nevertheless,
authors noted some differences in adverse events. Some statistical differences in onset of
action were noted, however these differences may not be clinically significant since most
response rates were similar after four weeks of treatment and all seven studies that examined
speed of response were funded by manufacturer.
*
The great majority of antidepressant studies included here were funded by pharmaceutical companies.
In almost all cases, at least some results favored the drug manufactured by the funder.
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 In a separate sub-analysis, Gartlehner et al. (2008b)(5) assessed the comparative harms
of second-generation Antidepressants for MDD by reviewing 104 studies (83 head-to-head
RCTs (N > 17,000) and 21 observational studies (N > 740.000)). Outcome measures were
rates of adverse effects, specific adverse effect reported, and overall rate of adverse effect.
Adverse effects profiles of second-generation antidepressants were similar; nausea, vomiting,
diarrhea, dry mouth, sweating, headache, dizziness, sexual dysfunction and weight gain were
commonly reported adverse effect. However, individual drugs differed in frequencies of
specific adverse effects, which might be clinically relevant and influence the choice of
treatment for individual patients (on a case-by-case basis).
 Roughly 63% of patients in efficacy trials experienced at least one adverse effect.
No significant difference was detected between second-generation antidepressants and
SSRIs, except for venlafaxine, which had higher discontinuation from adverse effects and
higher rate of nausea and vomiting than SSRIs [(Relative Risk (RR) discontinuation from
adverse effects: 1.42 (95% CI: 1.15 to 1.75); RR = from nausea and vomiting: RR = 1.53
(95% CI: 1.26 to 1.86); NNH = 9 (95% CI: 6 to 23)].
 Compared with other second-generation antidepressants, paroxetine frequently was
associated with higher rates of sexual dysfunction and bupropion with lower rates of sexual
dysfunction; mirtazapine and paroxetine were associated with more weight gain (up to 3
kg, although not always specified); and sertraline was associated with higher rates of
diarrhea. However, differences did not lead to significantly different discontinuation rates.
 Cipriani et al. (2009a)(8) evaluated the efficacy and acceptability of 12 second-generation
antidepressants in a meta-analysis of 117 RCTs (N = 25,928). Only seven of these trials
were in primary care settings. Included studies were of short duration. Fifteen unpublished
studies from industry were included, it was not specified how many of these favored the
funder’s antidepressant (no funnel plots or assessment of publication bias was noted, and it
was not clear how many of these studies were also included in the FDA trial database).
Authors noted a small number included in each pair-wise comparison. Mirtazapine,
escitalopram, venlafaxine, and sertraline were more efficacious treatments for depression
response (remission was not assessed). Escitalopram, sertraline, bupropion, and citalopram
were better tolerated than other antidepressants. Reboxetine, fluvoxamine, paroxetine, and
duloxetine tended to have lower efficacy and tolerability than other antidepressants.
Numbers needed to treat or harm were not calculated, making it difficult to assess the
absolute differences in each analysis. Additionally, statistical significance (defined as
p < 0.05 in this analysis) was not adjusted for multiple comparisons, so many differences
could have been due to chance.
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Escitalopram vs. Other Antidepressants
 Cipriani et al. (2009b)(6) examined the efficacy and tolerability of escitalopram compared to
other Antidepressants in 22 RCTs. Patients with medical comorbidity were excluded,
limiting the potential applicability to primary care settings. In terms of efficacy,
escitalopram was shown to be significantly more effective than citalopram in achieving acute
response (OR = 0.67, 95% CI: 0.50 to 0.87) and remission (OR = 0.53, 95% CI: 0.30 to
0.93). In terms of tolerability, fewer patients allocated to escitalopram withdrew from trials
due to any cause compared to duloxetine (OR = 0.62, 95% CI: 0.38 to 0.99). This analysis is
limited by potential publication and sponsorship biases and potential selective reporting of
results.
Milnacipran vs. Other Antidepressants
 Nakagawa et al. (2009)(9) examined milnacipran versus other antidepressants in a metaanalysis of 16 RCTs (N = 2777). When compared to TCAs, patients taking milnacipran were
associated with fewer dropouts due to adverse events (OR 0.55; 95% CI: 0.35 to 0.85) and
there was a trend that suggested fewer adverse events of sleepiness/ drowsiness, dry mouth or
constipation. No other significant differences in efficacy, acceptability and tolerability were
detected when comparing milnacipran with other antidepressive agents. However, authors
noted that there remained “inadequate evidence to conclude whether milnacipran is superior,
inferior or the same as other antidepressive agents in terms of efficacy, acceptability and
tolerability in the acute phase treatment of major depression.” Milnacipran is not currently
available in the United States.
Fluvoxamine vs. Other Antidepressants
 Omori et al. (2009)(10) reviewed the efficacy and tolerability of fluvoxamine and other
antidepressants in 53 RCTs (N = 8,244 for efficacy; N = 6,440 for tolerability). In terms of
efficacy, no significant differences were detected in response and remission rates between
fluvoxamine and other antidepressants as a class (TCAs, heterocyclics, SNRIs, SSRIs) in
early or end of acute phase of treatment. In addition, dropouts for any reason or for adverse
effects were not significantly different between fluvoxamine and other antidepressants as a
class or individually. Nausea or vomiting and weight loss or anorexia were more frequent
with fluvoxamine than with TCAs and some other antidepressants (mianserin, milnacipran,
and newer antidepressants); constipation and dry mouth were more common with TCAs than
with fluvoxamine. The authors concluded that “the initial selection of an antidepressant
medication will and should largely be based on the anticipated side effect profile and
patient’s preference.”
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Sertraline vs. Other Antidepressants
 Cipriani et al. (2009c)(22) assessed the efficacy and tolerability of sertraline compared to
other antidepressants in 59 RCTs (N = 9,950). Evidence favoring sertraline over some
individual antidepressants for the acute phase treatment of major depression was found,
either in terms of treatment response (fluoxetine) or acceptability/tolerability (amitriptyline,
imipramine, paroxetine, and mirtazapine). No statistically significant difference in remission
between fluoxetine and sertraline was noted. However, some differences favoring other
antidepressants over sertraline in terms of response (mirtazapine, amitriptyline) and
acceptability (bupropion) were also noted. Sertraline was generally associated with a higher
rate of participants experiencing diarrhea. Overall, the quality of included studies was low,
not all pre-specified outcomes were reported in included studies, and outcomes of clear
relevance to patients and clinicians were not reported in any of the included studies.
No analysis of publication bias was conducted. Few studies reported remission rates, those
that did were underpowered to detect clinical significance. Analysis of sertraline vs. other
antidepressants as a class was not conducted.
 Cipriani et al. (2008)(11) evaluated sertraline compared to other antidepressants in a metaanalysis of 56 RCTs (N = 8,507 for efficacy; N = 8,387 for tolerability). There was
substantial overlap of studies in this analysis and the analysis conducted in Cipriani et al.
(2009a)(8), thus many of the same limitations (short duration of included trials, few trials
conducted in primary care settings) apply. Trials including patients with medical disorders
were excluded from this analysis, also limiting applicability to the primary care setting. FDA
trial databases and similar European trial databases were searched for study inclusion in this
analysis; most included studies were funded by the maker of sertraline. This analysis also did
adjust the level of significance to p < 0.01 to account for multiple comparisons. Included
studies used different dosing schedules, making it difficult to determine differences (or lack
thereof) between equivalent effective doses of antidepressants. Sertraline was more
efficacious than other SSRIs [RR = 0.88 (99% CI: 0.78 to 0.99), p = 0.009; NNT = 17],
particularly fluoxetine [RR = 0.85 (99% CI: 0.74 to 0.98); p = 0.004; NNT = 12].
But sertraline’s efficacy was not significantly different from TCAs [RR = 0.95
(99% CI: 0.83 to 1.09)] or any other antidepressants, For acceptability, no significant
differences were detected between sertraline and TCAs [RR = 0.83 (99% CI: 0.66 to 1.04)],
SSRI [RR = 0.9 (99% CI: 0.68 to 1.18)], or any other antidepressants. In the conclusions
section, the authors site “cardiovascular physicians’ belief and clinical care practices” in
treating depression in patients with cardiovascular disease as observational evidence
supporting their conclusion of sertraline “as a candidate for initial choice of antidepressant.”
Venlafaxine vs. Other Antidepressants
 Van den Broek et al. (2009)(12) compared the effectiveness of venlafaxine to TCAs in seven
RCTs (N = 947). There were no significant differences for response [OR = 0.88
(95% CI: 0.66-1.16)] or withdrawal [OR = 1.21 (95% CI: 0.89-1.64)] of TCA vs.
venlafaxine. However, authors noted that “because of the heterogeneity of the odds ratios,
one cannot conclude that they are of equal efficacy.”
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 Weinmann et al. (2008)(13) evaluated the efficacy and tolerability of venlafaxine compared
with SSRI in 17 RCTs (N = 3,523 for response analysis; N = 3,142 for remission analysis).
There were no statistically significant differences between venlafaxine and the SSRI group
with respect to response [random-effect RR = 1.05, (95% CI: 1.00 to 1.10); NNT = 27] and
remission [random-effect RR = 1.04, (95% CI: 0.96 to 1.13); NNT = 34]. Total rate of
treatment discontinuation did not differ between venlafaxine and SSRIs (RR = 1.05,
95% CI: 0.93 to 1.2, NNH = 100), but there were significantly more dropouts due to adverse
effects in the venlafaxine vs. SSRIs group [RR = 1.38, 95% CI: 1.08 to 1.77, NNH = 32].
Mirtazapine vs. Other Antidepressants
 Watanabe et al. (2008)(14) conducted a systematic review on 25 RCTs (N = 4,842) on the
effectiveness and tolerability of mirtazapine compared with other antidepressants (TCAs,
SSRIs, SNRIs, and other). Results were stratified according to treatment duration, including
early phase (2 weeks), end of acute-phase (6 to 12 weeks), and end of continuation phase
(4 to 6 months).
 Analysis of efficacy at early phase of treatment found no significant differences between
mirtazapine and TCAs in response [RR = 0.9 (99% CI: 0.69 to 1.18)] and remission
[RR = 0.87 (99% CI: 0.52 to1.47)]; mirtazpine was superior to SSRIs in both response
[RR = 1.36 (99% CI: 1.13 to 1.64); NNT = 11] and remission [RR = 1.68
(99% CI: 1.2 to 2.36); NNT = 25], particularly, significantly better than paroxetine in
response [RR = 2.02 (99% CI: 1.09 to 3.75); NNT = 8] and sertraline in remission
[RR = 1.73 (99% CI: 1.01 to 2.98); NNT = 12]; and mirtazapine was significantly superior
to SNRI in terms of response [RR = 1.77 (99% CI: 1.08 to 2.89); NNT = 6] but not in
remission [RR = 2.21(99% CI: 0.93 to5.26)].
 At the end of the acute phase (6 weeks), no statistical significant differences were detected,
except for superior remission outcome in comparison of mirtazapine with paroxetine
[RR = 1.34 (99% CI: 1.04 to 1.73); NNT = 10)].
 At the end of the continuation phase (24 weeks), one study examined mirtazapine with
paroxetine and no significant differences were detected.
 No significant differences in tolerability were identified between patients treated with
mirtazapine and TCAs (RR = 0.87 (95% CI: 0.7 to 1.08)], SSRIs (RR = 1.07
(95% CI: 0.92 to 1.26)], SNRI (venlafaxine) [RR = 0.82 (95% CI: 0.58 to 1.16)], or other
antidepressants (trazodone) [RR = 0.93 (95% CI: 0.58 to 1.5)].
 Mirtazapine dropouts due to adverse effects were similar to SSRI [RR = 1.22 (95% CI:
0.87 to 1.73)], SNRI [RR = 0.59 (95% CI: 0.27 to 1.29)], and trazodone [RR = 0.66 (95%
CI: 0.3 to 1.46)]. Subgroup analysis found mirtazapine had lower withdrawals due to
adverse effects compared with sertraline [RR = 2.58 (95% CI: 1.28-5.24); NNH = 11].
 Based on findings authors concluded that “although mirtazapine is highly likely to have
better efficacy profile than paroxetine or venlafaxine in terms of early response, in view of
similar efficacy of mirtazapine and other antidepressants, results suggest that clinicians
should also focus on other practically or clinically relevant considerations such as
differences in the side effect profiles, to tailor treatment to best fit an individual patient’s
needs.”
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Antidepressants vs. Placebo*
 Arroll et al. (2009)(15) reviewed 14 RCTs examining the effectiveness of TCAs and/or SSRIs
compared to placebo. Both TCAs and SSRIs were significantly more effective than placebo
for depression reduction and symptoms [RR = 1.24 (95% CI: 1.11 to 1.38) and
NNT = 7 to 16; and RR = 1.28 (95% CI: 1.15 to 1.43) and NNT = 7 to 8, respectively]. More
adverse effects were associated with TCAs than with SSRIs [NNH = 4 to 30 vs. 20 to 90,
respectively].
 Hansen et al. (2008)(16) compared MDD relapse and recurrence rates during continuation
and maintenance phase treatment with second-generation antidepressant compared with
placebo in 27 RCTs. Results were stratified by duration (those <1 year were categorized as
relapse prevention and trials ≥ 1 year were categorized as recurrence prevention). NNTs for
relapse prevention over a (mean of eight months) and recurrence (mean of 16 months) were
each five [RR = of relapse: 0.54 (95% CI: 0.46 to 0.62), RR = of recurrence: 0.56
(95% CI: 0.48 to 0.66)]. In addition, loss to follow-up because of adverse events was not
significantly different between active treatment and placebo (RR = 1.42,
95% CI: 0.92 to 2.20).
 Nelson et al. (2008)(20) reviewed 10 RCTs (N = 2377) on the efficacy of second-generation
antidepressants for depression in late-life (> 60 years) with respect to treatment response,
remission, and tolerability. Those assigned to active drug treatment had significantly greater
response [OR = 1.4 (95% CI: 1.24 to 1.57); NNT = 13] and remission [OR = 1.27
(95% CI: 1.12-1.44); NNT = 20] compared with placebo. Response rates were higher in the
longer trials compared to the shorter trials [10 to 12 weeks OR = 1.73 (95% CI: 1.42 to 2.09)
vs. 6 to 8 weeks OR = 1.22 (95% CI: 1.05 to 1.42)]. However, compared with placebo, there
were increased odds of overall medication discontinuation [OR = 1.22 (95% CI: 1.06 to 1.4);
I2 = 48.2%] and discontinuation due to medication adverse effects [OR = 1.84 (95% CI:
1.51 to 2.24)]. Evidence did not suggest superiority of one class of medication over another.
Authors concluded that “for every 100 patients treated, eight would show a response and five
a remission in excess of placebo and for every two patients who responded, one discontinued
prematurely because of adverse effects.”
 Deshauer et al. (2008)(23) pooled 6 RCTs (N = 1299) to evaluate SSRIs versus placebo
for MDD. Treatment response at sic to eight months showed SSRIs to be superior to placebo
[OR = 1.66 (95% CI: 1.12 to 2.48)], particularly in depressed patients without other
comorbidities [OR = 2.13 (95% CI: 1.11 to 4.08)]. There were no statistically significant
differences in remission [OR = 1.46 (95% CI: 0.92 to 2.32)] or drop-out rates [OR = 0.87
(95% CI: 0.67 to 1.14)] between SSRI and placebo.
*
The great majority of antidepressant studies included here were funded by pharmaceutical companies.
In almost all cases, at least some results favored the drug manufactured by the funder.
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Paroxetine vs. Placebo
 Barbui et al. (2008)(18) compared paroxetine with placebo in a meta-analysis of 40 RCTs
(N = 6391). The primary outcome was discontinuation and the secondary outcome was
response. Significantly more patients assigned to receive paroxetine left the study because of
side effects [random effect RR = 1.77 (95% CI: 1.44 to2.18); NNH = 17], reported any
adverse effects [OR = 1.27, 95% CI: 0.88 to 1.83, NNH = 9], and experienced suicidal
tendencies compared with patients given placebo OR = 2.55 (95% CI: 1.17 to 5.54);
NNH = 142]. Patients who received paroxetine were more likely to experience an
improvement in depressive symptoms compared to patients receiving placebo
[random effect RR = 0.83 (99% CI: 0.77 to 0.90); NNT = 9].
Suicide Risk – Antidepresants vs. Placebo
 Barbui et al. (2009)(17) conducted a meta-analysis of eight observational studies
(> 200,000 patients) to assess the risk of suicide based on SSRI exposure. Overall, there
was an increased risk of attempted or completed suicide among adolescents exposed to
SSRIs [random-effect OR = 1.92 (95% CI: 1.51 to 2.44)]. In subgroup analysis, paroxetine
and venlafaxine were associated with increased risk. However there was a decreased risk
of attempted or completed suicide among adults and elderly individuals exposed to SSRIs
(≥ 65 years) [OR = 0.57 (95% CI: 0.47 to 0.70); OR = 0.46 (95% CI: 0.27 to 0.79)]. No
individual antidepressant was significantly associated with completed or attempted suicide in
adults. Patients may have had additional comorbidities that may have influenced selection of
treatment and have unaccounted for effects on suicide risk. Funnel plot suggested that small
negative studies may not have been published and included in the analysis.
Discussion:
In aggregate, updated evidence suggests no significant differences in efficacy among the
different classes of antidepressants (TCAs, SSRIs, SNRIs; N = 4 new studies(21), (4), (5), (24)). Five
newly identified meta-analyses/systematic reviews ((20), (16), (17), (25), (23)) support the proposition
that antidepressant treatment for MDD is more efficacious than placebo, especially among
patients without other comorbidities.(23) One study (Nelson 2008(20)) found that response to
treatment is greater in longer trials (10 to 12 weeks) compared with shorter trials (6 to 8 weeks),
supporting findings of the STAR*D trial (reviewed previously). Three studies ((21), (4), (5)) did not
detect significant differences among antidepressant drug classes in discontinuation for any
reason and/or from side effects. However, one study (Arroll 2009(15)) suggested that more
adverse events were associated with TCAs than SSRIs and another study (Nelson 2008(20)) noted
increased odds for discontinuation of medication treatment compared to placebo. One study
(Barbui 2009(17)) reported a decreased risk of suicide attempts or completion in depressed adults
treated with SSRIs, but supported previously found associations between antidepressant
exposure and suicide risk in adolescents. Although significant differences in tolerability were
not detected in several studies, there was some evidence that showed marginal differences in the
adverse event profiles among individual antidpressants ((4), (5), (13)).
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A variety of results were reported among studies that assessed the effectiveness and tolerability
of individual antidepressants relative to other antidepressants or placebo. In a head-to-head
comparison study of 12 new second-generation antidepressants, Cipriani et al. (2009a)(8) reported
that mirtazapine, escitalopram, venlafaxine and sertraline were among the most efficacious while
reboxetine, fluvoxamine, and duloxetine were the least efficacious. One study (Watanabe
2008(14)) found that mirtazapine was equivalent to TCAs and more efficacious than SSRIs,
(particularly paroxetine); no significant differences in tolerability were detected between
mirtazapine and other antidepressants. Cipriani 2009b(6) showed statistically better response for
escitalopram compared with citalopram and better escitalopram tolerability compared with
duloxetine. Two studies demonstrated no significant differences in efficacy between venlafaxine
and SSRI(13) or TCAs,(12) although one study found more dropouts due to adverse events in
venlafaxine treated patients compared with SSRI patients(13). Cipriani (2009c(7)) found better
response for sertraline compared with fluoxetine, and a trend in favor of mirtazapine for efficacy
and bupropion for tolerability over sertraline. Another Cipriani analysis (2008(11)) reported no
differences in efficacy and tolerability between sertraline, TCAs, and other antidepressants while
sertraline was superior to SSRI, especially fluoxetine, in efficacy. There were significant
overlaps in the studies included in these two Ciprani analyses. One study(9) found better
tolerability of milnacipran compared with TCAs; however, the authors noted that there was
insufficient evidence to establish the overall effectiveness and acceptability of milnacipran
compared to other antidepressants (milnacipran is not available in the United States). One
study(10) reported no significant differences in tolerability between fluvoxamine and other classes
of antidepressants. Finally, one study (18) concluded that paroxetine was superior to placebo in
response, but more withdrawals due to adverse events were observed in patients allocated to
paraoxetine than placebo.
Altogether, the NNT for antidepressant treatment, either as a class or individually, ranged from
4 to 34 and the NNH ranged from 9 to 90. As a result, the benefits of antidepressant treatment
for MDD appear to outweigh the identified harms.
Several important limitations were present in most of the included systematic review and metaanalyses that warrant cautious interpretation of the reported results. The majority of included
studies were funded by the pharmaceutical industry, which tends to favor the funded medication.
Unpublished results were likely missing from many of the analyses. The same small group of
researchers published many of the studies included, and in some cases, separate analyses were
presented that included several common trials, making it appear that there is stronger evidence to
support a conclusion than really exists. Only a minority of studies in some analyses was
conducted in primary care settings, and several studies excluded patients with comorbidities,
making generalization to primary care difficult. Data was unavailable for many head-to-head
comparison studies of individual antidepressants, and selective reporting of results may have
occurred in several of the included trials. Selective participation of symptomatic volunteers was
observed in most included trials, which may potentially overstate the true effectiveness in real
world settings. Most studies reported on symptom response rather than symptom remission.
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Many trials included multiple comparisons, increasing the risk of finding a statistically
significant result that is truly a chance finding. Data on tolerability based on dropout rates due
to adverse events were also difficult to interpret due to the variability among individual drug
adverse effects profiles. Methodological concerns such as inadequate blinding and analytical
methods (e.g., completer analyses and last observation carried forward methods of imputing
missing data) may bias studies in favor of active treatment). Variability in dosing strategies can
lead to higher effective doses of one medication being compared with lower effective doses of
another. Although some studies found statistically significant results, whether these findings
translate to significant clinical relevance is questionable.
Conclusion:
New evidence from systematic reviews of mostly lower quality studies did not suggest the need
to change the previous guideline recommendation regarding antidepressants for treatment of
severe MDD. Although individual studies suggest marginal benefit for specific antidepressants,
in aggregate there is no consistent “directionality” amongst the studies. Furthermore, the
absolute clinically important difference between antidepressants is uncertain, due to the limited
quantity of the comparison studies.
Therefore, the GDT continues to find that the balance of evidence supports the use of
antidepressant medication as a first-line treatment for MDD. The GDT continues to recommend,
consistent with the previous guideline recommendations, that any class of antidepressant (SSRI,
TCA, SNRI, NRI, or DA) may be prescribed as first-line treatment of MDD. Similarly, the GDT
maintains that clinicians base the choice of antidepressant on a patient’s prior response, patient
and clinician preference, potential side effects, and cost.
2008 Guideline
No new evidence was found, the recommendation remains unchanged.
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2006 Guideline
New evidence was found that did not change the existing recommendation.
Antidepressants Alone or vs. Placebo*
 Montgomery, et al. (2003)(26) reviewed four RCTs examining the effectiveness of reboxetine
in the treatment of severe depression. In three of the four trials, the reboxetine group had a
significantly greater decrease in Hamilton Depression Scale (HAMD) score when compared
with placebo. In three of the four trials, antidepressant efficacy occurred significantly faster
(at two weeks) in the reboxetine group when compared with the placebo group. In three of
the four trials, the responder rate (50% improvement from baseline HAM-D score) was
significantly higher in the reboxetine group (56 to 74%) compared with placebo (20 to 52%).
Patients unresponsive to previous antidepressant treatment were excluded. Remission rates
were not reported. Limitations of this analysis include: small number of studies, all studies
included were funded by Pharmacia, the manufacturer of reboxetine, and a systematic review
was not performed (unpublished studies may not have been included), the four studies were
not similar in terms of duration or number of subjects, and one of the four studies had a
higher baseline mean HAMD score than the rest (35.4 vs. 26.4, 27.0, and 27.2).
 One systematic review(27) found in the Cochrane Database found that TCAs, SSRIs, and
MAOIs are all effective in treating older adult patients with depression and a severe medical
illness. The results, using a fixed effects model, for the three groups respectively were:
TCAs: OR = 0.32 (95% CI: 0.21 to 0.47); SSRIs: OR = 0.51 (95% CI: 0.36 to 0.72);
MAOIs: OR = 0.17 (95% CI: 0.07 to 0.39).
 Another Cochrane review(28) analyzed the effectiveness of antidepressants compared with
“active placebos”, based on growing concerns that differential rates of side effects between
active antidepressant drugs and inactive (inert) placebos in RCTs may lead to “unblinding”
of patients and clinicians to their treatment group and may potentially bias results in favor of
active medication.
 All the studies in the review produced a pooled estimate of effect of 0.39 standard deviations
(95% CI: 0.24 to 0.54) in favor of antidepressants. When one strongly positive trial was
omitted, sensitivity analysis reduced the pooled effect size to 0.17 (95% CI: 0.00 to 0.34).
The review concludes that differences between antidepressants and active placebos are small.
 In their analysis of five systematic reviews and seven subsequent RCTs, Clinical Evidence
(Issue 14, January 2006) found a positive treatment effect of antidepressants over placebo for
adults in primary and secondary care with MDD. They note, however, that there is relatively
little information given about severe side effects when compared with placebo, and that
publication bias has been found in RCTs of selective serotonin reuptake inhibitors.
 On average, 69% of people taking placebo had worse outcomes over a mean of six weeks
than the average person taking antidepressant drugs (mean effect size = 0.5 for change in
score with antidepressant drugs versus placebo).(29)
*
The great majority of antidepressant studies included here were funded by pharmaceutical companies.
In almost all cases, at least some results favored the drug manufactured by the funder.
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 Low-dose TCAs significantly increased the proportion of people who responded at four
weeks and at three to 12 months (RR = 1.65, 95% CI: 1.36 to 2.00) compared with placebo
(RR = 2.14, 95% CI: 1.41 to 3.26).(30)
 Newer antidepressants significantly increased the proportion of people who responded
compared with placebo (51% vs. 31% respectively; RR = 1.6, 95% CI: 1.5 to 1.7).(31)
 Antidepressants significantly increased the proportion of people who responded to treatment
over four to 12 weeks compared with placebo (RR = 1.9, 95% CI: 1.6 to 2.3).(32)
 Reboxetine significantly increased the proportion of people who responded at six weeks
compared with placebo (74% vs. 20% respectively, p < 0.001).(33)
 Reboxetine at any dose significantly increased the proportion of people who responded over
four weeks compared with placebo (60% vs. 35% respectively; p < 0.05).(34)
 Reboxetine significantly improved mean Social Adaptation Self-Evaluation Scale score at
eight weeks compared with placebo (35.3 vs. 27.2 respectively, p < 0.05).(35)
 Escitalopram significantly improved depressive symptoms compared with placebo at eight
weeks (change in MARDS score: -15 with escitalopram, -12 with placebo, p = 0.002).(36)
 Escitalopram 10 mg daily, escitalopram 20 mg daily, and citalopram 40 mg daily all
significantly improved depressive symptoms compared with placebo at eight weeks (change
in MADRS score from baseline: -12.8, -13.9, -12.0, -9.4 respectively; p ≤ 0.05 for all
treatments versus placebo).(37)
 Duloxetine significantly improved depressive symptoms compared with placebo (change in
HAM-D score from baseline: -10.9 vs. -6.1 respectively, p < 0.001).(38)
 In a meta-analysis (nonindustry funded) examining the efficacy and tolerability of tricyclic
antidepressants and SSRIs compared with placebo in primary care, Arroll, et al. (2005)(39)
extracted pooled data showing that both classes of antidepressant were significantly more
effective than placebo. Most studies were of short duration (less than eight weeks) and of
lower methodologic quality. For TCAs, the pooled NNT for improvement was about four;
the NNH for withdrawal due to side effects was 5 to 11. Low doses of tricyclic
antidepressants (75 to 100 mg of amitriptyline or equivalent) were as effective as higher
doses. For SSRIs, the NNT for improvement was six, the NNH for withdrawal due to side
effects ranged from 21 to 94. This meta-analysis included many more studies comparing
TCAs with placebo than those comparing SSRIs with placebo, and patients’ severity of
depression was heterogeneous across studies. The authors conclude that “prescribing
antidepressants in primary care is a more effective clinical strategy than prescribing
placebo.”
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Head-to-Head Comparisons of Antidepressants*
 At the end of an eight week randomized trial with no placebo control subjects, Moore, et al.
(2005)(40) found that patients treated with escitalopram had significantly greater adjusted
(2.1 points, p < 0.05) decrease in MADRS (Montgomery-Asberg Depression Rating Scale)
scores from baseline and higher responder (76.1% vs. 61.3%, p < 0.01) and remitter rates
(56.1% vs. 46.3%, p < 0.05) compared with patients treated with citalopram. Adverse effects
and treatment withdrawals were not significantly different between groups. Both the
difference in mean score changes from baseline, and the calculated difference between mean
MADRS scores at endpoint (13.9 vs. 15.4 points) are of marginal clinical significance.
 In a small Japanese study examining the efficacy and safety of fluvoxamine and nortriptyline,
Otsubo, et al. (2005)(41) found no significant differences in total HAMD score change
(-9 vs. -12, p = 0.14), CGI (Clinician rating of Global Improvement) scores (figures not
reported, p = 0.055), responder rates (55.6% vs. 57.9% on HAMD, 52.8% vs. 44.7% on CGI)
or HAMD remission rates (38.9% vs. 26.3%). The authors state that the incidence of adverse
events was generally higher in nortriptyline-treated patients, but no statistical analysis of
significance was reported.
 In a six week study with small sample sizes (n = 41 patients), Wehmeier, et al. (2005)(42)
found that geriatric patients taking fluoxetine had the same HAMD treatment response
(57.1% vs. 60.0%) and improvement in HAMD scores (11.9 vs. 15.8 points) as those taking
trimipramine. The fluoxetine group reported fewer adverse events than the trimipramine
group (54.5% vs. 66.7%) but no statistical analysis of significance was performed. The
authors conclude that the two drugs are similar in terms of effectiveness and tolerability.
 In a two-phase study (eight week acute phase and six month continuation phase) Detke,
et al. (2004)(43) tested the effectiveness of duloxetine (both 80 mg and 120 mg doses) and
paroxetine against a placebo control. In the acute phase, the authors found both doses of
duloxetine and paroxetine to be statistically significantly different from placebo on all of the
following outcomes: HAMD score reduction (range -11 to -12.1 points), response rates
(70 to 82%), and remission rates (47 to 58%). In the continuation phase, of all the treatment
groups, the higher dose of duloxetine had the longest time to loss of response when compared
with placebo (p = 0.023). The adverse events ranged from 4 to 11.4%, statistical significance
was not reported). Despite the implication of superiority of duloxetine, it should be noted
that there was no statistical analysis comparing duloxetine with paroxetine, and duloxetine
was used at doses higher than currently recommended by the manufacturer.
 Sechter, et al. (2004)(44) compared milnacipran and paroxetine and found no significant
differences between the two drugs on any of the following measures: HAMD score
reduction from baseline (-11.8 vs. -12 points), MADRS score reduction (-16.2 vs. -16.8
points), response rate (58.1 vs. 60.3%), and remission rate (33.1% vs. 35.1%). The
paroxetine group had significantly greater post-treatment discontinuation symptoms
(31.8% vs. 13.0%) (p = 0.032). The study was funded by the manufacturer of milnacipran.
*
The great majority of antidepressant studies included here were funded by pharmaceutical companies.
In almost all cases, at least some results favored the drug manufactured by the funder.
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 In a multicenter, 22 week study of 151 geriatric outpatients, Allard, et al. (2004)(45) examined
the efficacy and tolerability of venlafaxine compared with citalopram, and found that both
treatment groups showed comparable improvements in MADRS score (-18 vs. -17.4 points)
over time. The incidence of spontaneously reported side effects/adverse effects was higher in
the venlafaxine group than in the citalopram group (62% vs. 43% respectively), but no
statistical analysis was performed to evaluate this difference. Treatment discontinuation due
to side effects was rare (less than 10% in each group).
 In an eight week trial, Montgomery, Huusom, & Bothmer (2004)(46) compared escitalopram
and venlafaxine and found no significant differences between groups on MADRS (-20.7 vs.
-20.4 points) or HAMD (-14.4 vs. -14 points) scores. The escitalopram group achieved
response and remission significantly faster than the venlafaxine group (4.6 days p < 0.05
and 6.6 days p < 0.001 respectively). These authors found greater incidences of side effects
in the venlafaxine group, specifically nausea, constipation and sweating (p < 0.05), but
overall treatment discontinuation rates were similar (14.4% vs. 13.3%).
 Rapaport (2003)(47) studied the efficacy of paroxetine controlled release (CR) compared with
paroxetine immediate release (IR) and placebo. A statistically significant adjusted difference
compared with placebo was found for both active treatments in HAMD total score change
(-12.1 and -12.3 points vs. -9.5 points), CGI response rate (43% and 44% vs. 26%) and
HAMD remission rate (72% and 65% vs. 52%) at 12 weeks. Post-hoc analysis noted that
patients with chronic depression (duration of more than two years) responded as well as those
with short-term depression. Statistical comparisons between active treatments were not
reported. Withdrawal due to adverse events was highest in the paroxetine IR group, (16% vs.
12.5% vs. 8.3% for placebo) but statistical significance was not evaluated. Two authors were
either employees or major stockholders of the company funding the study.
 Sauer, Uppertz-Helmhold & Dierkes (2003)(48) found noninferiority of venlafaxine ER
compared with amitriptyline ER, based on equivalent changes in HAMD total scores
(-10.5 vs. -10.4 points). Adverse effects (70.9% vs. 81.8%, p = NS) and adverse drug
reactions (55.7% vs. 71.4%, p = 0.04) were high in both groups.
 In a 2003 study, Wade, et al.(49) found no significant difference between mirtazapine and
paroxetine in HAMD score changes (-18.2 vs. -16.6 points), response (87% vs. 78%,
p = 0.28) and remission rates (61% vs. 42%, p = 0.075) at 24 weeks. However, there were
statistically significant two point differences in HAMD scores in favor of mirtazapine at two
and four weeks (p = 0.012, and p = 0.030 respectively). Overall adverse effects were high
and similar in each group 79% vs. 85%); the mirtazapine group had higher incidences of
fatigue while the paroxetine group had significantly more sweating, headache and nausea.
More than fifty percent of patients in each group discontinued treatment.
 In a comparison of venlafaxine and nortriptyline in older adult patients, Gasto, et al.
(2003)(50) found no significant differences in remission rates (approximately 70% overall for
each drug), regardless of the severity of the depressive episode. Both drugs were similarly
well tolerated; side effects were frequent (73.5% vs. 82.3%) but generally mild. Venlafaxine
scored lower on the autonomic side effects subscale.
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 Hansen, et al. (2005)(51) conducted a systematic review of RCTs, meta-analyses, and
observational studies examining the efficacy and safety of second-generation antidepressants,
and found similar outcomes among different SSRIs, and comparing SSRIs with other second
generation antidepressants on all of the following outcome measures: efficacy, speed of
response, quality of life, and tolerability/adverse effects. The authors concluded that
“overall, second generation antidepressants probably to not differ substantially for treatment
of Major Depressive Disorder.”
The majority of systematic reviews and RCTs reported in Clinical Evidence (Issue 14, January
2006) found no significant differences in outcomes among different classes of antidepressants
(tricyclic antidepressants, selective serotonin reuptake inhibitors, or monoamine oxidase
inhibitors). The two most relevant reviews are reported here.
 One review suggested that TCAs were more effective than MAO inhibitors, but may be less
effective in depression with atypical biological features (increased sleep, increased appetite).
Specific data were not cited.(52)
 Another review cited in Clinical Evidence found that about twice as many people taking
TCAs compared with SSRIs had dry mouth, constipation, and dizziness; but that slightly
more people taking SSRIs had nausea, diarrhea, anxiety, agitation, insomnia, nervous-ness,
and headache. It concluded differences in overall side effects were small, but didn’t quantify
the magnitude of difference.(53)
 One Cochrane systematic review(54) found that SSRIs show only a modest advantage in
tolerability over TCAs. Specifically, in 136 trials, participants taking SSRIs had significantly
lower drop-out rates than those taking tricyclic/heterocyclic antidepressants (OR = 1.21,
95% CI: 1.12 to 1.30). The authors note that this difference from short duration, RCTs may
not have clinical significance over the longer term.
 Another Cochrane review(55) found no clinically significant differences in effectiveness
between SSRIs and TCAs: the standardized effect size was 0.030 (95% CI: -0.018 to 0.09).
Given the apparent equal efficacy, the authors advise that treatment decisions should be
based on “patient acceptability, toxicity, and cost.”
 Another Cochrane review(56) found amitriptyline as effective as other TCAs or newer
compounds. Compared with SSRIs, however, amitriptyline was not as well-tolerated:
OR = 0.84 (95% CI: 0.75 to 0.95).
 The evidence-based NICE (National Institute for Clinical Excellence)(57) guideline found
strong evidence showing a statistically significant difference favoring SSRIs over TCAs on
reducing the likelihood of patients leaving treatment early due to side effects (RR = 0.69,
95% CI: 0.62 to 0.67). However, other reviews, such as the Cochrane review cited above,
show that all cause discontinuation rates do not vary significantly among antidepressant
classes.
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Psychotherapy vs. Antidepressants
 In a study comparing cognitive therapy with antidepressants for treatment of moderate to
severe depression, DeRubeis, et al. (2005)(58) found both active treatments were significantly
more effective than placebo at eight weeks in improving depression symptoms (50% antidepressants, 43% cognitive therapy, 25% placebo), with no significant difference between
active treatments. At 16 weeks the response rate was still similar for both active treatments
(58%), although the remitter rate was significantly different, in favor of anti-depressant
medication (46% vs. 40%, p = 0.04). These results should be interpreted with caution,
since the antidepressant group had twice as many subjects as the cognitive therapy group
(120 vs. 60 respectively) and a significant interaction effect was noted for site of intervention
(p = 0.02), suggesting that therapists experience levels were not equal between the two sites
used in the study.
Combination Therapy
 In a complex study with multiple outcome measures and several limitations de Jonghe
(2004)(59) found that patients with mild to moderate MDD initially treated with
psychotherapy alone and patients treated with combination psychotherapy and
antidepressants each experienced improvement over six months (primary outcome change
in HAMD score: -6.79 points in psychotherapy group vs. -8.46 points in combined therapy
group, p = 0.083). Combination therapy did not lead to significantly greater improvements
in depressive symptoms in the intent to treat sample compared with psychotherapy alone.
In the per-protocol sample, there were minor differences favoring combined therapy on some
measures, but not others. The authors conclude that the benefits of combination therapy in
this population are “equivocal.”
 In a study of specialty mental health outpatients, Kool, et al. (2003)(60) found that
antidepressant treatment (initially fluoxetine, changed to amitriptyline if initially intolerant,
then moclobemide [a MAOI] if still intolerant) combined with 16 sessions of short
psychodynamic supportive psychotherapy (SPSP), starting two weeks after the initiation of
medication, was more effective than pharmacotherapy alone for depressed patients with
personality disorders (change in HAMD scores -9.02 vs. -5.86, p = 0.04), but not in
depressed patients without personality disorders (change in HAMD scores -8.61 vs. -9.1,
p = 0.74). The generalizability of this study to primary care is uncertain; most patients with
depression and personality disorders are referred to specialty mental health for treatment.
A search of Clinical Evidence (Issue 14, January 2006) yielded two systematic reviews and two
subsequent RCTs:
 The first review found that combination therapy significantly improved depressive symptoms
compared with drug treatment alone (OR = 1.86, 95% CI: 1.38 to 2.52). A greater effect was
found in longer duration (12-week) studies with shorter treatment times (OR = 2.20,
95% CI: 1.22 to 4.03).(61)
 The second review found a small yet significant effect of combination pharmacotherapy and
psychotherapy over either intervention alone (effect size: Cohen’s d = 0.34 with BDI and
0.18 with HRSD; further details not reported).(62)
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Clinical Evidence also cited the studies by de Jonghe (2004)(59) and Kool (2003)(60) which were
reviewed by the GDT and discussed above.
 Another RCT(63) of 102 older patients (older than 60 years) with MDD compared
desipramine plus cognitive behavioral therapy, desipramine alone, and/or cognitive
behavioral therapy alone. All three groups showed a significant reduction in symptoms from
baseline as assessed using the HAM-D after 16 to 20 weeks of treatment. It found that
combined treatment significantly improved symptoms compared with desipramine alone
(p < 0.05), but there was no significant difference between combined treatment and cognitive
behavioral therapy alone.
Other Interventions
 Proudfoot, et al. (2004)(64) found that, compared with usual care (with or without
antidepressants), a computerized CBT intervention yielded a significantly greater
improvement in depressive symptoms, assessed primarily by BDI scores at three months
(6.5 point difference favoring intervention group); differences continued to be present at
eight months (5.8 point difference favoring the intervention group). Slightly over half of
each patient group received pharmacotherapy. It is unclear how many patients in the usual
care group received pharmacotherapy – if many usual care patients received no treatment,
it would bias results in favor of the intervention group. Both authors have commercial
interests in the computerized CBT intervention.
 In a poorly reported study, Sirey, Bruce, and Alexopoulous (2005)(65) examined the
effectiveness of The Treatment Initiation Program (TIP), an individualized, early intervention
to address older adults’ attitudes about depression and barriers to care. The control group
was given pharmacotherapy as usual; the intervention group was given both pharmacotherapy and TIP. The intervention group showed greater (71% vs. 42%) remission (defined
with a low threshold as HAMD scores < 10) after 24 weeks. The intervention group had
significantly lower HAMD scores at baseline, suggesting poor randomization; and overall
changes in HAMD scores were not reported (lower pretreatment scores in the intervention
group might bias remission results in favor of the intervention group, when in fact both
groups could have equal changes in HAMD scores). The authors claim, but do not quantify,
that patients in the intervention group were more likely to remain in treatment.
Discussion:
There has been increasing discussion about the “true efficacy” of antidepressants compared with
placebo. Concerns have been raised about publication bias, especially since analyses show that
published studies funded by the pharmaceutical industry overwhelmingly tend to favor the
funder’s medication. Some studies have found statistically significant differences on some
outcomes (differences between changes in scores on depression rating scales) whose clinical
relevance is debatable. The methodological quality of studies, especially as it relates to blinding
and analytic methods (completer analyses and last observation carried forward methods of
imputing missing data may bias studies in favor of active treatment). Interestingly, a recent
analysis(66) notes that over the past 20 years, overall antidepressant response and placebo
responses have both increased This suggests that study design factors and other external factors
(patient awareness, direct to consumer and other antidepressant marketing) might be influencing
trial results.
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Almost all clinical trials include some degree of “attention” for patients receiving placebo, and
patients who enroll in clinical trials may be more “responsive” to placebo than patients at large;
therefore, the placebo response in trials may be higher than the placebo response that would be
found in the ‘real world’, that is, uncontrolled clinical conditions with a wider range of patients.
While trials may overstate the magnitude of benefit of antidepressants, the NNT for
antidepressant treatment still would likely remain more favorable than the NNH in most
analyses.
Considering all this information, the GDT concludes that the balance of evidence supports the
use of antidepressant medication for treatment of MDD, but also underscores the need (given
studies showing it’s effectiveness) to consider structured psychotherapeutic treatment options
(Interpersonal Therapy, Cognitive Behavioral Therapy, or Problem-Solving Therapy) and the use
of shared decision-making with patients.
New evidence did not surface to suggest the need to change the previous guideline
recommendation regarding combined antidepressant and psychotherapy for treatment of severe
MDD. Although this combination may provide marginal benefit in patients with milder forms of
depression, the benefit is small in light of the additional resources required, so the GDT
recommends, consistent with the previous guideline recommendation, limiting combination
therapy in this group of patients to patients who fail to respond to initial treatment, which by
definition includes patients with chronic depression (see the recommendations for second-line
treatment). Patients with personality disorders and depression are usually treated in specialty
behavioral health settings.
After review of the new evidence summarized here, the GDT believes that the previous
recommendations are still valid.
2004 Guideline
Supporting Evidence for Antidepressants versus Placebo
Since the previous revision of the Depression Guidelines, three RCTs and one systematic review
were found which looked at the efficacy of antidepressants versus placebo.
 Detke(38) included adult patients with MDD that had a baseline score of ≥ 15 on the 17-item
Hamilton Rating Scale for Depression (HAM-D-17). The study was a randomized, doubleblind, placebo controlled trial. The study compared a SNRI (duloxetine), 60 mg /day
(n = 121) and inert placebo (n = 115) for efficacy. This study also compared duloxetine
(n = 123) and inert placebo (n = 122) for safety analysis. The duration of study was nine
weeks. Duloxetine was significantly superior to placebo (4.8 point difference on the HAMD-17 scale (p < 0.001), NNT to achieve one additional remission = 4). Significant side
effects associated with duloxetine versus placebo included: nausea (p < 0.001), dry mouth
(p < 0.001), somnolence (p < 0.001). Other statistically significant side effects of duloxetine
were dizziness (p = 0.010), diarrhea (p = 0.006), insomnia (p = 0.021), and constipation
(p = 0.001).
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 Goldstein(67) included adult patients with MDD that had a baseline score of at least 15 on the
HAM-D-17 scale for depression. The study was a randomized, double-blind, placebo
controlled trial comparing a SNRI (duloxetine), 40 mg/day to 120 mg/day (n = 70) and inert
placebo (n = 70) for a period of eight weeks. An SSRI (fluoxetine), 20 mg/day (n = 33) was
included as an internal control to be sure patients were antidepressant responsive. Duloxetine
was statistically superior to placebo in reducing the symptoms of MDD, with a 3.1 point
difference between treatments on the HAM-D-17 scale (p = 0.009), and a NNT = 4 to
achieve one additional remission compared with placebo. Insomnia was significantly more
common with SNRI treated patients (p = 0.046, NNH = 13 to 14). There was a mean
increase in standing diastolic blood pressure for SNRI treated patients of 2.8 mm Hg
(p = 0.041). The study also showed a small but statistically significant (p = 0.005) reduction
in body weight (0.59 kg) in SNRI treated patients. The clinical significance of the latter two
findings is questionable.
 Wade(68) included adult patients between ages of 18 and 65. There was a 3:1 ratio of women
to men, with more than 97% being Caucasian. All patients met the DSM-IV criteria for
MDD and had a baseline Montgomery-Asberg Depression Rating Scale (MADRS) total
score between 22 and 40. The study was a randomized, double-blind, placebo controlled trial
comparing a SSRI (escitalopram) (n = 191) and inert placebo (n = 189) for a period of eight
weeks. Escitalopram (10 mg/day) was statistically superior to placebo, with a 2.7 point
greater adjusted mean change in MADRS total score from baseline to week eight (p = 0.002)
(NNT not given). Headache and nausea were the most frequent adverse events, but nausea
was the only adverse effect that was statistically significant in SSRI treated patients
(p ≤ 0.05, NNH = 20).
 Moncrieff(69) reviewed six randomized and quasi-randomized, double-blinded studies of men
and women of all age groups with a primary diagnosis of depressive disorder. These studies
compared TCA drugs and an active placebo containing atropine. The duration of studies
varied from three to 12 weeks. Change in mood at the end of treatment was the outcome of
interest in these studies. The majority of trials found only small differences
(p not stated) between TCA antidepressants and active placebos.
 The Cochrane systematic review, Wilson,(27) included 17 trials that assessed the efficacy of
different antidepressants in older adult patients (over 60 years) with MDD. All trials
compared SSRIs, TCAs, or MAOIs (monoamine oxidase inhibitors) with placebo, no headto-head active drug comparisons were reported. The authors concluded that TCAs, SSRIs,
and MAOIs were effective in the treatment of older community patients and they
recommended that at least six weeks of antidepressant treatment to achieve optimal
therapeutic response.
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Clinical Evidence, Vol. 9, was also searched and our recommendations are in line with their
conclusions.
 They note that systematic reviews in people aged 16 years or greater have found that
antidepressant drugs (monoamine oxidase inhibitors, selective serotonin reuptake inhibitors,
or tricyclic antidepressants) versus placebo improve symptoms in acute treatment of all
grades of depressive disorder. One systematic review in people aged 55 years or greater with
all grades of depressive disorder has found that tricyclic antidepressants, selective serotonin
reuptake inhibitors, or monoamine oxidase inhibitors versus placebo significantly reduce the
proportion of people who fail to recover over 26 to 49 days. They found no specific evidence
on adverse effects in older adults.(70)
Overall Conclusion:
Since the previous revision of these guidelines, three RCTs and one meta-analysis were found
that supported the use of antidepressants compared with inert placebo. One systematic review
found only a small difference between treatment and active placebo. Although antidepressants
have side effects, they are superior to placebo in treating MDD.
Supporting Evidence for Psychotherapy vs. Placebo
Volume 9 of Clinical Evidence,(70) most recent search date November 2003, was searched and
one systematic review was found showing benefit of cognitive therapy vs. placebo in younger
and older adults with mild to moderate depression.
 RCTs in younger and older adults with mild to moderate depression found that problemsolving treatment or interpersonal psychotherapy versus placebo significantly improved
depressive symptoms in the short term. One systematic review in people aged ≥ 55 years
with mild to moderate depression found five of six comparisons of cognitive or cognitivebehavioral therapy vs. no treatment lead to significant mean changes of -7.3 points on the
HAM-D rating scale (95% CI: -10.1 to -4.4); however, there were no significant differences
found between active treatments and “nonspecific attention” control groups. This review
was based on a small number of studies, the populations varied (although most were
community samples), and many of the studies were short term. RCTs found limited evidence
about the effects of psychological treatments in severe depression. This evidence of the
efficacy of psychotherapy versus placebo is summarized in Table 1.26, Effects of Specific
Psychological Treatments for Depressive Disorders, in Appendix B.
No additional systematic reviews or RCTs since the Clinical Evidence review were found that
addressed this question.
Other Considerations:
There is insufficient evidence across trials to determine the optimal number of sessions for each
type of psychotherapy, and some concern that rigorous study protocols may not be delivered in
“real world” settings, potentially affecting the achieved effectiveness of psychotherapy in
different settings.
Overall Conclusion:
The evidence supports the efficacy of structured forms of psychotherapy (cognitive, cognitivebehavioral, interpersonal, or problem-solving therapy) delivered by behavioral health
professionals as a first-line treatment option for patients with Major Depression.
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Supporting Evidence for Antidepressants versus Psychotherapy or
Combination of Antidepressants and Psychotherapy
One systematic review that addressed this issue was found.
 Six multiple-cell, randomized, controlled, double-blind trials were included in the
Casacalenda(1) systematic review. The studies included adults with nonpsychotic Major
Depression. These studies compared medication (five studies used tricyclics and one used
phenelzine, a MAOI) (n = 261) and psychotherapy (three studies used cognitive behavior
therapy, three used interpersonal therapy, one used problem-solving) (n = 352) and placebo
(n = 270). Intention-to-treat analyses indicated that pharmacotherapy and psychotherapy
were significantly more efficacious than control conditions (p < 0.0001) but were not
significantly different from each other when treating mildly to moderately depressed patients.
 Structured forms of psychotherapy have established efficacy in treating the symptoms of
Major Depression. Mynors-Wallis(1, 71) compared the following:
 Problem-solving therapy delivered by a general practitioner
 Problem-solving therapy delivered by a nurse
 Antidepressant medication (either fluvoxamine or paroxetine)
 Combination of psychotherapy and medication.






Patients receiving psychotherapy met with the doctor or nurse for one hour on the
first visit and for 30 minutes on subsequent visits.
All patients received 12 weeks of treatment and at 52 weeks had follow-up
interviews.
A total of 151 patients participated in the study. All patients had "probable" or
"definite" acute Major Depression according to Diagnostic Research Criteria.
Patients receiving psychotherapy had lower completion rates (completed all 52 weeks
of treatment) at the end of the study (64% and 68% respectively) as compared with
medication alone or combination therapy (83% and 86% respectively).
At 52 weeks, there were no statistically significant differences between patients who
received problem-solving therapy, medication, or combination therapy (as determined
by a 50% reduction in depression symptom score on the Hamilton Depression Rating
Scale and the Beck Depression Inventory). Therefore, the authors concluded that
problem-solving therapy and medication were effective treatments for Major
Depression. However, patients receiving problem-solving therapy had higher dropout
rates than those in the medication or combination group.
The Mynors-Wallis study showed that patients assigned to medication experienced
higher rates of symptom resolution at 12 weeks (67% versus 54%, ARR = 13,
NNT = 8), therefore psychotherapy had slower onset of therapeutic effect.
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 Schulberg(72) compared usual care, nortriptyline, and Interpersonal Therapy (IPT) in
276 primary care patients.
 Patients were aged 18 to 64 years and had to meet DSM-III-R(73) criteria for MDD.
 Patients were followed for eight months.
 The authors concluded that the severity of depressive symptoms was reduced more rapidly
and more effectively among patients randomized to pharmacotherapy or psychotherapy
than among patients assigned to a physician's usual care.
 Among treatment completers, approximately 70% of patients participating in the full
pharmacotherapy or psychotherapy protocol achieved resolution of symptoms but only
20% of usual care patients were judged as recovered at eight months. However, this
intervention is very resource intensive.
Clinical Evidence(70) was also searched and our recommendations are in line with their
conclusions. The following are their findings:
 One systematic review in people aged over 18 years with recent onset psychological
problems, including depression, found that brief, nondirective counseling versus usual care
by a physician significantly reduced symptom scores in the short term (less than six months),
but found no significant difference in scores in the long term (more than six months).
 They found one nonsystematic review showing that the combination of psychotherapy and
antidepressant medication in patients age 18 to 80 with severe MDD is more beneficial than
either treatment alone.
 One RCT was also found showing that combination antidepressant treatment is more
effective than either treatment alone for patients with mild to moderate Major Depression.
Overall Conclusion:
New evidence since the previous Depression Guideline revision shows that combining
antidepressant medication and psychotherapy may be more beneficial than either treatment alone
for patients with severe, and perhaps even mild to moderate, Major Depression. However, many
patients with mild to moderate depression will respond to monotherapy (either antidepressants or
psycho-therapy used alone), and extra resources are required to provide combined treatment to
all depressed patients. Therefore, the GDT recommends that combining antidepressants and
psychotherapy be reserved as an option for those patients with mild to moderate depression who
do not initially respond to either treatment alone.
However, for patients with severe MDD, who are most adversely affected, most significantly
impaired, and are at higher risk for suicide, the added cost of initially starting with both
antidepressant medication and psychotherapy in combination may be worth the incremental cost
(in time and resources). Therefore, the GDT believes that combined antidepressantpsychotherapy is appropriate first-line treatment for patients with severe MDD.
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Supporting Evidence For Head-To-Head Comparison of Antidepressants
Since the previous revision of the Depression Guidelines, one RCT and one nonsystematic
review were found that compared the efficacy of antidepressant against each other.
 Thase,(74) a nonsystematic review, included eight randomized, double-blinds studies
comparing a SNRI (venlafaxine) and SSRIs (fluoxetine, paroxetine, and fluvoxamine) and
placebo for six to eight weeks (only four of eight trials were placebo controlled). Studies
included adults (18 and older) who met the DSM-III-R or DSM-IV criteria for MDD for at
least one month. All studies were funded by the SNRI manufacturer. Remission rates (using
Hamilton Rating Scale for Depression, HRSD) were significantly higher (10%) with SNRI
(venlafaxine) than with an SSRI (fluoxetine, paroxetine, and fluvoxamine). Odds ratio
indicated that venlafaxine-treated patients had a 50% greater chance of attaining remission
than patients treated with an SSRI (NNT = 10). However, the reported SSRI remission rates
in this analysis (35%) are noticeably lower than the SSRI remission rates seen in other trials,
raising the possibility of publication bias.
 Mulsant(75) included outpatients and inpatients age 60 and older with MDD and a HAM-D-17
score of 15 or above. The population was 71.6% female and 86.2% white. The study was a
12 week randomized double-blind trial comparing a TCA (nortriptyline, 25 to 50 mg) and a
SSRI (paroxetine, dose range of 10 to 20 mg). There was no statistical difference in efficacy
based on HAM-D-17 scores (p = 0.16). Patients were twice as likely to discontinue TCA
(33%) as SSRI (16%) due to a significant side effect (p = 0.04), but the overall
discontinuation rates did not differ significantly, p = 0.30.
 AHRQ’s systematic review, Mulrow(76) included 81 trials that addressed efficacy of
antidepressant medications. The majority of trials were conducted in outpatient setting.
All trials were in patients with MDD.
All trials were double-blind and were six to eight weeks in duration.
All studies were sponsored by pharmaceutical companies.
The review included 80 studies that demonstrated that multiple newer antidepressants
(SSRIs, SNRIs, and NRIs) were equally as effective as older tricyclic antidepressants.
In 55 studies reporting response rates, SSRIs were compared with TCA1 (n = 38),
TCA2 (n = 5), triazolopyridine (trazodone) (n = 4), tetracyclic antidepressants (n = 7),
and MAOI (n = 1).
SSRIs were equally effective compared with TCA1 (RR = 1.0, 95% CI: 0.9 to 1.1),
TCA2 (RR = 1.1, 95% CI: 0.9 to 1.3), triazolopyridine (RR = 1.1, 95% CI: 0.7 to 1.6),
tetracyclic (RR = 1.1, 95% CI: 0.9 to 1.3), and MAOI antidepressants (RR = 0.9,
95% CI: 0.7 to 1.3).
There is no evidence that any one medication is more efficacious than any other. SSRIs
have a small, short-term advantage in six week continuation rates over TCAs and
heterocyclic medications (NNT = 20 to 33).
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The two subsequent systematic reviews in the Cochrane database included Geddes and Barbui.
 Geddes(77) compared SSRIs with a variety of antidepressants, including TCAs and
heterocyclics. This systematic review included 98 studies conducted in primary and
secondary care in 13,336 inpatients and outpatients with MDD.
 All the trials were double-blind and were six weeks in duration.
 The analysis of efficacy was based on 5,044 patients treated with an SSRI or related drug
and 4,510 treated with an alternative antidepressant. The standardized effect size for SSRIs
and related drugs together versus alternative drugs using a fixed effects model was 0.035.
(95% CI: -0.006 to 0.076; Q = 149.25, df = 97, p < 0.001).
 The standardized effect size for SSRIs alone versus TCAs was 0.044 (95% CI: -0.020 to
0.107). There was no evidence of statistically or clinically significant differences between
the drugs.
 In AHRQ’s systematic review(76) less than 10% of the trials addressed adherence.
These trials demonstrated that overall dropouts did not differ significantly between active
treatments.
 In the Geddes(77) review, 27.7% of patients treated with SSRIs dropped out, compared with
32.7% of patients treated with TCAs (ARR = 5%, NNT = 20).
 Barbui’s systematic review(78) focused on adherence and included 136 trials, 58%
of which were conducted in the primary care setting, the total N was not reported.
The majority of trials were six weeks in duration (84%) and nearly all studies were in
patients with Major Depression.
 The estimate of overall dropout rates showed significantly fewer dropouts in the SSRI
group compared with TCAs. (OR = 1.21, 95% CI: 1.12 to 1.30)
 On average, 27 out of every 100 patients taking SSRIs will dropout compared with
30 of every 100 taking TCAs. (ARR = 3%, NNT = 33)
 The authors concluded that there was a small difference in dropout rates between SSRIs
and TCAs (amitriptyline, imipramine, clomipramine, desipramine, dothiepin, doxepin,
lofepramine, and nortriptyline).
Eight studies were found since the Cochrane systematic review that addressed treatment of MDD
in older patients.
 Of these, Finkel(79) and Newhouse(80) compared sertraline with fluoxetine in 75 (university
center) and 236 (outpatients) respectively. The trials were 12 weeks in duration. Finkel
reported results that favored sertraline; however, this study was sponsored by Pfizer and
there was evidence of selection bias. Newhouse concluded that both drugs were equally
efficacious in this population; however, the authors didn't report any head-to-head
comparisons and not all comparisons were reported. In addition, Newhouse used a one
week placebo run-in, which doesn't control for the difference in half-life between sertraline
and fluoxetine.
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 Bondareff(81) and Oslin(82) compared sertraline with nortriptyline in specialty care
(n = 210 and 76) and nursing home patients (n = 97). Trials ranged from 10 to 12 weeks in
duration. The studies report conflicting results; Bondareff and Finkel favor sertraline while
Oslin favors nortriptyline. Oslin compared sertraline open-label patients with double-blind
treated nortriptyline (regular and low-dose) patients. Bondareff also reported that
nortriptyline patients over 70 had poorer prognosis. Bondareff excluded placebo responders.
 Schweizer(83) compared imipramine and buspirone with placebo in 177 primary care
outpatients. Results indicated that imipramine was superior to placebo but no head-to-head
comparisons were reported. More patients taking imipramine also used over the counter
medications (such as painkillers, etc.).
 Mulsant(84) compared nortriptyline with paroxetine in 80 mixed setting patients (inpatients
and outpatients). The trial was six weeks in duration. The authors concluded that both drugs
were equally efficacious.
 Forlenza(85) compared sertraline with imipramine in 55 specialty care outpatients. The trial
was six weeks in duration. The authors concluded that both drugs were equally efficacious;
while there was no significant difference in overall dropout rates, the majority of patients
taking imipramine dropped out in the first two weeks. The trials were short in duration; had
selection and publication bias; and small N’s.
Clinical Evidence, Vol. 9,(70) was searched and it was found that our recommendations are in line
with their conclusions. The followings are their findings:
 Two systematic reviews have found no clinically significant difference in outcomes with
different kinds of antidepressant drug, although one systematic review found that monoamine
oxidase inhibitors were less effective than tricyclic antidepressants in people with severe
depressive disorders, but may be more effective in atypical depressive disorders, for example
increased sleep, increased appetite, mood reactivity, and rejection sensitivity. Systematic
reviews have found that antidepressant drugs differ in their adverse event profiles. One
systematic review has found that, on average, people seem to tolerate selective serotonin
reuptake inhibitors a little better than tricyclic antidepressants, but the difference was small.
Another systematic review and one retrospective cohort study found no strong evidence that
fluoxetine was associated with increased risk of suicide. One RCT and observational data
suggest that abrupt withdrawal of selective serotonin reuptake inhibitors is associated with
symptoms including dizziness and rhinitis, and that these symptoms are more likely with
drugs with a short half-life, such as paroxetine.
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Other Considerations
Group Health Cooperative’s 2003 Adult Major Depression Guideline included one additional
study on venlafaxine vs. SSRIs identified from a Medline search using similar mesh terms that
did not appear in our PubMed search (Smith(86)).
Group Health concluded:
 “This study (Smith) found that venlafaxine was more effective than other antidepressants at
treating depression. The difference in effect size was equal to about 1.2 points on the HAMD which, although statistically significant, may not be a clinically significant difference.
The meta-analysis was funded by Wyeth Laboratories, the manufacturer of venlafaxine,
and this may have introduced bias in the study design, analysis, or reporting. The existing
evidence is not sufficient to recommend the use of venlafaxine as first-line medication rather
than well-established antidepressants such as SSRIs.”
Overall Conclusion
The preponderance of evidence suggests that generally, all antidepressants are equally effective.
While some evidence suggests that venlafaxine may be more effective that SSRIs in achieving
remission in the first few weeks of treatment, due to concerns about publication bias and the lack
of longer-term outcomes data, the GDT believes that currently there is insufficient evidence to
preferentially recommend venlafaxine over other antidepressants for first-line treatment of MDD
in the primary care setting.
2.
Hypericum (St. John’s Wort) for MDD
2A
The GDT makes no recommendation for or against providing hypericum (St. John’s
wort) in patients with mild-to-moderate Major Depression.
There is fair evidence of effectiveness of hypericum in this population. However, due to
lack of consistency of preparation and dosage across trials, and concerns about lack of
FDA oversight and consistency of hypericum preparations, the balance of benefits,
harms, and costs compared with other treatments cannot be determined.
Evidence-based: C
The GDT recommends against providing hypericum (St. John’s wort) to patients with
severe Major Depression. Evidence-based
2B
Evidence Grade
Evidence for Recommendation 2A: Fair
Evidence for Recommendation 2B: Evidence-based
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Rationale:
2008 Guideline
New evidence was found that did not change the existing recommendations.
Search Strategy
We found four RCTs comparing hypericum with placebo and/or standard antidepressants:
 Kasper et al. (2006)(87) found that hypericum decreased depressive symptoms significantly
more than placebo in patients with mild-to-moderate Major Depressive Disorder. The
percentages of responders (NNT = 3) and remitters (NNT = 5) were higher
in patients receiving hypericum than in patients receiving placebo as well.
 Gastpar et al. (2005)(88) found that hypericum was not inferior to sertraline in reducing
depressive symptoms in moderately depressed patients (score 20 to 24 on the Hamilton
Depression Scale) meeting the ICD-10 diagnosis for moderate depression, with at least four
or more DSM-IV typical depression symptoms. Although no placebo group was studied, the
percentage of responders did not differ between treatment groups either. Due to the inclusion
criteria, it is possible that not all patients would meet the DSM-IV classification for Major
Depressive Disorder.
 Gastpar et al. (2006)(89) found that hypericum was not inferior to citalopram in reducing
depressive symptoms in moderately depressed patients (score 20 to 24 on the Hamilton
Depression Scale and diagnosis of Major Depressive Disorder), whereas both hypericum and
citalopram were superior to placebo. The percentage of responders was higher in both
treatment groups than in the placebo group as well.
 Fava et al. (2005)(90) found that patients with mild-to-moderate Major Depressive Disorder
diagnosed by Structured Clinical Interview for DSM-IV who were taking hypericum showed
a significant improvement in depressive symptoms over patients taking fluoxetine
(NNT = 12), and reported a trend toward superiority for hypericum over placebo (NNT = 6).
Overall Conclusion
We found no new evidence on the use of hypericum for patients with severe Major Depressive
Disorder. Therefore, there is no change in the recommendation on use of hypericum in these
patients.
Three of the four studies we reviewed studied patients with Major Depressive Disorder,
addressing one of the GDT’s concerns about the heterogeneity of study populations in previous
studies. However, the GDT has persistent concerns regarding the lack of standardization of
dose and preparation of hypericum across trials. Given the lack of FDA oversight, it is uncertain
whether trial preparations and doses of hypericum would be consistently available to patients for
routine use. The GDT is, therefore, unable to determine the balance of benefit and risk of
hypericum for mild-to-moderate Major Depression compared with other existing evidence-based
therapies.
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For the 2008 Guideline, the health outcome of “change in symptoms” was the only relevant
outcome for which evidence was found. In addition, all three health interventions – prescription
antidepressants, hypericum, and no treatment - were addressed in this 2008 Guideline.
2006 Guideline
We found four RCTs comparing hypericum with placebo and/or standard antidepressants, with
mixed results:
 Gelenberg, et al. (2004)(91) found that the lack of hypericum efficacy in previous studies was
unlikely to be attributable to treatment-resistant subjects.
 Uebelhack, et al. (2004)(92) found that moderately depressed patients taking hypericum
showed a significant improvement in depressive symptoms over placebo control subjects.
 Szegedi, et al. (2005)(93) showed decreases in depressive symptoms in both patients taking
hypericum and patients taking paroxetine, and concluded that hypericum is not inferior to
paroxetine.
 Bjerkenstedt, et al. (2004)(94) found a significantly higher remission rate among mild to
moderately depressed subjects who had taken hypericum versus those who had taken
placebo, but study duration was short (four weeks) and there was no comparison of remission
rates between hypericum and fluoxetine subjects.
 The Cochrane systematic review(95) included 37 trials comparing hypericum with placebo or
antidepressant. Larger placebo-controlled trials restricted to patients with Major Depression
showed only minor effects of hypericum (RR = 1.15, 95% CI: 1.02 to 1.29); older, smaller
trials including patients with minor depression showed more marked effects (RR = 2.06,
95% CI: 1.65 to 2.59).
 Trials comparing hypericum extracts and standard antidepressants were heterogeneous.
Patients given hypericum extracts had fewer adverse effects than those given SSRIs
specifically, but the difference was not statistically significant (OR = 0.60, 95% CI:
0.31 to 1.15). The authors conclude that current evidence regarding hypericum is
“inconsistent and confusing.”
 Some trials involving patients with Major Depression suggest hypericum has a minimal
beneficial effect, while others suggest the effect is comparable with standard antidepressants.
 Furthermore, the pharmaceutical quality of hypericum preparations varies considerably, and
trial results are limited and specific to preparations used in the study.
Clinical Evidence (Issue 14, January 2006) also cited the Linde & Mulrow systematic review and
the authors made similar conclusions about the quality of the trials and the concerns about
pharmaceutical quality of hypericum. They emphasize the need to interpret RCTs on the
efficacy of hypericum cautiously due to the lack of standardization of preparations used across
trials and the varying doses of comparator standard antidepressants.
We found no trials comparing hypericum with psychotherapy.
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Overall Conclusion
The statement that the evidence is "insufficient and confusing" is an appropriate summary of the
studies we reviewed. Based on this finding and other concerns expressed in previous reviews
(varying definitions and inclusion criteria for depression, concerns over adequacy of blinding in
the studies, and short trial duration), the GDT believes that there is insufficiently consistent
evidence to recommend hypericum instead of prescription antidepressants for the treatment of
MDD.
2004 Guideline
Supporting Evidence for Hypericum (St. John’s Wort) versus Placebo
Two RCTs examining the efficacy of hypericum versus placebo for treatment of MDD were
found.
 The hypericum Depression Trial Study Group(96) was a randomized, double-blind, controlled
trial including adults (at least 18 years old) with MDD and a minimum score of 20 on
the HAM-D scale for depression. The study compared hypericum (900 to 1,500 mg/dl)
(n = 113) and placebo (n = 116) for eight weeks, with sertraline (50 to 100 mg/day)
(n = 111) as an active comparator to evaluate the study’s sensitivity.
The study found no evidence that hypericum is more effective than placebo in treating
moderately severe Major Depression (p = 0.59). The only significant adverse event with
hypericum was anorgasmia (p = 0.04).
 Kalb(97) included adult outpatients between 18 and 65 years old with mild to moderate single
episode or recurrent MDD and a total score of greater than 16 on HAMD-17 scale. The
study was a randomized, double-blind, controlled trial comparing hypericum extract WS
5572 (3 x 300 mg/day) (n = 37) and placebo (n = 35) for six weeks.
 The study concluded that the standardized hypericum extract WS 5572 has superior
efficacy compared with placebo and very good tolerability in the acute treatment of mildly
to moderately depressed patients.
 There was a significant decrease in HAM-D scores (p < 0.001) in hypericum (54.8%,
or 10.8 points) compared with placebo (29.2%, or 5.7 points).
 There was no significant difference in the percentage of patients with at least a 50%
improvement in HAM-D scores (a commonly used measure of antidepressant response)
62.2% for hypericum vs. 42.9% for placebo, p = 0.10, but the study may have been
underpowered to detect this difference.
 There was, however, a significant difference in percentage of patients with at least a 60%
improvement in HAM-D scores (51.4% vs. 17.1%, p = 0.002); however, this measure is not
commonly used in other antidepressant efficacy trials.
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Clinical Evidence(70) was also searched and our recommendations are in line with their
conclusions. They concluded:
 Two systematic reviews in people with mild to moderate depressive disorders have found
that St. John's wort (Hypericum perforatum) versus placebo significantly improves
depressive symptoms over four to 12 weeks, and have found no significant difference in
symptoms with St. John's wort versus prescription antidepressant drugs. However, these
findings have not yet been repeated in people with all grades of depression using
standardized preparations of St. John's wort.
 The evidence cited must be interpreted cautiously because it is unclear how closely people in
these trials match people in clinical practice, and the preparations and doses of H. perforatum
and types and doses of standard antidepressants varied. More studies are needed on clearly
defined, clinically representative people using standardized preparations. Interactions with
other drugs are possible and should be considered.
 Shelton(98) compared St. John's wort with placebo in 167 outpatients attending academic
medical centers for the treatment of severe Major Depression. The authors concluded that
St. John's wort was no more effective than placebo in treating severe Major Depression.
Since severe Major Depression is associated with morbidity and an increased risk for suicide,
also since there are other effective available treatments, and the only study of St. John's wort in
severely depressed patients showed no efficacy, the GDT recommends that St. John's wort not be
used in patients with severe Major Depression.
Supporting Evidence for Hypericum (St. John’s Wort) Versus Antidepressants
One RCT examining the efficacy of hypericum versus antidepressants for treatment of MDD was
found since the previous revision of the Depression Guidelines.
 Behnke(99) included adult patients (18 to 73 years old) with mild to moderate Major
Depression and HAM-D scores between 16 and 24. The study was a randomized, doubleblind, controlled trial comparing hypericum (150 mg twice daily) (n = 35) and SSRI
(fluoxetine, 20 mg twice daily) (n = 35) for six weeks. There was no placebo control group.
The study concluded that Hypericum perforatum is therapeutically equivalent to fluoxetine
and therefore a rational alternative to synthetic antidepressants. There was a significant
decrease in HAM-D score (p < 0.001) in both hypericum (50%) and fluoxetine (58%), but it
was not significantly different (p = 0.23) between the two groups.
 Five RCTs of patients with milder forms of depression were reviewed. All were six to eight
weeks in duration. Harrer,(100) Philipp,(101) Schrader,(102) and Woelk(103) studied patients with
mild to moderate depression, while Brenner(104) looked at 30 patients with MDD (number of
patients with severe MDD not specified), dysthymia, adjustment disorder, and depression not otherwise specified.
 Harrer(100) and Schrader(102) compared St. John's wort with fluoxetine in 161 older adult and
238 outpatients with mild to moderate depression. The authors concluded that both
medications are equally efficacious in treating mild to moderate depression. However,
the Harrier study used low doses of fluoxetine (11 mg/day) that in many instances may be
insufficient to achieve symptom remission. Comparisons with higher yet commonly used
fluoxetine dosage regimens were not included in the Harrier study, and no placebo group
was included to control for possible no effect of low-dose fluoxetine in this setting.
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 Both Philipp(101) and Woelk(103) compared St. John's wort with imipramine in 263 and 288
outpatients with mild to moderate depression. The authors concluded that both medications
are equally efficacious but patients tend to tolerate St. John's wort better than imipramine.(103)
Philipp's study used low doses of imipramine that are often not sufficient to induce remission
of depressive symptoms. Woelk's study was conducted in primary and specialty care
patients.
 Brenner's(104) study compared St. John's wort with sertraline in 30 patients with Major
Depression (number of patients with severe MDD not specified), dysthymia, adjustment
disorder, and depression - not otherwise specified. The authors concluded that both
medications were equally efficacious in treating mild to moderate depression. This study
may be underpowered to detect significant differences, and no placebo control group was
included.
The GDT expressed several concerns about St. John's wort including:
 Wide range of dosages and different preparations of St. John's wort used across trials
(some preparations may have other, undetermined active ingredients).
 Short duration of the trials (longer-term results are not clear).
 The definitions and classification of depression varied in trials, making it difficult to translate
the results consistently into practice.
 Many of the patients in the reviewed trials with mild depression had adjustment disorders or
minor/subsyndromal depression. There is no current evidence that suggests these types of
depression need treatment with medication. Therefore, without a placebo control group in
these trials, it is possible that while St. John's wort was equal to a comparator medication,
neither medication may have been superior to placebo.
 Potential for bias due to difficulty in patient blinding (due to the characteristic taste and smell
of St. John's wort).
 The products used in trials may not be widely available commercially.
 Dietary supplements are not subject to evaluation for safety and efficacy by the US Food and
Drug Administration (FDA) nor is their manufacture held to compliance with the FDA’s
Good Manufacturing Practices. As a result of the lack of standardization and quality control,
herbal content and efficacy vary, and contamination and misidentification of plant species
may occur.
 St. John's wort is not approved by the FDA for treatment of depression.
 Traditional treatment alternatives (regulated antidepressant medication, structured
psychotherapy) are readily available, well-tested, known to be effective, and subject to
oversight.
 St. John's wort can cause potentially serious drug interactions, which were not adequately
addressed in the reviewed studies.
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Overall Conclusion
There is no evidence that St. John’s wort is effective for severe MDD. There is lower quality
evidence of short-term effectiveness in milder forms of depression. These trials often lacked
placebo controls and included patients with subsyndromal forms of depression, who often remit
spontaneously and therefore, it is unclear that any medication is indicated. Due to concerns
about the quality of the evidence, absence of data on longer-term outcomes, and reports of
adverse drug-hypericum interactions that are not yet routinely documented in prescribing
decision-support software, the GDT believes there is insufficient evidence for or against
St. John's wort as an alternative to other effective, regulated treatments for mild to moderate
Major Depression.
The GDT recognizes that some patients may initiate discussions about St. John's wort, or may
already be taking St. John's wort at the time they consult a clinician. In these instances, the GDT
suggests that clinicians discuss the evidence and concerns with patients, using a shared decisionmaking approach.
3.
Antidepressants In Patients With MDD Expressing Suicidal
Ideation, Intent, Or Plan
3A
For patients with Major Depression expressing suicidal intent or plan, the GDT
recommends consultation with specialty behavioral health. Consensus-based
For patients with suicidal ideation or who have made previous suicide attempts, the GDT
recommends consultation or collaboration with a psychiatrist before prescribing TCAs or
venlafaxine. Consensus-based
3B
Rationale:
2008 Guideline
No new evidence was found, the recommendations remain unchanged.
2006 Guideline
We found four studies that examined the association of antidepressants with suicidal intent or
behavior.
 Yerevanian, et al. (2004)(105) found no difference in rate of suicidal behavior between patients
taking tricyclic antidepressants (TCAs) versus those taking selective serotonin reuptake
inhibitors (SSRIs). They did, however, find a significant increase in suicidal behavior in the
discontinuation period of both classes of antidepressant.
 Martinez, et al. (2005)(106) showed no difference in rate of suicidal behavior in patients
prescribed SSRIs versus those prescribed TCAs. There was a similar risk for different
SSRIs, as well as for different TCAs.
 Fergusson, et al. (2005)(107) found no difference in odds of suicide attempts in patients
receiving SSRIs versus those receiving TCAs.
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 Gibbons, et al. (2005)(108) did not find a significant association between all prescribed
antidepressants and suicide rate. The authors did find a significant positive association
between TCAs specifically and suicide rate, but since this was an ecological study and
individual patient data was not collected, it cannot be concluded that a causal relationship
exists.
A Clinical Evidence (Issue 14, January 2006) systematic review, one retrospective cohort study,
and two case control studies specifically examined the risk of suicide between different classes
of antidepressants.
 The systematic review found no difference in risk of suicide between SSRIs and TCAs
(OR = 0.88, 95% CI: 0.54 to 1.42). It should be noted that RCTs were included in this
review regardless of treatment condition and 59% of the RCTs used were in people who
had a diagnosis other than MDD.(109)
 The retrospective cohort study found that the risk of suicide was higher in people who
received fluoxetine (19/10,000 person years, 95% CI: 9/10,000 person years to 34/10,000
person years) than in those receiving dosulepin (dothiepin; RR = of suicide vs. dosulepin 2.1,
95% CI: 1.1 to 4.1). However, a subgroup analysis of people with no history of suicidal
behavior or previous antidepressant prescription broadened the confidence interval to make
the result nonsignificant (RR = 2.1, 95% CI: 0.6 to 7.9).(110, 111)
 One case control study reported no significant increase in suicide risk in people prescribed
SSRIs compared with TCAs (OR = for suicide 0.57, 95% CI: 0.26 to 1.25).(106)
 Another case control study found no significant increase in suicide risk with individual
SSRIs (amitriptyline, fluoxetine, paroxetine) compared with dothiepin (amitriptyline:
OR = 0.83, 95% CI: 0.61 to 1.13; fluoxetine: OR = 1.16, 95% CI: 0.90 to 1.50;
paroxetine: OR = 1.29, 95% CI: 0.97 to 1.70).(110)
Overall Conclusion
There is little consistent evidence of differences in all-cause suicide between classes of
antidepressants. However, the consensus of the GDT remains that due to potential toxicity in
overdose, TCAs and venlafaxine should be prescribed to suicidal patients only after consultation
or collaboration with a psychiatrist.
2004 Guideline
No studies were found with a design that directly addressed our question. However, we did find
two studies on safety of antidepressants in overdose situations.
 Buckley(112) calculated the fatal toxicity index expressed as death per million prescriptions
for antidepressants. The serotoninergic drug class overall had a much lower index (1.6) than
the tricyclic antidepressants (34.8) and monoamine oxidase inhibitors (20.0). Venlafaxine
had a higher index (13.2) than the individual and combined results of other serotoninergic
drugs.
 Shah(113) examined trends in suicide from drug overdose in older adults (65 years old
and older) between 1993 to 1999. Antidepressants were the third (15%) most commonly
used drugs in overdose leading to suicide. Of these deaths, 95% were due to tricyclic
antidepressants. Death rates increased with age, with highest rates in men over 75.
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Volume 9 of Clinical Evidence,(70) most recent search date November 2003, was also searched,
and our recommendations are in line with their conclusions. They found:
 One systematic review (search date not stated, which included RCTs completed by
December 1989) pooled data from 17 double-blind RCTs in people with depressive disorders
aged 12 to 90 years comparing a TCA (731 people) versus fluoxetine (1,765 people) or
versus placebo (569 people). It found no significant difference in the rate of suicidal acts
[attempts] between the groups (TCAs 0.4%, fluoxetine 0.3%, and placebo 0.2%), but
development of suicidal ideation was less frequent in the fluoxetine group (1% fluoxetine
vs. 3% placebo, p = 0.04; and vs. 4% TCAs, p = 0.001).
 One historical cohort study followed 172,598 people who had at least one prescription for
one out of ten antidepressants during the study period in general practice in the UK.
The risk of suicide was higher in people who received fluoxetine (19/10,000 person years,
95% CI: 9 to 34) than those receiving the TCA dosulepin (RR = of suicide vs. dosulepin 2.1,
95% CI: 1.1 to 4.1).
 In a nested case controlled, subanalysis in people with no history of suicidal behavior or
previous antidepressant prescription, the risk remained the same, although the confidence
interval broadened to make the result nonsignificant (RR = 2.1, 95% CI: 0.6 to 7.9).
Although the apparent association may be because of residual confounding, there remains
uncertainty about the possible association between fluoxetine and suicide. However, any
absolute increase in risk is unlikely to be large.
One systematic review was found that addressed suicide attempts or completions.
 AHRQ's review(2) included 15 studies, two cohort studies, and 13 meta-analyses. Only one
of these studies was conducted in primary care. Nine trials compared fluoxetine with
placebo or TCA, two trials compared fluvoxamine with placebo or TCA, three trials
compared paroxetine with placebo, and one trial compared fluoxetine with placebo or a TCA.
 There is no evidence that any one medication is associated with higher rates of attempted or
completed suicides, when all methods of suicide are considered in the primary care setting.
 Evidence suggests that there is a higher rate of completed suicide by overdose with TCA.
 Evidence also suggests that there is a lower rate of suicide by overdose with SSRIs than
expected.
On closer examination of the studies, Henry(114) looked at the relative mortality of
antidepressants in the UK.
 The authors calculated the number of deaths per million prescriptions during the six years for
all drugs taken together, for each of the four groups of antidepress-ants, and for each drug
individually. The chi-square test was applied to the groups of antidepressants. The expected
numbers of deaths were given for the individual drugs, with the Fisher’s exact probability
applied to the data. The authors concluded that TCAs had a higher ratio of observed to
expected rates of suicide by overdose as compared with all antidepressants taken together.
 SSRIs has a lower ratio of observed to expected rates of suicide by overdose.
 A head-to-head TCA to SSRI comparison was not done.
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 The Jick(111) study had small N’s underscoring the low frequency of suicide in primary care
settings, and was probably not sufficient to draw conclusions.
 Studies or reviews might not have large enough N's to account for differences in rare events.
There may be unreported differences in trials because patients with suicidal ideation or
severe forms of depression are often excluded from studies.
 These trials include not only patients with suicidal ideation, intent, or plan; but also patients
without these characteristics. However, the GDT believes that the evidence above could be
extrapolated to patients with suicide ideation, intent, or plan.
Other Considerations and Overall Conclusion
There is no evidence to support referring patients with suicidal intent or plan to specialty
behavioral health. However, retrospective studies and expert opinion note that patients who
express intent to commit suicide or have a specific plan to commit suicide are at higher risk for
completed suicide. Therefore, consistent with current practice and common sense, and for
clarity, the GDT recommends patients who endorse suicidal intent or plan be referred to
specialty behavioral health.
In contrast, many patients with depression will endorse occasional thoughts of suicide but deny
intent or plan, and will agree not to commit suicide. These patients can be and often are
managed successfully in primary care. However, observational evidence suggests that certain
classes of antidepressants (TCAs and venlafaxine) are associated with higher incidences of death
by overdose than other anti-depressants. But there are some patients who might benefit from
receiving these antidepressants instead of other available alternatives. For example, patients may
have other medical comorbidities where TCAs are useful in treatment (for example, chronic
pain). In other instances, patients may have responded to these antidepressants in the past, and
are an established patient well known to their provider. In these instances, the GDT would not
automatically exclude these patients from receiving these medications, but recommends that the
provider discuss the potential risks and benefits with a psychiatrist.
(Note: MAOIs are excluded from this guideline, as this class of antidepressants is not
recommended for use by primary care clinicians in treating depression).
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4.
Second-Line Treatment Of MDD
4A
For patients with MDD whose symptoms fail to remit after first-line treatment, the GDT
recommends an assessment of the adherence to the initial treatment regimen.
Consensus-based
For patients with MDD whose symptoms fail to remit after adherence to first-line
treatment, the GDT recommends that treatment options include:
4B
 Combining antidepressants and psychotherapy. Evidence-based
 Increasing the dose of the initial antidepressant. Consensus-based
 Switching to a different antidepressant of the same or different class.
Consensus-based
 Switching from psychotherapy to antidepressants or from antidepressants to psychotherapy.
Consensus-based
 Combined pharmacologic treatment (monitoring for toxicity, side effects, and drug
interactions) with SSRIs and
 mirtazepine, or
 low-dose TCAs, or
 lithium, or
 bupropion, or
 liothyronine (T3).
 buspirone, or
Consensus-based (all in this list)
4C
The GDT makes no recommendation for or against providing folate or inositol to patients
whose MDD symptoms fail to remit after adhering to first-line treatment.
Evidence-based: I
4D
The GDT makes no recommendation for or against providing atypical antipsychotics to
primary care patients with (nonpsychotic, nonbipolar) MDD whose symptoms fail to
remit after adherence to first-line treatment. Evidence-based: I
4E
The GDT recommends against providing augmentation with pinodol for patients with
MDD whose symptoms fail to remit after adherence to first-line treatment.
Evidence-based
Rationale:
Evidence for Recommendation 4C: Insufficient
Evidence for Recommendation 4D: Insufficient
Evidence for Recommendation 4E: Evidence-based
Note: It is the expert opinion of the GDT, based on criteria used in trials of Major Depression
treatment, that partial response is usually seen within four weeks of initiating treatment for
MDD, and that remission, if it is going to occur, usually occurs within six to 12 weeks of
initiation of treatment. For purposes of this guideline, patients whose symptoms have not
improved by four weeks or resolved by six to 12 weeks after initiation of treatment are
candidates for second-line treatment.
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2008 Guideline
New evidence was found that did change the existing recommendations.
Five RCTs and one new meta-analysis were identified that address a second line of treatment for
patients whose symptoms did not resolve after initial treatment.
 Mahmoud et al. conducted a six-week, multicenter, double-blind, placebo-controlled trial of
augmentation of antidepressant therapy with risperidone (Risperdal) (up to 2 mg per day) in
patients with Major Depressive Disorder whose symptoms had not resolved after a minimum
of four weeks.(115) In the intention-to-treat analysis, remission of depression was seen in
significantly more patients in the active treatment group than in the placebo group (24.5% vs
10.7%, p = 0.004, NNT = 7). The intervention group also had a higher percentage of patients
with response (50% improvement in HAM-D scores; 46.2% vs. 29.5%, p = 0.004, NNT = 6).
The 2.8 point mean change in HAM-D scores between groups, although statistically
significant, is of marginal clinical significance. Patients who received risperidone gained an
average of 2.8 lb in six weeks vs. an average of 0.3 lb in the placebo group (p < 0.001).
 One meta-analysis and one RCT were identified that addressed the efficacy of augmentation
of antidepressant therapy with atypical antipsychotic agents.
 Papakostos et al. (2007)(116) published a meta-analysis that pooled the results of ten
randomized placebo-controlled trials of augmentation with three atypical antipsychotic
agents, olanzapine, quetiapine, and risperidone. Of these trials, four were published in the
peer-reviewed literature and six were data from unpublished scientific reports (the quality of
the latter studies cannot be explicitly determined). Data from a total of 1500 patients were
pooled. These authors found that remission rate and symptom scores were significantly
improved in the actively treated population (NNT for response and remission, ~ 4). There
was no difference in overall discontinuation rates, but more patients in active treatment
discontinued medication due to side effects (NNH not determined).
 In a randomized, double-blind, placebo-controlled trial (Berman et al., 2007)(117) the efficacy
and safety of apiprazole as augmentation therapy for patients with treatment-resistant
depression. Both remission rates and improvement in depression scores were reported to be
improved in actively treated patients. While the overall rate of adverse effects was high, the
discontinuation rate due to adverse effects was only 2.2% in the apiprazole group.
 The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial reported the
results of comparing treatment modalities as second-step therapy after initial treatment
failure with citalopram monotherapy. Both augmentation and substitution strategies were
examined. Comparable outcomes were seen with cognitive therapy and pharmacotherapy
with several different medications, although fewer than one-third of participants consented to
randomization strata that permitted comparison of pharmacotherapy with cognitive therapy.
Switch to cognitive therapy seemed to be associated with fewer side effects than switch to
medication, but because of the small sample size, the differences were not statistically
significant (NNT undetermined). When it was used as augmentation of citalopram, the effect
of pharmacotherapy was seen more rapidly than that of cognitive therapy, with mean time to
first remission (for those who did remit) 40 days in the pharmacotherapy group compared
with 55 days in the cognitive therapy group.(118)
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 In a comparison of sustained-release bupropion, sertraline, and extended-release venflaxine,
Rush et al. studied the substitution of these drugs as monotherapy for patients whose
depression had not responded adequately to SSRIs.(119) All three strategies resulted in the
same degree of improvement; no significant difference in side effects was seen among the
three treatment groups.
 Trivedi et al. compared augmentation of monotherapy with bupropion or buspirone. Both
groups had similar rates of remission, but a greater reduction in the severity of symptoms and
fewer side effects (NNT = 8 for discontinuation due to side effects) were seen with
bupropion treatment.(120)
Two RCTs were identified that compared third-line treatment for patients who had not achieved
remission in two separate therapeutic trials.
 Fava et al.(121) compared mirtazapine and nortriptyline as sole medications for patients who
had not achieved remission with, or had been unable to tolerate, two previous therapies in the
STAR*D trial. Both groups achieved similar results, with remission rates lower than 20%.
 In another study in the third level of the STAR*D trial, Nierenberg et al.(122) compared
lithium with triiodothyronine as augmentation therapy for patients who did not have
remission of symptoms after two previous trials. Outcomes were similar in the two groups,
but triiodothyronine use was associated with fewer side effects (NNT = 14).
Overall Conclusion:
 The STAR*D trial is a national, multicenter, academic and community, private and public
sector equipoise RCT. Patients not responding to initial treatment with citalopram (an SSRI)
at mean doses of 41 mg were randomized to different, multiple follow-up treatment options,
but patients could be excluded from consideration of randomization to treatments they found
unacceptable. (This design mimics real-world discussion of shared decision making.)
Patients who failed to adequately respond to second-phase treatment proceeded to third-stage
treatment with similar patient “opt out” possibilities; continued refractory patients proceeded
to stage 4 treatment. The STAR*D and other trials reinforce, or in some cases add, options
for primary care clinicians treating patients with Major Depression who fail to remit with
initial treatment. Because of the lack of placebo in these trials, the GDT did not feel these
recommendations deserved an “evidence-based” rating, unless previous placebo RCTs
supported specific recommendations. (It is possible that some patients would have
responded to placebo in these trials as a result of the nonspecific “attention” effect of being
in a clinical trial.) Also of note, the STAR*D population might not exactly reflect the Kaiser
Permanente population (STAR*D patients tended to be more socioeconomically
disadvantaged, a high percentage were uninsured, and 15% to 18% expressed suicidal
ideation).
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 Contrary to previously reviewed evidence on atypical antipsychotic augmentation for Major
Depression, the Mahmoud and Berman studies and the Papakostis meta-analysis suggest that
short-term augmentation with risperidone may be beneficial. All of these trials were drug
company sponsored and of short duration. Some of the findings (i.e., the Mahmoud study)
were of questionable clinical significance, whereas the Papakostis meta-analysis suggests
some potentially clinically significant findings. All of these studies compared atypical
antipsychotic augmentation with placebo, not with other proven or established augmentation
or second-line strategies.
 Additionally, concerns have been raised about cardiometabolic side effects and safety of
atypical antipsychotics. Patients taking these medications require laboratory, as well as
mood, monitoring (consensus statement: Diabetes Care 2004: 27:596-601). Finally, atypical
antipsychotics are currently significantly more costly than other available strategies.
 There is fair evidence of short-term effectiveness for use of atypical antipsychotic agents to
augment antidepressants in patients with nonpsychotic, nonbipolar MDD who fail to remit
with initial treatment. However, due to the lack of longer-term data, the known
cardiometabolic risks of treatment with these medications, and the lack of comparison data
against other strategies, the balance of benefits, harms, and costs compared with other
treatments cannot be determined.
The GDT sought evidence of both health outcomes and health interventions for the clinical
question listed above. The only relevant health outcome found in the previous guideline pertains
to change in depression symptoms among participants in the various trials listed above.
Health interventions were sought in: changing antidepressant medication, increasing existing
antidepressant dose, switching to psychotherapy, adding psychotherapy, adding another
antidepressant to existing antidepressant, augmentation to existing antidepressant, rTMS, and
vagus nerve stimulation. Relevant information on all listed health interventions were found in
the studies listed above. However, to avoid duplication of efforts, the GDT has decided to defer
the recommendations for vagus nerve stimulation and rTMS to those made by KP’s Interregional
New Technology Committee (INTC).
Excerpts from Kaiser Permanente’s INTC recommendations on vagus nerve stimulation and
repetitive transcranial magnetic stimulation (rTMS) are summarized below:
Vagus Nerve Stimulation
The INTC maintains its prior recommendation: There is insufficient evidence to determine
whether vagus nerve stimulation is a medically appropriate treatment for any patient with
treatment-resistant depression. The existing evidence is of insufficient quantity and quality.
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Repetitive Transcranial Nerve Stimulation
Based upon a review conducted by the INCT in Oct. 2003, there is insufficient evidence to
determine whether repetitive transcranial magnetic stimulation (rTMS) is a medically appropriate
treatment for any patient.
For more information on vagus nerve stimulation and Repetitive Transcranial Magnetic
Stimulation (rTMS) for the treatment of Depression, please refer to the following, updated
statements made by (INTC):
 Vagus Nerve Stimulation: http://cl.kp.org/pkc/national/cpg/intc/topics/01_31_080.html
 rTMS: http://cl.kp.org/pkc/national/cpg/intc/topics/10_20_032.html
2006 Guideline
We found several studies that address a second-line of treatment for patients whose symptoms
did not resolve after initial treatment.
 Schatzberg (2005)(123) found that patients with Major Depression who failed to respond to
initial treatment with nefazodone or CBASP (cognitive behavioral therapy) both showed
statistically significant improvement when switched to the alternate therapy. Patients who
switched from nefazodone to CBASP showed a significantly greater improvement in
depressive symptoms than those who switched from CBASP to nefazodone, possibly due
to a decrease in medication-related side effects when switching to CBASP. There was no
nonresponder control group continuing in the initial treatment.
 Parker, Brotchie & Parker (2005)(124) found that the addition of olanzapine to antidepressants
did not significantly improve symptoms in patients with nonpsychotic Major Depression
when compared with control subjects who were treated with antidepressants exclusively.
 Perry, et al. (2004)(125) found that, when compared with control, pindolol augmentation did
not have a significant effect on depressive symptoms of patients who previously did not
respond to SSRIs.
 Kauffmann (2004)(126) found a significantly positive effect of right prefrontal transcranial
magnetic stimulation (rTMS) over ten days in a small group of patients who failed to respond
to at least two standard antidepressants given at adequate doses for at least eight weeks.
 Rumi (2005)(127) studied the effect of rTMS on patients with severe nonpsychotic Major
Depression and found that rTMS had a significantly better impact on depressive symptoms
and remission rates when compared with control.
Clinical Evidence reports several RCTs within systematic reviews that found positive
improvement in depressive symptoms after the addition of an antidepressant to psychotherapy,
or the addition of psychotherapy to an antidepressant. These findings are consistent across all
severities of depression – mild, moderate, and severe. For more details, see the rationale
statements under “First-line treatment” recommendations.
Clinical Evidence found one systematic review and one subsequent RCT examining
augmentation of prescription antidepressant drug treatment with lithium or pindolol versus
placebo in adults with treatment-resistant depression.
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 One systematic review found no significant difference in the proportion of people who
responded over one to eight weeks between pindolol augmentation and placebo; responders:
10/53 [19%] with pindolol augmentation vs. 6/53 [11%] with placebo; absolute risk
difference +8%, 95% CI: -6 to +21%; RR = not reported). The same review found that
lithium augmentation significantly increased the proportion of people who responded over
two weeks compared with placebo; 11/26 [42%] with lithium vs. 4/24 [17%] with placebo;
absolute risk difference 25%, 95% CI: 2% to 49%; RR = not reported.(128)
 The subsequent RCT found no significant difference between lithium augmentation and
placebo in the proportion of people who responded over six weeks was 2/18 [11%] with
lithium vs. 3/17 [18%] with placebo; reported as nonsignificant, CI not reported.(129)
 A Cochrane review(130) yielded two RCTs (151 patients) that examined the use of folate in
addition to other treatments for Major Depression. It found that patients treated with folate in
addition to other treatments had an additional average decrease in Hamilton Depression Scale
ratings of 2.65 points (95% CI: 0.38 to 4.93); fewer folate patients experienced an inadequate
response to treatment (less than 50% decrease in depression scores from baseline) with a
NNT of 5. The trials did not reveal any problems with the safety or acceptability of folate.
The Cochrane review suggests that limited evidence to suggest folate may be of benefit as a
supplement to other treatments for depression, but it is unclear if this benefit depends on
baseline serum folate levels (or presence of baseline folate deficiency).
 Another Cochrane systematic review(131) examined the effectiveness of inositol as an adjunct
to antidepressants. Combining continuous measures using Standardized Weighted Mean
Difference (SMD), no statistically significant overall heterogeneity of effect between trials
was observed (Chi-square = 3.57, df = 3, p = 0.31). The authors concluded that there was no
clear therapeutic benefit and that further research would be needed before a recommendation
for this intervention could be made.
 Cochrane also examined the therapeutic efficacy and safety of rTMS for depression.(132)
Five studies compared rTMS with a sham rTMS intervention and showed statistical
homogeneity. The relative risk, using a fixed effects model was 0.81 (95% CI: 0.36 to 1.83;
p = 0.6). The authors concluded that there is “no strong evidence for benefit from using
transcranial magnetic stimulation to treat depression, although the small sample sizes do not
exclude the possibility of benefit.”
 In their systematic review of the literature, the National Institute for Clinical Excellence
(NICE)(57) found strong evidence suggesting there is a clinically significant difference
favoring combined CBT and antidepressants over antidepressants alone on increasing the
likelihood of remission in people with chronic depression (which, by definition, is refractory
to initial treatment). (N = 1, n = 454, RR = 0.73, 95% CI: 0.62 to 0.84).
Overall Conclusion
The evidence continues to support our previous recommendations for treatment of patients with
MDD whose symptoms do not resolve after the initial treatment. Additional wording was
included to clarify that these recommendations assume that patients were adherent to the initial
treatment but resistant to it (differentiating lack of adherence from true treatment nonresponse).
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Psychotherapy
We found one new study that supports changing from antidepressants to psychotherapy or vice
versa in patients who fail to respond to initial treatment for Major Depression after 12 weeks.
 There was no control group (continuing on previous therapy) in this study, therefore it is
unclear how many patients would have responded to the initial therapy given more time.
However, clinically, a change in therapy for nonresponse is usually initiated before 12 weeks.
Given that this is the only study we identified that suggests that switching is effective for
nonresponse to initial treatment for Major Depression, and the presence of more evidence for
other treatment options, the GDT does not believe that it can make an evidence-based
recommendation for this strategy at this time. However, structured psychotherapy (CBT,
IPT, and PST, as outlined in the problem formulation) and antidepressants have been shown
to be equivalent treatment options for initial treatment for many patients with Major
Depression. Extrapolating from this, the GDT believes that offering the alternative treatment
as one of several strategies (albeit a strategy without as much direct evidence as others) for
patients who fail to respond to initial MDD treatment to consider is reasonable, and includes
this as a consensus option.
Lithium Augmentation
Evidence remains mixed on lithium augmentation. The Fava RCT(133) reviewed by the GDT in
2004 was not included in the systematic reviews covered above. We therefore have one
systematic review and one RCT (although the latter has some limitations as discussed in the
2004 review) favoring lithium augmentation, and one RCT finding no significant difference.
The weight of the evidence seems to favor use of lithium as a potential augmentation strategy,
with a consensus-based (rather than evidence-based) recommendation. Primary care clinicians
(the main audience for this guideline) seldom initiate lithium therapy, although they commonly
see patients taking lithium prescribed by a psychiatrist. Therefore, the GDT recommends
consultation with psychiatry for patients in whom this option is being considered.
Transcranial Magnetic Stimulation
Since our previous iteration of the guideline, we found two studies on transcranial magnetic
stimulation. Although these studies showed benefit, the studies were small and of short duration,
the technology is not readily available, no comparisons have been made with other augmentation
strategies, and the added value has not been quantified. Therefore, the GDT agrees with the
Cochrane review that there is insufficient evidence at this time to recommend this intervention
for the treatment of MDD.
Folate
The GDT discussed the Cochrane reviews on folate in combination with antidepressants for
treatment of Major Depression. The GDT believes that more studies are needed, particularly
examining differences in patients with normal vs. below-normal serum folate levels, before this
strategy can be recommended.
Inositol
The GDT concurs with the Cochrane review on inositol. The authors concluded that there was
no clear therapeutic benefit and that further research would be needed before a recommendation
for this intervention could be made.
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Vagus Nerve Stimulation
The following rationale statement on Vagus Nerve Stimulation for depression comes from the
Kaiser Permanente Interregional New Technologies Committee (INTC) meeting of November
14, 2005:
“The INTC reviewed this topic in July of 2004 and had an update March 2005.
At that time, the INTC found there is insufficient evidence to determine whether
vagus nerve stimulation (VNS) is a medically appropriate treatment option for
any patient with Major Depressive Disorder. The existing evidence regarding
how VNS effectively treats Major Depressive Disorder (MDD) is of insufficient
quantity and quality. The published studies are not blinded, report incomplete
data sets of short-term results, and fail to follow intent-to-treat principles, which
can cause results to be overestimated. Recent publications and requests from
TPMG, NWPMG, and TSPMG are bringing this topic back to the INTC. Marc
Meisner, MD, TPMG Chief of Psychiatry, presented this topic to the committee.
Recent publications, an ECRI Target 10/05, Hayes 10/05, and BCBSA TEC 08/05
assessment served as the basis for the discussion.
“The vagus nerve stimulation (VNS) Therapy System, developed by Cyberonics,
Inc., Houston, TX, consists of an implanted pacemaker-like pulse generator and
nerve stimulation and delivers intermittent stimulation to the patient's left vagus
nerve. The device costs $15,500.
“In 1997, the FDA approved this Cyberonics technology for treatment-resistant
seizures in epilepsy patients. The mechanism of action of VNS for treatmentresistant depression (TRD) remains unknown. However, the vagus nerve projects
into areas of the brain associated with neuropsychiatric disorders, neuroimaging
studies have shown changes in areas of the brain linked to mood regulation with
VNS, and evidence of mood improvement was seen in VNS for epilepsy studies
irrespective of seizure control.
“In July 2005, the FDA approved Cyberonics' VNS pre-market approval
application for "the adjunctive long-term treatment of long term treatment of
chronic or recurrent depression for patients 18 years of age or older who are
experiencing a major depressive episode and have not had an adequate response
to four or more adequate antidepressant treatments." With its approval, the FDA
required two post-approval studies to examine optimal stimulation dosing with
one-year follow-up for 450 patients in a randomized double-blind study and
five-year patient outcomes in 1,000 implanted patients.
“Of the 18 million people in the United States who experience a major depressive
episode in one year, four million suffer chronic or recurrent pharmacoresistant
depression. Some of these latter patients have TRD per the July 2005 FDAlabeled indication for VNS.
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“Four published studies, all sponsored by Cyberonics, compose the scientific
evidence for VNS for TRD. They involved a total of 422 patients with TRD.
Dr. Meisner provided an overview on the pilot study (D-01), the Acute and
Long-Term Pivotal Study (D-02), and the Comparative Study (D-04). Recent
publications from Rush and George 2005, focused on D-02 and D-04.
“An open label study of 60 patients (pilot study D-01) who received VNS implant
showed a response, defined as greater or equal to a 50% reduction on the
Hamilton Rating Scale for Depression (HRSD), of 31% at 12 weeks, 44% at one
year, and 42% at two years. Remission, defined as less than ten on the HRSD,
was 15%, 27% and 22% for the same periods, respectively. However, differences
in response rates between periods were not statistically significant.
“Rush, 2005, reported that in the D-02 12-week, pivotal double-blind, randomized
controlled trial, active VNS therapy (n = 112) was no more effective than sham
VNS (n = 110) in alleviating symptoms of depression among a population of
adults diagnosed with Major Depressive Disorder or bipolar disorder. Active and
sham treatment groups were well balanced with respect to baseline characteristics.
At week 12, there was no significant difference between active and sham VNS in
treatment response rates (15.2% versus 10.0%, respectively), nor were there
significant differences between active and sham VNS groups for 4 of 5 scales
used as secondary measures of efficacy. The only endpoint to show a significant
difference between the two study arms was the self-administered Inventory of
Depressive Symptomatology-Self-Report (IDS-SR) (17% vs. 7%).
“A two-year follow-up active treatment study (long-term pivotal study D-02,
Rush 2005) consisted of patients from both active and sham arms of the acute
pivotal study. This open label study demonstrated statistically significant
improvement in depression scores measured by the 24-item HRSD and the 30item IDS-SR. The study found an HRSD response of 27% at one year and 21%
at two years as well as HRSD remission in 16% of patients at one year follow-up.
Dr. Meisner discussed various study limitations. Comparisons of long-term
outcomes must also be interpreted with caution, as patients were not randomized
or blinded to treatment in longer-term trials. Patients treated with long-term VNS
in clinical trials were allowed to receive additional concomitant treatments,
raising the possibility that the observed response was not a result of VNS.
Stimulation parameters varied among patients, which may have affected treatment
outcomes. The manufacturer supported these studies, and a number of
investigators listed as authors in these studies have disclosed individual financial
relationships with the manufacturer, therefore, the potential for bias cannot be
excluded.
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“A fourth study (comparative study D-04) examined outcomes for the more than
200 patients in the long term pivotal study relative to those of more than 120
patients with TRD from a separately recruited control group who had not received
VNS implants and were being treated with standard of care therapies. This trial
resulted in a statistically significant HRSD response rate at one year of 27% for
the VNS group, which could also use standard of care remedies, versus 13%
HRSD response for the group only allowed standard of care treatment. Study
limitations were also noted with the D-04 comparative study. The patients from
the comparison control group were recruited separately, after results from D-02
were known, so do not represent adequate controls for the long-term effect of
VNS.
“These studies, together with prior experience with VNS therapy in seizures,
confirmed that surgical complications for VNS implant, including infection and
vagus nerve damage, are low. More than half of implanted patients report
stimulation-related voice alteration; much smaller percentages note increased
cough, dyspnea, neck pain and other VNS-induced discomforts which tended to
lessen with time. Further, VNS therapy does not appear to pose a greater risk for
mania, suicide, and worsening depression.
“Overall, the evidence is limited by the studies' designs and the data quality
suffers from inadequate controls and blinding, placebo effect, research site
differences, heterogeneous stimulation parameters, various concomitant
treatments allowed, and possible investigator bias.
“The updated Hayes Assessment from 10/05 concluded that the currently
available evidence is insufficient to permit conclusions regarding the efficacy and
safety of VNS as an adjunct therapy in treatment-resistant Major Depression and
bipolar disorder. A Hayes Rating of C is assigned for VNS as an adjunctive
therapy in adults with severe Major Depression or bipolar disorder when
symptoms associated with a major depressive episode are refractory to multiple
regimens of standard medication and other therapies, including electroconvulsive
therapy (ECT) and psychotherapy; D is assigned for VNS in patients with other
types of depression and in patients with Major Depression or bipolar disorder who
respond to medical treatment, psychotherapy, and/or ECT; and D is assigned for
VNS in patients with contraindications to VNS. These Ratings reflect the paucity
or lack of evidence regarding the safety and/or efficacy of VNS in these patient
populations.
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“The updated ECRI Assessment also concludes there is limited ability to draw
strong conclusions about the efficacy of VNS to treat treatment-resistant
depression (TRD) using the available evidence. "All studies thus far have been
manufacturer-sponsored with notable design weaknesses. The largest study fails
to follow intent-to-treat principles, potentially overestimating results by not
reporting outcomes of all patients entered in the study. Although VNS therapy
lacks the severe side effects (e.g., long-lasting cognitive impairments, renal and
thyroid toxicity, hypertensive crises, anticholinergic effects) of the treatments
typically offered to patients with TRD, conclusions cannot be drawn regarding
adverse events associated with long-term use of VNS therapy for depression due
to incomplete adverse event reporting in the larger of the two trials used to write
this report."
Apart from the KP Northwest, which intends to use VNS for highly select patients with TRD,
no other region expressed support for its use at this time as no definitive benefit of VNS for TRD
has been yet shown in a large, prospective, randomized trial with adequate follow-up. There is
insufficient evidence to determine whether vagus nerve stimulation is a medically appropriate
treatment for any patient with treatment-resistant depression. The existing evidence is of
insufficient quantity and quality.
Pindolol Augmentation
We found one additional negative study on pindolol augmentation. Combining this with our
previous findings on pindolol, the GDT recommends against the use of pindolol as an
augmenting agent for Major Depression at this time.
Assessing Adherence
Finally, we found no evidence examining the benefit of assessing adherence to initial treatment
before attempting other treatment alternatives. However, the studies on alternative treatments we
reviewed included patients who were adherent to initial treatment regimens. Furthermore,
assessing patient adherence is consistent with patient-centered practices designed to promote
self-care, and is a generally accepted tenant of practice. Therefore, the GDT elected to include
this consensus recommendation in order to be thorough.
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2004 Guideline
Supporting Evidence For Antidepressant or Psychotherapy Alone Versus
Combined Treatment of Antidepressant and Psychotherapy
One RCT looked at efficacy of combined psychotherapy and antidepressant treatments versus
psychotherapy or antidepressant medication alone in patients with chronic MDD.
 Hirschfeld(134) (n = 681) included adult patients with chronic Major Depression (who by
definition have failed initial treatment) between the ages of 18 and 75. The population was
65% female, 91% white. The study was a randomized, open-label, controlled trial comparing
a SNRI (nefazodone 200 to 600 mg/day) and Cognitive Behavioral Analysis System of
Psychotherapy (CBASP) and the combined nefazodone/CBASP treatment for 12 weeks.
There was no placebo control group. HAM-D score analysis (taken from the original
publication of the study by Keller(135)) indicated that that the combined treatment was
statistically superior to either treatment alone; p ≤ 0.001 for nefazodone vs. combined
treatment, p ≤ 0.001 for CBASP vs. combined treatment. SF-36 general health indicated the
same results, p = 0.0003 and p = 0.02 respectively. There was also greater improvement in
psychosocial functioning when combined treatment was used (p = 0.02 and p = 0.02).
We also searched Volume 9 of Clinical Evidence,(70) most recent search date November 2003,
and found that our recommendations are in line with their conclusions. They found:
 One nonsystematic review showing that the combination of psychotherapy and
antidepressant medication in patients age 18 to 80 with severe MDD is more beneficial
than either treatment alone.
 Two RCTs showing that combination antidepressant-psychotherapy treatment is more
effective than either treatment alone for patients with mild to moderate Major Depression.
One of these studies specifically examined patients with chronic, refractory, or depression
recurring on treatment (who by definition have failed first-line treatments).
Overall Conclusion
Combining antidepressant treatment with psychotherapy is more effective than either treatment
alone for patients who have failed first-line treatment or for patients with severe MDD.
See discussion in the rationale for first-line treatment of MDD for discussion of the role of
initially combining antidepressant-psychotherapy for patients with mild to moderate MDD.
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Supporting Evidence For Increasing Existing Antidepressant Dose, Switching
Antidepressants, Adding Another Antidepressant to Existing Antidepressant or
Adding An Augmenting Agent to The Existing Antidepressant
Four RCTs looked at second-line treatment strategies for the treatment of MDD in adults whose
symptoms did not resolve after the first treatment.
 Fava (n = 101) included outpatients with MDD (initial HAM-D-17 score of ≥ 16) between
ages of 18 and 65 who were either partial responders or nonresponders to (133)eight weeks of
treatment with SSRI (fluoxetine, 20 mg/day). The study was a randomized, double-blind,
controlled trial comparing increasing the SSRI (fluoxetine) dose (40 to 60 mg/day), adding
low dose desipramine (25 to 50 mg/day) to existing 20 mg/day fluoxetine, and adding an
augmenting agent (lithium, 300 to 600 mg/day) to existing 20 mg/day fluoxetine for a period
of four weeks.
 Mean change in HAM-D-17 score (from visit one to endpoint) showed no statistically
significant differences among these patients (p = 0.4, for all comparisons). The difference
in response rates (patients who showed at least a 50% reduction in HAM-D scores) across
these three treatment groups was also not significantly significant (p = 0.5, for all
comparisons). There was also no significant differences in dropout rates across the three
groups (p = not stated).
 The study did not include a placebo group, so placebo response to augmentation or an
eventual response to continued treatment at the same does cannot be excluded, and the
study may not have had sufficient power to detect true differences between groups.
 Peet(136) included patients aged 18 to 70 with HAM-D-17 score of 15 or more despite
ongoing treatment with a standard antidepressant at an adequate dose. The study was a small
(n = 70), randomized, double-blind, controlled study comparing augmenting with ethyleicosapentaenoate (E-EPA) at 1 g/dl, 2 g/dl, 3 g/dl; liquid paraffin placebo for a period of
12 weeks.
 Change in 17-item Hamilton Depression Rating Scale (HDRS) score (p = 0.02),
Montgomery-Asberg Depression Rating Scale (MADRS) score (p = 0.006) and Beck
Depression Inventory (BDI) score (p = 0.007) for the intention-to-treat population showed
that augmentation with ethyl-eicosapentaenoate at a dosage of 1 g/dl was statistically
significant in treatment of Major Depression in patients who remain depressed despite
adequate standard therapy.
 Nemets(137) included adults 18 to 75 years old with a current diagnosis of MDD (24-item
Hamilton Depression rating Scale of 18 or higher).
 The study was an extremely small (n = 20), randomized, double-blind, controlled study
comparing ethyl-eicosapentaenoate (E-EPA at 2 g/day) and placebo for a period of four
weeks. The author concluded that the study showed significant benefits in adding E-EPA
to the existing treatment (p = not stated).
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 Perez(138) included adults 18 to 65 years old with single or recurrent MDD, with the current
episode resistant to pharmacological treatment. The study was a small (n = 80), randomized,
double-blind, controlled study comparing augmenting with pindolol and placebo for a period
of ten days. There was no significant difference in the change in HAM-D score from day 0
to day 10 between pindolol and the placebo groups (p not given). The study does not support
the hypothesis that the addition of pindolol results in a rapid augmentation of the effects of
SSRIs in depressed patients resistant to treatment.
Other pindolol studies (of mixed results) were found, but those studies addressed the effect of
adding pindolol to antidepressants at the onset of treatment for Major Depression, rather than
augmenting antidepressants with pindolol after initial nonresponse to antidepressants. As these
studies examine a different clinical question (improving speed of initial response to antidepressants rather than augmentation in cases of nonresponse), these studies were excluded from
formal review.
Other Considerations
 E-EPA may not be widely available in a standardized preparation, and the two E-EPA trials
were small. Therefore, the GDT considers the E-EPA findings preliminary, and pending
further study, does not currently recommend E-EPA be used regularly by primary care
physicians as an augmentation strategy.
 No evidence was found on the efficacy or safety of combining antidepressants from the same
class in the treatment of MDD that has failed to respond to initial treatment.
 There are theoretic safety concerns about the increased risk of serotonin syndrome when
combining SSRIs or using SSRIs with other highly serotonergic antidepressants (SNRIs).
 MAOIs are generally not recommended for use by primary care, given their potential toxicity
and drug interactions, and have been excluded from this guideline. Combining MAOIs and
SSRIs have been associated with adverse patient outcomes and are contraindicated.
 Only one RCT was found on combining low-dose TCAs and SSRIs for MDD that failed to
respond to initial treatment and it used desipramine, a “later generation” TCA with fewer
side effects and more noradrenergic action than most other TCAs. There are theoretic
reasons that augmenting serotonergic agents with norepinephrinergic agents would lead to
improved outcomes (by affecting two different neurotransmitter systems). However, we did
not find good evidence that so-called dual action antidepressants (enhancing both serotonin
and norepinephrine) are superior to either SSRIs or TCAs in the treatment of depression.
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There was also no consensus among the GDT that the TCA augmentation effect seen in this
study can be extended to other TCAs as a class-effect. Therefore, the GDT elected to limit the
recommendation to desipramine because it had been specifically studied. The recommendation
is labeled “consensus” because of the limitations in the Fava study discussed above.
 Combined use of SSRIs and higher doses of TCAs increases the risk of TCA toxicity,
primarily manifested as cardiac arrhythmia. Therefore, only low doses (< 50 mg) of TCAs
should be used, and the GDT recommends careful monitoring for symptoms of TCA toxicity.
Most primary care physicians do not prescribe lithium, due to complexities in dosage and
laboratory monitoring. Some primary care physicians may be comfortable prescribing
lithium, but in general the GDT believes that consultation with psychiatry should occur when
this treatment option is being considered.
 Group Health Cooperative’s 2003 Adult Major Depression Guidelines included three
additional studies from a Medline search using similar mesh terms that did not appear in our
PubMed search: Bauer,(139) Appelberg,(140) and Thase.(141)
 Group Health concluded: “Bauer found that lithium augmentation was superior to placebo
for nonresponders to antidepressants. The majority of the studies included initial treatment
with TCAs and findings may be less applicable to SSRI treatment.”
 Appelberg did not find a significant difference between augmentation with buspirone
or placebo among patients initially treated with SSRIs. In the Appelberg study,
“33% of patients responded to buspirone augmentation and 31% responded to placebo
augmentation…the Appelberg RCT may have been underpowered…a substantial
proportion of patients responded to placebo augmentation, so it is difficult to draw
conclusions from studies that do not include a placebo group.”
 “Thase conducted an RCT in which patients who did not respond to initial treatment with
SSRIs or TCAs switched to the other class of medication. There was no significant
difference in outcomes between groups after switching. A substantial proportion of
patients in each group experienced a remission after switching, 32% in the imipramine to
sertraline group and 55% in the sertraline to imipramine group.”
 Despite the presence of observational studies and case reports, we did not find any RCTs or
quasi-experimental trials evaluating the use of Cytomel, carbamazepine, valproic acid, or
methylphenidate for augmentation of antidepressants. Clinical Evidence did not examine this
question.
Overall Conclusion
Increasing the dose of the initial antidepressant; adding low-dose desipramine to an SSRI;
switching antidepressants; or adding lithium 300 to 600 mg/day are potential treatment options
for patients with MDD whose symptoms do not remit after initial treatment. Due to complexities
in management, most primary care clinicians will not prescribe lithium without psychiatric
consultation or assistance, so the GDT added consultation with psychiatry to this consensus
option to reflect real world practice.
Due to methodological limitations, including lack of control groups simultaneously maintained
on pre-existing treatment, the evidence is not as strong as the evidence for combining
psychotherapy and antidepressants, so the GDT has labeled these recommendations “consensusbased.”
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5.
Length Of Treatment With Antidepressants In Patients With MDD
Patients Who Achieve Symptom Remission
5A
The GDT recommends that patients with MDD who achieve symptom remission with
antidepressants should continue antidepressants at the same dose for at least an additional
six to 12 months. Evidence-based
Patients With One Lifetime Episode of MDD
5B
Based on patient and provider preference, the GDT recommends that a trial of
antidepressant discontinuation is optional for patients in their first lifetime episode of
MDD, who are being treated with antidepressants, achieve remission, and remain
asymptomatic for six to 12 months after acute phase treatment. Consensus-based
Patients with Two or More Lifetime Episodes of MDD
5C
The GDT recommends that patients with two or more lifetime episodes of MDD, who are
being treated with antidepressants and remain asymptomatic after acute phase treatment
should be maintained on the medication and dose with which they achieved remission for
at least an additional 15 months to five years after acute phase treatment.
Consensus-based
Patients with Chronic MDD or MDD with Concurrent Dysthymia*
5D
The GDT recommends that patients with chronic MDD (continual symptoms for more
than two years) or Double Depression (MDD and dysthymia) who improve with
antidepressants during acute phase treatment should continue antidepressants for at least
an additional 15 to 28 months after acute phase treatment.
Evidence-based
Rationale:
2008 Guideline
No new evidence was found, the recommendations remain unchanged.
2006 Guideline
Our search yielded three RCTs that examined depression relapse or recurrence rates in an
extended continuation phase with antidepressants:
 Keller, et al. (2005)(143) found that over a 44 week continuation phase, there was a
significantly lower percentage of relapse in gepirone ER treated patients compared with those
treated with placebo.
 Montgomery, et al. (2004)(144) found that over a 52 week continuation phase, the cumulative
probability of recurrence was significantly lower in patients treated with venlafaxine versus
those treated with placebo.
* Dysthymia = Depressed mood plus at least two additional DSM-IV(142) symptoms present more days than not
for at least two years.
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 Rapaport, Bose & Zheng (2004)(145) found that over a 36 week continuation phase, the
cumulative rate of relapse was significantly lower in patients treated with escitalopram versus
those treated with placebo.
Clinical Evidence found one systematic review that underscored the importance of the
continuation phase. Patients continuing on a course of antidepressants after recovery had a
reduced risk of relapse over one to three years. This effect was independent of duration of initial
treatment, duration of previous antidepressant treatment, or underlying risk of relapse.
 The review found that, overall, continuing antidepressant drugs in people who had responded
to them significantly reduced the proportion of people who relapsed compared with placebo
(31 RCTs, 4,410 people with first episode or recurrent depression; numbers relapsing:
465/2,527 [18%] with continuing antidepressants vs. 1,031/2,505 [41%] with placebo;
OR = 0.30, 95% CI: 0.22 to 0.38).(146)
 In their systematic review of RCTs, the National Institute for Clinical Excellence (NICE)(57)
depression guideline makes an evidence-based recommendation that patients with moderate
to severe depression should continue antidepressants for at least six months after remission.
This conclusion is based primarily on the findings of two studies in which a greater
percentage of patients on SSRIs were able to complete six months of treatment than those
taking TCAs.
 An RCT conducted in the USA randomized 536 adults to receive desipramine, imipramine,
or fluoxetine (Simon, et al., 1996).(147) Sixty percent of the fluoxetine patients completed
six months of treatment compared with less than 40% of the TCA patients. Those who
discontinued one antidepressant were offered another. There were no differences in overall
completers or response rates at endpoint suggesting that initial drug choice did not affect
outcome. However, outside of clinical trials, patients may not return to their general
practitioner to have their treatment changed and outcome may be less positive.
For example, a Swedish study of 949 patients found that 35% only ever received one
prescription irrespective of whether it was for a TCA or a SSRI (Isacsson, et al., 1999).(148)
After six months, 42% of SSRI patients were still receiving prescriptions compared with 27%
of TCA patients. There is some evidence from this study that the relapse rate may have been
higher in the TCA group: 28% of TCA treated patients received a subsequent prescription for
an antidepressant after a nine-month treatment-free gap compared with 10% of SSRI
patients.
Overall Conclusion
Evidence consistently shows that continuing antidepressants after remission of symptoms of
MDD reduces the risk of relapse. This new evidence, in combination with some of the evidence
reviewed previously, suggests that a minimum of six months of antidepressant continuation after
acute phase treatment and symptom remission may be more appropriate than the previously
recommended four month minimum continuation phase. Consistent with all the previously
reviewed evidence, these new studies support continuation at the same antidepressant dose that
was used to achieve remission. Therefore, the GDT recommends continuation phase treatment
should last at least six to 12 months following acute phase antidepressant treatment of MDD.
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2004 Guideline
How Long Should Patients With MDD Who Have Responded To Antidepressant
Medication Continue Taking Medications Beyond The Acute Phase Of
Treatment?
Acute Phase:
Up to three months after starting treatment (period to assess for response to treatment/remission.)
Continuation Phase:
Next four to 12 months.
Maintenance Phase:
Treatment beyond continuation phase.
Supporting Evidence for Minimal Length of Treatment With Antidepressants in
Patients With MDD after Acute Phase Symptom Remission
Two new RCTs were found that addressed this issue.
 Weihs(149) studied men and women at least 18 years old with moderate to severe, recurrent
Major Depression based on Diagnostic and Statistical Manual-IV (DSM-IV) criteria who had
a minimum score of 18 on the 21-item Hamilton Depression Scale (HAMD). The current
depressive episode must have been preceded by at least one other episode within the last 60
months.
All patients (n = 816) were received open label treatment for eight weeks (acute phase), with
bupropion SR (150 to 300 mg/day). Patients who responded to the treatment and
continued to meet the selection criteria entered a 44-week (11 months) randomized,
double-blinded, placebo controlled continuation phase with bupropion SR, 300 mg/day
(n = 207) or placebo (n = 210).
The study showed that treatment with bupropion SR for up to 44 weeks decreases the
risk of depression relapse. Time to depression relapse (time from randomization to
intervention) was 44 weeks for bupropion SR treated patients and 24 weeks for the
placebo group (p = 0.003, favoring continuation treatment).
Survival estimates indicated 52% of placebo treated patients and 37% of bupropion patients
would have become depressed by the end of the study (p = 0.004 favoring bupropion).
By the end of one year treatment, the odds of placebo-treated patients requiring treatment
intervention for a relapse of depression were 1.83 times greater that those of bupropion
SR-treated patients (confidence interval not specified).
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 Reimherr(150) studied male and female outpatients 18 to 65 years of age that met
DSM-III-R criteria for Major Depression with a duration of at least one month and had a
modified 17-item Hamilton Depression Rating Scale score of at least 16.
After a five to nine day medication-free baseline phase, all patients (n = 839), received
12 to 14 weeks of open-label acute therapy phase with fluoxetine, 20 mg/day. The 395
remaining patients were then randomized into one of four double-blind continuation
treatment groups: 14 weeks of continuation therapy with fluoxetine followed by 38 weeks
of placebo (n = 97), 38 weeks of continuation therapy with fluoxetine followed by 14
weeks of placebo (n = 100), 50 weeks of continuation therapy with fluoxetine (n = 102),
or 50 weeks of placebo (n = 96).
Relapse rates were calculated during 12 week periods after each double-blind transfer from
fluoxetine to placebo (weeks 12, 26, and 50). Relapse rate (Kaplan-Meier estimates)
were 26.4% for the fluoxetine-treated group and 48.6 for the placebo group after 12
weeks of continuation treatment (p < 0.001, favoring continuation treatment), and 9.0%
for the fluoxetine-treated group and 23.2% for the placebo group after 26 weeks of
continuation treatment (p < 0.001, favoring continuation treatment).
There was no statistical difference (p = 0.54) in the relapse rate between the fluoxetine
group (10.7%) and placebo (16.2%) after 50 weeks of continuation treatment (possibly
due to lack of statistical power due to patient attrition).
 The British Medical Journal(151) review consisted of six RCTs with a total sample size of 312
patients on current treatment with antidepressant medication.
Findings indicated that continuation of antidepressant medication four to six months after
acute phase treatment reduced the relapse rate by nearly half.
The authors also pointed out that several more RCTs confirm the reduction in risk of early
relapse with continuing medication for six to 12 months after acute phase treatment.
Based on this evidence, the GDT recommends that depressed patients treated with
antidepressants who are asymptomatic at the end of the acute phase (three months) of
MDD treatment be maintained on antidepressants for an additional four to 12 months, to
decrease the risk of early symptom relapse.
Clinical Evidence,(70) Volume 9, included the above studies in their review. Their conclusions
are consistent with ours.
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Supporting Evidence For A Trial Discontinuation For Patients With One Lifetime
Episode of MDD
No new evidence was found.
 A published review(152) notes that patients in their first episode of MDD have a lifetime risk
of relapse of approximately 50%.
 Viguera(153) examined data from 27 randomized trials to determine the effects of
discontinuation on relapse rates. Of these, two trials included only patients in their first
episode of depression. In both of these trials, amitriptyline was the anti-depressant used, one
trial included combination amitriptyline and lithium. Both trials were published before 1984.
This review did not separately analyze the data in these two trials from five other trials whose
inclusion criteria included “one or more” lifetime episodes of depression.
 Among patients with one or more past episodes, the corresponding two year survival rates
(symptom-free at two years) were not statistically different: 64.1% with treatment (95% CI:
58.7% to 69.4%) versus 52.7% without (95% CI: 42.9% to 62.6%). The relative weighting
of patients with only one lifetime episode vs. one or more lifetime episodes in this data is
unknown.
No additional trials were identified that specifically examined the risk of relapse in patients with
one lifetime episode of MDD. Based on the paucity of data, and recognizing that some patients
might choose, based upon their individual circumstances, to continue antidepressant treatment if
made aware of the 50% lifetime risk of recurrence, the GDT has labeled this an “option” for
patients. Because the GDT was unable to identify “clean” data in the systematic review that
adequately addresses this question, this recommendation has been labeled as “consensus-based.”
Supporting Evidence For Maintenance of Medication For Patients With Two or
More Lifetime Episodes of MDD
Two new RCTs were found that addressed this issue.
 Hochstrasser(154) studied mental health in- and out-patients 18 to 65 years of age with
recurrent unipolar Major Depression (DSM-IV), a Montgomery – Asberg Depression Rating
Scale (MADRS) score of ≥ 22 and two or more previous depressive episodes, one within the
past five years.
 Four hundred, twenty-seven patients entered acute phase treatment with citalopram,
20 to 60 mg/day. Patients who responded after six to nine weeks (n = 327) continued
citalopram for an additional 16 weeks (continuation phase). Patients whose depressive
symptoms remained in remission (MADRS score < 11, n = 269) were then randomized
in a double-blind fashion to maintenance treatment with citalopram (n = 132) versus
placebo (n = 132) for an additional 48 to 77 weeks. Data from five patients initially
assigned to the placebo group was excluded due to “major protocol violations.” Time
to recurrence was longer in patients taking citalopram than in patients taking placebo
(p < 0.001), with crude rates of recurrence of 0.22 recurrences /person-year at risk in the
citalopram vs. 0.76 recurrences/person-year at risk in the placebo group.
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 Gilaberte(155) studied male and female outpatients, 18 to 65 years of age, who met DSM-III-R
criteria for unipolar Major Depression, had at least one previous major depressive episode in
the last five years, a score of at least 18 on the 17-item Hamilton Rating Scale for depression
(HAM-D-17) and at least four on the Clinical Global Impression (CGI) severity scale. All
patients (n = 253) completed 32 weeks of open-label treatment phase consisting of both an
acute (eight weeks) and a continuation period (six months) before being randomized to a
double-blind maintenance phase with fluoxetine, 20 mg/day (n = 70) or placebo (n = 70) for
48 weeks. The recurrence rate was 20% for the fluoxetine-treated group compared with 40%
for placebo (p = 0.010, favoring maintenance fluoxetine treatment). The symptom-free
period was significantly longer for patients treated with fluoxetine vs. placebo (295 days vs.
192 days; Kaplan-Meier estimates, log-rank test, p = 0.002).
 In the Viguera(153) analysis, a total of 3,037 depressed patients were treated for 5.78
(0 to 48) months and then followed for a mean of 16.6 (5 to 66) months with antidepressants
either continued or discontinued. Compared with patients whose antidepressants were
discontinued, those with continued treatment showed much lower relapse rates (1.85 versus
6.24% per month), longer time to 50% relapse (48.0 vs. 14.2 months), and lower 12 month
relapse risk (19.5 versus 44.8%) (all p < 0.001). A survival analysis presented in the Viguera
article shows a statistically significant difference in symptom remission between patients
continuing medication and patients not continuing medication, which persisted through 54
months of follow-up.
 Among patients with more than two or more past episodes, the corresponding one year
survival rates (symptom-free at one year) were: 79.5% with treatment (95% CI: 73.2% to
85.8%) versus 56.5% without treatment (95% CI: 48.9% to 64.2%). Viguera did not
differentiate between patients in their second lifetime episode of MDD and those with more
than two lifetime episodes.
 In patients with at least three past episodes or a chronic course, the two year survival rate
(no recurrence of depressive symptoms) was 71.7% (95% CI: 64.6% to 78.9%) with
antidepressant versus 14.7% (95% CI: 7.10% to 22.2%) without antidepressant - a highly
significant 4.88 fold difference.
 Viguera did not differentiate between patients with and without psychiatric comorbidities
or history of suicide attempt.
 Frank(156) found that active imipramine at a dose of 200 mg per day is effective at
maintaining remission for three years in patients with three or more lifetime episodes of
MDD.
 Kupfer(157) followed a smaller subset of patients from the Frank study for an additional two
years and found that imipramine 200 mg per day continued to effectively prevent recurrence
of symptoms for up to five years. There is no patient outcomes data available to demonstrate
the effect on patients maintained on medications for more than five years.
The studies examined all include maintenance therapy with antidepressants at the same or higher
dose that achieved symptom remission or resolution. No evidence was found examining the
effect of different dosage strategies, or changing medication, on disease-free interval.
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A recently published review(152) notes that patients with three or more episodes of MDD have a
lifetime risk of relapse of approximately 90%. Patients with two prior lifetime episodes of
depression have a lifetime risk of relapse of 70%, intermediate to those with one prior episode
and those with three or more prior episodes. No additional studies were found that examined
outcomes of maintenance therapy specifically for patients with two past episodes of Major
Depression.
Conclusion
Our systematic review did not identify any RCTs or meta-analyses on length of antidepressant
treatment that clearly distinguished between patients with a history of two lifetime episodes vs.
three or more lifetime episodes of MDD. There is insufficient “clean” evidence to make
different recommendations for patients with two lifetime episodes of MDD and patients with
three or more lifetime episodes of MDD. The data, in aggregate, suggest benefit to long-term
continuation of antidepressants in patients with at least two lifetime episodes of MDD who
respond to antidepressant treatment. The optimal duration of treatment is not clear from
available data, but it appears that a minimum of 15 months and in some cases as long as five
years of treatment after the acute phase response demonstrates benefit. It is possible that longerterm treatment (beyond five years) also provides continued benefit, but studies have not been
conducted to examine the benefits of longer-term antidepressant treatment compared with
discontinuation after five years. Because of these limitations, the GDT has labeled this
recommendation “consensus-based.”
Supporting Evidence For Patients With Chronic MDD or Double Depression to
Continue Medication
Two new RCTs were found that this addressed this issue.
 Kocsis(158) studied out patients who met DSM-III diagnostic criteria for “pure” dysthymia
(40%), chronic Major Depression (10%), and dysthymia with current Major Depression
(“double depression”) (50%). All patients were treated with desipramine 50 to 325 mg/d
during the acute phase (ten weeks) and continuation phase (16 weeks = four months).
Patients who responded to treatment were then randomized to double-blind maintenance
treatment with desipramine (n = 28) or placebo (n = 25) for 24 months. 15% of patients
receiving long-term maintenance treatment with desipramine experienced a relapse,
compared with 52% of patients receiving placebo (ARR = 37%, NNT = 3, p = 0.01).
Fourty percent of patients studied did not have MDD (they had dysthymia only), although
response in each patient subgroup did not differ in either the acute, continuation, or
maintenance phases.
 Keller(159) studied outpatients meeting a DSM-III-R structured clinical interview diagnosis
of chronic Major Depression (symptoms for at least two years) or dysthymic disorder with
Major Depression (double depression) and a minimum baseline severity of 18 on the 24-item
Hamilton Depression Scale (HAM-D). All patients (n = 253) completed 12 weeks of
treatment (acute phase) and four months of continuation phase treatment with sertraline
50 to 200 mg/day. Responders were then randomized to 48 weeks of double-blind
maintenance phase with sertraline (n = 77) or placebo (n = 84). Sertraline treated patients
had significantly fewer recurrences than placebo treated patients (6% vs. 23%), p = 0.002
for the log-rank test of time-to-recurrence distributions. Clinically significant depressive
symptoms reemerged in 26% of patients treated with sertraline versus 50% in the placebo
group (p = 0.001).
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 The available evidence suggests benefit to long-term continuation of antidepressants in
patients with chronic MDD or double depression (MDD with concurrent dysthymia) who
respond to initial acute phase antidepressant treatment. The optimal duration of treatment is
not clear from available data, but it appears that a minimum of 15 to 28 months of treatment
after acute phase response demonstrates benefit. It is possible that longer-term treatment also
provides continued benefit, but studies have not been conducted to examine the benefits of
longer-term antidepressant treatment compared with discontinuation after 28 months.
6.
Follow-Up For Patients In The Acute Phase
(First Three Months) of Treatment For MDD
6
For patients who are starting treatment with antidepressants for Major Depression, the
GDT recommends that the minimum recommended follow-up frequency be one patient
contact within the first month, and at least one additional patient contact four to eight
weeks after the first contact. Assess for adherence, side effects, suicidal ideation, and
patient response during both these visits. Consensus-based
Rationale:
Note: HEDIS requires three follow-up contacts in the first 12 weeks of treatment with
antidepressants, one of which must be with a prescribing clinician. HEDIS allows one of the
three follow-up contacts to be by telephone; currently the other two contacts must be in-person
visits. The HEDIS requirements are not evidence-based.
2008 Guideline
No new evidence was found, the recommendation remains unchanged.
2006 Guideline
We found one RCT examining an intervention for patients in the first three months (acute phase)
of treatment for MDD:
 Swindle, et al. (2003)(160) tested whether the services of a Clinical Nurse Specialist (CNS)
would improve symptoms of primary care patients receiving treatment for depression or
dysthymia. The CNS coordinated a treatment plan including medication, cognitive
behavioral therapy, referral to Mental Health, and monitoring through telephone and/or
in-person visits. Monitoring occurred at two weeks, one month, and two months after the
initial visit.
The authors found no significant difference in depression symptoms, patient satisfaction, or
rates of antidepressant prescribing or adequate dosing between patients with CNS
services versus those without. Patients in the intervention group did have significantly
more recorded depression diagnoses and referrals to mental health in the medical record.
Specific data on the follow-up frequency of patients in the usual care group were not
provided. However, CNS’s often chose to use watchful waiting with patients in the
intervention group (disagreeing clinically with depression scale diagnoses), thus affecting
the fidelity of the intervention.
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Overall Conclusion
The Swindle, et al. study, due to reasons outlined above, adds no new information that helps
determine a follow-up schedule for newly diagnosed Major Depression patients. Given the lack
of additional information, the previous consensus-based recommendations still seem valid.
However, recognizing the discrepancy between this recommendation and the HEDIS guidelines
(which, albeit not evidence-based, are a standard on which health plans are judged) the GDT
suggests clarifying the previous recommendation, by adding that the MINIMUM recommended
follow-up frequency for patients who are starting treatment with antidepressants for Major
Depression is one patient contact within the first month, and at least one additional patient
contact four to eight weeks after the first contact. Research on this topic does not differentiate
between modalities for follow-up (in-person visits, phone calls, email messages). The GDT
believes that the “active ingredient” is the follow-up per se, and not the modality of follow-up;
therefore we recommend that any of these types of contacts are acceptable.
2004 Guideline
Supporting Evidence For Follow-Up Frequency in the Acute Phase Treatment of
MDD
 There is no evidence that determines the optimal number or frequency of follow-up for adults
in the acute phase (first 12 weeks of treatment) of Major Depression.
 There is no evidence that suggests that in-person visits during acute phase follow-up are
superior to phone contacts.
 Despite the lack of evidence, HEDIS requires three follow-up contacts in the first 12 weeks
of treatment with antidepressants, one of which must be with a prescribing clinician. HEDIS
allows one of the three follow-up contacts to be by telephone, but currently the other two
contacts are defined as in-person visits.
The GDT recommends targeting at least one contact within the first month and at least one
additional contact four to eight weeks thereafter to evaluate treatment adherence, symptom
response, potential side effects, suicidal ideation, and the need for treatment adjustment. This
recommendation is based on medication discontinuation patterns seen in short-term trials of
antidepressants (where patient dropouts tend to occur within the first month or between the
second and third month of treatment), and the clinical experience and consensus of the GDT.
Additional contacts may be needed for patients who are not tolerating or responding to treatment.
There is no evidence that patients who are tolerating and responding to treatment will achieve
additional benefit with three contacts (as HEDIS suggests) as opposed to two contacts as outlined
above (meaning extra patient and clinician time and resources may be utilized in some cases for
no appreciable added benefit). Since there is no evidence that directly addresses this question,
the GDT decided to base its recommendation on indirect evidence from the literature,
recognizing that this recommendation would also be consensus-based.
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The GDT recognizes that this recommendation may be viewed by some as an “opposition” to the
current HEDIS standard (which is based solely on expert opinion without reference [that we
found] to any systematic literature review to support it). However, by specifying a minimum
number of visits in the Depression Guidelines; clinicians, teams, and regions still have the option
to base performance benchmarks on the HEDIS criteria.
The GDT believes also that antidepressant continuation rates (also a HEDIS measure and also
addressed in this guideline) are founded on better evidence and are better proxies for processes
and outcomes of care. The recommendation for follow-up, with at least some basis in evidence
(however indirect), provides flexibility for clinicians and teams to focus on and address other
aspects of quality depression care, while also providing a “prompt” for teams to examine their
care processes if the number of contacts falls below this minimum recommendation.
In March, 2004, the FDA issued a directive that the ten most commonly used antidepressants
(fluoxetine, paroxetine, sertraline, bupropion, citalopram, fluvoxamine, mirtazapine, nefazodone,
escitalopram, and venlafaxine) carry a warning that thoughts about suicide sometimes occur in
people taking antidepressants. The findings have been noted in antidepressant studies of children
and adolescents. Even though to date there have not been specific concerns raised about
depressed adults being treated with antidepressants in primary care settings, the FDA chose to
issue the directive for all patients as a precautionary measure.
The essence of the FDA direction is to advise patients of the possibility that thoughts about
suicide may arise, particularly at the onset of treatment and with changes in treatment (dosage
and/or medication changes), and to encourage patients to inform clinicians immediately if these
thoughts occur. Regardless of the treatment option selected, the GDT believes that primary care
patients should be screened for suicidal ideation, intent, or plan at the diagnosis of Major
Depression, with each follow-up visit for depression, and with any adjustments in treatment.
Consultation with mental health should occur as indicated.
7.
Follow-Up For Patients In The Continuation Phase
(Months Four To 12) of Treatment of MDD
7
After achieving symptom remission, the GDT recommends at least one follow-up
contact* during the fifth or sixth month of treatment in patients with Major Depression.
Assess for continuing symptom remission and dosage/treatment adjustment during this
contact.
The GDT recommends additional patient follow-up to consider either continuing
treatment beyond the continuation phase, or attempting a trial of treatment
discontinuation. Consensus-based
*
Follow-up contact may include in-person visits, phone calls or email between patient and clinician, or phone
calls/email between patient and a care manager. The use of email between patients and providers is relatively
new, and has not been a widely utilized means of communication to date. However, it is being increasingly
advocated as part of a patient-centered, more efficient (“less visit dependent”) model of care. At least one
member of the GDT uses this modality regularly and deems it effective for follow-up contacts.
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Rationale:
2008 Guideline
No new evidence was found, the recommendation remains unchanged.
2006 Guideline
No new evidence was found. Research on this topic does not differentiate between modalities
for follow-up (in-person visits, phone calls, email messages). The GDT believes that the “active
ingredient” is the follow-up per se, and not the modality of follow-up; therefore recommends that
any of these types of contacts are acceptable.
2004 Guideline
Supporting Evidence for Follow-Up Frequency In The Continuation Phase
Treatment of MDD
Clinical Evidence(70) identified one RCT that addressed patient follow-up during the continuation
phase of MDD treatment.
 Three hundred eighty-six people aged 19 and older, with recurrent Major Depression or
dysthymia, who had largely recovered after eight weeks of antidepressant treatment were
randomized to a relapse prevention program (two primary care visits and three telephone
calls) versus usual care for one year. Patients in relapse prevention had significantly
improved depressive symptoms over one year (p = 0.04), but no significant difference in
relapse rates (35% in both groups).
 While this study supports follow-up after symptom remission, we found no studies
comparing different numbers or appropriate timing of follow-up contacts for patients with
MDD. Furthermore, this study also included patients with dysthymia, and did not provide
separate outcome data for patients with Major Depression only.
 The Depression Outcomes Report V(161) reports show that adherence with antidepressant
treatment continues to decline between the third and sixth month of treatment. Premature
discontinuation of antidepressants is associated with sub-optimal patient outcomes (see
recommendations and rationale on length of treatment with antidepressants).
Conclusion
We found only one RCT, conducted in a mixed population (MDD or dysthymia), that addressed
follow-up during continuation phase treatment of MDD. We found no studies addressing
different numbers or timing of follow-up contacts for patients in the continuation phase of MDD.
The optimal number and timing of follow-up contacts is therefore undetermined. Adopting a
strategy of five follow-up contacts, as suggested by the Clinical Evidence review, would have
major impact on patient convenience, patient expense, clinician time, and access to care.
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Nevertheless, the Clinical Evidence study, our review of evidence on duration of treatment and
our own observational evidence from the Depression Outcomes report suggest that some level of
follow-up is beneficial. Due to these considerations, the GDT believes (by consensus) that a
minimum of one follow-up contact in the fifth or sixth month of treatment should be made to
monitor for symptom relapse, to adjust treatment, and to stress ongoing treatment adherence.
This would potentially capture most of the patients who have discontinued antidepressants
prematurely.
Some patients will be eligible for, or desire, discontinuation of antidepressant treatment after
successful continuation phase treatment. Therefore, additional patient follow-up should occur as
the decision is made to either continue treatment past the continuation phase, or attempt a trial of
treatment discontinuation. There is no evidence to support this recommendation, which is based
upon usual clinical care and consensus of the GDT.
8.
Follow-Up For Patients In Maintenance Phase
(Beyond 12 Months) of Treatment of MDD
8A
For asymptomatic patients with Major Depression who are continuing on antidepressants
beyond 12 months, the GDT recommends at least one annual follow-up contact to assess
for continuing symptom remission, the need for ongoing treatment, and dosage/treatment
adjustment. Consensus-based
8B
The GDT recommends that additional follow-up for asymptomatic patients with Major
Depression who are continuing on antidepressants beyond 12 months should be based on
patient preference and response. Consensus-based
Rationale:
2008 Guideline
No new evidence was found, the recommendations remain unchanged.
2006 Guideline
No new evidence was found. Research on this topic does not differentiate between modalities
for follow-up (in-person visits, phone calls, email messages). The GDT believes that the “active
ingredient” is the follow-up per se, and not the modality of follow-up; and therefore recommends
that any of these types of contacts are acceptable.
2004 Guideline
Supporting Evidence for Follow-Up Frequency in the Maintenance Phase
Treatment of MDD
There is no evidence that determines optimal number or frequency of follow-up for
asymptomatic patients on long-term antidepressant treatment for Major Depression. The GDT
believes that a minimum of one annual follow-up contact should be made with patients on
maintenance phase treatment, to assess for ongoing symptom control and potential treatment
adjustment.
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9.
Discontinuation of Antidepressants in Patients with MDD
9A
Fluoxetine may be discontinued, without tapering, with a relatively low risk of adverse
effects. Evidence-based
The GDT recommends tapering other antidepressants (other SSRIs, TCAs, SNRIs, NRIs,
and DAs) over a two to four week period. Consensus-based
9B
Rationale:
2008 Guideline
No new evidence was found, the recommendations remain unchanged.
2006 Guideline
Our search yielded one RCT addressing the issue of discontinuing antidepressants:
 Sunder, et al. (2004)(162) designed a study to differentiate between symptoms of
antidepressant discontinuation vs. depression relapse in women treated with sertraline or
placebo for postpartum depression. Both sertraline and placebo were tapered over three
weeks, starting at week 18. The authors found that a three week taper did not lead to
emergence of symptoms typical of SSRI antidepressant withdrawal. The study was not
designed to compare a three week taper with a more rapid discontinuation schedule.
We found no further studies addressing methods of discontinuing fluoxetine.
Overall Conclusion
Although the Sunder study is limited to postpartum women, it is consistent with earlier studies
suggesting that antidepressants with short half lives (such as sertraline) should be tapered.
Therefore, the previous recommendation that fluoxetine may be discontinued without tapering
with a relatively low risk of adverse effects, while other antidepressants should be tapered over a
two to four week period, is still valid.
2004 Guideline
One new study was found since the previous revision of the Depression Guidelines that
addressed this issue.
 Judge(163) studied outpatients aged ≥ 18 with a diagnosis of unipolar depressive disorder
successfully treated with fluoxetine or paroxetine whose Montgomery-Asberg Depression
Rating Scale (MADRS) score was 12 or less (indicating symptom remission). Patients
(n = 150) received a blinded drug equivalent to their current daily maintenance dose
(fluoxetine 20 to 60 mg or paroxetine 20 to 50 mg) at visit one. Patients were then
randomized to two different treatment groups comparing fluoxetine (n = 75) and paroxetine
(n = 75) with periods of treatment interruptions lasting three to five days in each group.
 Mean change following treatment interruption for Discontinuation Emergent Signs and
Symptoms (DESS) was 0.2 for the fluoxetine group and 2.2 for the paroxetine group
(p = 0.001 favoring fluoxetine-treated patients). Mean change in the MADRS was 0.2
for fluoxetine patients and 1.8 for paroxetine patients (p = 0.021).
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 Paroxetine-treated patients also had significantly greater increases in Clinical Global
Impressions–Severity (CGI-Severity scores) than did fluoxetine-treated patients following
treatment interruption. The deterioration from baseline within the paroxetine treatment
group was also significant for both MADRS (p = 0.010) and CGI scores
(p = 0.001).
 This study did not evaluate for discontinuation side effects beginning after five days of
treatment interruption, when side effects might be expected to appear with a long half-life
antidepressant such as fluoxetine.
Two studies were found both of which looked at the effects of discontinuing SSRIs.
 Zajecka(164) compared fluoxetine (varying treatment lengths) with placebo in 395 patients
(274 women, 121 men, mean age ± SD = 40 ± 10 years) who were randomly assigned to
continuation treatment with fluoxetine (n = 299) or placebo (n = 96).
 Subjects were men and women who initially met DSM-III-R(73) criteria for Major
Depression and had a 17-item HAM-D score ≥ 16 and whose depressive symptoms
significantly improved during the Acute Phase of a multicenter examination of fluoxetine
in the maintenance treatment of depression. (Improvement was defined as a HAM-D 17
score ≤ 7 after 12 weeks of acute treatment with fluoxetine 20 mg daily).
 Upon completion of this acute phase of treatment, subjects were assigned by random
allocation to double-blind placebo (n = 96) or to one of three arms of ongoing active
treatment with fluoxetine 20 mg daily (n = 299) for various periods of time. (These three
arms were pooled for analysis purposes in this study.)
 Fluoxetine treatment was discontinued without a tapering-off period in patients assigned to
placebo.
 Patients were seen at weeks one, two, four, and six after randomization. Reports of new or
worsened adverse events were similar for both groups at each visit after randomization.
 The authors concluded that abrupt discontinuation of fluoxetine was well-tolerated.
 Rosenbaum(165) compared discontinuation syndromes in patients with a history of unipolar
(Major) Depressive Disorder on sertraline, paroxetine, and fluoxetine as compared with
placebo in 231 patients. Fluoxetine had the least problems when discontinued, followed by
sertraline and paroxetine.
No studies were found since the previous revision of the Depression Guidelines comparing
discontinuation of higher doses of fluoxetine (40 to 60 mg/day) with lower doses (10 to 20
mg/day). All studies found included lower and higher dose fluoxetine patients in the same
treatment group.
It takes approximately 5.5 half lives for medications to be “cleared” from the bloodstream.
Medications which short half lives (and thus more rapid clearance) are more prone to produce
symptoms upon discontinuation than medications with longer half-lives. The half-life of
fluoxetine is 96 hours, sertraline is 24 hours, and paroxetine is 17 to 22 hours.
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No evidence was found for tapering TCAs. The two to four week time period recommended by
the GDT is consistent with clearance of these agents, based on their half-lives.
Conclusion
There is some evidence that fluoxetine can be discontinued without a high risk of many adverse
effects. This is consistent with its known long half-life. Extrapolating from the Rosenberg study
and principals of pharmacology, SSRIs with shorter half-lives should be tapered, rather than
discontinued. There is no evidence that determines the optimal tapering regimen. The two to
four week time period recommended by the GDT is consistent with clearance of these agents,
based on their half-lives.
Pharmacotherapy of Antidepressant Medications:
Half-life (Active Metabolite)(166)
Half-Life in Hours
(Active Metabolite)
Medication
SSRI
TCAs
Others
Fluoxetine (Prozac)
Sertraline (Zoloft)
Paroxetine (Paxil)
Citalopram (Celexa)
Desipramine (Norpramin)
Nortriptyline (Pamelor)
Amitriptyline (Elavil)
Imipramine (Toframil)
Doxepin (Sinequan)
Bupropion (Wellbutrin)
Venlafaxine (Effexor)
Nefazodone (Serzone)
Mirtazapine (Remeron)
24 - 72 (146)
26 (66)
24
33
12 to 28
18 to 56
9 - 46 (18 - 56)
6 - 28 (12 - 28)
11 to 23
10 to 21
4 (10)
4 - 5 (4 - 18)
20 to 40
10.
Treatment Preferences For MDD In Different Ethnic Groups
10
Because patient preferences for treatment may vary based on their ethnicity and culture,
the GDT recommends asking patients from different ethnic groups about treatment
preference, when discussing treatment options for MDD. Evidence-based
Rationale:
2008 Guideline
No new evidence was found, the recommendation remains unchanged.
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2006 Guideline
We found one study that addressed the preferences of one particular ethnic group.
 Dwight-Johnson, et al. (2004)(167) used conjoint analyses to assess the preferences of low
income Latinos. They found that this population preferred individual over group treatment,
combination therapy over counseling or medication alone, and all treatment settings equally.
Overall Conclusion
The GDT believes that the Dwight-Johnson study is consistent with our previous analysis and
recommendation, which remains that patients from different ethnic groups should be asked about
their treatment preferences for MDD.
2004 Guideline
Supporting Evidence for Treatment Preferences for MDD in Different Ethnic
Groups
PubMed (1/1/2001 through 4/1/2003) and PsychInfo (1985 through 4/1/2003) databases were
searched and no new evidence on this topic was found since the previous revision of the
Depression Guidelines.
One article was found from another search that did not show up in the above search due to
indexing issues in Pub-Med.
 Cooper, et al.(168) conducted a telephone survey of 829 adult patients (659 non-Hispanic
whites, 97 African Americans, 73 Hispanics) recruited from primary care offices across the
United States who reported one week or more of depressed mood or loss of interest within
the past month and who met criteria for major depressive episode in the past year.
 Within this cohort, they examined differences among African Americans, Hispanics, and
non-Hispanic whites in acceptability of antidepressant medication and acceptability of
individual counseling.
 African Americans (adjusted OR = 0.30; 95% CI: 0.19 to 0.48) and Hispanics (adjusted OR
= 0.44; 95% CI: 0.26 to 0.76) had lower acceptance of antidepressant medications
compared with Whites.
 African Americans had somewhat lower odds (adjusted OR = 0.63; 95% CI: 0.35 to 1.12),
and Hispanics had higher odds (adjusted OR = 3.26; 95% CI: 1.08 to 9.89) of finding
counseling acceptable than non-Hispanic whites.
 Racial and ethnic differences on preferences for treatment modalities were found.
Clinicians should consider patients' cultural and social context when negotiating treatment
decisions for depression.
The AHRQ(169) report did not find any data on patient preference and ethnic background.
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Two studies were found previously on this topic.
 Dwight-Johnson's(167) longitudinal study surveyed 1,187 English and Spanish speaking
patients regarding their treatment preferences for depression. Nearly all had MDD. Patients
were given five treatment options to choose from; including free medication for six months;
individual or group counseling; and watchful waiting. Eighty-three percent of the total
sample reported wanting active treatment for depression; of these, 27% preferred
antidepressant medication, 29% individual counseling, and 26% group counseling. Patient
characteristics of those who chose counseling included being African American and having a
greater knowledge of counseling. It is important to note that treatment preference may have
been influenced by cost (total cost for medication was $480, individual counseling $300, and
group counseling $75). Patients were not necessarily actively diagnosed with depression at
the time of the survey but had to have experienced a two-week period of depression over the
prior two-year period.
 Chilvers(170) examined treatment preference in 323 general practice MDD patients, patients
could either choose counseling or medication, or agree to be randomized into either treatment
arm. The study did not analyze results by ethnic group. The study concluded that patients
who chose their care did better than those who were randomized into treatment. Also,
patients taking antidepressant medication got better faster than patients receiving counseling.
Consult the National Diversity Handbooks on culturally competent care approaches in Latinos;
Asian/Pacific Islanders; African American; and Lesbian, Bisexual, Gay, and Transgender groups.
To order, please contact Kaiser Permanente’s National Diversity Institute for Culturally
Competent Care. All orders for the products must be submitted in writing. Download the order
form at this website: http://diversity.kp.org/2main-library/online-resources.html and fax to
(510) 271-5757.
Overall Conclusion
Patients from different cultural/ethnic backgrounds may have different understandings of and
frames of reference on depression. Therefore, they may express different treatment preferences
for Major Depression. Many primary care clinicians are not aware of these cultural
considerations. Since patient outcomes or satisfaction may be related to choice of treatment, the
GDT recommends approaching the treatment of Major Depression in adult patients from
different cultural and ethnic backgrounds in the context of the patient’s cultural beliefs.
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11.
Patient Self-Management Strategies for Improving Symptoms of MDD
Internet Resources
11A The GDT recommends scientifically validated internet-based patient self-help materials
as an optional adjunct strategy (in addition to antidepressants or psychotherapy) for
treating symptoms of MDD. Evidence-based: B
Exercise
11B The GDT recommends exercise as an adjunctive strategy (in addition to antidepressants
or psychotherapy) for treating the symptoms of MDD. Evidence-based :B
Bibliotherapy
11C The GDT recommends scientifically validated bibliotherapy as an optional adjunct
strategy (in addition to antidepressants or psychotherapy) for treating the symptoms of
MDD.* Consensus-based
Befriending
11D The GDT recommends befriending as an optional adjunct to antidepressants or
psychotherapy for treating the symptoms of MDD.† Consensus-based
Patient-Initiated Combined Phone/Computer Programs
11.E. There is insufficient evidence for or against using patient-initiated combined
phone/computer programs in the treatment of MDD. Evidence-based: I
Light Therapy
11F The GDT makes no recommendation for or against light therapy as a primary or
adjunctive treatment for nonseasonal forms of MDD. Evidence-based: I
Music Therapy
11G The GDT makes no recommendation for or against music therapy as an adjunct to
antidepressants or psychotherapy for treating the symptoms of MDD. Evidence-based: I
Life Review Therapy
11H The GDT makes no recommendation for or against life review therapy as an optional
adjunctive depression management strategy for depressed older adult patients who are
concurrently receiving regular social services care. Evidence-based: I
*
Bibliotherapy: Advising people to read specific written material based on cognitive-behavioral approaches to
depression treatment.
†
Befriending: Consists of a designated befriender who meets the depressed person to talk and socialize with for
at least one hour per week.
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Evidence Grade
Evidence for Recommendations 11A: Fair; F, G, and H: Insufficient.
Search Strategy
Some studies found and used in this guideline did not appear in PubMed search results due to the
way studies are indexed in PubMed. The Clarke (2005)(171) study was not identified by the
search due to PubMed Indexing, but was identified by a GDT member and reviewed due to
relevance. Systematic reviews and meta-analyses with search dates outside the range of current
searches were excluded.See Appendix B for more information on the search strategy.
2010 Update
New evidence was found, recommendations have been changed based on expert/consensus
opinion.
Our recent search yielded two relevant RCTs (Craft, 2007(172); Meyer, 2009(173)) that address the
different categories of self-management strategies. The studies included patients with symptoms
of depression, which consisted of participants with minor depression and dysthymia as well.
Studies provided little detailed information about concurrent use of antidepressants or
psychotherapy in the intervention groups. One RCTs (Meyer, 2009(173)) evaluated the
effectiveness of an internet-based therapy and one RCT (Craft, 2007(172)) assessed an exercise
intervention. Please refer to Evidence Tables 11.1 and 11.2 for study details.
Exercise
 Craft et al. (2007)(172) conducted a randomized pilot study to compare the effectiveness
between a home-based versus a clinic-based exercise intervention for depressive symptoms
in low-income, minority women. A total of 32 women were assigned to home-based (N =
16) or clinic-based (n = 16) exercise program for 3 months. Overall, both interventions were
associated with improvements in depressive symptoms (effect size: -0.97 and -1.3 for home
and clinic based, respectively) and time spent in physical activity. However, at 3-month
follow-up, there were no significant between-group effects for depressive symptoms, selfreported physical activity, body composition, or cardiovascular fitness. It is important to
note that the study is limited by lack of control group, (it is essentially a pre-post study with
post comparisons of the two groups) small sample size, lack of power, short duration, and
low generalizability. Therefore, interpretation of results should be done with caution. Please
refer to Evidence Table 11.1 for study details.
Overall Conclusion
Results from one low-quality study identified does not warrant changes to the 2008
recommendation. Although the study found modest short-term improvement in depressive
symptoms with exercise, no long-term effect was observed and it was not designed to substitute
exercise for antidepressant or psychotherapy treatments; thus, it can not be definitively
concluded that exercise may be used effectively instead of antidepressant medication or
structured psychotherapy.
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Internet/Computer
 Meyer et al. (2009)(173) randomized 396 participants from an internet depression forum in
Germany to internet-based psychotherapy intervention plus treatment-as-usual (n = 320)
or to wait-list control plus treatment-as-usual (n = 76) for nine weeks and followed-up at
18 weeks and six months. Continuation rates were reported at 54.5% at nine weeks, 36.9%
at 18 weeks, and 25% at six months. About three quarter of the sample were women, many
were unemployed, and 58% currently received treatment for depression. At nine weeks,
intent-to-treat (ITT) analysis found significant reduction in depression symptoms and social
functioning in the internet group compared to no change in wait-list controls (effect size for
depression symptoms: d = 0.3; effect size for social functioning: d = 0.36). Changes were
also maintained at six-months follow-up among completers (d = 0.74). In addition, 25.4%
of those in the internet group vs. 1.9% of the wait-list control reached the criteria of clinical
significant improvement/ recovered (change of at least 8.46 points on BDI, with post test
score of < 14.29, p < 0.001). Based on findings, authors suggested that “the program could
serve as an adjunctive or stand-alone treatment tool for patients suffering from symptoms of
depression.” However, limitations such as no placebo-controlled group, participants not
clinically diagnosed with MDD, high attrition rate, selection bias, and low generalizability
warrant cautious interpretation of results. Please refer to Table 11.1 for study details.
Overall Conclusion
Only one trial on internet-based self-study intervention was identified and outcomes from the
trial did not warrant changes to the 2008 recommendation. The trial found positive results
among participants assigned to the internet intervention in terms of social functioning and
reduction in depressive symptoms compared to wait-listed control. Authors stated some
participants were concurrently under other treatments for depression; however, it was unclear
whether all participants were clinically diagnosed with MDD, which makes it difficult to draw a
definitive conclusion on the effectiveness of the internet program exclusively.
Editorial note: no new evidence was found on bibliotherapy. The wording of the
recommendation was modified by consensus approval of the GDT to be consistent with the
wording of the internet-resources recommendation. In addition, no new evidence was found for
combined phone/computer programs; however, the language for this recommendation was also
modified by consensus approval to reflect the insufficient evidence based on only one previously
identified study.
2008 Guideline
New evidence was found, the recommendation remains unchanged.
One relevant RCT(174) was identified that studied the effect of providing patients with
personalized workbooks that addressed various aspects of depression in addition to providing
them with usual care. No differences in Beck Depression Inventory scores were seen between
groups, although the patients in the group given workbooks were more likely to report that they
felt well educated about depression. Please refer to Table 11.1 for study details.
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Overall Conclusion
We found only one trial on the above list of patient self-management strategies in our 2008
update. This negative trial on adjunct bibliotherapy is the first trial identified since the original
guideline recommendations. The overall evidence is mixed. However, even in this new trial,
patients gained some benefit from understanding their condition. Since there is little apparent
harm in providing patient education materials as an adjunct to other clinician-directed therapy,
the GDT retained its belief in the use of bibliotherapy as an optional adjunct strategy.
Bibliotherapy was the only health intervention for which new evidence was found. A change in
symptoms as a result of bibliotherapy is the only health outcome addressed in this new evidence.
The overall evidence on bibliotherapy remains mixed, so our recommendation remains
unchanged.
2006 Guideline
Our recent search yielded a number of studies that address the different categories of selfmanagement strategies. Most studies were designed to compare these self-management
strategies with treatment or with different intensities or types of the same general selfmanagement intervention. Many studies included patients with symptoms of depression, but
were not designed to specifically study (nor did they specify the number of patients with) MDD.
Few compared self-management strategies with “traditional” first-line treatment approaches;
most studies provided little if any detailed information about concurrent use of antidepressants or
psychotherapy in the intervention groups. Please refer to Table 11.1 for study details.
In reviewing the evidence as noted below, the GDT concluded that due to limitations in the
current body of evidence, there is insufficient evidence to recommend for or against these selfmanagement strategies as first-line “monotherapy” for patients with MDD. However, when
appropriate (as discussed below), pending appropriately designed studies, the GDT extrapolated
the findings to make consensus recommendations for considering selected self-management
strategies as an adjunct to other evidence-based treatment for MDD.
Exercise
Dunn (2004)(175) found that mild to moderately depressed subjects partaking in a public
health dose of exercise (17 kcal/kg/week) for at least three days a week had a significantly
greater reduction in depression symptoms when compared with those partaking in a low dose
(7 kcal/kg/week) or no exercise. None of the subjects were involved in another treatment for
depression.
Clinical Evidence (Issue 14, January 2006) found one systematic review examining the
effectiveness of exercise as a treatment option for depression.
 The review found limited evidence that exercise may improve symptoms compared with no
treatment [standardized mean difference in effect size -1.1, 95% CI: -1.5 to -0.6; weighted
mean difference in Beck depression inventory -7.3, 95% CI: -10.0 to -4.6, and that exercise
may be as effective as cognitive therapy (standardized mean difference -0.3, (95% CI:
-0.7 to 0.1)]. However, according to the authors, the following methodological problems
rendered the results inconclusive: randomization was adequately concealed in only three
RCTs, intention to treat analysis was undertaken in only two, and assessment of outcome was
blinded in only one RCT.(176)
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 One RCT involving older adults and included in the systematic review above found no
significant difference among groups (aerobic exercise, sertraline, and combination treatment)
in the proportion of people who recovered (60% with exercise, 69% with sertraline, and 66%
with combination treatment). A ten month follow-up of this RCT found significantly lower
relapse rates with exercise than with antidepressant drugs (30% with exercise, 52% with
sertraline, and 55% with combination treatment; p = 0.28 for exercise vs. either treatment).
However, about half of the people in the medication group engaged in exercise during
follow-up, making it difficult to draw firm conclusions. The authors conclude that “the
clinical importance of the observed difference at ten months remains unclear.”(177)
Overall Conclusion
The evidence comparing exercise with antidepressants or psychotherapy as first-line strategy
for treatment of adults with Major Depression is relatively sparse. The study populations,
inclusion criteria, and outcome measures are heterogeneous. The GDT does not believe that
there is sufficient evidence at this time to recommend for or against exercise as a sole treatment
option for MDD. However, exercise is often recommended for other health reasons, and is
(in appropriately selected patients) a low risk self-management strategy. Extrapolating from
the available evidence, the GDT believes that exercise is an adjunctive strategy (in addition to
antidepressants or psychotherapy) for treating the symptoms of MDD.
Bibliotherapy
No new evidence was found.
Overall Conclusion
Many of the limitations noted with studies of exercise above also apply to studies of
bibliotherapy found in earlier iterations of this guideline. In light of these past findings, the GDT
believes that the previous recommendation should stand: Bibliotherapy is an optional adjunct
strategy (in addition to antidepressants or psychotherapy) for treating the symptoms of MDD.
Computer/Internet
 Christensen, Griffiths, & Jorm (2004)(178) placed subjects with depression (and not being
treated by a psychologist or psychiatrist) into one of three groups: 1) “Blue Pages,” – and
internet program to improve depression literacy, 2) “MoodGYM” – an internet-based
cognitive behavioral therapy, or 3) attention control. The researchers found that both Blue
Pages and MoodGYM were significantly more effective than control in reducing symptoms
of depression; neither internet intervention was more effective than the other. There was no
information on how many patients in each study arm were being treated with antidepressants.
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 Clarke, et al. (2005)(171) conducted a follow-up to their 2002 study examining the
effectiveness of the internet-based intervention “Overcoming Depression in the InterNet
(ODIN),” available at www.believebetter.org. The authors concluded that the 2002 trial
found no significant differences between the internet and control interventions because
participant usage of the internet site was low. In the 2005 update they attempted to increase
participant adherence by using postcard and telephone reminders. The authors did in fact
find that the addition of the reminders yielded significant results: those in the either
intervention group (postcard or telephone reminders) showed greater decreases in CES-D
depression scores than those in the treatment-as-usual control group who did not have access
to the site at all. This difference was even greater in those who had more severe depression
at baseline. However, enrollment rates in the study were very low, and more patients
dropped out of the treatment groups than the control group.
Overall Conclusion
The specific web-based interventions studied by Christensen, Griffiths, and Jorm, and the 2005
Clarke intervention were found to be effective for reducing symptoms of depression, although
the data do not suggest that these sites can be used in lieu of antidepressants or psychotherapy.
It should also be noted that the interventions examined in the previously reviewed studies by
Clarke(179) and Patten(180) in the 2004 update were ineffective. The effectiveness of
web-based interventions may depend on a number of factors, potentially including patient
motivation to utilize the resources, the specific content utilized and the usability of the website.
The GDT believes that some internet-based interventions may be beneficial adjuncts in reducing
symptoms of depression, but based on the currently available (heterogeneous) evidence, the
recommendation should be limited to specific interventions (Blue Pages, Mood GYM, and
ODIN).
Note: The GDT acknowledges that internet sites are dynamic and continually evolving. Prior to
referral to the aforementioned sites, care should be taken to ensure the information provided is
still accurate and up-to-date.
Befriending
 Clinical Evidence Volume 14 found one small RCT that provided insufficient evidence to
assess befriending in people with mild to moderate depression. It found that befriending
significantly increased the proportion of women with remission of mild depression symptoms
at 13 months compared with waiting list control (86 women with chronic depression, aged
18 years and older, primarily aged 25 to 40 years; 65% with befriending vs. 39% with
control; p < 0.05; NNT = 4, 95% CI: 2 to 18).(181)
Overall Conclusion
The Clinical Evidence update above is consistent with previously reviewed evidence suggesting
some benefit of befriending in patients with depression. None of the studies specified how many
patients were receiving other forms of depression treatment, nor did they differentiate between
patients with Major and Minor Depression (the latter often resolves spontaneously). However,
given the potential for some effect, and the low risk of befriending as a strategy, the GDT makes
a consensus extrapolation from the available evidence to consider befriending as an option for
patients as an adjunct to (but not a substitute for) treatment of Major Depression.
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Automated Telephone Programs
We found no new evidence to support for or against the use of automated telephone programs.
Overall Conclusion
The GDT previous recommendation stands; use of automated telephone programs is not
currently recommended as adjunctive therapy for MDD.
Light Therapy
Note: These analyses address the use of light therapy for nonseasonal forms of MDD. The
use of light therapy for Seasonal Affective Disorder (SAD) is currently being systematically
reviewed by the Cochrane Collaborative. Seasonal Affective Disorder is beyond the scope
of these current recommendations. Therefore, conclusions are limited to nonseasonal Major
Depression.
 Leppamaki, et al. (2004)(182) examined the effect of three interventions on mood
improvement: 1) aerobics in bright light, 2) aerobics in normal light, and 3) relaxation and
stretching in bright light. They found that a significant number of subjects who responded to
one of these treatments were given light therapy. This study should be interpreted with
caution, however, since it is unclear how many participants had Major Depression or
Seasonal Affective Disorder (SAD - a subtype of Major Depression where light therapy is
considered to be effective); nor did the authors provide information on the concurrent use of
other treatments.
 In a study examining the effectiveness of adjunctive bright light for nonseasonal Major
Depression, Martiny, et al. (2005)(183) treated all subjects with sertraline and concomitantly
had them exposed to either dim light or bright light. At the end of the five week study
period, the authors found a significant reduction in HAMD scores in the bright light group (p
< 0.01). This group also had significantly higher response (p = 0.006) and remission (p =
0.015) rates when compared with the dim light group. While these results
are promising, it should be noted that the two groups had unequal durations of treatment
(30 minutes for dim light vs. 60 minutes for bright light), and it is unclear how this factor
might have affected the overall results.
The Cochrane Collaboration has reviewed the evidence on light therapy for treatment of
nonseasonal depression.(184)
 Twenty studies were included in the review. Seventeen studies reported on participants
mostly suffering from MDD. Ten studies had both unipolar and bipolar patients in their
sample. Inclusion and exclusion criteria varied among studies. Almost all studies took place
in the hospital or long-term care facility. Only two studies assessed outpatients. None of the
studies were multicenter. Only five studies reported on the time of the year when the study
was performed.
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 Bright light therapy was administered in a wide range of intensities. The duration of active
treatment varied between 30 minutes and nine hours. Eleven studies administered bright
light in the morning. Most of the studies applied bright light as adjunctive treatment to drug
therapy, sleep deprivation, or both. Light was administered adjunctive to sleep deprivation in
nine studies, and in two additional studies the participants were awakened before their usual
wake up time for light treatment. Standardized adjunctive pharmacotherapy was applied in
seven studies, and in ten studies, concomitant drug treatment of the participants was kept
unchanged.
 All included studies described themselves as randomized, but presented little methodological
detail to elaborate on the truly random nature of allocation. Blinding of assessment in
administration of light therapy is more difficult than in studies with drug intervention, since
the active treatment due to its brightness looks dissimilar to the control treatment. Subjects
cannot fail to perceive the treatment and cannot be literally blind to treatment, though they
may not know which is intended as the active treatment.
 In general, the quality of reporting was poor. All but two trials reported the randomization
procedure without adequate information on allocation concealment. Blinding procedures
were also generally inadequately described. Many studies did not report the number of dropouts and did not specify reasons for drop-out. The trials did not report if intention-to-treat
analysis was performed.
 According to the criterion of 50% decrease in the HDRS score, there was no difference
between groups: 20 out of 39 patients (51%) in the bright light group and 17 out of 32
patients (53%) in the control treatment group were not improved (three studies, 71 patients,
relative risk (RR) 0.94, CI: 0.61 to 1.46). The treatment response in the bright light group
was better than in the control treatment group, but did not reach statistical significance in
random effects models. The result was mainly based on studies of less than eight days of
treatment.
 In studies using a light box, a fixed effect model approach showed that bright light was more
effective than the control treatment (12 studies, 275 patients, standardized mean difference
(SMD) = -0.50, CI: -0.75 to -0.25), and the statistical significance remained even when a
random effects model was applied (SMD = -0.47, CI: -0.86 to -0.08). The response to bright
light was significantly better than to control treatment in high-quality studies (SMD = -0.90,
95% CI: -1.50 to -0.31), in studies applying morning light treatment (SMD = -0.38,
CI: -0.62 to -0.14), and in sleep deprivation responders (SMD = -1.02, CI -1.60 to -0.45).
 Evaluation of the effect of combination of concomitant drug and morning bright light showed
that there was no difference between the two morning light conditions with or without
pharmacotherapy. With a fixed effect model approach, both conditions were statistically
significantly in favor of bright light over control treatment (combination treatment: nine
studies, 243 patients, SMD = -0.32, CI: -0.60 to -0.08; light only: two studies, 54 patients,
SMD = -0.57, CI: -1.14 to -0.01), but with a more conservative random effects model the
statistical significance was lost (combination treatment: SMD = -0.36, CI: -0.79 to 0.07;
light only: SMD = -1.03, CI: -2.63 to 0.58).
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 Many reviews did not report adverse effects systematically. Hypomania was more common
in the bright light group compared with the control treatment group (RR = 4.91, CI: 1.66 to
14.46; NNH = 8, CI: 5 to 20). The reviewers noted that categorizing the drop-out subjects as
"failures" might overestimate the number of subjects with this adverse effect as well as with
other poor outcomes.
 The reviewers conclude that in patients suffering from nonseasonal depression, light therapy
may offer modest antidepressive efficacy when administered in the morning, during the first
week of treatment and as an adjunctive treatment to sleep deprivation responders. These
benefits need to be balanced against the potential for hypomania. Finally, the reviewers note
that “due to limited data and heterogeneity of studies these results need to be interpreted with
caution.”
Overall Conclusion
In discussing the results of the above studies and in particular, the details of the Cochrane
review, the GDT believes that, based on the information available, it would be difficult to
formulate specific recommendations for patients with nonseasonal MDD on how to specifically
utilize light therapy as a self-help strategy. Due to the heterogeneity of the studies, and pending
further clarification, the GDT concluded that there is insufficient evidence at the current time to
recommend for or against the use of light therapy as a self-help strategy for patients with
nonseasonal forms of MDD.
Music
We found no new evidence to support for or against the use of music therapy.
Overall Conclusion
The GDT’s previous recommendation stands: There is currently insufficient evidence to
recommend for or against music therapy as an adjunct to antidepressants or psychotherapy for
treating the symptoms of MDD.
Life Review
 Serrano & Latore (2004)(185) tested life review therapy on a population of older adults
(65 to 93) with clinically significant symptoms of depression and receiving social services
regularly. The life review consisted of “autobiographical retrieval practice that entailed
focusing on a particular life period each week – childhood, adolescence, adulthood, and
summary.” When compared with controls, the life review therapy group had significantly
greater improvements in depressive symptoms. This study was conducted in Spain; it is
unclear if it is generalizable to populations in other countries.
Overall Conclusion
As with other self-management strategies, this study was not designed to test the relative efficacy
of this strategy vs. “standard” (psychotherapy or antidepressant) treatment for MDD. Due to the
limited population studied (and the unknown generalizability), the GDT believes that currently
there is insufficient evidence to recommend for or against life review therapy an optional
adjunctive depression management strategy.
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2004 Guideline
Supporting Evidence for Self-Management Strategies for Improving Depressive
Symptoms in Patients with MDD
Effect of Exercise
Three RCTs and one systematic review were found that addressed this issue.
 Singh(186) studied patients age 60 and older with Beck Depression Inventory (BDI) score of
greater than 12 and a diagnosis of either unipolar major or minor depression or dysthymia
according to DSM-IV diagnostic criteria. The patient population was 37% male and 63%
female.
 In phase one, patients (n = 32) were randomized to two treatment groups comparing ten
weeks of supervised exercise in a laboratory setting (intervention group), with health
education lectures (control group).
 In phase two (weeks 11 to 20), (n = 15) intervention patients received unsupervised
exercise at home, laboratory or health club setting (n = 15, 18 ±2 weight lifting exercise
sessions), while control patients (n = 14) received no further intervention. The BDI score
at 20 weeks decreased significantly from 21 ±2.0 to 9.2 ±2.8 for the exercise group
(p = 0.036), while the score for the control group decreased from 18.4 ±1.7 to only
14.4 ±2.2.
 At the 26 month follow-up, the BDI score for the exercise group decreased from 21 ±2.0 to
13 ±2.2, and the score for the control group decreased from 18.4 ±1.7 to 14.4 ±2.2,
p = 0.036 (favoring exercise group). The exercise group showed a statistically significantly
reduced depression severity compared with control group at both 20 weeks and 26-month
follow-up. The difference between BDI scores between groups may not be clinically
significant. The effect may not be evident if exercise is not continued. Over time, the
severity of depression also improved in the control group.
 McNeil(187) studied older adult outpatients with a mean age of 72.5 years and a BDI score of
12 to 24. Patients (n = 30) were randomized to three treatment groups comparing exercise
(walking between 20 to 40 minutes, three times a week) with social contact (two home visits
(20 to 40 minutes each week by an undergraduate psychology student) and a wait-list
(control group) for a period of six weeks. The total BDI score decreased from 16.6 to 11.1
for the exercise group, 16.0 to 11.8 for the social contact group, and 15.2 to 14.7 for the
control group (p < 0.05, favoring exercise or social contact). Exercise and social contact both
resulted in significant reductions in both total and the psycho-social subscale of the Beck
Depression Inventory. The exercise condition, however, resulted in decreased somatic
symptoms of the BDI (p < 0.05).
 Mather(188) studied outpatients 53 years and older with a diagnosis of depression and a score
of at least ten on the Geriatric Depression Scale (GDS). The patient population was 16%
male and 84% female. Patients (n = 86) were randomized to two treatment groups
comparing exercise (n = 43, 45 minutes of predominantly weight-bearing exercise; two
sessions per week) with a nonexercise social control group (health education talks,
n = 43) for ten weeks.
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 Change in 17-item Hamilton Rating Scale for Depression (HRSD) from baseline at
ten weeks for the exercise group was 55% and for the control group was 33% (p = 0.05,
favoring exercise group). Response was defined as a ≥ 30% reduction in HRSD score from
baseline, a threshold that is lower than the usual 50% decrease in symptoms used
in most other studies (thus “setting the bar lower” for a positive effect). The study
found that ten weeks of twice-weekly exercise was associated with a modest reduction
in depression symptoms in a group of older people with depression. There was
preponderance of women in the exercise group.
 North(189) systematically reviewed 80 studies on the effect of exercise on depression. Patients
ranged from 11 to 55 years with a mean age of 31.8 ±12.4 years. Twenty studies included
males only and 16 studies included all females. Studies included looked at the effect of
different variables on depression (sixty three studies looked at age effect on depression and
thirty six studies were included for the effect of gender.) Studies varied from four weeks to
24 weeks with the majority of studies being between five to 12 weeks. The studies compared
exercise (aerobic endurance and/or muscular strength, varying in number of sessions) with
comparison groups (no intervention control, leisure activity, or psychotherapy).
 The overall Effect Size (ES) of the studies included, was -0.53 ±0.85, indicating that
patients in exercise groups decreased their scores an average of 0.53 standard deviations
more than subjects in the comparison groups (p < 0.001). A significant, negative corelational relationship was found between mean age and ES (p < 0.05), suggesting that the
older the subjects, the greater the decrease in depression with exercise. The ES for males
and females were not significantly different (p > 0.05) suggesting equal benefit of exercise
on depression in both genders.
 The overall results indicate that exercise has a beneficial effect on improving symptoms of
depression. There are multiple differences in the designs of the studies included in this
meta-analysis, including mode of exercise, length of the exercise programs and types of
control groups. This meta-analysis also excluded people older than 55. No heterogeneity
data was reported. Results should be interpreted with caution due to internal validity
issues.
Our search and Clinical Evidence(70) identified one systematic review (search date 1999,
14 RCTs, 851 people).
 This review found limited evidence that exercise versus no treatment may improve
depressive symptoms, and that exercise may be as effective as cognitive therapy. However,
it suggested that these results were inconclusive because of methodological problems in all of
the RCTs; randomization was adequately concealed in only three of the RCTs, intention-totreat-analysis was undertaken in only two, and assessment of outcome was blinded in only
one of the RCTs.
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Older Adults
 The systematic review identified one RCT (156 people with Major Depression, mean age 57
years) comparing aerobic exercise, sertraline hydrochloride (a selective serotonin reuptake
inhibitor), and combined treatment for 16 weeks. It found that the proportion of people who
recovered (those no longer meeting criteria for depression or with a Hamilton Depression
Rating Scale score < 8) was not significantly different across the treatment groups (60% with
exercise vs. 69% with sertraline vs. 66% with combined treatments). A ten-month follow-up
of this RCT found lower rates of relapse with exercise versus medication (30% with exercise
vs. 52% with sertraline vs. 55% with combined treatment). However, about half of the
people in the medication group engaged in exercise during follow-up, making it difficult to
draw firm conclusions about effects of exercise. The clinical importance of the observed
difference at ten months remains unclear. (Note that this RCT did not include a control
group.)
Conclusion
There is evidence that exercise, at least in the short term, may be helpful in reducing symptoms
of depression. Most studies were not designed to substitute exercise for antidepressant or
psychotherapy treatments, so we can not conclude that exercise may be used effectively instead
of antidepressant medication or structured psychotherapy. Most of these studies do not describe
how many patients in the exercise group were receiving other forms of depression treatment, and
many did not differentiate between patients with Major Depression and other forms of
depression. Given the beneficial effect of exercise in general and on many often comorbid
medical conditions, the GDT believes that exercise can be recommended as an adjunctive
strategy for patients with MDD. The type of exercise will depend in part on the presence or
absence of other medical conditions.
Effect of Bibliotherapy (Patient Handouts and Other Reading Material)
Two RCTs that addressed this issue were found.
 Jamison(190) studied patients with mean age of 40 years and a score of ten or greater on the
Hamilton Rating Scale for Depression 21-item version (HRSD) and score of ten or greater on
the 21-item Beck Depression Inventory (BDI). All patients met the DSM-III-R criteria for
mild to moderate Major Depression. Patients (n = 80) were randomized to two treatment
groups comparing cognitive bibliotherapy (n = 33) with control group (wait list,
n = 39) at four weeks (treatment phase) and three months (follow-up phase).
 In treatment phase, the HRSD score decreased from 20.2 to 9.9 for the bibliotherapy group
and decreased from 19.6 to 19.0 for the control group (p < 0.05, favoring bibliotherapy).
BDI scores showed comparable results with p < 0.05 (favoring bibliotherapy).
 In the follow-up phase, HRSD score further decreased, from 10.0 to 9.2 for the treatment
group and decreased from 18.7 to 10.0 (p < 0.05, favoring treatment when starting from
baseline). (Note that the control group experienced a large decrease in depression scores in
the follow-up phase, to within a point of the intervention group). BDI score again showed
similar outcomes (p < 0.05, favoring treatment when starting from baseline).
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 This study suggests that cognitive bibliotherapy for depression is an effective treatment for
depression, with participants experiencing more rapid symptom improvement compared
with nonparticipants. Treatment gains in the intervention group were maintained over a
three-year follow-up (Smith(191)) period, as participants (n = 50)
were less depressed than when they began the program.
 There was a significant decrease in HRSD and BDI scores from pretreatment to follow-up
(p < 0.05 each), with no changes from post treatment to follow-up (p > 0.05 each). This
study suggests that there maybe long-range benefits to participants in structured, minimalcontact bibliotherapy programs for depression.
 There was no control group in the three-year follow-up period. Sensitivity analysis was not
included to account for patients who completed the initial study but did not participate in
the follow-up (some of whom may have relapsed).
 Scogin(192) studied 57 female and ten male patients 60 years and older with score of ten or
higher on the Hamilton Rating Scale for Depression (HRSD) and score of eight or higher on
the Mental Status Questionnaire. Patients (n = 67) were randomized to three treatment
groups comparing behavioral bibliotherapy (n = 23, reading a copy of Control Your
Depression (Lewinsohn(193)), cognitive bibliotherapy (n = 22, reading a copy of Feeling Good
(Burns, 1980(194))) and delayed treatment (control group) (n = 22), for an initial study period
of four weeks and a six month follow-up.
 The two treatment groups were assessed before treatment (first time), immediately
following treatment (second time) and six months later (third time). The control group
participants were assessed at the first time and at one month following the second time, at
which point their own treatment began, and a third time immediately following treatment.
HRSD Score (first time, second time and third time) for the behavioral bibliotherapy group
were 17.8 to 9.7 to 9.1, and were 16.3 to 7.5 to 8.9 for the cognitive bibliotherapy group.
Control group scores were 16.4 to 15.9 to 7.2.
 There were statistically significant differences between cognitive bibliotherapy and control
group (p < 0.05, favoring cognitive bibliotherapy), and between behavioral bibliotherapy
and control group (p < 0.05, favoring behavioral bibliotherapy).
 There were no significant differences between the two bibliotherapy groups. This study
supports the efficacy of self-paced bibliotherapy for mild to moderate depression in older
adults. Bibliotherapy’s effect for mild to moderate depression in older adults was
maintained after two years.(195) HRSD scores post-treatment and at a two-year follow-up
for the treatment groups (behavioral and cognitive bibliotherapy, n = 22) decreased from
8.1 to 7.4, p < 1.00, indicating no significant effect for time.
 There were no male participants and no control group in the two-year follow-up study.
 Sensitivity analysis not included to account for patients who completed the initial study but
did not participate in the follow-up (some of whom may have relapsed).
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Our search and Clinical Evidence(70) identified two systematic reviews (search date not stated
and search date 1999).
 The first review identified six small, short-term RCTs of bibliotherapy versus waiting list
control in 273 people (described as adults in four RCTs and older adults in two RCTs; no age
range provided) recruited by advertisement through the media and probably with only mild
depression. The mean effect size of bibliotherapy was 0.82 (95% CI: 0.50 to 1.15). Seventy
nine percent of the people in the waiting list control group had a worse outcome than the
average person in the bibliotherapy group.
 The second systematic review identified eight randomized and nonrandomized trials in
younger and older people, but only one of them included people with depression. It found
that, in people with combined anxiety and depression, anxiety, or chronic fatigue,
bibliotherapy may improve symptoms over two to six months compared with standard care.
The RCT identified by the second review that included people with depression found that
bibliotherapy versus standard care significantly improved symptoms of anxiety over four
weeks as assessed using the Hamilton Depression Rating Scale, but found no significant
difference in symptoms of depression at four or 12 weeks.
 Clinical Evidence found no systematic review or RCTs specifically in older adults.
Conclusion
There is evidence, albeit not unanimous (or as strong as the evidence for exercise), that
bibliotherapy may be helpful in reducing symptoms of depression. Most of these studies do not
describe how many patients were receiving other forms of depression treatment, and many did
not differentiate between patients with Major Depression and other forms of depression. But the
majority of studies support the use of bibliotherapy and the GDT believes that bibliotherapy is an
optional adjunctive strategy for patients with MDD.
Effect of Befriending
The McNeil study(187) discussed earlier noted a statistically significant improvement in
depressive symptoms in patients randomized to the social contact group.
Our search and Clinical Evidence identified one small additional RCT of befriending versus
waiting list control.
 This trial had 86 women with chronic depression, aged > 18 years, primarily aged 25 to 40
years, based in London, UK. Initial identification was by postal screening of women
registered with, but not attending, primary care. It found that befriending versus waiting
list control significantly increased the proportion of women with remission of symptoms at
13 months (65% with befriending vs. 39% with control; p < 0.05; NNT 4, 95% CI: 2 to 18).
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Older Adults
We found no systematic review or RCTs specifically in older adults.
Conclusion
These two small studies provide some evidence suggesting that befriending may be helpful in
reducing symptoms of depression. The studies did not describe how many patients were
receiving other forms of depression treatment, and it did not differentiate between patients with
Major and Minor Depression (the latter often resolves spontaneously). Due to the available
evidence the GDT believes that befriending is an option for patients as an adjunct to (but not a
substitute for) treatment of Major Depression.
Effect of Music Therapy
We found one RCT that addressed this issue.
 Hanser(196) studied older adults (61 to 86 years old, 77% female) with diagnosis of Major or
Minor Depressive Disorder, based on a structured interview using the Schedule of Affective
Disorders and Schizophrenia.
 Patients (n = 30) were randomized to three treatment groups comparing home based
structured music therapy (n = 10), with self-administered music therapy (n = 10) and a
wait-list control group (n = 10) for eight weeks.
 Geriatric Depression Scale (GDS) scores (pre-test to post-test) was 17.30 to 7.70 for the
home based music therapy, 17.60 to 12.30 for the self-administered music therapy, and
15.30 to 16.20 for the control group (p < 0.05, favoring the two music therapy groups).
 Follow-up results at nine months revealed no significant differences on the GDS score from
post-test results in all three groups. This study supports the use of music therapy strategies
with older adults experiencing symptoms of depression.
Conclusion
This one small study suggests that music therapy may be helpful in reducing symptoms of
depression. The study was not large enough to differentiate between patients with Major and
Minor Depression (the latter often resolves spontaneously). While there seems to be little
apparent harm in recommending music therapy as adjunctive treatment (particularly if patients
enjoy music), formal music therapy is associated with added cost without clear proven benefit.
Pending more and larger studies, the GDT believes there is insufficient evidence to recommend
for or against formal music therapy as an adjunctive strategy for patients with MDD.
Effect of Depression Internet Sites or Automated Telephone Programs
Two RCTs were found that addressed this issue.
 Clarke(171) studied a combination of depressed and nondepressed participants (n = 299) who
were randomized to two treatment groups comparing access to a Depression Internet site
(n = 144, depression cases n = 107) with usual care (n = 155, depression cases n = 116), for
a period of 32 weeks. Much of the Internet site content was adapted from group CBT
psychotherapy manuals. The mean (SD) age for the internet group was 43.3 (12.2) years
with 73.6% females.
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 The mean age for the control group was 44.4 (12.4) years with 77.4% females.
In depressed patients, mean (SD) scores on the Center for Epidemiologic Studies—
Depression scale (CES-D) (baseline to week 32) were 30.7 (12.9) to 22.2 (12.8) in the
internet group and 31.3 (11.5) to 25.2 (14.2) in the control group (p = 0.12).
 Stratified analyses by high vs. low baseline CES-D scores, gender, and age greater or less
than 45 all showed no statistically significant between group differences. The study found
no differences between the control and experimental conditions on self-reported depression
(CES-D) over the study period, indicating a lack of treatment effect.
 Patten(180) studied patients with Major Depression diagnosed by the Composite International
Diagnostic Interview (95% CIDI) who had a mean age 45.2 ±11.9 years. The population was
90.1% female, and 9.9% male. Patients (n = 786) were randomized to two treatment groups
comparing use of web and telephony-based program (n = 420) with control group (n = 366)
for three months.
 The intervention consisted of an interactive computer program accessible through the
internet or by interactive voice telephone. The percentage of patients exceeding Center for
Epidemiological Studies Depression rating scale (CES-D) score of more than 15 in the
active group was 37.4% (baseline of 35.7%) and 34.1% (baseline of 33.3%) for the control
group (p = not stated). The study did not find any significant differences between the
groups.
Conclusion
Based on the available evidence, the GDT does not recommend Internet or automated telephonebased programs for the treatment of MDD.
12.
Behavioral Health Education Classes For Adults With MDD
(Cognitive Behavioral Skills or Problem-Solving Classes)
12
For patients with mild to moderate MDD, the GDT recommends behavioral health
education classes as an adjunctive treatment option. However, these classes should not be
used in lieu of either antidepressant medication or psychotherapy. Evidence-based
Rationale:
2008 Update
No new evidence was found, the recommendation remains unchanged.
2006 Update
No new evidence was found, the recommendation remains unchanged. It should be pointed out
that there are several elements of behavioral health education classes that could have an impact
on depressive symptoms, including but not limited to the content of the curriculum (which may
be cognitive, behavioral, or problem-solving), the class setting, or the social aspects of a class
setting. The curriculum was different in the studies cited in the 2004 update, and may be
heterogeneous from setting to setting. It is therefore not currently possible to define which of the
variables in of behavioral health education classes are the ‘active ingredients’ of treatment, or to
which degree each variable contributes to patient outcome.
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2004 Guideline
Supporting Evidence for Behavioral Health Education Classes in Improving
Depressive Symptoms in Patients with MDD
 Brown(197) studied adults 16 to 65 years old (70% female) with a Beck Depression Inventory
(BDI) score of 22.2 (consistent with mild to moderate Major Depression) and a diagnosis of
unipolar depression according to Research Diagnostic Criteria (RDC). Patients receiving
other forms of treatment concurrently for depression were included.
 The number of patients with severe Major Depression was not disclosed, although severe
depression was not mentioned as an exclusion criterion. Patients with concurrent substance
abuse were excluded. The study did not specify if patients with chronic Major Depression
were excluded. Patients (n = 63) were randomized to three treatment groups and a control
group. The “Coping with Depression” course curriculum was standardized across the three
treatment conditions, and consisted of 12 sessions over an eight week period plus a visit or
phone contact at one and six months post-treatment.
 The study compared group class format (n = 25), individual tutoring (n = 13) and phone
contact (n = 14) against a wait-list control group (n = 11). Participants in the three
treatment groups improved more during the eight-week period than did the wait-list control
group (p < 0.05). There were no statistically significant differences among the three
treatment groups, when compared at eight weeks (treatment duration), one and six months
follow-up sessions. Among the participants in the three treatment groups, only 25% still
met the criteria for depression at the six-month follow-up session. From an economic point
of view, the in-person class condition was by far the most cost effective.
 The difference in response between those receiving concurrent treatment and those not
receiving other treatment for depression was not specified. 34 of 122 individuals chose not
to participate in the study, with differences between enrolled and not enrolled group not
specified. Among patients participated in the study, dropout rate was 4.6%.
 Dowrick(198) studied adults, ages 18 to 65, with DSM-IV diagnoses of MDD (52% single
episode, 19% recurrent) dysthymia (16%), adjustment disorder (4%) or other depressive
disorders (9%).
 Suicidal patients and patients with concurrent substance abuse were excluded from the
study; it is unclear if patients with severe Major Depression who were not suicidal were
included. Patients (n = 452) were randomized to three treatment groups comparing six
individual sessions of problem-solving treatment delivered in a setting convenient for the
patient (usually the patient’s home) by behavioral health, allied health, or nursing personnel
(N = 128), eight group sessions (2.5 hours each) of a course on prevention of depression (n
= 108), and a control group (n = 189).
 Outcomes were assessed at six and 12 months using intention-to-treat-analysis.
 Mean difference in Beck Depression Inventory (BDI) score for the problem-solving group
at six months was -2.63 (95% CI: -4.95 to -0.32), p = 0.026. At 12 months, the BDI score
was -1.00 (95% CI: -3.31 to 1.31), p = 0.398.
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 The prevention of depression group had a BDI mean difference of -1.50 (95% CI:
-4.16 to 1.17), p = 0.272 at six months and 1.11 (95% CI: -1.30 to 3.52), p = 0.901 at
12 months (not significant).
 There were significant improvements in SF36 scores (mental role, social function, and
mental health) at six months for patients in the depression prevention group compared with
controls at six months (p = 0.042, 0.048, and 0.028 respectively).
 There were also significant improvements in SF36 scores (mental role, social function, and
mental health) at six months for patients in the problem-solving therapy group compared
with controls at six months (p = 0.030, 0.012, and 0.005 respectively). Neither treatment
group had statistically significant improvement in any of these SF36 domains at 12 months,
compared with controls. Statistical comparison of SF 36 scores comparing the two
treatment groups with each other was not assessed.
 At six months 17% fewer patients in the problem-solving group were depressed compared
with controls (NNT = 6) and 14% fewer patients assigned to prevention of depression were
depressed compared with controls (NNT = 7). At 12 months there were no differences
between either study condition and controls.
 More patients completed problem-solving therapy than the course on prevention of
depression (the authors attribute this difference to better acceptance of the former
treatment).
 This study concludes that both problem-solving treatment and the course on prevention of
depression reduced the severity and duration of depressive disorders over the short term,
and improves subjective mental and social functioning. Results in this mixed population
(patients with different types of depression, not all MDD) were not stratified by condition.
The number of different individuals delivering the problem-solving therapy was not
specified, the problem-solving therapy protocol was not specified, and the inter-provider
variability of adherence to the therapy protocol was not assessed. Therefore, this may not
be directly comparable to the problem-solving therapy delivered by trained mental health
personnel in traditional behavioral health settings.
Other Considerations
Behavioral health education experts on the GDT report that these classes in KP target patients
with acute depressive symptoms. KP Behavioral Health education classes for Major Depression
exclude patients with severe depression symptoms, and like the Brown and Dowrick studies,
exclude patients with concurrent substance abuse.
From the available literature and KP experience, therefore, the role of behavioral health
education classes for patients with severe Major Depression or substance abuse is not clear.
Controlled studies are needed to verify and more accurately quantify the initial benefit seen in
pre-post analyses of Behavioral Health Education classes for MDD in KP Northern California
and KP Northwest.
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Overall Conclusion
There is limited evidence that behavioral health education classes may be effective in reducing
symptoms and improving functioning for some patients with MDD. There is insufficient
evidence that health education classes should be used in lieu of antidepressants or structured
psychotherapy for treatment of MDD. Therefore, the GDT believes that health education classes
(if available) are an optional adjunctive treatment for patients with mild to moderate MDD, but
does not recommend that health education classes be used instead of antidepressants or
psychotherapy at this time.
13.
Antidepressants To Avoid During Pregnancy or Breastfeeding
Pregnancy
13A Do not start paroxetine in women who are pregnant. Evidence-based: D
13B Use caution in starting other selective serotonin re-uptake inhibitors (SSRIs) in women
who are pregnant. Consensus-based
 Discuss risks to the mother and fetus of untreated maternal depression, as well as the
risk of fetal adverse effects from antidepressants.
13C If drug therapy is a consideration for treatment of maternal MDD during pregnancy
and/or breastfeeding, then:
 Individualize according to patient history and need for medication, and
 Discuss the benefits and harms of the various treatment options with the patient.
Consensus-based
13D If MDD is in remission and a woman becomes pregnant while taking antidepressants
during the continuation or maintenance phase of treatment, then:
 Discuss the risks to the mother and fetus of untreated maternal depression or
depression relapse after antidepressant discontinuation, as well as the risk of fetal
adverse effects from continuing antidepressants, and
 Monitor for first trimester fetal malformations if taking paroxetine.
Consult OB/GYN for considerations on fetal malformation screening.
Consensus-based
Breastfeeding
13E Do not start fluoxetine and/or citalopram in breastfeeding women in most circumstances.
If used, they should be used with caution, and only in patients who had good results with
these medications during pregnancy or a previous depression episode. Consensus-based.
13F In women taking antidepressants during pregnancy whose depression is in remission and
who desire to breastfeed:
 Discuss the risks to the mother and fetus of untreated maternal depression or
depression relapse after antidepressant discontinuation and the risk of adverse
effects in the nursing newborn of mothers continuing antidepressants, and
 Consider changing treatment for depression if the newborn shows potential
antidepressant-related adverse effects (withdrawal symptoms) during the first few
hours after birth.
Consensus-based
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Evidence Grade
Evidence for Recommendation 13A: Fair
Search Strategy
Some studies found and used in this guideline did not appear in PubMed search results due to the
way studies are indexed in PubMed. The Pedersen (2009)(199) study was not identified by the
search due to PubMed Indexing, but was identified by a GDT member and reviewed due to
relevance. See Appendix B for more information on the search strategy.
Rationale:
2010 Update
New evidence has been identified, and recommendations have been changed based on both new
evidence and expert/consensus opinion.
Our recent search yielded 11 relevant studies, including six cohort studies (Pedersen 2009(199);
Wichman 2009(200); Jordan 2008(201); Diav-Citrin 2008(202); Kallen and Olausson 2008(203);
Oberlander 2008(204)) and 5 case-control studies (Andrade 2009(205); Toh 2009(206); Ramos
2008(207); Salkeld 2008(208); Maschi 2008(209)) that addressed adverse effects associated with the
use of antidepressant medication during pregnancy. Outcomes examined included congenital
malformation (n = 5), neonatal hypertension (n = 2), neonatal withdrawal syndrome (n = 2) and
maternal adverse events (n = 2). No new studies were identified that evaluated potential risks
associated with antidepressant use during lactation. Please refer to 13.2 for study details.
Congenital Malformations
 Pedersen et al. (2009)(199) conducted a retrospective cohort of 493,113 children born in
Denmark between 1996-2003 to assess the association between SSRI during the 1st trimester
of pregnancy and congenital malformations. Results indicated that filled prescription for
SSRIs was not associated with overall major malformation, but was significantly correlated
with septal heart defects [OR = 1.99 (95% CI: 1.13 - 3.53)]. In particular, septal heart defects
were highly associated with Sertraline [OR = 3.25 (95% CI: 1.21 to 8.75)] and Citalopram
[OR = 2.52 (95% CI: 1.04 to 6.1)]. In women with one or more redemptions for
antidepressants (mostly multiple SSRIs), there was a two-fold increase in risk septal heart
defects [OR = 4.7 (95% CI: 1.74 to 12.7)]. However, the absolute increase in prevalence of
septal heart defects was low [unexposed: 0.5% vs. any SSRI exposure: 0.9% vs. more than
one SSRI: 2.1%].
 Wichman et al. (2009)(200) examined whether the use of SSRIs during pregnancy was
associated with congenital heart disease (CHD), in particular, ventricular septal defects
(VSDs), and PPHN among 25,214 deliveries at the Mayo Clinic. Of the 25,214 deliveries,
808 of study participants took a SSRI at some point during pregnancy and results found three
cases of CHD and no cases of persistent pulmonary hypertension (PPHN) or VSD in this
group. Sertraline was the most frequently prescribed SSRI (36.6%). The prevalence of CHD
was similar between the exposed (4%) and unexposed (8%) neonates, p = 0.23. None of the
newborns from the 134 mothers who took paroxetine were diagnosed with VSDs. Thus,
authors concluded that there was no association between CHD or PPHN and SSRI use during
pregnancy. However, the study was underpowered to detect a small association and other
major methodological concerns warrant cautious interpretation of results.
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 Ramos et al. (2008)(207) conducted a case-control study of pregnant women (N = 2,339) with
psychiatric disorder prior to pregnancy to evaluate the effect of duration of antidepressant use
during the 1st trimester of pregnancy and the risk of major congenital malformation (MCM).
Results found no significant association between antidepressant use during 1st trimester and
MCM [adjusted OR = 1.1 (95% CI: 0.75 - 1.62)]. Subgroup analysis also indicated nonsignificant difference between duration of antidepressant used and risk for MCM [adjusted
OR = for 1 to 30 days vs. 0 day: 1.23 (95% CI: 0.77 - 1.98); 31 to 60 days vs. 0 day: 1.03
(95% CI: 0.63 - 1.69); 561 days vs. 0 day: 0.92 (95% CI: 0.50 - 1.69)]. Additionally, the
class of antidepressant used was also not significantly associated with major birth defects.
 Oberlander et al. (2008)(204) investigated the incidence of congenital anomalies following
prenatal exposure to SSRI monotherapy and/or in combination with benzodiazepines (BZ)
using maternal and neonatal data linked to prenatal prescription records for all live births in
British Columbia from 1998 to 2001 (N = 119,547). After adjusting for confounders, no
significant risk differences were detected for major congenital anomalies for SSRI only,
BZ only, or SSRI + BZ compared to no exposure. However, SSRI + BZ was significantly
associated with increased risk for cardiovascular congenital defects [regression-adjusted
incidence risk difference: 1.18 (95% CI: 0.18 - 2.18)], whereas SSRI alone was significantly
associated with increased in risk for ASD [regression-adjusted incidence risk difference 0.21
(95% CI: 0.05 - 0.36)]. Among the SSRI used, citalopram was the only SSRI significantly
associated with cardiovascular congenital defects [RR = 2.28 (95% CI: 0.19 - 4.36)] while
fluoxetine + BZ significantly increased the risk for major congenital anomalies [RR = 5.18
(95% CI: 0.3 - 10.07)], although numbers were very small (n = 7 and n = 3, respectively).
In addition, no association was detected between risk and 1st trimester medication dose/day.
 Diav-Citrin et al. (2008)(202) reported on the risk of paroxetine and fluoxetine compared
to nonteratogens exposure during pregnancy and major congenital anomalies. A total of
2,276 women who contacted the Israeli, Italy, and Germany Teratology Information Services
(TIS) were followed-up (rates ranged: 44 to 91%). Among participants, 463 were exposed
to paroxetine, 346 were exposed to fluoxetine and 1467 were exposed to nonteragens
(controls). Rates of major anomalies were significantly greater in the paroxetine and
fluoxetine group compared to controls (5.2% vs. 6.3% vs. 2.9%, p < 0.05), mostly from
cardiovascular anomalies. No significant differences in rates of noncardiovascular anomalies
were detected among the three groups (3.4% for paroxetine vs. 3.2% for fluoxetine vs.
2.4% for control). After adjusting for confounders, cardiovascular risk remained significant
for fluoxetine [OR = 4.47 (95% CI: 1.31 to 15.27)] and smoking ≥ 10 cigarettes/day
[OR = 5.4 (95% CI: 1.76 to 16.54)].
Neonatal Pulmonary Hypertension
 Andrade et al. (2009)(205) reported on a retrospective case-control study of 1104 women
exposed to antidepressants (SSRIs, tricyclics, an miscellaneous) during the 3rd trimester and
matched controls (n = 1104) that found no significant association between SSRIs use during
late pregnancy and PPHN in newborn. PPHN prevalence was 2.14 per 1000 [95% CI:
0.26 to 7.74] vs. 2.72 per 1000 [95% CI: 0.56 to 7.93] for infants whose mothers were
exposed and not exposed to SSRI in the 3rd trimester. However, the study was underpowered
to detect a difference and other major methodological concerns limit the generalizability of
results.
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 Kallen and Olausson (2008)(203) assessed the effect of SSRI use during pregnancy and
PPHN in newborns using data from the Swedish Medical Birth Register. A total of 506
infants were born between 1997 and 2005 with PPHN and after adjusting for maternal age,
BMI, smoking status and parity, a significant association between maternal use of SSRI and
PPHN in births after 34 weeks was detected in women who reported drug use in early
pregnancy [RR = 2.38 (95% CI: 1.19 - 4.25]. For women who reported SSRI use in early
and later in pregnancy, the risk increased to 3.57 with wide confidence interval (95% CI:
1.16 - 8.33). SSRI use among the women included citalopram, sertraline, fluoxetine, and
paroxetine; however, the study was underpowered to evaluate the effect of specific SSRI on
neonatal PPHN.
Neonatal Behavioral Syndrome
 Maschi et al. (2008)(209) conducted a case-control study of 200 cases and 1,200 controls to
investigate the association between antidepressant use during pregnancy and adverse effects,
particularly, poor neonatal adaptation. After adjusting for possible confounders, results
found no statistically significant difference in the incidence of poor neonatal adaptation in the
exposed group compared to the unexposed control, although there was a trend for an
increased risk in newborns exposed during the 2nd and 3rd trimester. However, the study was
underpowered to detect small differences between the two groups and misclassification error
could have occurred due to the conglomeration of conditions that constitute poor neonatal
adaptation.
 Jordan et al. (2008)(201) investigated the severity of neonatal behavioral syndrome (NBS,
e.g., irritability, jitteriness, hypo- or hypertonia, hyperreflexia, apnea, hypoglycemia, etc.)
among infants of mothers with psychiatric illness taking SSRI during pregnancy (n = 46)
compared to infants born to women with psychiatric illness not treated with medication
(n = 59). No significant differences in the overall number of NBS (28% of SSRI-treated
pregnancies vs. 17% in non-treated pregnancies), need for transfer to a higher level nursery
for NBS (11% vs. 10%), or length of hospital stay (2 vs. 6 days) was detected between the
two groups. However, study was underpowered with relatively small sample size.
Summary of Findings for Neonatal Outcomes
For infant adverse events, evidence of potential cardiovascular congenital defects was reported
in three studies. One large cohort study found that multiple antidepressant redemptions (mostly
SSRIs) and the combination of SSRIs and benzodiazepines increase the risk for cardiovascular
congenital defects. Additionally, citalopram (n = 2), sertraline (n = 1) and fluoxetine (n = 1)
were shown to be significantly associated with cardiovascular congenital defects, although the
studies had small sample sizes which make it difficult to generalize results. The trend in recent
studies suggests a possible SSRI class effect on associations with cardiovascular congenital
defects. Conversely, two studies found no significant differences between antidepressant
exposure and non-exposure for major congenital and congenital cardiovascular malformations.
Two studies found conflicting results on the effect of antidepressant use and persistent
pulmonary hypertension in newborns, with the one study suggesting an SSRI class effect
(but being underpowered to detect if the effect was related to only specific SSRIs).
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Maternal Adverse Events
 Toh et al. (2009)(210) evaluated a subgroup of 199 women who participated in the multicentered case-control Slone Epidemiology Center Birth Defects Study, who received SSRI
during pregnancy, and who gave birth to non-malformed and non-hypertensive newborns.
Gestation hypertension was detected in 19.1% vs. 9% and of women with and without
exposure [RR = 1.9 (95% CI: 1.35 - 2.67)] to SSRI and hypertension with preeclampsia was
detected in 9% vs. 2.4% [3.16 (95% CI: 1.89 - 5.29)] in women with and without exposure.
Adjusted relative risk for hypertension with preeclampsia for women who discontinued SSRI
before the end of the 1st trimester was 1.37 (95% CI: 0.5 - 3.76) and 4.86 (95% CI:2.7 - 8.76)
for those who continued SSRI. However, the study was underpowered to assess the
attributable risk associated with specific SSRIs.
 Salkeld et al. (2008)(208) conducted a case-control to investigate the effect of antidepressant
use during 3rd trimester of pregnancy on postpartum hemorrhage among 2,460 cases and
23,943 matched controls. Results did not suggest a significant association between risk for
postpartum hemorrhage and late-term exposure to SSRIs relative to non-SSRIs [adjusted OR
= of SSRIs within 90 days before index date: 1.30 (95% CI: 0.98 - 1.72) vs. 1.12 (95% CI:
0.62 - 2.01) for non-SSRIs; p = 0.065]. Sensitivity analysis at 30, 60, and 180 days before
index date also found consistent findings. However, cautious interpretation of outcomes is
warranted due to unclear definition of postpartum hemorrhage and difficulty with drug
adherence measurement.
For maternal health, one study suggested no significant association between antidepressant use
during pregnancy and postpartum hemorrhage while the other found increased in risk for
hypertension with preeclampsia for women who continue on SSRI through late-pregnancy.
There were several important concerns that warrant cautious interpretation of the results.
First, most studies extracted data related to drug intake from pharmacy registries, interviews,
or physician prescriptions, which are not indicative of actual drug adherence. Second, specific
SSRIs could not be evaluated individually in some studies due to power limitation and were
often lumped together by class of SSRI, tricyclics or antidepressant drugs in general. Third,
major congenital malformations were defined differently among studies to either include or
exclude congenital cardiovascular defects. Fourth, several outcomes such as PPHN and NBS
do not have explicit criteria or diagnosis and frequently require expert evaluations. The
combinations of these limitations plus heterogeneous study methodologies make it difficult to
draw definitive conclusion.
Overall Conclusion
Overall, updated evidence combined with previously reviewed evidence suggests no significant
associations between major neonatal non-cardiovascular congenital malformations (n = 5 new
studies) and neonatal behavioral syndrome (n = 2 new studies) with antidepressant use during
pregnancy. In addition, two new studies did not observe significant increases in risk associated
with treatment dose or duration (Oberlander 2008(204); Ramos 2009(207)).
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Newer studies provided conflicting evidence on neonatal cardiovascular congenital anomalies
and neonatal pulmonary hypertension. Overall (including previously reviewed evidence)
evidence continues to suggest an association of paroxetine use in pregnancy with congenital
cardiovascular malformations; the newer studies reviewed raise the possibility of a potential
SSRI class effect. Maternal adverse events were reported in two studies, one of which found no
significant association between antidepressant use during pregnancy and postpartum hemorrhage
while the other found increased in risk for hypertension with preeclampsia for women who
continue on SSRI through late-pregnancy.
The new available evidence is based on heterogeneous poor- to fair-quality studies, with limited
assessment on attributable risk associated with specific SSRIs due to small sample size. Studies
showed conflicting results. Combined with previously reviewed evidence, there still appears to
be an association of paroxetine use during pregnancy and fetal cardiovascular malformations,
therefore the 2008 recommendation against new starts of paroxetine in pregnancy remains
unchanged. The newer studies suggest an association with pre-natal use of citalopram (two
studies), sertraline and fluoxetine (one study each) and congenital cardiovascular malformations.
Other new studies suggest (albeit not consistently) associations between SSRI use and fetal
pulmonary hypertension and maternal pre-eclampsia. Consequently, the GDT has added a new
recommendation recommending caution in starting other selective serotonin re-uptake inhibitors
(SSRIs) in pregnant women. A single study, with detection bias limitations, suggests a
synergistic association between prenatal use of SSRIs + benzodiazepines with fetal
cardiovascular malformations compared with benzodiazepines alone.
The GDT continues to recommend that the balance of risks and benefits of medication treatment
and the risks of untreated depression be discussed with the mother.
The recommendations for infant adverse effects due to antidepressant exposure from
breastfeeding remain unchanged from 2008 due to no new evidence identified at this time.
2008 Guideline
New evidence was found, the recommendation remains unchanged.
In our search exploring antidepressant efficacy for treatment of Major Depression in adults,
we did not distinguish between adults in general and women who were pregnant or
breastfeeding. In some antidepressant efficacy studies (particularly of newer medications)
pregnant or breastfeeding women are excluded; however, they are not excluded from all studies.
Our evidence search for this problem formulation did not identify any studies specifically
relating to efficacy of antidepressants in pregnant or breastfeeding women. Thus, we have
extrapolated from the “general efficacy evidence” that the efficacy of first-line treatment options
for adults with Major Depression would be similar in pregnant or breastfeeding women.
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Five systematic reviews with meta-analyses of pooled data and a single case-control cohort study
were selected for analysis. These publications addressed the adverse effects associated with the
use of antidepressant medication on gestational outcomes. These outcomes included
spontaneous abortion, congenital malformation, neonatal withdrawal syndrome or other neonatal
central nervous system abnormality. There was some overlap of included studies in these metaanalyses; however, different outcomes were being evaluated. Please refer to Evidence Tables
13.1 and 13.2 for details.
 A meta-analysis of six cohort studies of women taking antidepressants in pregnancy(211)
reported a rate of spontaneous abortion of 12.4% compared with 8.7% in women not taking
antidepressants. The risk ratio was calculated to be 1.45. (95% CI: 1.19 to 1.77). No
significant difference in risk was seen between classes of antidepressants. (In this study,
eight different antidepressants results were blended together).
 Lattimore et al. published a meta-analysis of data from nine prospective cohort studies of the
effect of maternal SSRI use during pregnancy.(212) This meta-analysis did not analyze results
by different medications in this class. It also included some studies in which intervention
group women were using other psychotropic medications (primarily benzodiazepines); the
extent to which this inclusion biases the results is unknown. Nonsignificant increases were
seen in the rates of prematurity, low birth weight, special-care nursery admissions, and the
diagnosis of poor neonatal adaptation. None of the effects cited in this study reached
statistical significance at the p = 0.01 level.
 Moses-Kolko et al. reported that a meta-analysis of data from five cohort studies showed that
compared with early or no SSRI exposure, late gestational exposure was associated with an
overall risk ratio of 3.0 (95% CI: 2.0 to 4.4) for neonatal behavior syndrome.(213) This selflimiting syndrome has been characterized as including neonatal irritability, agitation,
tremors, increased muscle tone and respiratory and digestive disturbances.
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 A meta-analysis of nine studies of SSRI exposure in the first trimester and throughout
pregnancy addressed outcomes including spontaneous abortion, major malformation,
cardiovascular malformation, and minor malformation.(214) The authors reported an
association between maternal use of any SSRIs and spontaneous abortion (12.5% vs. 7.6%
OR = 1.7 (95% CI: 1.28 to 2.24)), but no statistically significant increased risk of major or
minor malformations were detected.
 Bar-Oz, et al.(215) reported the results of a meta-analysis of seven studies that compared
the pregnancy outcomes of women using paroxetine in the first trimester with those of
women using other potentially teratogenic drugs or other antidepressants. They reported
a 74% relative increase in the risk for cardiovascular malformation in the infants of women
exposed to paroxetine in the first trimester compared with women who were not taking
antidepressants (95% CI: 1.22 to 2.42). This was similar to the increase in risk of 70% for
paroxetine exposure when compared with other antidepressants. The increase in risk for
other abnormalities was not statistically significant. However, detection bias may have
influenced the results, as significantly more women reported using paroxetine than other
SSRIs for anxiety disorders, and women using SSRIs had approximately twice as many
prenatal ultrasounds compared with women who took no antidepressants. This study also
used teratogens and other anti-depressants as controls, no true controls.
 In response to earlier reports of persistent pulmonary hypertension of the newborn (PPHN)
associated with maternal use of antidepressants, Chambers et al.(216) studied the occurrence of
this diagnosis in the infants of women who used antidepressants during pregnancy. Data
collected from 377 women whose infants were diagnosed with PPHN was compared with
data collected from 836 controls. The two groups were comparable in terms of maternal
education, ethnicity, age, body mass index, maternal diabetes, smoking status, and NSAID
use. Fourteen infants with PPHN were born to mothers who had used SSRIs after the 20th
week of gestation, compared with six infants in the control group (OR = 6.1, 95% CI: 2.2 to
16.8). Please refer to Table 13.2.
Two meta-analyses were identified in the peer-reviewed medical literature that addressed the
potential risks associated with antidepressant use during lactation. Please refer to Table 13.3 for
details.
 Rubin et al.(217) collected 129 publications on breastfeeding and maternal use of CNS-acting
medications. Their findings indicated that the majority of CNS-acting drugs, including all
antidepressants do not reach a concentration of greater than 10% of the maternal dosage
when ingested via breast milk.
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 Weissman et al.(218) pooled the data in 57 studies of medication levels in the breast milk of
nursing mothers using antidepressant medication. The infant plasma level of most
medications (an intermediate, biological outcome) was found to be less than 10% of that of
the mother. However, 22% of infants exposed to fluoxetine and 17% of the infants exposed
to citalopram demonstrated plasma drug levels that exceeded 10% of the maternal level (a
level that researchers have adopted by consensus as defining an elevated level*).
In addition to weaknesses in the Bar-Oz study noted above, recommendations on paroxetine are
based on meta-analyses of studies that have not been evaluated for quality. The evidence about
fluoxetine and citalopram in breastfeeding is insufficient because the outcome variable is
intermediate, not clinical. The studies showing increased risk to the fetus with SSRIs are
insufficient because they are somewhat inconsistent, mostly lump all SSRIs together, and the
ORs are < 2.0, which is often taken as a threshold for inferring causation from an observational
study. There is significant heterogeneity for several studies (Hemels, Lattimore, Rahimi), and
the model used for analysis was not known for the other two (Moses-Kolko, Bar-Oz). There
were significant biases or potential biases cited for most of the meta-analyses. Therefore, all of
the recommendations in this problem formulation are consensus-based, because of the overall
insufficient nature of the evidence.
Other Considerations
The baseline rate of all fetal malformations is 3%; for fetal cardiac malformations the baseline
rate is approximately 1%. Ten to 25% of pregnant women and 10 to 20% of postpartum women
experience an episode of MDD.(219, 220) Untreated or relapsing depression during this time is
associated with adverse maternal outcomes (including suicide), increased risk of obstetrical
complications(212) low birth weight, premature birth, and fetal loss(221) and short- and long-term
neurological and cognitive-behavioral issues in these children, including increased risks of
depression later on in the child.(212, 222) One study(223) suggests that up to 68% of women who
stop antidepressants during pregnancy will experience a relapse of depression, compared with
26% of women who continue treatment (NNH = 2.4). Therefore, the GDT believes that, when
treating women who are pregnant or breastfeeding, the clinician should:
 Discuss pregnancy and what is known regarding antidepressant teratogenicity, perinatal,
neonatal and long-term effects.
 Discuss what is known regarding effects of maternal depression on pregnancy and infant
development.
 Advise that pregnancy does not ”protect” against the onset or effects of depression.
 For patients already taking antidepressants, discuss risks of depression relapse.
The Bar-Oz meta-analysis shows an increased risk of cardiac fetal abnormalities associated with
paroxetine exposure. In addition, the FDA has required a black box warning for fetal
abnormalities associated with the use of paroxetine in pregnant women. Therefore, the GDT has
made specific recommendations against new paroxetine starts during pregnancy.
*
Hale TW. Medications and Mothers’Milk, 12th edition. © 1992-2006, Amarillo, TX: Hale Publishing.
www.ibreastfeeding.com
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Overall Conclusion:
Potential adverse affects of prenatal antidepressant exposure include increased risk of fetal
malformations (for paroxetine), transient pulmonary complications, and transient neonatal
behavioral syndromes. Long-term risks to the child from exposure in-utero and breast feeding
seem to be relatively small, based on limited observational evidence.
Based on available evidence, the risk of untreated depression seems to outweigh the small
increase risk to the fetus from in-utero antidepressant exposure. Avoidance of new starts of
paroxetine during early pregnancy seems prudent due to the increased risk in cardiac
malformations compared with other antidepressants, especially in light of an FDA black box
warning on paroxetine for use in pregnancy. If the mother is already using paroxetine when
pregnancy is detected, the risk of teratogenicity due to exposure may have already occurred;
hence increased fetal surveillance for malformations seems clinically indicated. The potential
risk of depression relapse for the mother seems to outweigh the small increased fetal risk of
continued antidepressant exposure; however, the GDT recommends that the balance of risks and
benefits be discussed with the mother.
Evidence for actual infant adverse effects due to antidepressant exposure from breastfeeding is
limited at this time. In theory, higher levels of infant antidepressant exposure could increase the
risk for adverse effects. Therefore, given the availability of other antidepressant options, in
breastfeeding women, avoiding new starts of medications with long half-lives (fluoxetine) or
increased neonatal plasma levels (fluoxetine, citalopram) seems prudent, although the concerns
may mostly be theoretical, based on small numbers of infants studied, and are of unknown
clinical significance. However, for women who wish to breastfeed who are continuing
antidepressants taken during pregnancy, most fetal exposure will have already occurred in-utero.
In the absence of neonatal behavioral syndromes or pulmonary symptoms, the risk of
antidepressant discontinuation for the mother and the effect on maternal-fetal bonding is
probably greater than neonatal risks of continued exposure during breastfeeding. However,
the GDT also recommends a discussion of the balance of risks and benefits with mothers in this
situation.
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Appendix A: Criteria for Grading the Evidence
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Appendix B: Supporting Documentation
1.
First-Line Treatment of Major Depressive Disorder (MDD)
Problem Formulation 1
Clinical Question:
What first-line treatment methods should be used to treat adults with
MDD?
Intended Use of the
Guideline:
To assist primary care physicians and other health care professionals
in treating adults with Major Depression.
Population:
Health Problem:
Health Intervention:
Practitioners:
Setting:
Health Outcomes
(associated with the
intervention):
Side Effects
Associated With
the Intervention:
*
All adult (age 19 and older) patients with Major Depression
MDD
 Antidepressant treatment (SSRIs, TCAs, DAs, SNRIs, NRIs)*
 Psychotherapy (Interpersonal Therapy, Cognitive Behavioral
Therapy, Problem-Solving Therapy)
 Combination of antidepressants and psychotherapy
 No treatment
KP primary care physicians, physician assistants, nurse practitioners,
pharmacists, and health educators
Outpatient office visit, emergency department, urgent care clinics
 Change in symptoms
 Quality of life
 Missed school/work days
Sexual problems
Drowsiness
Headache
Nausea
Insomnia
Agitation/
nervousness
 Office/UCC/ER visits
 Hospitalizations
 Mortality
Dry mouth
Seizures
Elevated blood
pressure
Constipation
Diarrhea
Abdominal pain
Dizziness
Blurred vision
Weight gain
GI bleeding
Fall
SSRI = Selective Serotonin Reuptake Inhibitor TCA = Tricyclic Antidepressant DA = Dopamine Agonist
SNRI = Serotonin Norepinephrine Reuptake Inhibitor
NRI = Norepinephrine Reuptake Inhibitor
Cognitive Behavioral Therapy = Brief structured treatment, incorporating elements of cognitive therapy and
behavioral therapy. Behavioral therapy is based on learning theory and concentrates on changing behavior.
Interpersonal Therapy = Standardized form of brief psychotherapy primarily intended for outpatients with
unipolar nonpsychotic depressive disorders. It focuses on improving the person’s interpersonal functioning and
identifying the problems associated with the onset of the depressive episode.
Problem-Solving Therapy = Consists of three stages: (1) identifying the main problems for the person;
(2) generating solutions; and (3) trying out the solutions.
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Search Strategy
Database:
PubMed
PubMed
Article Type
and Other
Limits:
Search
Date
("Depression"[MeSH] OR "Major
Depressive Disorder"[All Fields]
AND (“systematic"[All Fields] OR
“systematic review"[All Fields] OR
“meta-analysis"[All Fields]))
Only items with
abstracts,
Humans,
English, All
Adult: 19+ years
8/2005
to
9/2007
9/2007 to
10/2009
0/129
"Antidepressive Agents/therapeutic
use"[ All Fields] OR "Antidepressive
Agents/therapeutic use"[MESH] OR
"psychotherapy"[MESH] OR
(cognitive[All Fields] AND
"behavior therapy"[MeSH Terms])
OR "interpersonal therapy"[All
Fields] OR ("Problemsolving"[MeSH Terms] AND
"therapy"[MeSH Subheading]))
Only items with
abstracts,
Humans,
Randomized
Controlled Trial,
English, All
Adult: 19+ years
Only items with
abstracts,
Humans, Metaanalyses,
English, All
Adult: 19+ years
Systematic
Review,
Meta-analyses
and RCTs
Systematic
Review,
Meta-analyses
Systematic
Reviews
8/2005
to
9/2007
0/222
9/2009 to
10/2009
0/70
Dec. 6,
2004
N/A
2007 2009
6/ N/A
Q4, 2005
2007 2009
Jan. 2006
3/131
4/86
2007 2009
0/2
Search Terms:
National
Depression
Institute
for Clinical
Excellence
(NICE)
Cochrane
Depression, Anxiety and Neurosis
Group
Clinical
Evidence
Chapter: Depressive Disorders
*
No.
Included
/ Total
Retrieved*
Systematic
Reviews and
RCTs
7/138
N/A
Note: “No. Included” refers to studies that are relevant to the problem formulation and, therefore, are included
in this analysis of the evidence. “Total Retrieved” refers to the number of studies retrieved in the search,
regardless of relevance. Because individual studies can be captured in multiple databases, they may be counted
more than once in the number included. Systematic reviews and meta-analyses with search dates outside the
range of current searches were excluded.
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Database:
Hand
N/A
Searches
Search Terms:
PubMed
("depression/drug effects"[MESH]
OR "depression/drug
therapy"[MESH] OR
"depression/therapy"[MESH] OR
"Major Depressive Disorder" [All
Fields]) AND ("Antidepressive
Agents/adverse effects"[MESH] OR
"Antidepressive Agents/therapeutic
use"[All Fields] OR "Antidepressive
Agents/therapeutic use"[MESH] OR
"psychotherapy"[MESH] OR
(cognitive[All Fields] AND
"behavior therapy"[MeSH Terms])
OR "interpersonal therapy"[All
Fields] OR ("Problemsolving"[MeSH Terms] AND
"therapy"[MeSH Subheading]))
AND Randomized Controlled
Trial[ptyp] AND English[Lang]
AND "adult"[MeSH Terms] AND
"humans"[MeSH Terms] AND
("2003/01/01"[PDAT] :
"2005/08/01"[PDAT])
Cochrane
Depression
Clinical
Evidence
Depression
Article Type
and Other
Limits:
Systematic
Reviews and
Meta-analysis
Randomized,
controlled trials,
All adults:
19+ years,
English, Human
Systematic
reviews
Systematic
reviews and
RCTs
© 2012 Kaiser Permanente Medical Care Program
Search
Date
2007 to
2009
No.
Included
/ Total
Retrieved*
1/1
01/01/03
08/01/05
17/236
03/05/03
1/295
03/05/03
1/80
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Article Type
and Other
Limits:
Clinical trials,
All adults 19+
years, English,
Human
Search
Date
1998
03/2001
No.
Included
/ Total
Retrieved*
3/222
Database:
Search Terms:
PubMed
(((((((((((depression/drug
therapy[MESH] OR
depression/therapy[MESH]) OR
("depressive disorder/drug
therapy"[MESH] OR "depressive
disorder/therapy"[MESH])) OR
("dysthymic disorder/drug
therapy"[MESH]OR "dysthymic
disorder/therapy"[MESH])) AND
("Serotonin Uptake
Inhibitors"[MESH] OR
"Antidepressive Agents,
Tricyclic"[MESH])) AND
notpubref[sb]) AND Randomized
Controlled Trial[ptyp]) AND
English[Lang]) AND notpubref[sb])
AND "adult"[MeSH Terms])
("depression/drug effects"[MESH]
Meta-analysis,
01/01/01
1/5
OR "depression/drug
All Adult: 19+
therapy"[MESH] OR
years English,
04/01/03
"depression/therapy"[MESH] OR
Human
"Major Depressive Disorder"[All
4/124
01/01/01
Controlled
Fields]) AND ("Antidepressive
Trials, All
Agents/adverse effects"[MESH] OR Adult: 19+ years 04/01/03
"Antidepressive Agents/therapeutic English, Human
use"[MESH] OR
"psychotherapy"[MESH] OR
(cognitive[All Fields] AND
"behavior therapy"[MeSH Terms])
OR "interpersonal therapy"[All
Fields] OR ("Problemsolving"[MeSH Terms] AND
"therapy"[MeSH Subheading]))
Some studies found and used in this guideline did not appear in PubMed search results due to the
way studies are indexed in PubMed. Casacalenda(1) study was indexed as a review article in
PubMed and did not show up in the search results due to the way PubMed indexing is done.
The GDTdecided to include this study, since it met the inclusion criteria.
Other Information Source:
 Evidence report on the Treatment of Depression-Newer Pharmacotherapies. AHRQ(169)
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Evidence Tables
First-Line Treatment of MDD
Table 1.1: Summary of Systematic Reviews and Meta-Analyses
Author &
Title
Mukai et al.
(2009)
Treatment of
depression in the
elderly: A review
of the recent
literature on the
efficacy of singleversus dualaction
antidepressants.
Search Database
/ Method
Study (N)
Characteristics
Databases: MEDLINE,
PsycINFO, and
PubMed (January 2003–
January 2009).
N: 18 RCTs (10 SSRIs
head-to-head or
placebo; 2 TCAs vs.
SSRIs; and 6 SNRIs vs.
placebo, TCA or SSRI)
% F: Participants
primarily female
Duration: 6 – 100 wks
Sample size: range 28
– 376
Search terms:
Antidepressant, SSRI,
SNRI, TCA, depression,
randomized controlled
trials, human trials, and
individual antidepressant
names.
Conclusions/
Limitations
Results

2 comparative trials found no significant difference in efficacy between TCAs vs. SSRIs

3 studies found no significant difference between venlafaxine vs. SSRIs

1 study of duloxetine vs. placebo found significant improvement in depression (reductions in HAM-D and GDS,
p<0.001) than placebo with addition reduction in pain (p<0.001) and cognition (p=0.013).

Data from 5 studies using various measures (including changes in MADRS, HAM-D, or Geriatric Depression Scale
[GDS] scores; response rates; and remission rates) suggested no additional efficacy benefit for the SNRI venlafaxine
compared with SSRIs or TCAs.
Inclusion criteria:
published double-blind
design; placebo control
Outcome measures:
Response (reduction of at or active comparator
least 50% from baseline
group; aged ≥59 years;
scores on HDRS,
patients with a
MADRS, or 1-2 on CGI); diagnosis of MDD;
remission (MADRS <9 to published meeting
<12 or HAMD<7 to <10); abstracts; publications
and tolerability
in any
(withdrawals due to AEs) language; studies
conducted in the
community, nursing,
 Method:
home, outpatient, and
hospital settings;
- Meta-analysis was
studies that enrolled
not conducted;
patients with comorbid
dementia or medical
- no assessment of
publication bias (e.g. illnesses; and studies of
funnel plot analysis); maintenance therapy for
depression.
- no information on
study funding was
Published meeting
reported
abstracts that meet the
Limited data suggest
that dual-action
agents such as TCAs
and SNRIs do not
appear to confer any
additional efficacy
benefits over singleaction agents such as
SSRIs in the
treatment of
depression in the
elderly.
Limitations:
heterogeneity among
study sample, design,
dosing and duration;
inconsistent diagnosis
of MDD or
comorbididites,
outcome definitions
and measures;
underpowered; small
number of studies
included; limited
head-to-head
comparison studies;
low generalizability,
no attempt to look for
unpublished studies.
criteria above were also
considered.
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Author &
Title
Search Database
/ Method
Study (N)
Characteristics
Databases: MEDLINE,
EMBASE, PsychLit,
Cochrane, International
Comparative
Pharmaceutical Abstracts
benefits and
(1980 - April 2007).
harms of second- Examined Center for
generation
Drug Evaluation and
antidepressants: Research database
background
(CDER) for unpublished
paper for the
research. Invited pharma
American College to submit dossiers.
of Physicians.
Search strategy: AHRQ
assisted in formulating
key questions and data
analysis. Search terms:
(‘adverse events’,
‘harms’, ‘drug reactions’,
‘toxicity’, with ‘major
depressive disorder
[MeSH]’ and 12 specific
second-generation
antidepressants
(bupropion, citalopram,
duloxetine, escitalopram,
fluoxetine, fluvoxamine,
mirtazapine, nefazodone,
paroxetine, sertraline,
trazodone and
venlafaxine). ‘Humans’
and ‘English” language.
N: 203 studies
[including 105 head-tohead trials; 66 placebo
trials; 6 SR; 23
observational studies
(>740,000 subjects); 15
studies with pooled
data.
Gartlehner et al.
(2008a)
Conclusions/
Limitations
Results

Of the 203 included studies, 140 (69.0%) were financially supported by pharmaceutical companies and 19 (9.3%) by
governmental agencies or independent funds. For 44 (21.7%) studies, we could not determine the funding source.
Inclusion criteria:
- Population: Adult
inpatients and
outpatients with MDD.
- Intervention: 12 AD
listed previously
- Study design:
Experimental and
observational head-tohead studies
- Minimum study
duration: 6 wks
- Minimum sample size:
none for experimental
designs; n ≥100 for
observational studies
Outcome measures:
- Outcomes of Overall
rate of adverse events
(AEs)
- Discontinuation because
of AEs
- Specific AEs (e.g.
gastrointestinal
symptoms, weight gain,
dizziness and others)
- Severe AEs (e.g.
suicidality,
hyponatremia, sexual
dysfunction and others)
Note: the 7 studies that suggest some differences with respect to onset of action were all supported by manufacturer of
mirtazapine and after 4 weeks of treatment, most response rates were similar.
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Current evidence
does not warrant the
choice of one
second-generation
antidepressant over
another on the basis
of differences in
efficacy and
effectiveness.
Nevertheless, there
were some
differences with
respect to onset of
action and adverse
events that may be
relevant for the
choice of a
medication.
Limitations: low
generalizability due to
highly selected
patient populations in
efficacy studies;
indirect comparisons
due to lack of headto-head evidence
resulted in low power
and wide confidence
intervals; residual
publication bias;
inconsistency and
variability among
studies in terms of
drug dose and
duration of treatment;
small number of
studies for individual
comparisons.
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Characteristics
Conclusions/
Limitations
Results
Method:
Indirect comparison was
calculated using metaregressions of placebocontrolled trials using
individual drugs as
covariates.
When number of trials
was insufficient for metaregression, modified
network meta-analysis
was used.
- meta-analysis of headto-head comparisons
(both random and fixedeffects model)
- test of heterogeneity (I2)
index)
- adjusted direct
comparison using metaregressions of placebo
trials using individual
drugs as covariates
- when there’s insufficient
trials available for metaregressions, used
modified network metaanalysis
- publication bias
assessed by funnel plots
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/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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Study (N)
Characteristics
Conclusions/
Limitations
Results
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/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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Gartlehner et al.
(2008b)
Comparative risk
for harms of
secondgeneration
antidepressants:
A systematic
review and metaanalysis.
Search Database
/ Method
Study (N)
Characteristics
Databases: MEDLINE,
EMBASE, PsychLit,
Cochrane, International
Pharmaceutical Abstracts
(1980 - April 2007).
Examined CDER for
unpublished research.
Invited pharma to submit
dossiers.
N: 104 studies [81
head-to-head trials
(>17,000 subjects) ; 21
observational studies
(>740,000 subjects)]
Search strategy:
(‘adverse events’,
‘harms’, ‘drug reactions’,
‘toxicity’, with ‘major
depressive disorder
[MeSH]’ and 12 specific
second-generation
antidepressants
(bupropion, citalopram,
duloxetine, escitalopram,
fluoxetine, fluvoxamine,
mirtazapine, nefazodone,
paroxetine, sertraline,
trazodone and
venlafaxine). ‘Humans’
and ‘English” language.
Inclusion criteria:
- Population: Adult
inpatients and
outpatients with MDD.
- Intervention: 12 AD
listed previously
- Study design:
Experimental and
observational head-tohead studies
- Minimum study
duration: 6 wks
- Minimum sample size:
none for experimental
designs; n ≥100 for
observational studies
Conclusions/
Limitations
Results
General tolerability

AE profiles of second-generation antidepressants were similar with nausea, vomiting, diarrhea, dry mouth, sweating,
headache, dizziness, sexual dysfunction and weight gain were commonly reported AEs. However, individual drugs
differed in frequencies of specific AEs.
About 63% of patients in efficacy trials experienced at least one AE.
Discontinuation rates

Overall, about 15% of patients treated with 2nd-gen antidepressant discontinue because of intolerable AEs.

No significant difference was detected between 2nd-gen antidepressants and SSRIs (refer to Figure 2). However,
pooled estimated indicated higher discontinuation from AEs for patients taking venlafaxine than SSRIs(RR: 1.42
(95% CI: 1.15-1.75)]
Gastrointestinal AEs (refer to Figure 3)

Venlafaxine had a statistically significantly higher rate of nausea and vomiting than SSRIs as a class [RR: 1.53 (95%
CI: 1.26 - 1.86); NNH = 9 (95% CI 6, 23)].
Other AEs

Compared with other 2nd-gen antidepressants, paraoxetine frequently led to higher and bupropion to lower rates of
sexual dysfunction; mirtazapine and paraoxetine led to higher weight gains; and sertraline to higher rates of diarrhea.
However, differences did not lead to different discontinuation rates.
Outcome measures:
- Outcomes of Overall
rate of adverse events
(AEs)
- Discontinuation because
of AEs
- Specific AEs (e.g.
gastrointestinal
symptoms, weight gain,
dizziness and others)
- Severe AEs (e.g.
suicidality,
hyponatremia, sexual
dysfunction and others)
Overall, the spectrum
of AEs was similar
between different 2ndgen antidepressants;
however, different
frequencies of
specific AEs might be
clinically relevant and
influence the choice
of treatment.
Limitations:
comparative risk for
rare AEs were
insufficient to draw
firm conclusion;
heterogeneity
between experimental
and observational
studies; low quality
assessment and
misclassification of
AEs based on
variation in
definitions; poor
reporting – lack of
objective scale;
under-reporting in
some studies; and
evidence was too
sparse to assess risk
of harms for all 66
possible comparisons
between 2nd-gen
antidepressants.
Method:
- when RCTs sufficient,
meta-analyses (fixed and
random effects) of RR =
was conducted (only
reported random effects);
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/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
otherwise, evidence were
synthesized qualitatively
- test of heterogeneity (I2)
was applied to both
random and fixed effects
model
- sensitivity analysis was
conducted when I2>60%
according to population
characteristics, dosages
or drug formulations
- When pooled outcomes
were significant, NNH
was calculated
- publication bias was
assessed using funnel
plots
- due to lack of data on
individual comparisons,
assessments were made
with SSRI as a class
Cipriani et al.
(2009a)
Comparative
efficacy and
acceptability of
12 newgeneration
antidepressants:
a multipletreatments metaanalysis
Databases: Cochrane
collaboration depression,
anxiety and neurosis
review group controlled
trial registers (1991 –
Nov, 30, 2007). Asked
pharmaceutical
companies, regulatory
agencies, and study
investigators to supply all
available information.
Search terms:
Not specified.
Outcome measures:
Response (>50%
reduction of baseline
N: 117 RCTs (25,928
subjects)
% F: 64%
Mean duration: 8.1
wks
Mean sample size:
109.8 (range: 9-357)
63% trials were done in
Europe and North
America.
53 studies included
people <65 years.
Inclusion criteria: only
RCTs that compared
any of the following 12
new-generation
Only 7 of 117 trials were in primary care settings; 15 unpublished studies from industry were included, it was not
specified how many of these favored the funder’s antidepressant and it was not clear how many of these studies were
also included in the FDA trial database
No funnel plots or assessment of publication bias was noted
Heterogeneity

Overall, heterogeneity was moderate, although for most comparisons the 95% CI included values that showed very
high or no heterogeneity, reflecting the small number of included studies for each pair-wise comparison.
Efficacy

Escitalopram, mirtazapine, sertraline, and venlafaxine were significantly more efficacious than duloxetine, fluoxetine,
fluvoxamine, paroxetine, and reboxetine (refer Figure 3)

Reboxetine was significantly less efficacious than all the other 11 antidepressants.
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Escitalopram and
sertraline might be
the best choice when
starting a treatment
for moderate to
severe major
depression because
they have the best
possible balance
between efficacy and
acceptability.
Reboxetine,
fluvoxamine,
paroxetine, and
duloxetine were the
least efficacious and
acceptable drugs,
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/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
HAM-D, MADRS, or who
scored much improved on
CGI) and dropout rates
during 8 wks of tx
(dropouts).
antidepressants
(bupropion, citalopram,  When using Fluoxetine as reference: Mirtazapine, escitalopram, venlafaxine, and sertraline were more efficacious
than fluoxetine, and fluoxetine was more efficacious than reboxetine
duloxetine,
escitalopram, fluoxetine, Acceptability
fluvoxamine,
milnacipran,
 duloxetine and paroxetine were less well tolerated than escitalopram and sertraline; fluvoxamine less well tolerated
Comparative efficacy
mirtazapine,
than citalopram, escitalopram, and sertraline; venlafaxine less well tolerated than escitalopram; reboxetine less well
analyses for the 12 drugs paroxetine, reboxetine,
tolerated than many other antidepressants, such as bupropion, citalopram, escitalopram, fluoxetine, and sertraline;
were done using
sertraline, and
and escitalopram and sertraline were better tolerated than duloxetine, fluvoxamine, paroxetine, and reboxetine.
fluoxetine as reference
venlafaxine) as
drug.
monotherapy in acute fluoxetine was better than reboxetine
phase tx of adults with
Method:
unipolar major
Ranking of Efficacy and Acceptability (refer to Figure 4)
- when dichotomous
depression.
efficacy outcomes were
 Mirtazapine, escitalopram, venlafaxine, and sertraline were among the most efficacious treatments, and
not reported tx response Study quality was rated:
escitalopram, sertraline, bupropion, and citalopram were better tolerated than the other remaining antidepressants
at 8 wks was estimated
adequate, unclear, or
- Responders to
inadequate, according
 Cumulative probabilities of being among the four most efficacious treatments were: mirtazapine (24·4%),
treatment were calculated to the adequacy of the
escitalopram (23·7%), venlafaxine (22·3%), sertraline (20·3%), citalopram (3·4%), milnacipran (2·7%), bupropion
on an intention-to-treat
random allocation
(2·0%), duloxetine (0·9%), fluvoxamine (0·7%), paroxetine (0·1%), fluoxetine (0·0%), and reboxetine (0·0%).
basis
concealment and
- pair-wise meta-analyses blinding.
 Cumulative probabilities of being among the four best treatments in terms of acceptability were: escitalopram
using random-effects
(27·6%), sertraline (21·3%), bupropion (19·3%), citalopram (18·7%), milnacipran (7·1%), mirtazapine (4·4%),
model
Studies that scored
fluoxetine (3·4%), venlafaxine (0·9%), duloxetine (0·7%), fluvoxamine (0·4%), paroxetine (0·2%), and reboxetine
- multiple-treatments
adequate or unclear
(0·1%).
meta-analysis
were included.
- heterogeneity was
assessed using forest
Exclusion criteria:
placebo
plots
groups present and
- sensitivity analyses
RCTs of women with
based on dose and
post-partum depression
imputation were
conducted
- meta-regression
analysis was conducted
to examine sponsorship
effect
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making them less
favorable options
when prescribing an
acute treatment for
major depression.
Furthermore, in terms
of acceptability,
reboxetine was the
least tolerated agent
among the 12
antidepressants and
was significantly less
effective than all the
other 11 drugs.
Therefore, reboxetine
should not be used as
a routine first-line
acute treatment for
major depression.
Limitations:
Short duration and
follow-up;
sponsorship bias; lack
of information on
randomization and
allocation
concealment;
variations in multipletreatments and direct
comparisons;
selection bias
(placebo-controlled
trials mainly designed
for regulatory
approval tend to
include patients with
mild form of disease);
residual confounding;
numbers needed to
treat or harm were not
calculated, making it
difficult to assess the
absolute differences
in each analysis;
statistical significance
(defined as p<0.05 in
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this analysis) was not
adjusted for multiple
comparisons, so
many differences
could have been due
to chance.
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Cipriani et al.
(2009b)
Escitalopram
versus other
antidepressive
agents for
depression
(review).
Cochrane review.
Search Database
/ Method
Study (N)
Characteristics
Databases: The
Cochrane Depression,
Anxiety and Neurosis
Group (CCDAN)
Controlled Trials Register
was searched, together
with a supplementary
search of MEDLINE,
PsycINFO, EMBASE,
LILACS, CINAHL,
PSYNDEX and hand
searches. Trial databases
of drug-approving
agencies were hand-
N: 22 RCTs (14
compared escitalopram
vs. SSRI; 8 compared
escitalopram vs.
(venlafaxine,
bupropion and
duloxetine)
% F: not reported
Age: Adults >18 years
Duration: 6 – 24 wks
Mean sample size:
280.8 + 103.9 (range
202-547)
Conclusions/
Limitations
Results

Escitalopram was shown to be significantly more effective than citalopram in achieving acute response (OR = 0.67,
95% CI 0.50 to 0.87).

Escitalopram was also more effective than citalopram in terms of remission (OR = 0.53, 95% CI 0.30 to 0.93).

Significantly fewer patients allocated to escitalopram withdrew from trials compared with patients allocated to
duloxetine, for discontinuation due to any cause (OR = 0.62, 95% CI 0.38 to 0.99).
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Some statistically
significant differences
favoring escitalopram
over other
antidepressive agents
for the acute phase
treatment of MDD
were found, in terms
of efficacy (citalopram
and fluoxetine) and
acceptability
(duloxetine). There is
insufficient evidence
to detect a difference
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/ Method
Study (N)
Characteristics
searched for published,
unpublished and ongoing
controlled trials. (July
2008)
Inclusion criteria:
RCTs comparing
escitalopram against
any other
antidepressant
(including nonconventional agents
such as
hypericum) for patients
with MDD (regardless of
the diagnostic criteria
used); aged >18 years;
studies in which less
than 20% of the
participants might be
suffering from bipolar
depression
were included
Search terms:
CCDANCTR-Studies:
Diagnosis = Depress* or
Dysthymi* or “Adjustment
Disorder*”
or “Mood Disorder*” or
“Affective Disorder” or
“Affective Symptoms”
and Intervention =
Escitalopram.
CCDANCTR-References:
Keyword = Depress* or
Dysthymi* or “Adjustment
Disorder*” or “Mood
Disorder*” or “Affective
Disorder” or “Affective
Symptoms”
and Free-Text =
Escitalopram
Outcome measures:
The primary outcome was
response (>50%
reduction in HAM-D or
MADRS or 1-2 on CGI
scores)
Conclusions/
Limitations
Results
between escitalopram
and other
antidepressants in
early response to
treatment (after two
weeks of treatment).
However, the
potential for
overestimation of
treatment effect due
to sponsorship bias
should also be borne
in mind.
Limitations:
publication bias due
to commercial
sponsorship; unclear
allocations; selective
reporting present in
many studies;
Exclusion criteria:
Participants diagnosed
with comorbid physical
or mental conditions;
concurrent primary
diagnosis of Axis I or II
disorders.
1) Early response:
between 1 and 4 weeks,
2) Acute phase treatment
response: between 6 and
12 weeks,
3) Follow-up response:
between 4 and 6 months
Method:
- meta-analysis using
random effects model
- Responders and
remitters to treatment
were calculated on the
intention-to-treat (ITT)
basis
- When there were
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/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
missing data “last
observation carried
forward” (LOCF) method
was used
- heterogeneity was
assessed using I2 and
forest plots
- Funnel plot was used to
assess publication bias
- sensitivity analyses
were also conducted to
account for excluded
trials, imputation, wish
bias, and sponsorship
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/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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Search Database
/ Method
Nakagawa et al.
(2009)
Databases: Cochrane
Collaboration Depression,
Anxiety
& Neurosis Controlled
Trials Registers
(CCDANCTR-Studies
and CCDAN-References)
(searched in December
2006; updated in August
2008). Trial databases of
drug-approving agencies
were hand-searched for
published,
unpublished and ongoing
controlled trials. Hand
searches also conducted.
Milnacipran
versus
antidepressive
agents for
depression
(review).
Cochrane review.
Search terms:
CCDANCTR-Studies:
Diagnosis = Depress* or
Dysthymi* or “Adjustment
Disorder*”
or “Mood Disorder*” or
“Affective Disorder” or
“Affective Symptoms”
and Intervention =
Milnacipran;
CCDANCTR-References:
Keyword = Depress* or
Dysthymi* or “Adjustment
Disorder*” or “Mood
Disorder*” or “Affective
Disorder” or “Affective
Symptoms” and FreeText = Milnacipran.
Outcome measures:
Response (>50%
reduction of baseline
HAM-D, MADRS, or who
scored much improved on
CGI)
Study (N)
Characteristics
N: 16 RCTs (2277
subjects)
% F: not reported
Age: Adults >18 years
Mean Duration: most
studies were 6-12 wks
Median sample size:
120 (range: 41-302)
Conclusions/
Limitations
Results

No statistically significant differences in efficacy, acceptability and tolerability when comparing milnacipran with other
antidepressive agents, with wide CIs.

However, compared with TCAs, patients taking milnacipran were associated with fewer dropouts due to adverse
events (OR = 0.55; 95% CI 0.35 to 0.85).

There was also some weak evidence to suggest that patients taking milnacipran experienced fewer adverse events
of sleepiness/ drowsiness, dry mouth or constipation compared with TCAs.
Inclusion criteria:
RCTs comparing
milnacipran with any
other active
antidepressive agents
(including nonconventional agents) as
monotherapy in the
acute phase of major
depression; age >18
years.
Exclusion criteria:
Studies using ICD9 to
diagnose depression;
participants diagnosed
with comorbid physical
or mental conditions;
concurrent primary
diagnosis of Axis I or II
disorders.
There is inadequate
evidence to conclude
whether milnacipran
is superior, inferior or
the same as other
antidepressive agents
in terms of efficacy,
acceptability and
tolerability in the
acute phase
treatment of major
depression. However,
there is some
evidence in favor of
milnacipran over
TCAs in terms of
dropouts due to
adverse events
(acceptability) and the
rates of experiencing
adverse events
(tolerability).
Limitations: data
reporting
of most studies was
incomplete; selective
reporting present in
many studies; small
number of studies
included; may be
underpowered to
detect significant
difference; no
sensitivity analysis to
examine other
modulating effects;
high drop-out rates
noted which reduce
outcome reliability;
most studies were
funded by industry.
Method:
- meta-analysis using
random effects model
- Responders and
remitters to treatment
were calculated on the
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/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
intention-to-treat (ITT)
basis
- When there were
missing data “last
observation carried
forward” (LOCF) method
was used
- heterogeneity was
assessed using I2 and
forest plots
- Funnel plot was used to
assess publication bias
- sensitivity analyses
were also conducted to
account for excluded
trials, imputation, wish
bias, and sponsorship
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Search Database
/ Method
Study (N)
Characteristics
Databases: Cochrane
Central Register of
Controlled Trials,
Efficacy,
MEDLINE,
tolerability and
EMBASE, CINAHL,
side effect profile pycINFO, PSYINDEX,
of fluvoxamine for LILACS
major
and hand searches (thru
depression:
June 2, 2006). Not
Meta-analysis.
limited to English
language. Trial databases
of drug-approving
agencies were handsearched for published,
unpublished and ongoing
controlled trials. Pharma
companies were asked to
submit studies that meet
inclusion criteria.
N: 53 RCTs (48 RCTs
for efficacy analysis
(N=6440); 49 for
tolerability analysis
(N=8244))
% F: not reported
Age: > 18 years
Duration: Mean 5.5
wks (range 2 – 10 wks)
Sample size: 38 RCTs
had <100 subjects
Omori et al.
(2009)
Search strategy:
Diagnosis or Keyword =
Depress* or Dysthymi* or
‘Adjustment Disorder*’ or
‘Mood Disorder*’ or
‘Affective Disorder’ or
‘Affective symptoms’ and
Intervention
or Free-text =
fluvoxamine.
Outcome measures:
Response at the end of
acute phase (between 6
and 12 weeks) (< 50%
reduction of HAMDS or
MADRS) and tolerability
(dropouts for any reason
and side effects).
Secondary outcome was
remission (<7 HAMDS).
Inclusion criteria:
RCTs comparing
fluvoxamine with all
other active ADs in
acute phase treatment
of major depression in
patients aged 18 or
older. The diagnosis
must have been
made based on
established
operationalised
diagnostic criteria
such as DSM-IV.
Conclusions/
Limitations
Results
Treatment efficacy

no significant differences in response and remission rates between fluvoxamine and other ADs as a class (TCAs,
heterocyclics, etc.) (refer to table 2) in early or end of acute phase of treatment.
Tolerability

The total number of dropouts for any reason or for side effects was not significantly different between fluvoxamine
and other ADs as a class and between fluvoxamine and individual comparator ADs (refer to table 3).

Side-effect profile: there is evidence of differing side-effects profiles, especially when comparing gastrointestinal side
effects between fluvoxamine and TCAs. Nausea or vomiting and weight loss or anorexia were experienced
significantly more frequently with fluvoxamine than with TCAs and some of other ADs (mianserin, milnacipran and
newer ADs). On the contrary, constipation and dry mouth were more common with TCAs than with fluvoxamine.
No substantial
difference exists in
the effectiveness
between fluvoxamine
and any of the ADs
including TCAs, such
as amitriptyline or
clomipramine,
in terms of response
or remission in any
clinical settings.
in terms of patients
acceptability, there
was no difference in
dropouts for any
reason or for side
effects between
fluvoxamine and other
ADs as a class
(TCAs, SSRIs, etc.)
or individually.
Therefore, the initial
selection of an
antidepressant
medication will and
should largely be
based on the
anticipated side effect
profile and patient’s
preference.
Exclusion criteria:
depressive patients with
primary diagnosis of
other Axis I or Axis II
disorders or a serious
concomitant medical
Illness; depression with
psychotic features and
those in which more
than 20% of the
participants suffered
from bipolar depression;
or fluvoxamine was
used as an
augmentation strategy.
Limitations: Probable
publication bias;
many studies were
sponsored by
pharmaceutical
companies; effects
maybe overestimated;
several comparisons
with small number of
subjects were highly
heterogeneous; error
in reporting due to
lack of standardized
instruments to
measure side effects;
Method:
- RRs were calculated
using random-effects
model
- if significant difference
was detected, NNT was
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/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
calculated
- heterogeneity was
assessed by I2 and forest
plots
- ITT analysis was
applied; otherwise, LOCF
was used
- publication bias
assessed by funnel plot
- sensitivity analyses for
sponsorship, wish bias,
and excluded trials were
conducted
- confidence interval was
set at 99% and
statitistical significance
set at p=0.01
and variability in
reporting.
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Title
Cipriani et al.
(2009c)
Sertraline versus
antidepressive
agents for
depression
(review).
Cochrane review.
Search Database
/ Method
Study (N)
Characteristics
Databases: MEDLINE
(1966 to 2008), EMBASE
(1974 to 2008), the
Cochrane Collaboration
Depression, Anxiety and
Neurosis Controlled
Trials Register and the
Cochrane Central
Register of Controlled
Trials up to July 2008.
Hand searches also
conducted. Trial
databases of drugapproving agencies were
hand-searched for
published,
unpublished and ongoing
controlled trials.
N: 59 RCTs (55 RCTS
and 9303 available for
efficacy; 57 RCTs and
9950 for tolerability)
% F: not reported
Age: Adults >18 years
Mean Duration: not
reported
Sample size: 17
studies included <100
subjects
Search terms:
CCDANCTR-Studies:
Diagnosis = Depress* or
Dysthymi* or “Adjustment
Disorder*”
or “Mood Disorder*” or
“Affective Disorder” or
“Affective Symptoms”
and Intervention =
Sertraline; CCDANCTRReferences: Keyword =
Depress* or Dysthymi* or
“Adjustment Disorder*” or
“Mood Disorder*” or
“Affective Disorder” or
“Affective Symptoms” and
Free-Text = Sertraline.
Exclusion criteria:
Studies using ICD9 to
diagnose depression;
participants diagnosed
with comorbid physical
or mental conditions;
concurrent primary
diagnosis of Axis I or II
disorders.
Conclusions/
Limitations
Results

A total of 59 studies, mostly of low quality, were included in the review, involving multiple treatment comparisons
between sertraline and other antidepressant agents.

Evidence favoring sertraline over some other antidepressants for the acute phase treatment of major depression
was found, either in terms of efficacy (fluoxetine) or acceptability/tolerability (amitriptyline, imipramine, paroxetine
and mirtazapine).

However, some differences favoring newer antidepressants in terms of efficacy (mirtazapine) and acceptability
(bupropion) were also found. In terms of individual side effects, sertraline was generally associated with a higher
rate of participants experiencing diarrhea.
Inclusion criteria:
RCTs allocating
patients with MDD to
sertraline versus any
other antidepressive
agent; age >18 years.
Results found a trend
in favor of sertraline
over other
antidepressive agents
both in terms of
efficacy and
acceptability, and
further suggest that
sertraline might be a
strong candidate as
the initial choice of
antidepressant in
people with acute
MDD.
Limitations: Overall
low quality of included
studies, not all prespecified outcomes
were reported in
included studies and
outcomes of clear
relevance to patients
and clinicians were
not reported in any of
the included studies;
no analysis of
publication bias due
to insufficient quantity
of studies; only few
studies reported
remission rates –
underpowered to
detect clinical
significance; limited
head-to-head
comparison studies
for individual ADs.
Outcome measures:
Efficacy (the number of
patients who responded
or remitted), acceptability
(the number of
patients who failed to
complete the study) and
tolerability (side-effects).
Method:
- meta-analysis using
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/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
random effects model
- Responders and
remitters to treatment
were calculated on the
intention-to-treat (ITT)
basis
- When there were
missing data “last
observation carried
forward” (LOCF) method
was used
- heterogeneity was
assessed using I2 and
forest plots
- Funnel plot was used to
assess publication bias
- sensitivity analyses
were also conducted to
account for excluded
trials, imputation, wish
bias, and sponsorship
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/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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Title
Search Database
/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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Title
Search Database
/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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Title
Search Database
/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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Title
Search Database
/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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Author &
Title
Search Database
/ Method
Study (N)
Characteristics
Databases: MEDLINE,
EMBASE, Cochrane
Collaboration for
Does randomized Depression, Anxiety and
evidence support Neurosis Register of
sertraline as first- Controlled Trials (1966line
August 2007). ƒ
antidepressant
for adults with
Search terms:
Diagnosis= depress* or
acute major
dysthymic* or adjustment
depression? A
systematic review disorder* or mood
disorder* or affective
and metadisorder or affective
analysis.
symptoms, and
intervention (or free text)=
sertraline. English and
non-English-language
articles.
N: 56 RCTs (8507
patients available for
examining efficacy;
8387 available for
acceptability)
% F: Not reported
Duration: 6- 24 wks
Sample size: 6 studies
had <100 subjects
Cipriani et al.
(2008)
Outcome measures:
Treatment response and
treatment acceptability.
- response was defined
as proportion of patients
who had reduction of at
least 50% from baseline
scores on HDRS or
MADRS or “much
improved” on CGI.
-tx acceptability was
proportion of patients who
left the study by any
cause during first 8 wks.
Inclusion criteria:
RCTs comparing
sertraline with all other
active antidepressants
as monotherapy in
acute phase (8-wk tx) tx
of depression.
Participants were both
sex and > 18 years with
primary diagnosis of
MDD.
Conclusions/
Limitations
Results
Treatment response

No significant difference in efficacy was detected between sertraline and TCAs [RR: 0.95 (99% CI: 0.38 – 1.09)] or
other antidepressants, and slightly better than SSRI (refer to Figure 3).

Statistically significant difference in efficacy in favor of sertraline over SSRI [RR=0.88 (99% CI: 0.78- 0.99), p =
0.009; NNT = 17], particularly sertraline over fluoxetine [RR: 0.85 (99% CI: 0.74-0.98); p = 0.004; NNT=12]
Acceptability

No significant difference in acceptability was detected between sertraline and TCAs [RR: 0.83 (99% CI: 0.66 – 1.04)],
SSRI [RR: 0.9 (99% CI: 0.68 – 1.18)], or any other antidepressants (refer to Figure 4).
2
High heterogeneity was detected for comparison of sertraline vs. fluvoxamine (I =53.4 and 57.9%); vs. paroxetine
2
2
(I =64.2 and 59.3%) for efficacy and acceptability; and vs. other antidepressants for acceptability (I =42.7%)
Funnel plots did not suggest evidence of publication bias.
In the conclusions section, the authors site “cardiovascular physicians belief and clinical care practices” in treating
depression in patients with cardiovascular disease” as observational evidence supporting their conclusion of sertraline
“as a candidate for initial choice of antidepressant.”
Exclusion criteria:
Quasi-randomized
trials; concurrent
medical disorder;
postpartum depression.
Method:
- Responders were
calculated according to
ITT basis or LOCF
Method:
- meta-analysis using
random effects model
- Responders calculated
on ITT basis
- When there were
missing data “last
observation carried
forward” (LOCF) method
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Results found
consistent although
not statistically
significant trend in
favor of sertraline
over other
antidepressants,
particularly SSRIs
and fluoxetine.
Sertraline may be a
candidate as the
initial choice of
antidepressant
treatment for people
with MDD.
Limitations: low
generalizability;
most included
studies were
funded by the
maker of
sertraline; high
heterogeneity in some
subgroup analysis;
some demographic
information on patient
population were not
available; different
dosing schedules
make it difficult to
determine
differences (or
lack thereof)
between
equivalent
effective doses of
ADs; There was
substantial
overlap of studies
in this analysis
and the analysis
conducted in
Cipriani et al.
(2009a) thus
many of the same
limitations (short
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/ Method
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Characteristics
Conclusions/
Limitations
Results
was used
- heterogeneity was
assessed using I2
- Funnel plot was used to
assess publication bias
- sensitivity analyses
were also conducted to
account for excluded
trials, imputation, wish
bias, and sponsorship
- NNT was calculated
when RRs were
statistically significant
- confidence interval was
set at 99% and
statitistical significance
set at p=0.01
duration of
included trials,
few trials
conducted in
primary care
settings) apply;
Trials including
patients with
medical disorders
were excluded
from this analysis,
also limiting
applicability to the
primary care
setting.
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Author &
Title
Van den Broek
et al. (2009)
Efficacy of
venlafaxine
compared with
tricyclic
antidepressants
in depressive
disorder: A metaanalysis.
Search Database
/ Method
Study (N)
Characteristics
Databases: PubMed,
Cochrane database of
Systematic
Reviews, Cochrane
Controlled Trial Register
and DARE, and manual
searches. If necessary,
unpublished data were
requested from authors.
N: 7 RCTs (N=947)
% F: not reported
Race not reported
Age: not reported
Duration: range 43
days – 8 wks
Sample size: range 50
- 82
Search strategy:
search terms were
((‘depressive
Disorder’[TIAB] NOT
Medline[SB]) OR
‘depressive
Disorder’[MeSH Terms]
OR ‘depression’[MeSH
Terms] OR
Depression[Text Word])
AND
Inclusion criteria:
Trials were included if
they were double-blind
randomized
studies comparing
venlafaxine with a TCA
for the treatment of
depression.
Conclusions/
Limitations
Results

No overall significance treatment effects were detected for response or withdrawal of TCA vs. venlafaxine (refer to
tables 2 and 3).

There was heterogeneity between studies in the estimates of response.
No significant
difference in
treatment effect
between venlafaxine
and TCAs was
detected and analysis
of tolerability by total
treatment dropouts
and dropouts
because of side
effects did not
suggest poorer
tolerability for
venlafaxine or TCAs.
However, because of
the heterogeneity of
the odds ratios, one
cannot conclude that
they are of equal
efficacy
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/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
(‘venlafaxine’[Substance
Name] OR
Venlafaxine[Text Word])
AND (‘imipramine’[MeSH
Terms] OR
imipramine[Text
Word]) AND Randomised
Controlled Trial[ptyp]
AND
‘humans’[MeSH Terms].
Outcome measures:
Response (50% reduction
in HADRS or MADRS)
Limitations: Small
sample size;
underpowered; short
study duration;
heterogeneous
studies; publication
bias assessment was
not reported (no
funnel plot); majority
of studies were
sponsored by
venlafaxine
manufacturer.
Method:
- analysis was based on
ITT method
- fixed and random-effect
models were used for
meta-analysis
- heterogeneity was
assessed using I2
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Title
Search Database
/ Method
Weinmann et al. Databases: Medline,
(2008)
EMBASE,
PsycINFO, PSYNDEX,
Re-evaluation of Cochrane Central
the efficacy and
Register of
tolerability of
Controlled Trials,
venlafaxine vs.
Cochrane Database of
SSRI: metaSystematic Reviews,
analysis.
DARE and guideline
databases and manual
searches (1966-Mar
2007).
Study (N)
Characteristics
N: 17 RCTs (2 had
patients > 65 years;
N=3523 for response
analysis; N=3142 for
remission analysis)
% F: not reported
Race not reported
Age: adult >18 years
Duration: ranged 6-24
wks (most were 6-8
wks)
Sample size: range 68382
Search strategy:
combination of
text and index terms as a
modification of the search
strategy
of the Cochrane
Depression and Anxiety
group.
Conclusions/
Limitations
Results
Remission rates

There was no statistically significant difference between venlafaxine and the SSRI group [random-effect RR: 1.04,
2
(95% CI: 0.96 - 1.13); fixed RR: 1.07 (0.99-1.15); NNT = 34; I = 18%]
Response rates

Venlafaxine was not significantly superior to the SSRI group [random-effect RR: 1.05, (95% CI:1.00–1.10); fixed RR:
2
1.06 (1.01-1.12); NNT = 27; I =32%]
The analysis does not
support a clinically
significant superiority
of venlafaxine over
SSRIs. However,
higher rate of study
withdrawal due to
AEs was associated
with venlafaxine.
Tolerability

The total rate of treatment discontinuation did not differ between venlafaxine and SSRIs (RR: 1.05, 95% CI=0.93-1.2,
NNH=100).
Inclusion criteria:
 However, there were significantly more dropouts due to adverse effects in the venlafaxine vs. SSRIs group
double-blind RCTs in
[RR=1.38, 95% CI: 1.08 - 1.77, NNH=32]
which venlafaxine was
compared to
citalopram,
escitalopram, fluoxetine, Subgroup analyses did not demonstrate clinically significant effect of venlafaxine compared to SSRIs (refer to table 1)
fluvoxamine, paroxetine
or sertraline with or
without a placebo
Outcome measures:
Response (50% reduction control; depression was
in HAM-D or MADRS)
diagnosed according to
and remission (HAM-D < ICD, DSM or
7 or MADRS < 10).
Research Diagnostic
Criteria (RDC); at least
Method:
6 weeks of treatment;
- analysis was based on
used HAM-D or MADRS
as outcome parameters
ITT method; otherwise
LOCF was used
- fixed-effect models was Exclusion criteria:
conference abstracts
used for meta-analysis
unless full-text
- heterogeneity was
publication could be
assessed using I2
- sensitivity analyses
obtained; Long-term
were also preformed on
studies >6 months
age, type of trial,
duration; more than
appropriateness of ITT,
20% of participants had
treatment setting, dose,
a primary diagnosis of
and intervention vs.
dysthymia or more than
control.
15% had a primary
- funnel plot was used to diagnosis of bipolar
evaluate publication bias disorder; measures
based on (CGI) or
Patient Global
Improvement (PGI)
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Limitations:
inconsistent remission
definitions from
included studies;
small number of
head-to-head
comparison studies;
underpowered;
possible publication
bias; and presence of
some heterogeneity;
no
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Title
Search Database
/ Method
Study (N)
Characteristics
Databases: Cochrane
collaboration depression,
anxiety and neurosis
Mirtazapine
review group controlled
versus other
trial registers
antidepressants
(CCDANCTR) (- June
in the acute2,2006). Trial databases
phase treatment of drug-approving
of adults with
agencies were handmajor
searched for published,
depression:
unpublished and ongoing
systematic review controlled trials. Hand
and metasearches of references.
analysis.
Pharma companies were
asked for studies that
meet inclusion criteria.
N: 25 RCTs (N=4842; 9
trials of TCA, 12 of
SSRI, 2 of SNRI, and 2
of other)
% F: Not reported
Age : elderly (>65
years) included in 16
trials; no other info
provided
Median Duration: 6
wks (range 5-24 wks)
Sample size: range 22
- 412
Watanabe et al.
(2008)
Search strategy:
Search terms: “depress*,
dysthymic*, adjustment
disorder*, mood
disorder*, affective
disorder, and affective
symptoms”; and
‘mirtazapine’
Outcome measures:
Primary outcome was
response (> 50%
reduction in HAMD-D or
MADRS scores);
secondary outcome was
remission (< 8 on HAMD)
Tolerability in terms of
dropout rates due to any
reason or due to AEs
were also considered.
Inclusion criteria:
RCTs of mirtazapine for
acute-phase tx; > 18
years; diagnosed with
unipolar MDD based on
DSM-IV or other explicit
clinical criteria
Exclusion criteria:
Patients with
depression with
psychotic feature; 20%
of participants with
bipolar depression;
concurrent Axis 1 or II
disorders; presence
serious concomitant
medical illness.
Outcomes were stratified
by early phase (at 2 wks
after tx), conclusion of
acute-phase (6-12 wks),
and conclusion of
continuation-phase (4-6
months)
Conclusions/
Limitations
Results
Efficacy
Early phase (at 2 wks) (refer to Table 2 and Figure 2)

Mirtazapine was not superior or inferior to TCAs in terms of response [RR: 0.9 (99% CI: 0.69-1.18)] or
remission [RR: 0.87 (99% CI: 0.52-1.47)]

Mirtazapine was superior to SSRIs in both response [RR: 1.36 (99% CI: 1.13-1.64); NNT=11] and remission
[RR: 1.68 (99% CI: 1.2-2.36); NNT=25]
In addition, mirtazapine was significantly better than paroxetine in response [RR=2.02 (99% CI:
1.09-3.75); NNT=8], but not in remission.
While mirtazapine was significantly better than sertraline in remission [RR=1.73 (99% CI: 1.012.98); NNT=12], but not in response.
o
o
Mirtazapine was significantly superior to SNRI in terms of response [RR: 1.77 (99% CI: 1.08-2.89); NNT=6] but
not in remission [RR: 2.21(99% CI: 0.93-5.26)]

No significant difference was detected in response and remission between mirtazapine and
trazodone [response RR: 1.11 (99% CI: 0.6-2.04); remission RR: 1.0 (99% CI: 0.29-3.4)]
o
Sensitivity analysis (included only trials without imputed data)
o
Although mirtazapine
is highly likely to have
better efficacy profile
than paraoxetine or
venlafaxine in terms
of early response, in
view of similar
efficacy of
mirtazapine and other
ADs, results suggest
that clinicians should
also focus on other
practically or clinically
relevant
considerations such
as differences in the
side effect profiles, to
tailor treatment to
best fit an individual
patient’s needs.
Mirtazapine was superior to SSRI I response [N=1789; RR: 1.39 (99% CI: 1.06-1.82); NNT=11)] and
remission [RR: 1.78 (99% CI: 1.2-2.64); NNT=17]; significantly better than paroxetine in response [N=726;
RR: 2.02 (99% CI: 1.09-3.75); NNT=8]; better than sertraline in remission [N=596; RR: 1.73 (99% CI: 1.012.98); NNT=13]
Limitations: None of
the trials reported
whether allocation
concealment was
adequately
End of acute phase (at 6 wks)
performed;
o
No statistical significant differences were detected, except for superior remission outcome in comparison of
publication bias due
martazapine with paroxetine [RR: 1.34 (99% CI: 1.04-1.73); NNT=10)
to pharmaceutical
support for included
o
However, significant heterogeneity and publication bias (p=0.01) was observed.
studies; heterogeneity
in study duration and
End of continuation phase (at 24 wks)
dosing that may lead
o
Only 1 study examined mirtazapine with paroxetine at continuation phase and no significant differences were results to bias toward
detected (refer to Table 2).
mirtazapine; and
generalizability due to
Tolerability (Refer to Table 3)
efficacy trials
recruiting mainly
o
There were no significant differences between patients treated with TCAs (RR: 0.87 (95% CI: 0.7-1.08)],
symptomatic
SSRIs (RR: 1.07 (95% CI: 0.92-1.26)], SNRI (venlafaxine) [RR: 0.82 (95% CI: 0.58-1.16)], other AD
volunteers.
(trazodone) [RR: 0.93 (95% CI: 0.58-1.5)]
o
Subgroup analysis showed that patients treated with mirtazapine were more likely than those
treated with sertraline to withdraw due to any reason [RR: 1.33 (95% CI: 1.01-1.75); NNH=14]
o
In terms of AEs, mirtazapine dropouts due to AEs were similar to SSRI [RR: 1.22 (95% CI: 0.87-1.73)], SNRI
[RR: 0.59 (95% CI: 0.27-1.29)], and trazodine [RR: 0.66 (95% CI: 0.3-1.46)]
o
Subgroup analysis found mirtazapine had lower withdrawals due to AEs compared with sertraline [RR: 2.58
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Search Database
/ Method
Study (N)
Characteristics
Clinical assessments
were categorized based
on RR = difference of 0.1
as: A (mirtazapine is
clinically better than
comparator); B (not
worse and probably
better than comparator);
C (uncertain); D (not
better and probably
worse); and E (worse
than comparator)
Conclusions/
Limitations
Results
(95% CI: 1.28-5.24); NNH=11]
Assuming that a difference in RR = of more than 0.1 is clinically important difference in efficacy, mirtazapine was
clinically not worse and probably better than paroxetine, sertraline and velafaxine and was uncertain to be clinically
significantly better or worse than other ADs in efficacy at 2 week during treatment phase.
After acute-treatment phase, mirtazapine was certainly clinically not worse and probably better than fluoxetine,
paroxetine and venlafaxine; with uncertain inferiority or superiority relative to other ADs (refer to Table 4).
Method:
- meta-analysis was
based on random-effect
model
- applied ITT analysis;
otherwise LOCF were
used
- Heterogeniety was
assessed using I2
- Funnel plot used to
examine publication bias
- sensitivity analyses
were conduced for
exclusion trials,
imputation method, and
sponsorship
- p-value was set at <0.01
and CI 99% for statistical
significance
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Search Database
/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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Author &
Title
Search Database
/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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Author &
Title
Search Database
/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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Author &
Title
Arroll et al.
(2009)
Antidepressants
versus placebo
for depression in
primary care
(review).
Cochrane review.
Search Database
/ Method
Study (N)
Characteristics
Databases: The
Cochrane Depression,
Anxiety and Neurosis
Group (CCDAN)
Controlled Trials Register
was searched, together
with a supplementary
search of MEDLINE,
PsycINFO, EMBASE,
LILACS, CINAHL and
PSYNDEX (Sept 2007).
Authors of selected
studies were asked if they
knew of additional
published or unpublished
studies.
N: 14 RCTs (10 TCAs,
2 SSRIs, and 2 included
both classes vs.
placebo)
% F: not reported
Age: Adults 18-65
Duration: 4 – 24 wks
Mean sample size: 52
– 380
Conclusions/
Limitations
Results
 Both TCAs and SSRIs are significantly more effective than placebo for both discrete and continuous outcomes.
 Evidence is clear for major depression and levels of depression greater than minor depression.
 Based on this evidence, tricyclic antidepressants could be considered and the dose kept at or below 100mg per day,
and waiting at least 4 weeks for a response may be worth considering.
 There is no dose information on SSRIs and no comment provided on the appropriate duration of treatment for either
Search terms:
Not specified.
TCAs or SSRIs.
Inclusion criteria:
TCAs
RCTs TCAs or SSRIs
versus placebo in adults
 RR= 1.24 (95% CI: 1.11-1.38) and NNT= 7 to 16 (median NNT 9) (patient expected event rate ranged from
(>18 years); patients
63% to 26% respectively)
had to be recruited from
a primary care setting.
SSRIs
For continuous
outcomes the HAM-D,
 RR = 1.28 (95% CI: 1.15 - 1.43) for SSRIs and NNT= 7 to 8 {median NNT 7) (patient expected event rate
MADRS was required.
ranged from 48% to 42% respectively).
Outcome measures:
The primary outcome was
depression
reduction, and on a
continuous measure of
depression symptoms
Exclusion criteria:
Older Patients (>65
years); participants
diagnosed with
comorbid physical or
mental conditions.
Method:
- meta-analysis was
based on random-effect
model when I2>50%
- applied ITT analysis;
otherwise, missing data
were approximated
- Heterogeniety was
assessed using I2
- Funnel plot used to
examine publication bias
- sensitivity analyses
were conduced for
exclusion trials,
imputation method, and
sponsorship
- p-value was set at <0.01
and CI 99% for statistical
significance
Both TCAs and
SSRIs are effective
for depression treated
in primary care, but
more adverse effects
can be expected with
TCAs.
An NNT of 7 means that one patient will benefit from treatment and six will not although up to half may get better on
placebo.
Adverse events

There appeared to be more adverse effects with TCAs than with SSRIs, however rates of withdrawal from
study medication due to adverse effects were very similar between the two antidepressant classes.

Adverse effects not leading to medication cessation seemed to be more common with TCAs than SSRIs.

NNH for withdrawal due to side effects ranged from 4 to 30 for TCAs (excluding three studies with no harmful
events leading to withdrawal) and 20 to 90 for SSRIs.
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Limitations: Most of
the studies were
supported by funds
from pharmaceutical
companies and were
of short duration;
publication bias were
noted in funnel plot;
some studies had
small sample size;
heterogeneity in
intervention duration
and treatment
strategies.
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/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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Author &
Title
Search Database
/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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Author &
Title
Search Database
/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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Author &
Title
Search Database
/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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Author &
Title
Search Database
/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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Author &
Title
Hansen et al.
(2008)
Meta-analysis of
major depressive
disorder relapse
and recurrence
with secondgeneration
antidepressants.
Search Database
/ Method
Databases: MEDLINE,
EMBASE, the Cochrane
Library,
PsycINFO, International
Pharmaceutical
Abstracts, Center for
Drug Evaluation and
Research, FDA, and
manual searches
(January 1980 – April
2007). CDER database
was also searched for
unpublished research
submitted to FDA.
Search strategy:
Not specified.
Outcome measures:
Loss of response or
remission (continuationphase relapse or
maintenance-phase
recurrence), defined as
increased in HAM-D or
MADRS scores above
predefined cut-off point
(set by study).
Method:
- meta-analysis was
based on random-effect
model
- applied ITT analysis;
otherwise LOCF were
used
- Heterogeniety was
assessed using I2
- Funnel plot used to
examine publication bias
Study (N)
Characteristics
N: 27 RCTs (4 head-tohead and 23 placebocontrolled trials)
% F: not reported
Mean Age : 40-50
Duration: 6-110 wks
Range sample size: 23
-932
Inclusion criteria:
head-to-head trials
comparing one
antidepressant with
another and placebocontrolled trials; adult
(>18 years); depressive
illness patients that
demonstrated response
to treatment or
remission; reported
relapse or recurrence
rates, regardless of
whether
participants were
randomly assigned
to treatment groups
after successful
acute-phase or
continuation-phase
treatment (that is,
extension versus
randomized substitution
trials).
Conclusions/
Limitations
Results
Trials shorter than one year: relapse prevention

Pooled RR = of relapse was .54 (95% CI=.46–.62), and the NNT to prevent one additional relapse over a
mean time of 8 months was 5 (CI=4–6). Heterogeneity among these trials was moderate (I2=47%).
Trials one year or longer: recurrence prevention

Pooled RR = of recurrence was .56 (CI=.48–.66) and the NNT to prevent one additional recurrence over a
mean time of 16 months was 5 (CI=4–6). Heterogeneity among these trials was moderate (I2=30%).
Adverse Events

RR = of dropping out for any reason was statistically significantly lower for active treatment than for placebo
(relative risk=.75, CI= .69–.83).

Loss to follow-up because of adverse events was not statistically significantly different between active
treatment and placebo (relative risk= 1.42, CI=.92–2.20).
This review confirms
the benefits of
continuation- and
maintenance-phase
treatment of major
depression with
second-generation
antidepressants.
Limitations: limited
quality and quantity of
head-to-head
comparison studies
and studies that
addressed clinical
question; low
generalizability;
residual publication
bias - most studies
were sponsored by
pharmaceuticals;
unclear demographic
characteristics of
included patients;
some heterogeneity
among studies;
variations in dosage
and treatment
duration.
For placebo-controlled
evidence; only studies
that
randomly assigned
participants after
demonstrating either an
acute-phase response
or lack of relapse during
the continuation phase
were included.
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Title
Search Database
/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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Author &
Title
Nelson et al.
(2008)
Efficacy of
second
generation
antidepressants
in late-life
depression: A
meta-analysis of
the evidence.
Search Database
/ Method
Study (N)
Characteristics
Databases: MEDLINE,
EMBASE, Cochrane
(1966 – August 2006).
Meeting abstracts from
geriatric psychiatric and
psychiatric professional
society meeting and hand
searches were also
conduced.
N:10 RCTs (N=2377
patients)
% F: mean ranged 46 –
76%
Age : mean age ranged
68 – 80 years
Duration: 6-12 wks
sample size: 84 – 368
Search strategy:
Search terms:
antidepressants,
fluoxetine, sertraline,
paroxetine, citalopram,
escitalopram,
venlafaxine, duloxetine,
mirtazapine, bupropion,
nefazodone, and
trazodone
Outcome measures:
Response (>50%
improvement from
baseline on HAMD or
MADRS); and remission
(as defined by individual
studies).
Inclusion criteria:
Acute phase, parallel
group, double-blinded,
placebo-controlled trial
of 2nd-gen AD (nonTCAs) marketed in US;
patients had
nonpsychotic, unipolar
MDD not associated
with other medical
disorder; patients in
community dwelling and
aged 60+ years;
number of patients,
outcomes and dropouts
obtainable. Trials can
include unpublished
reports or poster.
Conclusions/
Limitations
Results
Second-generation
Ads are more
effective than placebo
Those assigned to drug treatment had significantly greater response [OR: 1.4 (95% CI: 1.24-1.57)] and remission
during acute
[OR: 1.27 (95% CI: 1.12-1.44)] than placebo (refer to figure 2 and 4)
treatment of adults
Response rates were also higher in the longer trials [10-12 weeks OR: 1.73 (95% CI: 1.42-2.09)] compared to shorter >60 years in terms of
response and
trials [6-8 weeks OR: 1.22 (95% CI: 1.05-1.42)]
remission, but the
magnitude is small
NNT for response =13 and remission = 20
and variable.
Efficacy




No single class of medication was superior to another as evidenced in the overlapping ORs
Tolerability

There was an increased in odds for discontinuation on medication [OR: 1.22 (95% CI: 1.06-1.4); I2=48.2%],
increased discontinuation due to AEs on medication [OR: 1.84 (95% CI: 1.51-2.24); I2=61.1%] (refer to figure 3)
Funnel plot did not illustrate presence of publication bias.
For every 100
patients treated, 8
would show a
response and 5 a
remission in excess of
placebo and for every
2 patients who
responded, one
discontinued
prematurely because
of AEs.
Therefore, clinical
decision to employ
Ads will need to
weigh modest
benefits with more
robust effects on
prevention of relapse
or recurrence and
potential AEs. In
addition, duration of
treatment appeared to
response as well.
Method:
- meta-analysis was
based on fixed-effect
model
- Heterogeniety was
assessed using I2
- Funnel plot used to
examine publication bias
- p-value was set at <0.20
and CI 95% for statistical
significance
Limitations: Possible
patient selection bias;
high heterogeneity;
low generalizability;
small number of trials
included;
underpowered; all
trials were sponsored
by manufacturer of
one of the drugs; and
possible residual
confounding.
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/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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Title
Search Database
/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
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Author &
Title
Deshauer et al.
(2008)
Selective
serotonin
reuptake
inhibitors for
unipolar
depression: a
systematic review
of classic longterm randomized
controlled trials.
Search Database
/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
Databases: MEDLINE,
EMBASE, Cochrane
Central Register
of Controlled Trials
(1966- May 2007).
N: 6 RCTs (1299
Treatment response
patients)
% F: Not reported
 Pooled analysis of the 6 trials showed that selective serotonin reuptake
inhibitors were superior to placebo in
2
Duration: 6-8 months
treatment response at 6–8 months [OR: 1.66 (95% CI: 1.12–2.48); I = 63.9%]
Mean sample size: 217
Search terms:
index terms associated
with “serotonin uptake
inhibitors” and the text
terms “SSRI,”
“fluoxetine,” “Prozac,”
“sertraline,” “Zoloft,”
“paroxetine,”
“Paxil,” “fluvoxamine,”
“Luvox,” “citalopram” and
“Celexa”.
Inclusion criteria:
Trials had to involve
patients who had a
diagnosis of major
depression (by DSMMD), aged >18 years,
and who were randomly
assigned to receive
monotherapy with a
SSRI or placebo; Trials
reporting a 1- to 2-week
placebo run-in period
were eligible; there

Subgroup analysis showed a statistically significant treatment effect among patients with depression who had no
2
comorbidities [OR: 2.13 (95% CI 1.11–4.08); I = 76.8%] but not among those who had comorbidities [OR: 1.32 (95%
2
CI 0.84–2.06); I = 30.8%]
Remission

Pooled difference between SSRIs and placebo was not statistically significant [OR: 1.46 (95% CI 0.92–2.32); I =
38%].

However, participants without comorbidities had a significantly higher remission rate if they were taking SSRIs than if
2
they were taking placebo [OR: 2.06 (95% CI 1.41–3.01); I = 0%) while whereas the difference for participants with
2
comorbidities was not statistically significant [OR: 0.87 (95% CI: 0.44–1.72); I = 0%]
2
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Statistically significant
improvements in
response to treatment
but not in remission or
acceptability after 6–8
months of SSRI
therapy were
observed with greater
effects in patients
without comorbidities.
Limitations:
Small number of
studies identified;
underpowered; weak
studies due to unclear
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methodological
issues, short follow02/12
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Title
Search Database
/ Method
Outcome measures:
Treatment response,
remission, and treatment
acceptability.
- response was defined
as proportion of patients
who had reduction of at
least 50% from baseline
scores on HDRS
- remission was defined
by cut-point (score of <7
on HDRS)
-tx acceptability was total
number of drop-outs.
secondary outcomes:
quality of life; admission
to hospital;
psychotherapy;
pharmacotherapy or
electroconvulsive
therapy; self-harm
(including attempted and
completed
suicide); and back-towork status.
Study (N)
Characteristics
were no comorbidity
restrictions.
Conclusions/
Limitations
Results
Treatment acceptability
 No statistically significant difference between SSRIs and placebo [OR: 0.87 (95% CI: 0.67–1.14); I =21.3%]
Definition of long-term
treatment was treatment Secondary outcomes
over a period of at least
6 months.
 None of the trials provided information on back-to-work status or the need for specific rescue therapies,
including admission to hospital for psychiatric reasons, psychotherapy, pharmacotherapy or electroconvulsive
Trials were limited to
therapy
those published in
English.
 5 studies reported quality of life at the end of the trial
2


One of the 5 trials reported improvements in all domains of a multi-domain quality-of-life score; one
reported a quality-of-life summary statistic favoring SSRIs (p < 0.01); the 3rd reported 10-cm visual
analogue scale also favoring SSRIs; and one reported quality-of-life improvements restricted to mood
subscales.
up, outcomes
reported as “response
to treatment” instead
of “full remission” with
preset cut-offs, trials
could have
overestimated active
long-term
interventions by using
last-observation
carried forward
analysis, and possible
publication bias (4 of
6 studies were
commercially
sponsored).
2 trials that reported on suicide or self-harm, there was a total of 1 completed suicide among patients receiving
placebo and none among patients receiving SSRI
Method:
- meta-analysis of RR =
was based on randomeffect model
- Funnel plot was used to
assess publication bias
- Heterogeniety was
assessed using I2
Barbui et al.
(2008)
Effectiveness of
paraoxetine in
the treatment of
acute major
depression in
adults: a
systematic reexamination of
published and
unpublished data
from randomized
Databases: Cochrane
collaboration depression,
anxiety and neurosis
review group controlled
trial registers,
GlaxoSmithKline Clinical
Trial Register, MEDLINE,
EMBASE (1966 12/2006) were searched
for published and
unpublished trials.
Search terms:
Keyword = “major
N: 40 RCTs (6391
patients; 3704 received
paroxetine vs. 2687
placebo)
% F: Not reported
Mean duration: not
reported
Mean sample size: not
reported
63% trials were done in
Europe and North
America.
53 studies included
Dropouts

No positive effect of paroxetine in terms of the proportion of patients who discontinued treatment for any reason
[random effect RR = 0.99, 99% CI 0.88–1.11)]
Efficacy

Greater proportion of patients who received paroxetine had a statistical significant improvement of 50% or more
compared to placebo [random effect RR = 0.83 (99% CI 0.77–0.90)]; no statistically significant between-study
2
heterogeneity (I = 9.2%).

A statistically significant positive effect of paroxetine in terms of mean difference [standardized mean difference –
2
0.31 (99% CI: –0.40 to –0.22)]; there was no statistically significant between study heterogeneity (I = 31.5%).
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paroxetine was not
superior to placebo in
terms of tolerability
(participants
discontinuing
treatment for any
reason) and was
modestly better than
placebo in terms of
depression measures
(paroxetine exerted a
modest
antidepressant effect
relative to placebo,
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Title
trials.
Search Database
/ Method
depression” or
“depression” and free-text
=“paroxetin*”;
“randomized controlled
trial” or “random
allocation” or “doubleblind method.”
Study (N)
Characteristics
people <65 years.
Conclusions/
Limitations
Results

Number needed to treat (NNT) to avoid 1 additional failure = 9 (99% CI: 7–14)
Inclusion criteria: only Tolerability
RCTs hat compared
any of the following 12
 Significantly more patients assigned to receive paroxetine left the study because of side effects [random effect RR =
new-generation
1.77 (95% CI: 1.44–2.18)]; there was no statistically significant between-study heterogeneity (I2 = 2.0%).
antidepressants
(bupropion, citalopram,
 Number needed to harm (NNH) = 17 (95% CI: 14–25);
duloxetine,
Outcome measures:
Treatment discontinuation escitalopram, fluoxetine,  Significantly more patients assigned to receive paroxetine than of those given placebo reported any adverse event
was the primary outcome fluvoxamine,
[random effect RR = 1.15 (95% CI: 1.11–1.19)]; there was no statistically significant between-study heterogeneity (I2
and response was
milnacipran,
= 17.6%).
secondary outcome.
mirtazapine,
- response was defined
paroxetine, reboxetine,
 NNH = 9 (95% CI: 7–11) (Figure 5).
as reduction of <50%
sertraline, and
from baseline scores on
venlafaxine) as
 No statistically significant difference between paroxetine vs. placebo in terms of patients reporting any serious
HDRS, MADRS, or who
monotherapy in acuteadverse event (Peto OR = 1.27, 95% CI 0.88–1.83); no between-study heterogeneity detected (I2 = 0%).
scored much improved on phase tx of adults with
CGI.
unipolar major
Suicidal tendencies
- tx discontinuation
depression.
(tolerability) was
 Significantly more patients assigned to paroxetine experienced suicidal tendencies than of those given placebo (US
proportion of patients who Exclusion criteria:
Food and Drug Administration codes 1 to 9) [Peto OR = 2.55 (95% CI: 1.17–5.54)]; no significant between-study
left the study early for any placebo
heterogeneity detected (I2 = 0%).
reason, because of side groups present and
effects; with any adverse RCTs of women with
 NNH=142 (95% CI: 7–3333)
post-partum depression
events; with any serious
adverse events; patients
who completed or
No statistical significances were detected between trials using 20-mg dose vs. >20-mg dose; among patients with
attempted suicide or
moderate to severe depression vs. mild depression; and published vs. unpublished studies.
experienced worsening of
suicidal thoughts or
Funnel plot suggests possible publication bias.
emotional liability.
11% absolute risk
difference).
Limitations:
Studies were not
designed or powered
to measure primary
outcome; nonadherence; absolute
numbers of patients
with suicidal
tendencies were low
and definition was
problematic; unclear
whether suicidal
tendencies are good
proxy for suicide
attempts.
Method:
- meta-analysis of RR =
was based on randomeffect model
- Heterogeniety was
assessed using I2
- sensitivity analysis was
conducted to evaluate
fixed-effect model
- p-value was et at 0.01
for statistical significance
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Author &
Title
Barbui et al.
(2009)
Selective
serotonin
reuptake
inhibitors and risk
of suicide: a
systematic review
of observational
studies.
Search Database
/ Method
Study (N)
Characteristics
Databases: MEDLINE,
EMBASE, (January 1990
to June 2008).
N: 8 RCTs (>200,000
patients)
% F: 8 – 74%
Age : 10+
Duration: not reported
Mean sample size: not
reported
Search strategy:
Search terms:
“antidepressive agents”
or “antidepressive agents
second generation” AND
“suicide”
or “suicide attempted”
Outcome measures:
ICD 9-10 definitions of
completed or attempted
suicide. Suicide attempts
had to be sufficiently
serious to have led to
medical contact.
Method:
- meta-analysis of RR =
was based on rfixed and
andom-effect models
- publication bias was
evaluated by funnel plot
- Heterogeniety was
assessed using I2
- sensitivity analyses and
metaregression were
used to examine study
using completed suicide;
formal diagnosis of
depression, external
control group; quality
score >7, data for both
adolescents and adults;
age; and outlier studies.
Conclusions/
Limitations
Results

metaregression suggested a promoting effect of SSRI exposure on the risk of suicide among adolescents and a
protective effect among adults and elderly individuals

Among adolescents, exposure to SSRIs significantly increased the risk of completed or attempted suicide
2
[random effect OR: 1.92 (95% CI 1.51–2.44); I =0.0%]
 Among adults, SSRI exposure significantly
decreased the risk of completed or attempted suicide [random-effect
2
OR: 0.57 (95% CI 0.47–0.70); I =52.5%]
Inclusion criteria:
observational cohort
 Among elderly people (aged 65 or more
years), exposure to SSRIs had a significant protective effect [randomand case–control
2
effect OR: 0.46 (95% CI 0.27–0.79) I =0.0%]
studies that reported
data on completed or
 visual inspection of the funnel plot suggested possible selection bias (lack of small studies that failed to show an
attempted suicide
excess risk associated with SSRI exposure)
among people exposed
to SSRIs and among
Subgroup analysis
those who were not
exposed to
 Among adults, no individual antidepressant was significantly associated with completed or attempted suicide.
antidepressants; studies
that reported relative
 Among adolescents, exposure to paroxetine [random-effect OR: 1.77 (95% CI 1.05–2.99); I2=48.1%] and venlafaxine
risk [RR] estimates
[random-effect OR: 2.43 (95% CI 1.47–4.02); I2=0.0%) was significantly associated with increased risk
suitable for re-analysis;
only
studies that used ICD 910 definitions of
completed or attempted
suicide were retained.
Study participants were
of both sexes and any
age with a diagnosis of
major depression.
Studies adopting proxy
measures to identify
patients with depression
were included.
Relation between
exposure to SSRIs
and the risk of suicide
is influenced by age,
and prescribing
SSRIs to patients with
major depression is
safe.
However, children
and adolescents
should be followed
very closely because
of the possibility of
increased of risk
suicidal thoughts and
suicide. Paroxetine
and venlafaxine may
be better avoided for
most adolescents.
Limitations:
Confounding and
biases inherent to
observational studies
included; confounding
by severity of illness,
gender, age;
presence of
publication bias; small
sample of studies
included;
underpowered to
detect small
differences between
drugs – lack of longterm head-to-head
comparison studies.
Patients may have
had additional
comorbidities that
may have influenced
selection of treatment
and have
unaccounted for
effects on suicide risk.

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Author &
Title
Search Database
/ Method
Study (N)
Characteristics
Conclusions/
Limitations
Results
© 2012 Kaiser Permanente Medical Care Program
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Table 1.2
Study
Proudfoot, et al.
(2004) Clinical
efficacy of
computerised
cognitivebehavioural
therapy for
anxiety and
depression in
primary care:
randomised
controlled trial.
Funding:
NHS Executive
London and
Ultrasis UK Ltd.
Inclusion &
Exclusion Criteria
Age
Limitations /
Biases
Intervention and
dose
N and Final N
Inclusion:
18-75
274 general practice
patients, suffering from
depression, mixed
anxiety and depression,
or anxiety disorder
(assessment by GHQ-12
and CIS-R)
Outcomes measured Participants randomized
into:
by self-report.
Exclusion:
Concurrent
psychological treatment
or counseling.
Data analyzers not
blinded to treatment.
Patients not masked
to treatment.
No selective
attention control.
Some data missing.
Duration
8 weeks
Rx1: Computerised CBT
"Beating the Blues" (N =
146): 15-minute
introductory video
followed by eight 50minute therapy sessions.
These participants could
also receive medication if
the general practitioner
chose to prescribe it, but
not in person
psychotherapy.
Outcome
Primary outcome
measure was BDI-II
score at eight weeks.
Secondary outcome
measures were Beck
Anxiety Inventory,
Work and Social
Adjustment scale, ASQ
CoNeg, ASQ CoPos.
Results
p
value
NNT
Received pharmacotherapy:
Rx1: 55.5%
Rx2: 55.5% (p not reported)
At eight week post-randomization,
computerised CBT group had significant
improvement over Usual Treatment group in:
BDI (p=.0006)
Work and Social Adjustment (p=0.002)
ASQ, CoNeg (p<0.0001)
ASQ, CoPos (p<0.008)
0.0006
0.002
<0.0001
<0.008
Change in BDI scores
3 mos.
5 mos. 8 mos.
Rx1
-12.8
-15.3
-15.6
Rx2
-6.3
-8.3
-9.8
Authors have
commercial interests
in the specific
Rx2: Usual Treatment (N
computerized
= 128): Received
programs.
whatever therapy general
practitioner prescribed.
Unclear how many
patients in usual
care who did not
receive
pharmacotherapy
received
psychotherapy – if
many of these
patients went
untreated, it would
bias results in favor
of the intervention
group.
There was no significant difference found
between groups on the BDI (p=0.06).
0.06
There was no interaction effect found for
pharmacotherapy or duration of illness, or
severity of illness.
BDI scores continued to decline over time (at
3, 5, and 8 month follow-up points), with lower
scores in the computerized CBT group.
35% withdrawal rate in the intervention group.
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Table 1.3
Study
de Jonghe (2004)
Psychotherapy
alone and
combined with
pharmacotherapy
in the treatment
of depression
Funding:
Supported by an
unrestricted grant
from Wyeth
Nederland.
Inclusion &
Exclusion Criteria
Age
Inclusion:
18-65
Outpatient adults with
DSM-IV criteria for Major
Depressive Disorder
(with or w/out
dysthymia), and baseline
HAM-D score of 12-24
points (mild to moderate
depression).
Exclusion:
Standard clinical
pharmacotherapy
research exclusion
criteria.
Limitations /
Biases
Intervention and
dose – N and Final
N
Duration
Different instruments
produced varying
success rates.
Rx1:
Psychotherapy alone (N
= 107) using Short
Psychodynamic
Patients and treating Supportive
physicians not blinded Psychotherapy (SPSP).
to treatment.
One refused
intervention, therefore N
Complex protocol
= 106.
may not be
generalizable to the
Rx2:
real world.
Combined SPSP and
pharmacotherapy (N =
More patients in the
101). Antidepressant
psychotherapy only
program was stepped
arm were previously
(noradrenaline, SSRI,
unresponsive to
nortriptyline, and
psychotherapy (26% nortriptyline with lithium)
vs. 14%, biasing
to address nonresponse.
study in favor of
Sixteen patients refused
combined treatment. intervention, therefore N
= 85.
LOCF data analysis.
Outcome
Primary outcome
measure was
difference in HAM-D
score assessments
between baseline and
week 24. Secondary
measures were scores
on CGI-I, CGI-S, and
SCL-D between
baseline and week 24.
Multiple measures;
Bonferroni adjustment
to significance level.
Results
p
value
NNT
Both treatment groups improved over time on
several measures (per protocol effect sizes
were minimal - moderate, 0.26-0.49,
depending on the measure used, with the
lowest effect size on the primary measure).
No significant difference between groups on
any measure in the Intention-to-treat sample.
No significant differences in time to remission
between the combined (129 days) and
psychotherapy (138 days) groups (p=0.122)
No statistically significant differences in
dropouts between the two groups.
Small but statistically significant differences in
HAM-D score at week 12 (1.8 points, p=0.046)
in the per protocol group and at weeks 12 and
24 (approximately 2.5 points, p=0.009 and
p=0.046) in the observed cases (completers)
sample. No difference in HAM-D remission
rates in the per protocol sample, significant
difference in the observed cases sample at
week 12 only (ARR = 6.2%, NNT 16, p=0.043).
Variable improvement in different secondary
measures at different times in the secondary
outcome measures in both the per protocol and
observed cases samples.
In both the Per Protocol and Observed Cases
analyses, there were some small but
statistically significant intra-group differences
between baseline and week 24, in favor of
combined therapy:
© 2012 Kaiser Permanente Medical Care Program
Per Protocol: CGI-I (p<0.05)
Per Protocol SCL-D (p<0.001)
< 0.05
< 0.001
Observed Cases: HAM-D (p<0.046)
Observed Cases SCL-D (p<0.001)
< 0.046
< 0.001
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Table 1.4
Study
Moore, et al.
(2005)
Prospective,
multicentre,
randomized,
double-blind
study of the
efficacy of
escitalopram
versus citalopram
in outpatient
treatment of
Major Depressive
Disorder.
Funding:
Provided by H.
Lundbeck A/S
through an
unrestricted
grant.
Inclusion &
Exclusion Criteria
Inclusion:
Adult outpatients with
DSM-IV criteria for Major
Depressive Disorder,
baseline MADRS score
of at least 30.
Exclusion
Axis I disorders other
than MDD; history of
mania, bipolar disorder,
schizophrenia or other
psychotic disorder,
obsessive-compulsive
disorder, cognitive
disorder including mental
retardation or personality
disorder; substance
abuse or use of
antipsychotic, anxiolytic
or anticonvulsant
medications prior to
study.
Age
18-65
Limitations /
Biases
No placebo control
Statistical
significance found
may not translate
into clinical
relevance. (2.1
point difference in
MADRS scores of
marginal clinical
significance).
Industry funded.
Intervention and
dose – N and Final
N
Patients randomly
assigned to:
Duration
8 weeks
Rx1: Escitalopram – 10
mg daily during first
week; 20 mg daily for
remaining 7 weeks, (ITT
N = 138, Completer N =
132)
Rx2: Citalopram 40 mg
daily for 8 weeks, (ITT N
= 142, Completer N =
127)
Outcome
Primary outcome
measure was change
from baseline to
previous assessment
in MADRS total score.
Results
Decrease in MADRS score
Rx1: -22.4 ± 12.9
Rx2: -20.3 ± 12.7
Responder rate (50% decrease from initial
MADRS score)
Rx1: 76.1%
Rx2: 61.3%
7
0.008
Remission rate
Rx1: 56.1%
Rx2: 43.6%
9
0.04
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170
<0.05
1.5 point difference in mean endpoint MADRS
scores (Rx1 = 13/9, Rx2 = 15.4); calculation not
reported by authors
Tolerability/adverse events
Rx1: 14.8%
Rx2: 16.4%
© 2012 Kaiser Permanente Medical Care Program
p
value
NNT
0.70
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Table 1.5
Study
DuRubeis, et al.
(2005) Cognitive
therapy vs.
medications in
the treatment of
moderate to
severe
depression
Funding:
Supported by
grants from the
National Institutes
of Mental Health.
GlaxoSmithKline
(Brentford,
Middlesex, United
Kingdom)
provided
medications and
pill placebos for
the trial.
Inclusion &
Exclusion Criteria
Inclusion:
Diagnosis of MDD
according to DSM-IV
criteria, English
speaking, score of 20 or
higher on modified 17item HDRS at screen
and baseline visits,
separated by at least 7
days.
Exclusion:
History of bipolar
disorder, substance
abuse/dependence,
current or past
psychosis, another Axis I
DSM-IV disorder;
antisocial, borderline or
schizotypal disorder;
suicide risk requiring
hospitalization; medical
condition contraindicative
to study medications,
nonresponse to
adequate trial of
paroxetine in year
preceding.
Age
18-70
Limitations /
Biases
Intervention and
dose – N and Final
N
Placebo control ended Patients randomly
at 8 weeks.
assigned to:
Unequal number of
subjects in treatment
groups.
Rx1: Antidepressant
medication, N = 120*, for
16 weeks.
Study conducted at
two different sites:
University of
Pennsylvania and
Vanderbilt University.
Rx2: Cognitive therapy,
N = 60, for 16 weeks.
Duration
16 weeks
Rx3: Pill placebo, N =
60, for 8 weeks**
Outcome
Primary outcome
measure was change in
HDRS score at 16
weeks.
Results
Outcome at 8 weeks
Response rate
Rx1: 50%
Rx2: 43%
Rx3: 25%
**For ethical reasons, pill
placebo was
discontinued after 8
weeks; patients in this
group were offered
treatment without cost
after 8 weeks.
© 2012 Kaiser Permanente Medical Care Program
0.001
Rx2 vs. Rx3
0.04
Rx1 vs. Rx2
0.40
0.92
Remission rate
Rx1: 46%
Rx2: 40%
0.04
Site X Treatment Interaction
(greater change in Rx1 at Vanderbilt)
Authors attribute this difference to variance in
patient characteristics and therapists’
experience levels.
0.02
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171
0.006
Rx1 vs. Rx3
Outcome at 16 weeks
Response rate
Rx1: 58%
Rx2: 58%
*Rx1 had twice as many
patients because
responders to Rx1 at
week 16 were to be
randomized a second
time for a companion
study of subsequent
relapse prevention.
p
value
NNT
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National Adult Depression Clincial Practice Guideline
Table 1.6
Study
Otsubo, et al.
(2005) A
comparative
study of the
efficacy and
safety profiles
between
fluvoxamine and
nortriptyline in
Japanese
patients with
Major Depression
Funding:
Supported in part
by grants from
the Ministry of
Health, Labour,
and Welfare in
Japan.
Inclusion &
Exclusion Criteria
Age
Inclusion:
20-69
DSM-IV criteria for single
episode or recurrent
Major Depression; either
“depressed mood” or
“work & interests” score
of 2 or more in HAM-D.
Exclusion:
Failure to respond to two
or more prior
antidepressant trials in
current episode; medical
contraindications to
antidepressant therapy;
significant hematologic,
endocrine, or
cardiovascular disease
conditions; acute suicidal
tendencies, seizure
disorder, psychotic
disorder not associated
with depression, history
of drug or alcohol
dependence; experience
or receiving fluvoxamine
or nortriptaline treatment.
Limitations /
Biases
No placebo control.
Single blind study
design.
Intervention and
dose – N and Final
N
Duration
Patients randomly
8 weeks
assigned to one of two
treatment groups (singleblind, parallel treatment):
Dose level of
fluvoxamine generally
lower than that of
previous studies.
Rx1: fluvoxamine, N =
36
Small sample size.
For both treatment
groups:
There was a 7 day drugfree washout period.
Starting daily dose for
first week was 50
mg/day. Thereafter,
dose was flexible
between 25-150 mg
taken 1-3 times per day.
Patients were allowed to
take lormetazepam 1-2
mg a day at bedtime for
sleep if necessary.
Rx2: nortriptyline, N = 38
Outcome
Results
Primary outcome
Intention-to-Treat Analysis
measures were
No significant between-group difference for the
changes from baseline change in total scores of HAM-D (p = 0.14 NS)
in the scores of HAM-D
and CGI.
Rx1
Rx2
Baseline
21
23
Endpoint
12
11
p
value
NNT
NS
No significant between-group difference for the
change in total scores of CGI severity (p = 0.55
NS). Figures not reported.
Response rate (HAM-D score reduction of 50%
or more)
Rx1: 55.6%
Rx2: 57.9%
NS
Response rate (CGI improvement scale scores
of 1 or 2)
Rx1: 52.8%
Rx2: 44.7%
NS
Remission rate (HAM-D score of 7 or less)
Rx1: 38.9%
Rx2: 26.3%
NS
When compared with fluvoxamine, nortriptaline
had more patients reporting adverse effects,
specifically dysarthria (13.9% vs. 36.8%,
p=0.02) and orthostatic dizziness (13.9% vs.
42.1%, p=0.01).
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Table 1.7
Study
Wehmeier, et
al.(2005)
Fluoxetine versus
trimipramine in
the treatment of
depression in
geriatric patients
Inclusion &
Exclusion Criteria
Inclusion:
Geriatric patients with
diagnosis of Major
Depression per DSM-IIIR criteria; score of ≥ 16
on HAMD-17.
Exclusion:
Funding:
Reduction of HAM-D
Supported by Lilly total score of more than
Deutschland, Bad 25% between screening
Homburg,
visit and baseline visit;
Germany
serious suicidal risk;
severe organic brain
disorder, significant
organic illness, history of
seizures; history of
schizophrenia; recent
history of drug or alcohol
abuse.
Ag
e
Limitations / Biases
61-85 Study took place in two
centers. One center enrolled
only inpatients while the other
center enrolled both inpatients
and outpatients.
Small sample size – risk of
type II error.
Low number of male patients
(2 total in study vs. 39
females).
Intervention and dose
N and Final N
After a 7 day washout period,
patients were randomly
assigned to one of two
treatment groups:
Rx1: Fluoxetine 20 mg/day, N
= 20, final N = 15
Rx2: Trimipramine 150
mg/day, N = 21, final N = 18
Duratio
n
5 weeks
Outcome
Primary outcome
measure was sum
score on HAMD-17.
Results
Change in HAM-D scores
Fluoxetine Trimipramine
baseline
28.1
27.9
endpoint
16.2
12.1
response
57.1%
60.0%
p
value
NNT
>0.05
>0.05
>0.05
Tolerability/adverse events
Rx1: 54.5%
Rx2: 66.7%
Findings can only be
generalized to elderly patients.
Short duration.
No placebo control.
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Table 1.8
Study
Sirey, Bruce, and
Alexopoulous
(2005) The
Treatment
Initiation
Program: An
intervention to
improve
depression
outcomes in older
adults
Funding:
Supported by a
grant from the
National Alliance
for Research in
Schizophrenia
and Affective
Disorders and a
grant from NIMH
to Dr. Sirey.
Inclusion &
Exclusion Criteria
Inclusion:
Outpatient geriatric
psychiatry patients with
diagnosis of DSM-IV
Major Depressive
Disorder; score of ≥ 17
on HAMD-24.
Exclusion:
Cognitive impairment,
existing antidepressant
therapy.
Ag
e
Limitations / Biases
65-85 Patients were from Psychiatry
only, and not Primary Care.
At baseline, the intervention
group had a significantly lower
HAMD score than the
nonintervention group (mean
23.1 vs. mean 26.4, p<0.05),
suggesting poor
randomization. Lower
pretreatment scores in the
intervention group might bias
remission results in favor of
the intervention group, when
in fact both groups could have
equal changes in HAMD
scores.
No information given on type
of pharmacotherapy (i.e.
antidepressant dose, type,
and frequency)
Intervention and dose
N and Final N
Participants were randomly
assigned to one of two
groups:
Rx1: Pharmacotherapy as
usual, N = 24
Rx2: Pharmacotherapy
with Treatment Initiation
Program (TIP)*intervention,
N = 21
*TIP is an individualized,
early intervention to
address older adults’
attitudes about depression
and barriers to care. 7
sessions administered over
24 weeks.
Duratio
n
24 weeks
Outcome
Results
Primary outcome
measure was HAM-D
assessment at
admission and at 6,
12, and 24 weeks.
p
value
NNT
Intervention group showed greater
improvement in depression than
nonintervention group. No figures
reported.
0.005
Remission rate
Rx1: 42%
Rx2: 71%
0.04
At 12 and 24 weeks after seeking
treatment, more intervention patients
remained in treatment than
nonintervention patients (post hoc
analysis; no figures reported)
0.05,
0.04
“Similar proportions of patients in each
group received supportive
psychotherapy” (numbers not
reported).
Results only generalizable to
elderly population.
Small study sample.
Lower than usual threshold
used to define remission
(HAMD <10 instead of <7).
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Table 1.9
Study
Detke, et al.
(2004)
Duloxetine in the
acute and longterm treatment of
Major Depressive
Disorder: a
placebo- and
paroxetinecontrolled trial.
Inclusion &
Exclusion Criteria
Age
Inclusion:
18+
Adult patients with
DSM-IV Major
Depressive Disorder;
CGI-S ≥ 4, HAMD-17 ≥
15.
Exclusion:
Other Axis I disorders;
recent primary
diagnosis of anxiety
Funding:
disorder; bipolar
Funding not
disorder, psychosis, or
reported;
schizoaffective
however all
disorder; recent history
authors employed of substance abuse or
by Eli Lilly and
dependence; previous
Co.
of response to two
courses of
antidepressant therapy,
suicidal risk; serious
medical illness.
Limitations / Biases
Lack of generalizability:
patients had few to no
comorbid conditions and,
few were taking
concomitant medications.
Intervention and
dose
N and Final N
Participants were
randomized into one of
the following (doubleblind) groups for 8 weeks:
Rx1: Placebo, N = 93
Fixed dose design is not
customary in clinical
practice.
Rx2: Duloxetine 80
mg/day, N = 95
No comparison of
duloxetine and paroxetine.
Rx3: duloxetine 120
mg/day, N = 93
Secondary analyses likely
to be underpowered.
Rx4: paroxetine, 20
mg/day, N = 86
Industry funded
Patients who showed a ≥
30% HAMD improvement
at 8 weeks (N = 273)
entered the 6 month
continuation phase:
Duloxetine used at higher
doses than currently
recommended by the
manufacturer; probably not
equivalent to paroxetine
dose.
Duration
8 weeks (acute
phase)
6 months
(continuation
phase)
Outcome
Primary outcome measures
were HAMD total score,
HAMD subscales, MADRS,
HAMA, VAS, CGI-S, and
PGI-I.
p
value
Results
Acute phase
HAMD score reduction:
Rx1: -8.8
Rx1 vs. Rx2
Rx2 -11.0
Rx1 vs. Rx3
Rx3: -12.1
Rx1 vs. Rx4
Rx4 -11.7
0.001
<0.001
<0.001
Estimated probabilities of response (%)
Rx1: 47
Rx1 vs. Rx2
Rx2 70
Rx1 vs. Rx3
Rx3: 77
Rx1 vs. Rx4
Rx4 82
Rx1: Placebo, N = 58
Rx2: Duloxetine 80
mg/day, N = 70
Estimated probabilities of remission (%)
Rx1: 30
Rx1 vs. Rx2
Rx2 51
Rx1 vs. Rx3
Rx3: 58
Rx1 vs. Rx4
Rx4 47
Continuation phase
Patients in each active treatment group
(Rx2, Rx3, Rx4) achieved significant
within-group improvement in total
HAMD, MADRS, HAMA, CGI-S, and
PGI-I.
0.005
<0.001
<0.001
< 0.01
≤ 0.001
≤ 0.05
Time to loss of response
Rx1 vs. Rx2
Rx1 vs. Rx3
Rx1 vs. Rx4
Rx3: duloxetine 120
mg/day, N = 75
0.003
0.023
Frequently reported treatment-emergent 0.003
adverse events:
Rx2: viral infection (5.7%)
Rx3: diarrhea (4.0%)
Rx4: headache (11.4%)
Rx4: paroxetine, 20
mg/day, N = 70
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Table 1.10
Study
Sechter, et al.
(2004) A
comparative
study of
milnacipran and
paroxetine in
outpatients with
Major Depression
Funding:
Sponsored by
Pierre Fabre
Medicament,
inventors and
manufacturers of
milnacipran.
Inclusion &
Exclusion Criteria
Inclusion:
Adult outpatients with
DSM-IV Major
Depressive Disorder
without psychotic
features; MADRS total
score ≥ 20.
Ag
e
Limitations /
Biases
18-70 No placebo control.
Industry funded
(milnacipran).
Exclusion:
Significant suicide risk;
lack of response to two
adequate
antidepressant
treatments; history of
psychotic disorder;
major personality
disorder; agoraphobia,
social phobia, or
obsessive compulsive
disorder; current
alcohol or drug abuse
or dependence.
Intervention and
dose – N and Final
N
Patients were
randomized into one of
the following groups:
Duratio
n
6 weeks
Rx1: milnacipran 100
mg/day, N = 149
Rx2: paroxetine 20
mg/day, N = 153
Outcome
Outcome measures
were differences in
baseline in: HAMD-17
total score, MADRS
total score, CGI score
at 7, 14, 28, and 42
days.
Results
No significant differences between Rx1 and
Rx2 on any of the following measures:
HAMD-17 total
Rx1
Baseline 23.7
Endpoint 11.9
Rx2
23.4
11.4
MADRS score
Rx1
Baseline 29.8
Endpoint 13.6
Rx2
29.6
12.8
Responders (%)
Rx1
HAMD-17 58.1
MADRS 62.8
CGI
66.2
Rx2
60.3
64.9
64.2
Remissions (%)
Rx1
HAMD-17 33.1
MADRS 45.3
Rx2
35.1
47.7
For use within Kaiser Permanente only.
176
NS
NS
NS
Post-treatment discontinuation emergent
symptoms:
Rx1: 13.0
Rx2: 31.8
© 2012 Kaiser Permanente Medical Care Program
p
value
NNT
NS
0.032
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National Adult Depression Clincial Practice Guideline
Table 1.11
Study
Allard, et al.
(2004) Efficacy
and tolerability of
venlafaxine in
geriatric
outpatients with
Major
Depression: a
double-blind,
randomised 6month
comparative trial
with citalopram
Funding:
Wyeth, Lederle
Nordiska AB,
Sweden
Inclusion &
Exclusion Criteria
Inclusion:
Male and female
outpatients 65 and older,
with DSM-IV Major
Depression and in need
of antidepressant
therapy; MADRS score
20+; ≤ 20% change in
MADRS score between
pre-study and baseline
visits.
Age
64-89
Limitations /
Biases
No placebo control.
Industry funded
Exclusion:
Cognitive impairment,
alcohol or drug abuse,
psychotic disorder not
associated with
depression, recent (1
year) psychiatric
inpatient treatment;
acute suicidality; bipolar
disorder, dementia,
mental disorders due to
a general medical
condition, history of
seizure disorder,
significant cardiovascular
or cerebrovascular
disorder, uncontrolled
hypertension; significant
abnormalities assessed
in prestudy physical
exam.
Intervention and dose
N and Final N
Participants randomized into one
of two groups (double-blind,
parallel group design):
Rx1: Venlafaxine – IR 37.5 mg
once daily during first week, ER 75
mg once daily during following two
weeks, increase to 150 mg/day
during following two weeks if no
response, N = 76
Rx2: Citalopram – 10 mg once
daily during first week, 20 mg once
daily during following two weeks,
30 mg during following two weeks
if no response, N = 75
Duration
6 months
Outcome
Primary outcome measure
was change in MADRS score
from baseline to 8 weeks,
and baseline to 22 weeks
Results
p
value
NNT
Both treatment groups showed
comparable improvements in
MADRS scores over time.
There were no statistically
significant differences in
MADRS scores between the
two groups.
MADRS scores
Rx1
Baseline 27.6
Week 8 12.0
Week 22 9.6
NS
Rx2
27.0
11.5
9.6
MADRS responders
Rx1
Rx2
Week 8 75.4%
72.5%
Week 22 93.1%
93.2%
NS
Spontaneously reported side
effects/adverse events:
Rx1: 62%
Rx2: 43%
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Table 1.12
Study
Montgomery,
Huusom, &
Bothmer (2004)
A randomized
study comparing
escitalopram with
venlafaxine XR in
primary care
patients with
Major Depressive
Disorder.
Funding:
Sponsored by H.
Lundbeck A/S.
Inclusion & Exclusion
Criteria
Inclusion:
Primary care patients, DSMIV diagnosis of MDD; ≥ 18
score on MADRS.
Exclusion:
History of mania or bipolar
disorder, schizophrenia or
any psychotic disorder;
currently suffering from
obsessive compulsive
disorder; eating disorders,
mental retardation;
development or cognitive
disorder; MADRS score ≥ 5
on item 10 (suicidal
thoughts); alcohol or drug
abuse problems past one
year; treatment with
antipsychotics,
antidepressants,
psychotropics, serotonin
receptor agonists, lithium,
carbamazepine, valproate, or
alpromide; ECT; treatment
with behavior therapy or
psychotherapy; pregnant or
breast feeding.
Age
18-85
Limitations /
Biases
No placebo control.
Industry funded
Observed cases
analysis
Intervention and
dose
N and Final N
After one week run-in
period, patients were
randomized into one of
two groups (double-blind
design):
Duration
8 weeks
Rx1: Escitalopram. Initial
dose 10 mg/day. At week
2 or 4, dose could be
increased to 20 mg/day; N
= 146
Rx2: Venlafaxine XR.
Initial dose 75 mg/day. At
week 2 or 4, dose could
be increased to 150
mg/day; N = 142
Outcome
Results
Primary outcome measures MADRS scores (observed cases):
were changes in MADRS
Rx1
Rx2
and HAMD-17 total scores. Baseline 28.7
29.0
Week 8 8.0
8.6
HAMD-17 scores (observed cases)
Rx1
Rx2
Baseline 19.9
20.4
Week 8 5.5
6.4
p
value
NNT
NS
NS
Rx1 group achieved sustained
response significantly faster (4.6 days
faster) than Rx2 (p<0.05).
p<0.05
Rx1 group achieved sustained
remission significantly faster (6.6 days
faster) than Rx2 (p<0.001).
p<0.001
Rx2 group had significantly more
nausea, constipation, and increased
sweating (p < 0.05).
<0.05
Rx2 group had significantly more
discontinuation symptoms (p < 0.01).
<0.01
No difference in overall discontinuation
rates (14.4% vs. 13.3%)
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Table 1.13
Study
Rapaport, et
al.(2003) Efficacy
of controlledrelease
paroxetine in the
treatment of latelife depression.
Inclusion & Exclusion Criteria
Age
Inclusion:
60+
Elderly adults with DSM-IV Major
Depressive Disorder; HAMD-17 score
≥18 at both screening and baseline
visits.
Exclusion:
HAMD total score decreased by 25%
Funding:
or more between screening and
GlaxoSmithKline, baseline; concomitant therapy with
Research
psychoactive medication other than
Triangle Park, NC chloral hydrate; diagnosis of other
axis I disorder; history of brief
depressive episodes previousing ≤8
weeks with spontaneous remission;
neurological disorders contributing to
secondary depression; dementia;
MMSE score ≤24; serious medical
conditions contraindicative to
paroxetine; history of seizure
disorders; concomitant treatment with
warfarin, phenytoin, cimetidine,
sumatribtan, type 1C antiarrhythmic
agents, or quinidine; history of
substance abuse or dependence,
ECT within 3 months; unresolved or
abnormal ECG findings; suicidal or
homicidal tendencies.
Limitations /
Biases
Intervention &
dose
N and Final N
Study restricted to
elderly outpatients
(not those in
nursing homes,
etc.)
Participants
randomized into one of
three groups (flexible
dose, double-blind
study)
Excluded patients
with severe or
unstable medical
illness.
Rx1: Paroxetine CR up
to 50 mg/day, N = 104
Rx2: Paroxetine IR up
to 40 mg/day
Rx3: Placebo
Duration
12 weeks
Outcome
Primary outcome
measure was
change in HAMD
total score from
baseline to
endpoint.
Results
p
value
NNT
HAMD total score change from baseline in
Intention-to-Treat, LOCF population:
Rx1
Baseline 22.1
Endpoint 10.0
Change -12.1
Rx2
22.3
10.0
-12.3
Rx3
22.1
12.6
-9.5
Adjusted difference between Rx1 and Rx3
= -2.8 (95% confidence interval = -4.47 to
-0.73, p=0.007).
p=0.007
Adjusted difference between Rx2 and Rx3
= -2.8 (95% confidence interval = -4.65 to
-0.99, p=0.03).
0.03
Response rates (score of 1 or 2 on CGI-I):
Rx1: 72% (p<0.002 vs. Rx3)
Rx2: 65% (p=0.06 vs. Rx3)
Rx3: 52%
<0.002
0.06
Remission rates (HAMD ≤7):
Rx1: 43% (p<0.009 vs. Rx3)
Rx2: 44% (p=0.01 vs. Rx3)
Rx3: 26%
<0.009
0.01
Post-hoc analysis revealed that patients
with chronic depression (duration > 2
years) responded as well as patients with
short-term depression.
Withdrawal due to adverse events:
Rx1: 12.5%
Rx2: 16.0%
Rx3: 8.3%
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Table 1.14
Study
Sauer, UppertzHelmhold &
Dierkes (2003)
Efficacy and
safety of
venlafaxine ER
vs. amitriptyline
ER in patients
with Major
Depression of
moderate severity
Funding:
Study granted by
Wyeth Pharma
GmbH, Germany
Inclusion & Exclusion
Criteria
Inclusion:
Adult outpatients with ICD-10
Major Depression of moderate
severity; HAMD-21 score 20-26
at first screening; depressive
symptoms present for minimum
of 14 days prior to study.
Age
18-65
Exclusion:
Hypersensitivity to or previous
unsuccessful treatment with
venlafaxine or amitriptyline;
bipolar or psychotic disorders,
history of convulsive disorders,
hypertension, suicidality, HAMD
score decrease ≥ 4 between
screening and baseline; onset of
additional psychotherapy;
pregnancy or lactation, treatment
with sumatriptan or antipsychotic
medication, ECT within 30 days
prior, treatment with fluoxetine
within 30 days prior, treatment
with MAO inhibitors within 14
days prior, clinically relevant
findings concerning physical
exam, ECG or laboratory
parameters
Limitations /
Biases
Noninferiority study.
No placebo control.
Study conducted in
Germany, where
antidepressants are
prescribed at
generally lower
doses.
Intervention and
dose
N and Final N
After a one-week washout period, participants
were randomized into
Rx1: Venlafaxine ER
75mg, N = 79
Rx2: Amitriptyline ER: 2
mg on day one, 50 mg on
day two, 75 mg from day
three onwards, N = 77
Industry funded
In cases of insufficient
response, doses were
increased to 75 mg from
day 15 onwards.
© 2012 Kaiser Permanente Medical Care Program
Duration
6 weeks
Outcome
Results
Primary outcome
measure was
change in HAMD21 score.
Significant noninferiority of venlafaxine,
as reflected by change in HAMD scores
(Intention-to-Treat analysis):
Baseline
Endpoint
Change
Rx1
23.6
13.1
-10.5
Rx2
23.6
13.3
-10.4
Similar results found in ATP (According
to Protocol) analysis:
Rx1
Rx2
Baseline
23.6
23.6
Endpoint
13.0
12.6
Change
-10.6
-11.0
0.0042
0.01
Frequency of adverse events:
Rx1: 70.9%
Rx2: 81.8%
p=0.11
0.11
Frequency of adverse drug reactions:
Rx1: 55.7%
Rx2: 71.4
p=0.04
0.04
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Table 1.15
Study
Kool (2003)
Efficacy of
combined therapy
and
pharmacotherapy
for depressed
patients with or
without
personality
disorders.
Funding:
Supported by an
unrestricted
educational grant
from Eli Lilly
Nederland.
Inclusion &
Exclusion Criteria
Inclusion:
Adults with DSM-III-R
Major Depression (with
or without dysthymia;
with or without
personality disorder);
HAMD-17 ≥ 14.
Exclusion:
Patient considered “too
ill” or “too suicidal” to
participate in a clinical
trial; drug abuse or
psycho-organic,
psychotic, or dissociative
disorder; patient not
considered reliable
enough to participate in a
clinical trial.
Age
18-60
Limitations /
Biases
Small number of
subjects – risk of
Type II error.
Specialty mental
health setting -- ?
applicability to
primary care
settings.
Intervention and
dose
N and Final N
Patients randomized into
one of two groups:
Duration
24 weeks
Rx1: Pharmacotherapy
with three tiered protocol
(steps2 and 3 used if
steps 1 and 2 proved
ineffective):
1) fluoxetine 20 mg/day
2) amitriptyline 100-150
mg/day
3) moclobemide 300-600
mg/day
N = 56
Outcome
Outcome measures
were CGI-I, CGI-S,
HAMD-17, QLDS,
and SCL-90.
Results
Combined therapy was more effective than
pharmacotherapy alone for depressed patients
with personality disorders.
0.04
Combined therapy was not more effective than
pharmacotherapy alone for depressed patients
without personality disorders.
0.74
Change in HAMD scores:
Baseline
Rx1
with PD
20.75
Rx2
with PD
20.12
Rx1
w/o PD
21.20
Rx2
w/o PD
19.70
Rx2: Combined therapy:
pharmacotherapy as
described above plus 16
sessions of short
psychodynamic supportive
psychotherapy (SPSP)
starting two weeks after
the initiation of
medication.
N = 72
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Endpoint
14.89
11.10
12.10
11.09
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Table 1.16
Study
Wade, et al.
(2003) A
randomized,
double-blind, 24week study
comparing the
efficacy and
tolerability of
mirtazapine and
paroxetine in
depressed
patients in
primary care.
Inclusion &
Exclusion Criteria
Age
Inclusion:
18+
Male and female adults,
aged 18 and over; DSMIV criteria for single or
recurrent depressive
episode, HAMD-17 score
>18.
Exclusion:
Schizophrenia or bipolar
affective disorder,
suicidality, abuse of illicit
drugs, alcohol
dependence; recent
Funding:
treatment with other
Study funded by psychotropic drugs,
a clinical research hypersensitivity to
grant from
paroxetine or mirtazipine
Organon
(or use for current
Laboratories Ltd., depressive episode);
Dambridge
fluoxetine within 5
Science Park,
weeks, use of other
Cambridge UK.
antidepressants within 2
weeks of study; clinically
meaningful renal,
hepatic, respiratory,
cardiovascular or
cerebrovascular disease;
pregnancy or lactation;
investigator’s
assessment of
unsuitability for trial.
Limitations /
Biases
No placebo control.
Intervention and
dose
N and Final N
Participants randomized
into one of two groups:
Duration
24 weeks
No washout period.
High discontinuation
rates overall (>50%
each group).
Rx1: Mirtazipine 30
mg/day (between weeks
5-24 dosage could be
increased to 45 mg/day) N
= 99
Outcome
Primary outcome
measure was change
in HAMD-17 score
from baseline.
Results
NNT
There was no statistically significant difference
in HAMD improvement at 24 weeks.
Rx1: -18.2
Rx2: -16.6
p
value
0.15
At weeks 2, and 4 there was a statistically
significant difference in HAMD improvement, in
favor of mirtazapine:
Industry funded
Rx2: Paroxetine 20
mg/day (between weeks
5-24 dosage could be
increased to 30 mg/day),
N = 98
Week 2
Difference -2.0 (95% CI: -3.5 to -0.4; p=0.012)
Week 4
Difference -2.0 (95% CI: -3.8 to -0.2; p=0.030)
Overall adverse effects: Rx1: 79%, Rx2: 85%.
Tolerability/adverse events
Rx1 statistically significantly higher incidence of
fatigue.
0.012
Rx2 group reported statistically significantly
more sweating (p=0.010), headache (p=0.008)
and nausea (p<0.001).
HAMD response rates:
Rx1: 87%
Rx2: 78%
HAMD remission rates:
Rx1: 61%
Rx2: 42%
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Table 1.17
Study
Inclusion &
Exclusion Criteria
Age
Montgomery
(2003) The
antidepressant
efficacy of
reboxetine in
patients with
severe
depression
Inclusion:
18-65
Adult patients with DSMIII or DSM-IV criteria for
Major Depressive
Disorder of at least one
month’s duration and
baseline severity score ≥
20 on HAMD-21.
(analysis of 4
RCTs)
Exclusion:
Pregnancy or
breastfeeding,
hypersensitivity to
psychotropic
medications, recent
history of substance
abuse; other medical or
psychiatric conditions;
history of resistance to
antidepressant
medications.
Funding:
Data reported
supported by
grants from
Pharmacia
Corporation,
Peapack, NJ.
Limitations /
Biases
Small number of
studies analyzed.
The four studies were
not similar in terms of
duration or study
population (n).
Intervention and
dose – N and Final
N
After 4-14 day washout
period, patients were
randomized into one of
two groups:
Duration
28-56 days
Rx1: Reboxetine –
initiated at lower doses,
but maintained at 8-10
One of the four
mg/day divided into two
studies (Versiani et al, daily doses
2000) had a much
higher baseline mean Rx2: placebo
HAMD score – 35.4
vs. 26.4, 27.0, and
27.2).
Outcome
Primary outcome
measure was mean
change in HAMD
score from baseline
to previous follow-up
evaluation, in each
of the four trials.
Results
p
value
NNT
In three of the four trials, the reboxetine group
had a significantly greater decrease in HAMD
score when compared with placebo.
<0.001
In three of the four trials, antidepressant
efficacy occurred significantly faster (at two
weeks) in the reboxetine group when compared
with the placebo group.
<0.05
In three of the four trials, the responder rate
was significantly higher in the reboxetine group
(56-74%) compared with placebo (20-52%).
<0.05 <0.001
Patients unresponsive
to previous
antidepressant
treatment were
excluded.
Remission rates not
reported
All studies included
were funded by
Pharmacia, the
manufacturer of
reboxetine; a
systematic review was
not performed
(unpublished studies
may not have been
included).
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Table 1.18
Study
Gasto, et al.
(2003) Singleblind comparison
of venlafaxine
and nortriptyline
in elderly Major
Depression
Funding:
None reported.
Inclusion &
Exclusion Criteria
Age
Inclusion:
65+
In- and out- patients with
DSM-IV Major
Depression, with or
without endogenous or
psychotic features;
baseline HAMD-17 ≥21;
symptoms present for at
least one month.
Exclusion:
Uncontrolled medical
illness; manic or hypo
manic episode, history of
nonaffective psychosis,
substance dependence;
ECT therapy within 6
months of recruitment.
Limitations /
Biases
Single blind study
(psychiatrist only)
No placebo control.
Intervention and dose
N and Final N
After a two-week washout
period, participants were
randomized into one of two
groups:
Elderly patients only. Rx1: Venlafaxine –
Starting dose: 75 mg/d
Day 4: 150 mg/d
Day 8: 225 mg/day
Clinician option to increase to
300 mg/day at 2-week
evaluation.
N = 34
Rx2: Nortriptyline –
Starting dose: 12.5 mg/d
Day 4: 25 mg/d
Day 8: 50 mg/day
Clinician option to increase to
300 mg/day at 2-week
evaluation.
Plasma concentrations were
assessed after one week and
doses were adjusted to achieve
a plasma concentration
between 80 and 100 mg/ml
Maximum dose: 100mg/d
N = 34
© 2012 Kaiser Permanente Medical Care Program
Duration
6 months
Outcome
Primary outcome
measures were
scores on HAMD-17
and Newcastle
Scale.
Results
Intention-to-treat analysis (N = 61: Rx1 N
= 31, Rx2 N = 30)
Remission rates:
Rx1: 70.1%
Rx2: 70%
0.84 NS
Efficacy was not dependent on clinical
severity of the depressive episode.
Treatment groups were similar when subanalyses were performed evaluating the
following categories: endogenous,
nonendogenous, psychotic, nonpsychotic,
severe inhibition, mild inhibition.
0.94 –
1.00 NS
Both drugs were similarly tolerated. Side
effects were frequent (Rx1 = 73.5%, Rx2
=82.3%) but mild to moderate in intensity.
On the autonomic side-effects subscale,
Rx1 scored lower than Rx2 (2.03 and 2.91
respectively), suggesting a more benign
side-effect profile for venlafaxine.
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Table 1.19
Study
Hansen, et al.
(2005) Efficacy
and safety of
secondgeneration
antidepressants
in the treatment
of Major
Depressive
Disorder.
(Review)
Funding:
Dr. Gaynes
supported in
part by a
National
Institute of
Mental Health
K23 Career
Development
Award, the
Robert Wood
Johnson
Foundation, and
the Agency for
Healthcare
Research and
Quality.
Inclusion &
Exclusion
Criteria
Efficacy trials, N = 46
Head-to-head
comparison of one
antidepressant with
another; conducted in
Primary Care settings;
≥ 3 month duration of
follow-up; minimal
inclusion and
exclusion criteria (to
represent general
population); assessed
health outcomes
rather than immediate
outcomes; adequate
sample size to
determine a minimally
important difference
(from a patient’s
perspective) on a
health-related quality
of life instrument.
Safety and tolerability,
N = 21
Head-to-head trials;
placebo-controlled;
observation studies
with large samples
(>100) previousing at
least one year.
Limitations
/ Biases
Limited
quantitative
analyses due
to inadequate
evidence.
Intervention and dose
N and Final N
Qualitative analysis of
studies
Quantitative analysis when
more than three head-tohead trials compared the
Many trials
same treatments (primary
sponsored by
outcome measure
pharmaceutical treatment response).
companies;
possible
If treatment effects differed
publication
among studies, potential
biases.
reasons were assessed.
Heterogeneity tested for
treatment effects in metaanalyses.
Mean incidence and 95%
confidence intervals
calculated for specific
adverse events (significant
variance, should be
interpreted with caution)
Outcome
Results
Primary
outcome
measures for
head-to-head
comparison
trials were
efficacy, speed
of response,
quality of life
and
tolerability/adve
rse effects.
Primary
outcome
measure for
meta-analyses
was responder
rate.
Head-to-head comparison trials
Efficacy Overall, trials reported similar outcomes among the six SSRIs. Differences in treatment effects
between some trials that found a significant and those that didn’t could be attributed to small sample sizes
and publication bias in favor of the sponsoring pharmaceutical company’s antidepressant.
Trials comparing SSRIs with other second generation antidepressants showed similar efficacy.
Speed of response Overall, the trials reported no difference among SSRIs. Evidence of a faster response
to citalopram, fluvoxamine, and paroxetine than to fluoxetine is based on results of one trial or is
inconsistent with other evidence. Trials comparing SSRIs with other second generation antidepressants
showed an average speed of response of 4-6 weeks, with no statistically significant differences among
treatments. Evidence in some trials of a faster response rate with venlafaxine is equivocal.
Quality of life Overall, trials showed no significant difference among SSRIs in their ability to improve
health-related quality of life. One trial did report better sleep quality with fluovoxamine than with fluoxetine.
Trials comparing SSRIs with other second generation antidepressants reported no differences in overall
quality of life.
Tolerability/adverse effects Overall, incidence of adverse effects was similar among antidepressants.
Quality of reporting and methods used to report adverse effects differed among studies
Meta-analyses
Fluoxetine vs. paroxetine
Responder rate did not differ significantly between fluoxetine and paroxetine
(relative benefit 1.09, CI: 0.97 to 1.21).
Fluoxetine with sertraline
Pooled results showed a small treatment effect of sertraline compared with fluoxetine
(relative benefit, 1.10, CI: 1.01 to 1.22) although no individual trial showed significant differences.
Venlafaxine vs. fluoxetine
Pooled data from 6 studies showed that venlafaxine yielded more responders than fluoxetine (57.6% vs.
51.1%, ARR = 6.5%, NNT = 15; RR = 1.12, CI: 1.02-1.23). Most other individual studies comparisons for
venlafxaine vs. other SSRIs did not show a difference, pooled analysis for venlafaxine vs. all SSRIs not
performed.
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Table 1.20
Study
Arroll, et al.
(2005) Efficacy
and tolerability of
tricyclic
antidepressants
and SSRIs
compared with
placebo for
treatment of
depression in
primary care: a
meta-analysis
Inclusion &
Exclusion Criteria
Inclusion
Randomized, controlled
trials using TCAs and/or
SSRIs using primary
care patients; study
population of adults with
diagnosis of Major
Depression.
Exclusion:
Studies using
predominantly children or
the elderly.
Age
Limitations /
Biases
18+
Larger number of
(primar studies comparing
ily)
TCAs with placebo
than comparing
SSRIs with placebo.
Intervention and
dose
N and Final N
Three groupings of
studies, total N = 15:
Duration
N/A
TCAs vs. placebo, N = 10
SSRIs vs. placebo, N = 3
Studies lacked
consistency in
patients’ severity of
depression.
TCAs and SSRIs vs.
placebo, N = 2
Outcome
Primary outcome
measure was
efficacy of TCAs and
SSRIs in comparison
with placebo.
Results
NNT
Pooled efficacy data showed both TCAs and
SSRIs were significantly more effective than
placebo:
TCAs vs. placebo
Relative risk 1.26 (95% CI: 1.12 – 1.42)
NNT = 4, NNH (withdrawal)= 5-11.
4
6
SSRIs vs. placebo:
Relative risk 1.37 (95% CI: 1.21 – 1.55)
NNT = 6, NNH (withdrawal)=21-94.
Both low dose and high dose TCAs were
effective.
Funding:
Funding Body
Chief Scientist
Office, Scotland.
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p
value
Table 1.21
Study,
Total n
Detke, M.
2002 (RCT, double-blind)
Follow-up: 9 weeks
Initial n: 245
Final n: 225 (based on safety
analysis numbers)
Treatment Groups Size &
Intervention Description
Study Population
Results
For efficacy analysis
Men and women at least 18 years of age
Rx1: Duloxetine,
60 mg/day
(n = 121)
Adult patients with DSM-IV MDD baseline
score of ≥ 15 on the HAM-D-17 (17-item
Hamilton Rating Scale for Depression)
Rx2: Placebo
(n = 115)
Baseline score of ≥ 4 on the CGI-S
(Clinical Global Impressions-Severity)
For safety analysis
Rx1: Duloxetine,
60 mg/day
(n = 123)
Least square mean change
from baseline to previous
observation using HAM-D17 scale (primary efficacy
measure)
Rx1: -10.91
Rx2: -6.05
p < 0.001 (in favor of
duloxetine)
Estimated probability of
remission for duloxetine
patients = 44% vs. 16% for
placebo-treated patients
Rx2: Placebo
(n = 122)
Treatment-emergent adverse events
(safety measure)
Nausea
Rx1: 46.3% of patients
Rx2: 9.0% of patients
p < 0.001 (in favor of placebo)
Dry mouth
Rx1: 27.6%
Rx2: 6.6%
p < 0.001
Comments
Duloxetine in a once
daily dose of 60 mg/day
was significantly superior
to placebo in reducing
HAM-D-17 total scores,
starting at week 2, but is
associated with a
significantly increased
risk of side effects.
Somnolence
Rx1: 21.1%
Rx2: 4.9%
p < 0.001
The following adverse effects were also
statistically significant: dizziness,
diarrhea, insomnia, and constipation
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Table 1.22
Study,
Total n
Goldstein, D.
2002 (RCT, double-blind)
Treatment Groups Size &
Intervention Description
Follow-up: 8 weeks
Rx1: duloxetine, titrated in the first
three weeks from 40 mg
(20 mg b.i.d.) to 120 mg/day
(60 mg b.i.d.) (n = 70)
Initial n: 173
Rx2: placebo (n = 70)
Final n: 167
Rx3: fluoxetine,
20 mg q.d. (n = 33), was used as an
internal control
Study Population
Male and female outpatients
ages 18 to 65 with DSM-IV
Major Depressive Disorder
Clinical Global Impressions
(CGI)-Severity of Illness
score of at least moderate
severity (≥ 4)
17-item Hamilton Rating
Scale for Depression (HAMD-17) total score of at least
15
Results
Least square mean change
from baseline to previous visit
using HAM-D-17 scale
(primary efficacy measure)
Rx1: -9.73
Rx2: -6.61
Rx3: -7.75
p = 0.009 (duloxetine vs.
placebo) in favor of
duloxetine
Comments
Treatment-emergent adverse events
(safety measure)
Insomnia
Rx1: 20.0% of patients
Rx2: 7.1% of patients
Rx3: 9.1% of patients
p = 0.046 in favor of placebo (duloxetine vs.
placebo)
Duloxetine is statistically
superior to placebo in
reducing the symptoms of
MDD.
Duloxetine treated patients exhibited a small but
statistically significant reduction in body weight
relative to placebo
(0.59 kg) p = 0.005
Fluoxetine was included
as an internal control to be
sure patients were
antidepressant
responsive.
Estimated probability of
remission for duloxetinetreated patients was 56% vs. The mean increase in standing diastolic blood
32% for placebo-treated
pressure for duloxetine-treated patients was 2.80
patients,
mm Hg greater than for placebo-treated patients
p = 0.22
(p = 0.041)
Study was not designed to
be a comparison of
duloxetine and fluoxetine.
Clinical significance of
changes in BP and weight
uncertain.
The following adverse effects were not statistically
significant: dry mouth, headache, somnolence,
dizziness, diarrhea, nausea, and constipation
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Table 1.23
Study,
Total n
Wade, A.
2002 (RCT, double -blind)
Treatment Groups Size &
Intervention Description
Rx1: escitalopram (SSRI)
10 mg/day
(n = 191)
Follow-up: 8 weeks, following
an initial 1-week single-blind, Rx2: placebo
placebo period
(n = 189)
Study Population
Patients were aged between
18 and 65 years, 3:1 ratio of
women to men
> 97% Caucasian
Adjusted mean change in MADRS total
score from baseline to week 8
Patients fulfilled DSM-IV
criteria for MDD
Rx2: 13.6
Initial n: 380
Final n:320
Results
Rx1: 16.3
p = 0.002 (in favor of escitalopram)
Had a baseline MontgomeryAsberg Depression Rating
Scale (MADRS) total score ≥
22 and ≤ 40
Comments
Tolerability
Nausea (% of patients)
Rx1: 8.9%
Rx2: 3.7%
p < 0.05 (in favor of placebo)
This difference disappeared within
the first two weeks of double-blind
treatment
Headache (% of patients)
Rx1: 12%
Rx2: 10.1%
Not statistically significant
© 2012 Kaiser Permanente Medical Care Program
Escitalopram 10 mg/day had a
statistically significantly better
antidepressant effect than
placebo as early as week one,
and was safe and well tolerated.
The proportion of escitalopram–
treated patients in complete
remission was also statistically
significantly higher than that of
placebo-treated patients at week
eight. (p < 0.01)
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Table 1.24
Study,
Total n
Moncrieff, J.
1998 (metaanalysis)
Treatment Groups Size &
Intervention Description
Randomized and quasi
randomized trials
Study Population
Results
Participants of either sex
of all age groups with
primary diagnosis of
depressive disorder
(Individual studies)
Change in mood
Daneman, 1961
SMD = 1.1 (0.8 to 1.4)
# studies found: 12 Drugs used were all TCAs.
Inpatients and outpatients
# studies included:
9
Specialty behavioral
health settings
Uhlenhuth, 1963
SMD (unadjusted) = 0.60
(0.02 to 1.2)
SMD (adjusted for baseline values) = 0.35 (0.25 to 0.96)
Double-blinded
All trials used active placebos
containing atropine
Weintraub, 1963
SMD (for hospital director) = 0.14
(-0.34 to 0.62)
SMD (for ward doctor) = 0.63
(0.15 to 1.11)
Wilson, 1963
SMD = -0.26 (-1.10 to 0.58)
Hollister, 1964
SMD = 0.19 (-0.24 to 0.63)
Freidman, 1966
SMD = 0.13 (-0.37 to 0.64)
Comments
(Combined analysis)
Change in mood
All nine trials, using the more conservative
estimate from Weintraub, 1963 (rating by
hospital director)
SMD = 0.39 (0.24 to 0.54)
Heterogeneity p < 0.001
Eight trials, excluding Daneman, 1961 (due to
high degree of heterogeneity)
SMD = 0.17 (0.00 to 0.34)
Heterogeneity p = 0.29
Eight trials, excluding Daneman, 1961 and
using the higher estimate from Weintraub,
1963 (rating by ward doctor)
SMD = 0.23 (0.06 to 0.40)
Seven trials, excluding Daneman, 1961 and
Murphy, 1984 (participants received cognitive
therapy as well as medication)
SMD = 0.21 (0.03 to 0.38)
Majority of trials found only small
differences between
antidepressants and active
placebos
Unblinding effects may inflate the
efficacy of antidepressants in trials
using inert placebos.
Meta-analysis with small number
of trials
Short duration of trials (minimum
three weeks, maximum 12 weeks)
Studies old
Variety of depression instruments
used
Limited to TCAs-extrapolation to
other antidepressants may not
necessarily be true
Fixed effect model
Hussain, 1970
SMD = 0.79 (0.09 to 1.5)
Friedman, 1975
SMD = 0.14 (-0.14 to 0.42)
Murphy, 1984
SMD = -0.36 (-1.0 to 0.28)
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Table 1.25
Author &
Title
Wilson, K.
Last Updated &
Search Database
Most recent Update
March 2001
2002
Databases:
Cochrane Collaboration
Depression
Anxiety and Neurosis
Review Group
(CCDAN)
Reference lists of related
reviews
References of located
studies.
Contact was made with
authors working in the
field.
Search Terms:
Electronic databases
were searched using
optimally sensitive
search terms (exact
terms not stated).
Methodology &
Study Characteristics
Number of studies included:
17 trials were included
Setting: Not stated.
Study Inclusion / Exclusion:
The review included all randomized,
placebo controlled trials using
antidepressant drugs in the treatment of
depression in subjects described as
elderly, geriatric or senile or in trials
where all subjects are over the age of
60.
Trials that included subjects under the
age of 60 were excluded unless data
concerning subjects over the age of 60,
or those described as elderly, geriatric
or senile, were randomized and
analyzed separately.
Funding Source:
Wirral and West Cheshire Community
Trust UK
Drug Comparisons:
TCAs with placebo
SSRIs with placebo
MAOIs with placebo
Dosages:
Not stated
Stage of depression:
Not stated.
Characteristics of Study
Participants
Sample:
Depressive disorders:
n = 1,326
Major Depressive Disorder.
Inclusion Criteria:
Patients over 60 with depression.
Exclusion Criteria: Not stated.
Design of Trials:
RCT
Duration of Trial:
Not stated.
Other variables associated with the aging process
(such as physical ill health) are likely to influence
the outcome of trials. The effects of these aspects
of clinical heterogeneity were examined and trials
combined if appropriate.
Where possible, the influence of patient
characteristics, for example inpatient vs.
outpatient, subtypes of depression, under 75 vs.
over 75 was examined. The effect of the trial
length was examined. If enough studies were
identified, the year of publication and country of
publication was examined. A funnel graph to test
for publication bias was also used. In addition, a
formal test for statistical heterogeneity, the natural
approximate chi-square test was conducted.
Method of abstraction:
Three reviewers independently assessed the The standardized effect size for the three groups
relevance of each trial, blind to decisions
respectively were:
made by each other.
TCAs: OR = 0.32 (0.21 to 0.47),
Each trial was assessed against pre-set
criteria and rated on a scoring sheet. In
cases of disagreement open discussion was
undertaken and decision reached by
consensus. Reasons for exclusion and/or
inclusion were recorded. Two reviewers are
acknowledged expert in the field, the other
reviewer wasn’t. Reviewers were blind to
authorship of trials, journals and institutions
from which authors come. Blindness was
tested through reviewers’ 'best guessing'
authorship, journal and institution.
© 2012 Kaiser Permanente Medical Care Program
Results
(95% CI)
Heterogeneity
Efficacy:
Seventeen trials
contributed data to the
analyses comparing the
efficacy of
antidepressant treatment
and placebo.
Analyses of efficacy was
based on 245 patients
treated with TCAs (223
with placebo),
365 patients treated with
SSRIs (372 with
placebo) and 58 patients
treated with MAOIs
(63 with placebo).
SSRIs: OR = 0.51 (0.36 to 0.72),
MAOIs: OR = 0.17 (0.07 to 0.39).
Adverse
Dropout Rates:
Effects:
Not reported.
Not reported.
Statistical advice was sought through the
Cochrane Depression, Anxiety and Neurosis
Review Group and through the Cochrane
Statistical Support Group in Liverpool.
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Table 1.26: Effects of Specific Psychological Treatments for Depressive Disorders
INTERVENTION
Cognitive
therapy
EVIDENCE
1 SR (48 RCTs of psychological therapies [2,765
people, mean age 39.3 y] mainly outpatients in
secondary care; therefore, probably with mild to
moderate depression; people with psychotic or
bipolar symptoms were excluded); 20 RCTs
compared CT with waiting list or placebo and 17
compared it with drug treatment.
No SR. 1 large RCT (people with mild to
moderate depression, mean age 35 y) compared
Interpersonal
interpersonal psychotherapy vs. either drug
psychotherapy
treatment, CT or placebo plus clinical
management for 16 weeks.
Problemsolving
therapy
No SR. 1 large RCT (452 people aged 18 to 65 y
with mild to moderate depression or adjustment
disorders) compared PS, group treatment, and
control. 1 RCT (91 people aged 18 to 64 y with
mild to moderate depression) compared problemsolving, placebo, and amitriptyline.
BENEFITS
HARMS
79% of people receiving placebo were more
symptomatic than the average person receiving
CT (p < 0.0001). 65% of people receiving CT
were less symptomatic than the average person
treated with antidepressant drugs
(p < 0.0001).
DISADVANTAGES
Requires extensive
training. Limited
availability. RCTs
No
in primary care
harms
reported suggest limited
acceptability to
some people.
Rates of recovery from depression: interpersonal
No
Requires extensive
psychotherapy (43%; NNT = 5, 95% CI: 3 to
harms
training. Limited
19), imipramine (42%; NNT = 5, 95% CI: 3 to
reported availability.
22), placebo clinical management (21%).
PS vs. control significantly increased the
proportion of people who were not depressed at
No
Requires extensive
6 mo., but no significant difference at 1 y.
harms
training. Limited
PS vs. placebo significantly improved symptoms
reported availability.
at 12 weeks, and no significant difference in
symptoms with PS vs. amitriptyline.
Counseling vs. standard care significantly
improved symptoms in the short term (1 to 6
Nondirective
mo.; WMD -2.03, 95% CI: -3.82 to -0.24), but
counseling
no significant difference in the long term
(> 6 mo.; WMD -0.03, 95% CI: -0.39 to +0.32).
CT: cognitive therapy, mo.: month, PS: problem-solving, SR: systematic review, y: year
Clinical Evidence, November 2003(70)
1 SR (7 RCTs, 772 people aged over 18 y with
recent onset psychological problems including
depression in UK primary care) compared
counseling vs. standard physician care.
© 2012 Kaiser Permanente Medical Care Program
No
Requires extensive
harms
training. Limited
reported availability.
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Table 1.27
Study,
Total n
Casacalenda, N.
2002 (meta-analysis)
Follow-up: 10 to 34
weeks (median = 16
weeks)
# of studies found: 6
Treatment Groups Size &
Intervention Description
Rx1: Medication
(n = 261); five studies used tricyclics and
one used phenelzine
Rx2: Psychotherapy
(n = 352); three studies used cognitive
behavior therapy, three used interpersonal
therapy, one used problem-solving
(six studies total, one study used both CBT
and IPT)
# of studies included: 6
Study Population
Adults
All were diagnosed as having
nonpsychotic Major Depression
Results
Comments
Full remission (%)
(based on intention-to-treat analysis of the main analysis
of the studies)
Rx1: 46.4%
Intention-to-treat analyses indicated that
pharmochotherapy and psychotherapy were
significantly more efficacious than control
conditions but were not significantly different
from each other, when treating mildly to
moderately depressed patients
Rx2: 46.3%
Heterogeneity not stated.
Rx3: 24.4%
p < 0.0001 (favoring treatment groups)
RX3: Placebo (n = 270)
Intent- to treat analysis
All studies were randomized, control trials.
Definition of remission:
Definition varied by study.
Raskin Depression Scale score ≤ 5
Hamilton depression scale score ≤ 6
Hamilton depression scale score ≤ 7
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Table 1.28
Study,
Total n
Thase, E.
2001 (meta-analysis,
nonsystematic review)
Follow-up :
6 to 8 weeks
# of studies found: 8
#of studies included: 8
Treatment Groups Size & Intervention
Description
Rx1: venlafaxine (n = 851),
Dose range:
venlafaxine IR, 75 to 375 mg/day;
venlafaxine XR, 75 to 225 mg/day
Rx2: SSRIs
(fluoxetine 20 to 80 mg/day, paroxetine 20 to 40
mg/day, fluvoxamine 100 to 200 mg/day) (n = 748)
Rx3: Placebo
(four studies n = 446)
Eight randomized, double-blind studies
Study Population
Results
Remission rates (Hamilton Rating
Scale for Depression, HRSD total
score of ≤ 7)
Met the DSM-III-R criteria for Major
Rx1: 45%
Depressive Disorder and DSM-IV
criteria for MDD for at least one month Rx2: 35%
Rx3: 25%
Minimum score of 20 on HRSD
(Hamilton Rating Scale for
(NNT = 10) favoring venlafaxine
Depression) or 25 on MADRS
Rx1 vs. Rx3 = 2.2
(Montgomery-Asberg Depression
Rx2 vs. Rx3 = 1.4
Rating Scale)
Testing for homogeneity of the
odds ratio revealed no significant
difference (p = 0.28)
Patients were at least 18 years old
© 2012 Kaiser Permanente Medical Care Program
Drop-outs due to side
effects
(Rx1 vs. Rx3)
p = 0.001 (significant)
(Rx2 vs. Rx3)
p = 0.001 (significant)
(Rx1 vs. Rx2)
p = 0.185)
(not significant)
Comments
Absolute remission rates were
significantly higher (10%) with
venlafaxine (SNRI) than with an
SSRI
Only four of eight trials were
placebo controlled
All trials reviewed were funded
by the manufacturer of
venlafaxine.
SSRI remission rate lower than
seen in other trials, suggesting
possible publication bias
(nonsystematic review).
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Table 1.29
Study,
Total n
Mulsant, H.
2001 (RCT, double-blind)
Treatment Groups Size & Drug
Outpatients
Rx1: Nortriptyline, 25 mg in the evening,
placebo pills in the morning
Age 60 and older with MDD
Rx2: Paroxetine, 10 mg in the morning initially
and increased to 20 mg after one week,
placebo pills in the evening
86.2% white
Follow-up: 12 weeks
Initial n: 116
Study Population
Final n: 64
Inpatients
Rx1: Nortriptyline, 50 mg in the evening,
placebo pills in the morning
Rx2: Paroxetine, 20 mg in the morning,
placebo pills in the evening
Rx1: 54
Rx2: 62
71.6% female
17-item Hamilton Rating
Scale for Depression (HAMD) score of 15 or above
Mini-Mental State Exam
(MMSE) score of 15 or
above
Results
Comments
Hamilton Rating Scale for Depression for
intention-to treat groups
Rx1: 9.8 ± 5.2
Rx2: 11.5 ± 7.1
p = 0.16
(not statistically significant)
Efficacy of nortriptyline and paroxetine did not differ
significantly in older patients with MDD.
Dropouts attributed to a side effect were significantly higher
in patients treated with nortriptyline. No difference was
noted in overall frequency of side effects or dropouts for all
reasons.
Discontinuation:
Patients were twice as likely to discontinue
nortriptyline (33%) as paroxetine (16%) due
to a significant side effect (p = 0.04), but the
overall discontinuation rates did not differ
significantly, p = 0.30.
UKU side effects total score for intention-totreat groups
Overall reasons for dropout included items of questionable
clinical relevance for initial decision making when deciding
between two medications (i.e., transportation issues).
Separate analysis of dropouts due to patient perceived lack
of efficacy was not presented.
Study results based on both out patients and inpatients
outcomes. No separate statistical analysis given for
outpatients only.
Rx1: 12 ± 6
Rx2: 12 ± 7
p = 0.61 (not statistically significant)
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2.
Hypericum (St. John’s Wort) For Treatment of MDD
Problem Formulation 2
Clinical Question:
Should Hypericum (St. John’s Wort) be used for treatment of adults
with MDD?
Intended Use of
the Guideline:
To assist primary care physicians and other health care professionals
in treating adults with Major Depression.
Population:
Health Problem:
All adults (age 19 and older) with Major Depression
MDD


Health Intervention:


Practitioners:
Setting:
Health Outcomes
(associated with the
intervention):
Side Effects
Associated With
the Intervention:
Hypericum (St. John’s Wort) vs:
Prescription antidepressants (SSRI, SNRI, TCA, NRI, or
DA)
No treatment
Placebo
KP primary care physicians, physician assistants, nurse practitioners,
pharmacists, and health educators
Outpatient office visit, emergency department, urgent care clinics
 Change in symptoms
 Quality of life
 Missed school/work days
 Office/UCC/ER visits
 Hospitalizations
 Mortality




















Sexual problems
Drowsiness
Headache
Nausea
Insomnia
Agitation/nervousness
Dry mouth
Seizures
Photosensitivity
Bleeding
© 2012 Kaiser Permanente Medical Care Program
Serotonin syndrome
Elevated blood pressure
Constipation
Diarrhea
Abdominal pain
Dizziness
Blurred vision
Weight gain
GI bleeding
Falls
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Search Strategy
Database:
PubMed
Cochrane
PubMed
*
Article Type
and Other
Limits:
Search Terms:
("Depression"[MeSH] OR "Major
Only items with
Depressive Disorder"[All Fields]
abstracts,
AND (“systematic"[All Fields] OR
Humans,
“systematic review"[All Fields] OR
English, All
“meta-analysis"[All Fields]))
Adult: 19+ years
Depression
N/A
("depression/drug therapy"[MESH]
Randomized
OR "depression/therapy"[MESH] OR Controlled Trial,
"Major Depressive Disorder"[All
All Adult: 19+
Fields]) AND ("hypericum"[MeSH
years, English,
Terms] OR(("hypericum"[TIAB]
Human
NOT Medline[SB]) OR
"hypericum"[MeSH Terms] OR St.
John's wort[Text Word]))
Randomized,
((((depression/drug therapy[MESH]
controlled trial,
OR depression/therapy[MESH]) OR
All Adult: 19+
("depressive disorder/drug
years English,
therapy"[MESH] OR "depressive
Human
disorder/therapy"[MESH])) OR
("dysthymic disorder/drug
therapy"[MESH] OR "dysthymic
disorder/therapy"[MESH])) AND
("Serotonin Uptake
Inhibitors"[MESH] OR
"Antidepressive Agents,
Tricyclic"[MESH]))
Search
Date
No.
Included
/ Total
Retrieved*
8/2005
to
9/2007
0/129
2007
8/2005
to
10/2007
0/134
2/6
3/2001
to
9/2007
0/384
Note: “No. Included” refers to studies that are relevant to the problem formulation and, therefore, are included
in this analysis of the evidence. “Total Retrieved” refers to the number of studies retrieved in the search,
regardless of relevance. Because individual studies can be captured in multiple databases, they may be counted
more than once in the number included. Systematic reviews and meta-analyses with search dates outside the
range of current searches were excluded.
© 2012 Kaiser Permanente Medical Care Program
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Database:
Cochrane
Clinical
Evidence,
Issue 14
PubMed
Cochrane
Clinical
Evidence
Search Terms:
((((depression/drug therapy[MESH]
OR depression/therapy[MESH]) OR
("depressive disorder/drug
therapy"[MESH] OR "depressive
disorder/therapy"[MESH])) OR
("dysthymic disorder/drug
therapy"[MESH] OR "dysthymic
disorder/therapy"[MESH])) AND
"hypericum"[MeSH Terms])
("depression/drug therapy"[MESH]
OR "depression/therapy"[MESH] OR
"Major Depressive Disorder"[All
Fields]) AND ("hypericum" [MeSH
Terms] OR St. John's wort)
Article Type
and Other
Limits:
Randomized,
controlled trial,
All Adult: 19+
years English,
Human
Meta-analysis,
All Adult: 19+
years, English,
Human
Controlled
Clinical Trial
OR Comparative
Study, All
Adult: 19+
years, English,
Human
Depression, Anxiety and Neurosis
Systematic
Group
Reviews
Depressive Disorders
Systematic
Reviews and
RCTs
("depression/drug therapy"[MESH]
Randomized,
OR "depression/therapy"[MESH] OR controlled trials,
"Major Depressive Disorder"[All
All adults: 19+
Fields]) AND ("hypericum"[MeSH
years, English,
Terms] OR (("hypericum"[TIAB]
Human
NOT Medline[SB]) OR
"hypericum"[MeSH Terms] OR St.
John's wort[Text Word])) AND
Randomized Controlled Trial[ptyp]
AND English[Lang] AND
"adult"[MeSH Terms] AND
"humans"[MeSH Terms]
Systematic
Depression
reviews
Systematic
Depression
reviews & RCTs
© 2012 Kaiser Permanente Medical Care Program
Search
Date
10/2001
to
9/2007
No.
Included
/ Total
Retrieved*
2/20
4/03
to
10/2007
0/0
4/03
to
10/2007
0/9
Q4, 2005
1/131
January
2006
N/A
01/01/03
08/01/05
1/3
03/05/03
0/295
03/05/03
1/80
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Database:
Search Terms:
PubMed
Search #1 update on AHRQ
(((((((((((depression/drug
therapy[MESH] OR
depression/therapy[MESH]) OR
("depressive disorder/drug
therapy"[MESH]OR "depressive
disorder/therapy"[MESH])) OR
("dysthymic disorder/drug
therapy"[MESH] OR "dysthymic
disorder/therapy"[MESH])) AND
("Serotonin Uptake
Inhibitors"[MESH] OR
"Antidepressive Agents,
Tricyclic"[MESH])) AND
notpubref[sb])
((((((((((depression/drug
therapy[MESH] OR
depression/therapy[MESH]) OR
("depressive disorder/drug
therapy"[MESH] OR "depressive
disorder/therapy"[MESH])) OR
("dysthymic disorder/drug
therapy"[MESH] OR "dysthymic
disorder/therapy"[MESH])) AND
"hypericum"[MeSH Terms]) AND
notpubref[sb])
("depression/drug therapy"[MESH]
OR "depression/therapy"[MESH] OR
"Major Depressive Disorder"[All
Fields]) AND ("hypericum" [MeSH
Terms] OR St. John's wort)
© 2012 Kaiser Permanente Medical Care Program
Article Type
and Other
Limits:
Randomized,
controlled trials,
All adults: 19+
years, English,
Human
Search
Date
01/01/98
03/2001
No.
Included
/ Total
Retrieved*
4/4
Randomized,
controlled trials,
All adults: 19+
years, English,
Human
03/2001
10/2001
1/6
Meta-analysis,
All Adult: 19+
years English,
Human
Controlled
Trials, All
Adult: 19+ years
English, Human
01/01/01
04/01/03
0/0
01/01/01
04/01/03
3/3
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Evidence Tables
Table 2.1: Effects of Treatment with Hypericum for Major Depression (RCTs)
Name
Gastpar et al.,
2005
Gastpar et al.,
2006
Kasper et al.,
2006
Tx (N)
Mean
±SD Age
(yr)
%
Female
Follow-up
Rate (%)
Follow-up
Time
Mean ±SD
Baseline
HAMD
Mean ±SD
Follow-up
HAMD
24 weeks
22.0±1.1
5.7 ±4.8
22.1±1.1
7.1 ±6.3
21.9±1.2
Effect
Difference
p
Study
*
Quality
†
Biases
1.3
<0.0001
noninferiority
test
5
N
10.3 ±6.4
vs C: 0.1
Noninferior
5
N
21.8±1.2
10.3 ±6.4
vs P: 2.6
<0.0001
22.0±1.2
13.0 ±6.9
vs P: 2.5
<0.0001
22.8±3.3
11.2 ±7.0
vs P: 5.6
<0.001
5
N
85.0
22.6±3.8
11.8 ±8.3
vs H12 :0.8
NS
90.2
23.6±4.2
17.6 ±8.8
vs P: 4.8
<0.001
19.6±3.5
10.2 ±6.6
vs P: 2.1
0.096
3
1
Hypericum 612
(123)
48.3 ±12.7
79.4
73
Sertraline 50
(118)
49.5 ±13.8
69.4
77
Hypericum 900
(131)
50.8 ±12.1
65.6
79
Citalopram 20
(127)
49.3 ±10.7
64.6
82
Placebo (130)
49.4 ±12.7
73.1
81
Hypericum 600
(123)
46.3 ±11.5
67
90.2
Hypericum
1200 (127)
46.1 ±10.7
82
Placebo (82)
46.6 ±11.8
56
6 weeks
6 weeks
Comments: Support from pharmaceutical manufacturers
Fava et al.,
2005
Hypericum 900
(45)
37.4 ±11.7
53
60
Fluoxetine 20
(47)
36.7 ±9.6
53
51
19.6±3.1
13.3 ±7.3
vs F: 3.1
<0.05
Placebo (43)
37.8 ±12.0
65
49
19.9±2.9
12.6 ±6.4
vs P: - 1
NS
12 weeks
Comments: Support from pharmaceutical manufacturers
HAMD = Hamilton Depression Scale; NS, not significant
*
Study quality measured by Jadad trials scoring system (1 to 5 = low to high).
†
Biases: N: none; 1: sample attrition >15%; 2: sample selection bias; 3: detection bias (e.g., measurement error, power); 4: study procedure biases.
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Table 2.2
Study
Gelenberg (2004),
The effectiveness
of St. John's wort
in Major
Depressive
Disorder: A
naturalistic Phase
2 follow-up in
which
nonresponders
were provided
alternate
medication.
Inclusion &
Exclusion Criteria
Age
Men and women with
18+
DSM-IV Major Depressive
Disorder from tertiary care
clinics in academic
medical centers.
Limitations / Biases
Naturalistic, follow-up
design.
Few patients who
continued on St. John's
wort.
Intervention and
dose
N and Final N
Duration
Patients who did not
24 weeks
respond to hypericum (N =
43) or placebo (N = 55) in
Phase 1 treated with
antidepressants for 24
weeks (Phase 2).
Sample limited to
outpatients in a tertiary
care academic center not
necessarily interested in
herbal treatment – limited
generalizability.
Outcome
Results
Phase 2 changes in
HAM-D scores
between
nonresponders who
received hypericum
extract and those who
received placebo in
Phase 1.
Significant time effect for Phase 1
nonresponders over the 24 weeks of
Phase 2 treatment, indicating that
nonresponders in the initial trial were
not treatment resistant (nonresponders
in phase 1 did respond in phase 2).
p
value
NNT
< 0.001
HAM-D scores of Phase 1
nonresponders in Phase 2:
Baseline
Hypericum 18.3
Placebo
18.1
Endpoint
7.9
8.8
0.8
Small sample.
No significant effect of prior Phase 1
treatment (hypericum or placebo)
group.
Nonresponders not
blinded (open label).
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Table 2.3
Study
Uebelhack (2004).
Efficacy and
tolerability of
Hypericum extract
STW 3-VI in
patients with
moderate
depression: a
double-blind,
randomized,
placebo-controlled
clinical trial.
Inclusion &
Exclusion Criteria
Age
Inclusion:
18-70
Outpatients with moderate
depression disorder, a
total HAM-D score of 2024 at baseline.
Limitations / Biases
Adequacy of blinding not
assessed.
Remission rates not
assessed.
Exclusion:
Suicidal patients; those
with resistant depression.
Intervention and
dose
N and Final N
After a 7-day placebo runin period, 140 patients
were randomized into one
of two groups:
Rx1: Intervention (N =
70): Hypericum extract
900mg once daily for six
weeks.
Rx2: Control (N = 70):
Placebo once daily for six
weeks.
Primary outcome was
change in HAM-D score,
secondary measure was
responder rate (% of
patients with >50%
decrease from baseline
HAM-D score)..
© 2012 Kaiser Permanente Medical Care Program
Duration
6 weeks
Outcome
Results
Change in total HAMD score from baseline
to end of study.
Significant improvement in HAM-D
score in hypericum group when
compared with placebo group:
p
value
< 0.001
Baseline Endpoint
Hypericum 22.8
11.8
Placebo 22.6
19.2
Hypericum group showed significant
improvement in BfS score when
compared with placebo group:
< 0.001
Baseline Endpoint
Hypericum 38.8
20.7
Placebo 38.0
31.1
58.6% of Hypericum group assessed
as responders at end of study,
compared with 5.7% in placebo group.
23 adverse events reported by
patients, none considered serious, and
two cases suggested a connection to
the study medication.
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Table 2.4
Study
Szegedi (2005),
Acute treatment of
moderate to
severe depression
with hypericum
extract WS 5570
(St. John's wort):
randomised
controlled doubleblind noninferiority
trial versus
paroxetine.
Inclusion &
Exclusion Criteria
Inclusion:
Caucasian male and
female adult outpatients
with moderate to severe
MDD and total HAM-D
score ≥ 22
Exclusion:
Decrease in total
depression score of ≥
25% during run-in;
diagnoses of
schizophrenia, acute
anxiety, adjustment
disorder, other depressive
disorders, organic mental
disorder, or substance
abuse; suicidality or
previous suicide attempt.
Limitations /
Biases
Age
18-70
Placebo control not
used because of
“ethical reasons”
(studying patients with
moderate to severe
depression)
Patients at high risk of
suicide excluded.
Intervention and
dose
N and Final N
After 3-7 day placebo run
in period, participants
were randomized into one
of two groups:
Rx1: Hypericum (N =
122): 900mg hypericum
extract three times per
day for six weeks.
Rx2: Paroxetine (N =
122): 20mg paroxetine
once per day for six
weeks.
If participant showed no
response after two weeks,
dosage was increased: to
1800mg hypericum or
40mg paroxetine.
Duration
6 weeks
Outcome
Results
p
value
NNT
Change in HAM-D
HAM-D scores decreased for both
score from baseline to groups.
day 42.
ITT Analysis:
Baseline Endpoint
Hypericum
25.5
11.1
Paroxetine
25.5
14.1
Per-Protocol Analysis:
Baseline Endpoint
Hypericum
25.5
10.9
Paroxetine
25.5
13.5
Authors conclude from these findings
that hypericum is not inferior to
paroxetine.
More patients in hypericum group
(50%) than in paroxetine group (35%)
showed remission.
0.02
Incidence of adverse effects:
Hypericum: 0.035
Paroxetine: 0.060
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Table 2.5
Study
Bjerkenstedt
(2004) Hypericum
extract LI 160 and
fluoxetine in mild
to moderate
depression: a
randomized,
placebo-controlled
multi-center study
in outpatients.
Inclusion &
Exclusion Criteria
Inclusion:
Caucasian males and
females with mild to
moderate depression (as
defined by the DSM-IV)
with a total HAM-D score
≥ 21.
Exclusion:
Psychiatric disorders;
MAO-I treatment within 14
days prior to entry; history
of treatment-resistant
MDD, risk of suicide,
history of seizure disorder,
alcohol or substance
abuse; unstable medical
illness, impaired renal
function, pregnancy,
known intolerance to
study medications;
substantial placebo
response; treatment with
trial drug prior to study.
Age
Limitations / Biases
18-70
Fixed doses - dosing was
not increased for non- or
partial response, as it
might be in clinical
setting.
Short duration - only four
weeks - due to ERC
restriction.
Poor estimation of
compliance.
No statistical test done
on fluoxetine vs.
hypericum.
Dropout rates not
reported.
Intervention and
dose
N and Final N
After a 3-7 day run-in
period, 163 subjects were
randomized into one of
three groups:
Rx1: Hypericum (N = 54):
300mg tid for six weeks
Rx2: Fluoxetine (N = 54):
20mg per day for six
weeks
Rx3: Placebo (N = 55):
for six weeks. Per ERC
requirement, placebo
patients randomly
switched to hypericum or
fluoxetine after four
weeks, until end of study.
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Duration
6 weeks
Outcome
Results
Change in HAM-D
scores from baseline
to week 4.
p
value
Similar improvements among
treatment groups on HAM-D.
The only statistically significant finding
was remission rate (HAM-D total score
< 8):
Hypericum (24%) vs. placebo (7%)
Fluoxetine (28%) vs. placebo (7%)
0.02
0.005
Hypericum better tolerated than
fluoxetine
Number of adverse events:
Hypericum (38) vs. fluoxetine (52)
Hypericum (38) vs. placebo (27)
Fluoxetine (52) vs. placebo (27)
0.04
0.84
0.01
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Table 2.6
Study,
Total n
Hypericum
Depression Trial
Study Group
2002 (RCT,
double-blind)
Follow-up: 8
weeks
Treatment Groups
Size & Drug
Rx1: hypericum
(900 – 1,500 mg/dl)
(n = 113)
Rx2: sertraline
(50 – 100 mg/d)
(n = 111)
Study Population
At least 18 years old with current
diagnosis of Major Depression
Minimum total score of 20 on the
17-item Hamilton Depression
(HAM-D) scale
Results
HAM-D total score (week 8 – week 1)
Rx1: -8.68
Rx2: -10.53
Rx3: -9.20
(Rx1 vs. Rx3) p = 0.59
(not significant)
(Rx2 vs. Rx3) p = 0.18
(not significant)
Rx3: placebo (n = 116)
Initial n: 340
Final n: 245
One week run-in period
Full response rate (%)
Rx1: 23.9
Rx2: 24.8
Rx3: 31.9
Comments
Adverse Events
Diarrhea
(Rx1 vs. Rx3) p = 0.81
(not significant)
(Rx2 vs. Rx3) p = 0.003 (significant)
Nausea
(Rx1 vs. Rx3) p = 0.78
(not significant)
(Rx2 vs. Rx3) p = 0.02 (significant)
Anorgasmia
(Rx1 vs. Rx3) p = 0.04 (significant)
(Rx2 vs. Rx3) p = 0.002 (significant)
They found no evidence
that hypericum is more
effective than placebo in
treating moderately
severe Major
Depression.
The principal comparison
was between the
hypericum and placebo
groups. Sertraline
served as an active
comparator to evaluate
the study’s sensitivity.
(Rx1 vs. Rx3) p = 0.21
(not significant)
(Rx2 vs. Rx3) p = 0.26
(not significant)
Full response is indicated with a HAM-D
score of eight or less and a Clinical Global
Impressions Improvement (CGI-I) score of
one or two.
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Table 2.7
Study,
Total n
Kalb, R.
2001, (RCT, double-blind)
Treatment Groups Size
& Drug
Rx1: hypericum extract WS
5572
(3 x 300 mg/day) (n = 37)
Follow-up = 6 weeks
Rx2: placebo (n = 35)
Study Population
Male and female outpatients aged
between 18 and 65 years with
diagnosis of mild or moderate MDD
with single or recurrent episodes
according to DSM-IV criteria
Initial n: 72
Total score for the Hamilton Rating
Scale for Depression (HAMD, 17 –
item version) ≥ 16 at study entry and
during a subsequent baseline
investigation (3 to 7 days later).
Final n: 64
Results
Comments
Change (decrease) in HAM-D score (%)
The study concludes that the
standardized Hypericum extract
WS 5572 has superior efficacy
compared with placebo and very
good tolerability in the acute
treatment of mildly to moderately
depressed patients.
Rx1: 54.8% (19.7 ± 3.4 to 8.9 ± 4.3 points,
overall change -10.8 points)
Rx2: 29.2% (20.1 ± 2.6 to 14.4 ± 6.8 points,
overall change -5.7 points)
Difference 5.1 points, p < 0.001
(in favor of hypericum)
High placebo response rate.
% of patients showing at least a 50% reduction in HAM-D scores:
Study may be underpowered to
detect differences in 50% reduction
in HAM-D scores.
Rx1: 62.2% [95% CI: 46.5 to 77.8]
Rx2: 42.9% [95% CI: 26.5 to 59.3]
p = 0.10
% of patients showing at least a 60% reduction in HAM-D scores:
Rx1: 51.4% [95% CI: 35.2 to 67.5]
Rx2: 17.1% [95% CI: 4.7 to 29.6]
p = 0.002
Table 2.8
Study,
Total n
Treatment Groups Size & Drug
Study Population
Behnke, K.
2002 (RCT, double-blind)
Rx1: hypericum
(150 mg twice daily) (n = 35)
18 to 73 years of age with mild to
moderate depression
Follow-up = 6 weeks
Hamilton Rating Scale for
Depression of between 16 and 24
Initial n: 70
Rx2: fluoxetine
(20 mg twice daily)
(n = 35)
Final n: 61
No placebo control group
Results
Change (decrease) in HAM-D score (%)
Rx1: 50%
Rx2: 58%
The decrease was highly significant
(p < 0.001) in both groups but not significantly different (p = 0.23) between
groups
Comments
The study concludes that
Hypericum perforatum is
therapeutically equivalent to
fluoxetine and therefore a
rational alternative to
synthetic antidepressants.
No placebo control group
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3.
Antidepressants In Patients With MDD Expressing Suicidal
Ideation, Intent, or Plan
Problem Formulation 3
Clinical Question:
Intended Use of
the Guideline:
Population:
Health Problem:
Which antidepressants should be avoided for treatment of patients
with MDD expressing suicidal ideation, intent, or plan?
To assist primary care physicians and other health care professionals
in treating adults with Major Depression who are expressing suicidal
ideation, intent, or plan.
All adult (age 19 and older) patients with Major Depression treated
with antidepressant medication who are expressing suicidal ideation,
intent, or plan
Suicide ideation, intent, or plan in primary care patients taking
antidepressants
Health
Intervention:
Antidepressant treatment (SSRIs, TCAs, DAs, SNRIs, NRIs)
Practitioners:
KP primary care physicians, physician assistants, nurse practitioners,
pharmacists, and health educators
Setting:
Outpatient office visit, emergency department, urgent care clinics
Health Outcomes
(associated with the
intervention):


Hospitalizations
Attempted suicide
Side Effects
Associated With
the Intervention:


Suicide by overdose
Suicide (all cause)
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Search Strategy
Article Type
and Other
Limits:
Only items with
abstracts,
Humans,
Randomized
Controlled Trial,
English, All
Adult: 19+ years
Search
Date
8/2005
to
9/2007
Database:
Search Terms:
PubMed
(((("depression/drug effects"[MESH]
OR "depression/drug
therapy"[MESH]) OR
"depression/therapy"[MESH]) OR
"antidepressive
agents/poisoning"[MeSH] OR "Major
Depressive Disorder"[All Fields])
AND (("suicide"[MeSH Terms] OR
suicide[Text word]) OR "suicide,
attempted"[MeSH]))
Depression, Anxiety and Neurosis
Systematic
Q4, 2005
Cochrane
Group
Reviews
Clinical
Systematic
January
Evidence, Chapter: Depressive Disorders
Reviews and
2006
Issue 14
RCTs
PubMed
(((("depression/drug effects"[MESH]
All Adult: 19+ 01/01/03
OR "depression/drug
years,
therapy"[MESH]) OR
Publication Date 08/01/05
"depression/therapy"[MESH]) OR
from 2003/01/01
"antidepressive
to 2005/08/01,
agents/poisoning"[MeSH] OR "Major English, Humans
Depressive Disorder" [All
Fields])AND (("suicide"[MeSH
Terms] OR suicide[Text word]) OR
"suicide, attempted"[MeSH])) AND
English[Lang] AND "adult"[MeSH
Terms] AND "humans"[MeSH Terms]
AND ("2003/01/01"[PDAT] :
"3000"[PDAT]) AND English[Lang]
AND "adult"[MeSH Terms] AND
"humans"[MeSH Terms] AND
("2003/01/01"[PDAT] :
"2005/08/01"[PDAT])
*
No.
Included
/ Total
Retrieved*
0/411
0/131
N/A
1/187
Note: “No. Included” refers to studies that are relevant to the problem formulation and, therefore, are included
in this analysis of the evidence. “Total Retrieved” refers to the number of studies retrieved in the search,
regardless of relevance. Because individual studies can be captured in multiple databases, they may be counted
more than once in the number included. Systematic reviews and meta-analyses with search dates outside the
range of current searches were excluded.
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Database:
Search Terms:
Cochrane
Suicide
Clinical
Evidence
Suicide
PubMed
PubMed
(((((((((((depression/drug therapy
[MESH] OR depression/therapy
[MESH]) OR ("depressive disorder/
drug therapy"[MESH] OR "depressive
disorder/therapy" [MESH])) OR
("dysthymic disorder/drug
therapy"[MESH] OR "dysthymic
disorder/therapy"[MESH])) AND
("Serotonin Uptake
Inhibitors"[MESH] OR
"Antidepressive Agents,
Tricyclic"[MESH])) AND
notpubref[sb])
(((((((("depression/drug
effects"[MESH] OR "depression/drug
therapy"[MESH]) OR
"depression/therapy"[MESH]) OR
"antidepressive agents/poisoning"
[MeSH] OR "Major Depressive
Disorder"[All Fields]) AND
(("suicide"[MeSH Terms] OR
suicide[Text word]) OR "suicide,
attempted"[MeSH]))
Article Type
and Other
Limits:
Systematic
reviews
Systematic
reviews and
RCTs
Randomized,
controlled trials,
All adults 19+
years, English
All Adult: 19+
years English,
Human
Search
Date
06/05/03
No.
Included
/ Total
Retrieved*
0/80
06/05/03
1/6
1998
03/2001
0/222
01/01/01
04/01/03
1/67
Some studies found and used in this guideline did not appear in PubMed search results due to the
way studies are indexed in PubMed.
Buckley(112) did not show up in our search results due to the way PubMed indexing is done.
Other Information Source:
 Evidence report on the Treatment of Depression - Newer Pharmacotherapies. AHRQ(169)
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Evidence Tables
Table 3.1
Study
Yerevanian, et al.
(2004)
Antidepressants
and suicidal
behavior in
unipolar
depression
Inclusion &
Exclusion Criteria
Inclusion:
In clinical care with senior
author from 1978-2002;
DSM-IV criteria for Major
Depression and/or
dysthymia; minimum 6
month follow-up by senior
author; antidepressant
monotherapy; charts
contained specific
information about suicidal
behavior.
Limitations /
Biases
Intervention and
dose
N and Final N
43
Treatment
(mean) adherence not part
of methodology.
Patient charts (N = 521)
were followed and
reviewed.
Age
Duration
N/A
Outcome
Results
Number of the following
events during periods of
active treatment or
discontinuation with
SSRIs or TCAs.
1) completed suicide, 2)
suicide attempts, or
3)hospitalization for
serious suicidal thought
or intent
Exclusion:
Multiple antidepressant,
mood stabilization, or
antipsychotic regimens;
alcohol and substance
abuse.
© 2012 Kaiser Permanente Medical Care Program
p value
Rate of suicidal behavior
significantly higher in
discontinuation vs. active
treatment period (p <0.00001)
< 0.0001
Rate of suicidal behavior
significantly higher in
discontinuation vs. active
treatment period with TCAs
(p <0.00001)
< 0.0001
<0.0001
Rate of suicidal behavior
significantly higher in
discontinuation vs. active
treatment period with SSRIs
(p <.00001)
<0.0001
Rate of suicidal behavior similar for
active TCA vs. active SSRI
treatment (p =0.046)
0.046
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Table 3.2
Study
Martinez, et al.
(2005)
Antidepressant
treatment and
the risk of fatal
and nonfatal
self-harm in first
episode
depression:
nested case
control study.
Inclusion &
Exclusion Criteria
Patients (N = 146,095)
from Primary Care in
the UK with a new
diagnosis of
depression who were
prescribed
antidepressants for
the first time between
1995 and 2001.
Age
Limitations / Biases
≤ 90
Outcome under study might
in itself be the reason one
drug was prescribed over
another.
Intervention and
dose
N and Final N
Clinical records (N =
146,095) from the
General Practice
Research Database were
acquired and reviewed.
No consistent monitoring of
adherence to medication.
Large number of hypothesis
tests could have led to
change findings of
associations.
No comparison between
those prescribed SSRIs and
those with equivalent
morbidity not receiving
treatment (i.e. no control).
Duration
N/A
Outcome
Results
Risk of nonfatal selfharm and suicide
between users of
SSRIs and users of
TCAs.
NNT
p value
1968 cases of self-harm
69 suicides
Adjusted odds ratio of nonfatal
self-harm in people prescribed
SSRIs vs. TCAs was 0.99 (95% CI:
0.86 - 1.14)
NS
Adjusted odds ratio of suicide in
people prescribed SSRIs vs. TCAs
was 0.57 (95% CI: 0.26 - 1.25)
NS
No evidence risk of nonfatal selfharm varied among different
SSRIs.
0.35
No evidence risk of nonfatal selfharm varied among different TCAs.
0.69
No age-related differences in
nonfatal self harm between
patients prescribed SSRIs and
TCAs.
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Table 3.3
Study
Fergusson, et
al. (2005)
Association
between
suicide
attempts and
selective
serotonin
reuptake
inhibitors:
systematic
review of
randomised
controlled trials.
Inclusion &
Exclusion
Criteria
All RCTs (N = 702)
comparing SSRI
with placebo or
active non-SSRI
control. Treatment
condition not limited
to Major
Depression.
Age
Limitations /
Biases
Underreporting of
suicide attempts in
RCTs.
High rates of losses to
follow-up.
Small trial sizes and
durations.
Some trials restricted
eligibility to patients
who previously
tolerated SSRIs well.
Intervention and dose
N and Final N
Three separate meta-analyses
were conducted to evaluate the
association between suicide
attempts and the sue of SSRIs:
1) SSRIs compared with
placebo
2) SSRIs compared with TCAs
3) SSRIs compared with other
active forms of treatment.
Duration
Outcome
Number of fatal
and nonfatal
suicide
attempts.
Results
Significant increase in odds of suicide
attempts for patients receiving SSRIs
compared with placebo (odds ratio
2.28, CI: 1.14 to 4.55).
p
value
NNT
684
(NNT to
harm)
0.02
No difference in odds of suicide
attempts in patients receiving SSRIs
compared with TCAs (odds ratio 0.88,
CI: 0.54-1.42).
Increase in odds of suicide attempts
when comparing SSRIs with
therapeutic interventions other than
TCAs (odds ratio 1.94, 1.06 to 3.57).
239
(NNT to
harm)
Some trials did not
have a sufficient
washout period.
Did not compare TCAs
with placebo, or other
active treatment with
placebo.
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Table 3.4
Study
Gibbons, et al.
(2005) The
relationship
between
antidepressant
medication use
and rate of
suicide.
Inclusion &
Exclusion
Criteria
Suicides in all US
counties between
1996-1998;
adjusted for sex,
race, age and
income.
Age
5+
Limitations / Biases
Medication estimates based
on outpatient use.
Uncontrolled variability in
suicide rate data (definition of
suicide, qualifications of
medical examiner, extent of
case investigation, relationship
between prescription rates and
actual taking of medication,
quality of data)
Intervention and
dose
N and Final N
Analysis of relationship
between antidepressant
pharmacy prescription
volumes and overall
suicide rate.
Duration
N/A
Outcome
Results
Primary outcome
measure was number of
suicides for given
population size.
NNT
Overall relationship between all
prescribed antidepressant drugs and
suicide rate was not statistically
significant (p = 0.14).
0.14
For individual classes of
antidepressants, there was a
significant positive association
between TCAs and suicide rate
(p < 0.001).
< 0.001
Combination of SSRI and non-SSRI
or non-TCA prescriptions had a
significant negative association with
suicide rate (p < 0.001).
Possible selection bias
(different classes of
antidepressants may have
been selectively prescribed to
different patient groups).
< 0.001
No data on cause of suicide.
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4.
Second-Line Treatement of MDD
Problem Formulation 4
Clinical Question:
Intended Use of
the Guideline:
Population:
Health Problem:
Health
Intervention:
What strategies should be used in adults with MDD whose symptoms
do not resolve after the first-line treatment?
To assist primary care physicians and other health care professionals in
treating adults with Major Depression.
All adult (age 19 and older) with Major Depression who are
unresponsive to first-line treatment
MDD








Practitioners:
Setting:
Change antidepressant medication
Increase existing antidepressant dose
Switch to psychotherapy
Add psychotherapy
Add another antidepressant to existing antidepressant
Add an augmenting agent to the existing antidepressant
(lithium, beta-blocker, buspirone, Cytomel, carbamazepine,
valproic acid, methylphenidate, ethyl-eicosapentaenoate
(E-EPA), folate, inositol, atypical antipsychotic, risperidone,
aripiprazole
rTMS
Vagus nerve stimulation
KP primary care physicians, physician assistants, nurse practitioners,
pharmacists, and health educators
Outpatient office visit, emergency department, urgent care clinics
Health Outcomes
(associated with
the intervention):



Change in symptoms
Quality of life
Missed school/work days



Office/UCC/ER visits
Hospitalizations
Mortality
Side Effects
Associated With
the Intervention:









Sexual problems
Drowsiness
Headache
Nausea
Insomnia
Agitation/nervousness
Dry mouth
Seizures
Elevated blood pressure








Constipation
Diarrhea
Abdominal pain
Dizziness
Blurred vision
Weight gain
GI bleeding
Falls
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Search Strategy
Database:
Search Terms:
PubMed
("Depression"[MeSH] OR "Major
Depressive Disorder"[All Fields] AND
(“systematic"[All Fields] OR “systematic
review"[All Fields] OR “metaanalysis"[All Fields]))
Cochrane Depression
Systematic
Reviews
PubMed
((("depression/drug effects"[MESH] OR
"depression/drug therapy"[MESH]) OR
"depression/therapy"[MESH]) OR "Major
Depressive Disorder"[All Fields]) AND
((((("Antidepressive Agents/adverse
effects"[MESH] OR "Antidepressive
Agents/therapeutic use"[MESH]) OR
“apiprazole” [text word] OR “atypical
antipsychotic”[text word] OR
"carbamazepine"[MESH terms] OR
"valproic acid"[MESH terms] OR
"buspirone"[MESH terms] OR
"triiodothyronine"[MESH terms] OR
Cytomel[text word] OR "adrenergic betaantagonists "[MESH terms] OR beta
blocker[text word] OR
"methylphenidate"[MESH terms] OR
"psychotherapy"[MESH terms]) OR
(cognitive[All Fields] AND "behavior
therapy"[MESH Terms])) OR
"interpersonal therapy"[All Fields]) OR
("Problem-solving"[MESH Terms] AND
"therapy"[MESH Subheading])))
*
Article Type
and Other
Limits:
Only items
with
abstracts,
Humans,
English, All
Adult: 19+
years
N/A
Randomized
controlled
trials, only
items with
abstracts,
Humans,
English, All
Adult: 19+
years
Search
Date
8/2005
to
9/2007
2005
to
2007
8/2005
to
9/2007
No.
Included
/ Total
Retrieved*
0/129
0/134
5/271
Note: “No. Included” refers to studies that are relevant to the problem formulation and, therefore, are included
in this analysis of the evidence. “Total Retrieved” refers to the number of studies retrieved in the search,
regardless of relevance. Because individual studies can be captured in multiple databases, they may be counted
more than once in the number included. Systematic reviews and meta-analyses with search dates outside the
range of current searches were excluded.
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Database:
Article Type
and Other
Limits:
Search Terms:
Search
Date
No.
Included
/ Total
Retrieved*
National
Depression
Institute
for
Clinical
Excellence
(NICE)
Systematic
Review,
Metaanalyses and
RCTs
Decembe
r 6, 2004
N/A
Cochrane
Depression, Anxiety and Neurosis Group
Systematic
Reviews
Q4, 2005
3/131
Clinical
Evidence,
Issue 14
Chapter: Depressive Disorders
Systematic
Reviews and
RCTs
January
2006
N/A
PubMed
(((("depression/drug effects"[MESH] OR Randomized,
controlled
"depression/drug therapy"[MESH]) OR
trials
"depression/ therapy" [MESH]) OR
"Major Depressive Disorder"[All Fields])
AND ((((("Antidepressive Agents/adverse
effects"[MESH] OR "Antidepressive
Agents/therapeutic use"[MESH]) OR
"carbamazepine"[meSH terms] OR
"valproic acid"[meSH terms] OR
"buspirone"[meSH terms] OR
"triiodothyronine "[meSH terms] OR
Cytomel[text word] OR "adrenergic betaantagonists "[meSH terms] OR beta
blocker[text word] OR
"methylphenidate"[meSH terms] OR
"psychotherapy"[MESH]) OR
(cognitive[All Fields] AND "behavior
therapy"[MeSH Terms])) OR
"interpersonal therapy"[All Fields]) OR
("Problem-solving"[MeSH Terms] AND
"therapy"[MeSH Subheading]))) AND
Randomized Controlled Trial[ptyp] AND
English[Lang] AND "adult"[MeSH
Terms] AND "humans"[MeSH Terms]
AND ("2003/01/01"[PDAT] :
"2005/08/01"[PDAT])
01/01/05
08/01/05
6/239
Cochrane
Depression
03/05/03
0/295
Systematic
reviews
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Database:
Clinical
Evidence
PubMed
PubMed
Search
Date
No.
Included
/ Total
Retrieved*
Systematic
reviews and
RCTs
03/05/03
1/80
Meta-analysis,
All Adult: 19+
years English,
Human
01/01/80
12/31/00
0/12
Controlled
Trials, All
Adult: 19+
years English,
Human
01/01/80
12/31/00
0/576
Meta-analysis,
All Adult: 19+
years English,
Human
01/01/01
04/01/03
0/5
Controlled
Trials, All
Adult: 19+
years English,
Human
01/01/01
04/01/03
3/129
Article Type
and Other
Limits:
Search Terms:
Depression
(((("depression/drug effects"[MESH] OR
"depression/drug therapy"[MESH]) OR
"depression/therapy"[MESH]) OR "Major
Depressive Disorder"[All Fields]) AND
((((("Antidepressive Agents/adverse
effects"[MESH] OR "Antidepressive
Agents/therapeutic use"[MESH]) OR
"carbamazepine" [meSH terms] OR "valproic
acid" [meSH terms] OR "buspirone" [meSH
terms] OR "triiodothyronine " [MESH terms]
OR Cytomel [text word] OR "adrenergic betaantagonists " [MESH terms] OR beta blocker
[text word] OR "methylphenidate" [MESH
terms]OR "psychotherapy"[MESH]) OR
(cognitive[All Fields] AND "behavior
therapy"[MESH Terms])) OR "interpersonal
therapy"[All Fields]) OR ("Problemsolving"[MESH Terms] AND
"therapy"[MESH Subheading])))
/therapeutic use"[MESH]) OR "carbamazepine"
[meSH terms] OR "valproic acid" [meSH terms]
OR "buspirone" [meSH terms] OR
"triiodothyronine " [meSH terms] OR Cytomel
[text word] OR "adrenergic beta-antagonists "
[meSH terms] OR beta blocker [text word] OR
"methylphenidate" [meSH terms]OR
"psychotherapy"[MESH]) OR (cognitive[All
Fields] AND "behavior therapy"[MeSH Terms]))
OR "interpersonal therapy"[All Fields]) OR
("Problem-solving"[MeSH Terms] AND
"therapy"[MeSH Subheading])))
The rationale statement from the November 2005 KP Inter-regional New Technologies evidencebased review on vagus nerve stimulation was incorporated into these guidelines.
Some studies found and used in this guideline did not appear in PubMed search results due to the
way studies are indexed in PubMed. The Peet(136) study did not show up in the search results due
to the way PubMed indexing is done. The GDT decided to include this study, since it met the
inclusion criteria. The Perez(138) study did not show up in the search results because pindolol
was indexed as serotonin receptor antagonist rather than as a beta-blocker or an adrenergic betaantagonist.
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Evidence Tables
Table 4.1: RCTs of Second-Line Treatments for Depression
Name
Mean
±SD Age (yr)
N
%
Female
Follow
-up
Rate
Follow
-up
Time
Augmentation
with Cognitive
Therapy
%
Remissions N
AUG 40.0±12.8
65.4
14
SW 42.2±13.7
NR
23.1
61.5
weeks
N
Cognitive therapy not independently validated. No placebo control group included.
Thase,
2007
Name
Mean
±SD Age (yr)
N
%
Female
Follow
-up
Rate
Follow
-up
Time
15
Name
%
Female
Follow
-up
Rate
Follow
-up
Time
33.3
Bupropion-SR
%
Remissions
N
Rush,
41.8±12.8
14
58.7
NR
21.3
2006
727
weeks
Adverse effects were similar among treatment groups. No placebo control group included.
Mean
±SD Age (yr)
N
Augmentation
with Medication
%
Remissions
N
39
25.0
Sertraline
%
Remissions
N
17.6
42
51
Bupropion-SR
% Remissions
Switch to
Cognitive
Therapy
%
Remissions N
Switch to New
Medication
%
Remissions
N
9
27.9
24
Venflaxine-XR
%
Remissions
N
24.8
62
p
Study
Quality†
Biases*
NS
1
3, 4
p
Study
Quality†
Biases*
NS
1
4
p
Study
Quality†
Biases*
Buspirone
N
% Remissions
N
Trivedi,
41.1 ± 12.7
6
58.8
NR
29.7
83
30.1
86
NS
1
4
2006
565
weeks
Adverse effect burden was similar among treatment groups; however, fewer participants taking citalopram plus sustained-release bupropion stopped treatment because of intolerance than did those taking
citalopram plus buspirone (12.5 percent vs. 20.6 percent; ÷ 2 = 6.86; p<0.001). No placebo control group included.
Name
Mean
±SD Age (yr)
N
%
Female
Follow
-up
Rate
Follow
-up
Time
Risperidone
% Remissions
Placebo
N
% Remissions
N
p
Study
Quality†
Biases*
Mahmoud,
Risperidone 137
70.8
6
0.0
81%
25.4
26
10.7
12
4
2007
Placebo 131
76.3
weeks
04
Adverse effects were similar among treatment groups. Funded by manufacturer of risperidone.
AUG, augmentation; NR, not reported; NS, not significant; SW, switch
†Study quality measured by Jadad scoring system (1 to 5 = low to high
*Biases: N: none; 1: sample attrition >15%; 2: sample selection bias; 3: detection bias (e.g., measurement error, ITT analysis, power); 4: study procedure biases (e.g., blinding, randomization)
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Table 4.2: Meta-analyses of Augmentation with Atypical Antipsychotic Medications
Studies
Total N
Study Population
Group Size & Drug
Papakostos GI 2007
(meta-analysis)
All patients diagnosed with treatmentresistant depression
# studies found: 137
# studies included: 10
All trials compared adjunctive treatment
with atypical antipsychotics against
placebo treatment.
Total N = 1500
Heterogeneity: heterogeneity
addressed by use of randomeffects model
4 trials from published medical literature
6 reports from scientific meetings
5 reports of olanzapine
3 reports of quetiapine
2 reports of risperidone
Results
Remission:
RR = 1.75 (95% CI, 1.36– 2.24;
p<. 0001) for active treatment
versus placebo
Pooled remission:
Active treatment: 47.4%
Placebo: 22.3%
Pooled response:
Active treatment: 57.2%
Placebo: 35.4%
Comments
Discontinuation due to adverse effects:RR = 3.38
(95% CI, 1.98-–3.38; p<0. 0001) for active
treatment versus placebo
Authors’ conclusions: These results support the utility of
augmenting therapy for treatment-resistant depression with
atypical antipsychotic.
No difference noted in overall rate of
discontinuation:
RR = 1.18 (95% CI, 0.93–1.49; p =0.929)
Higher discontinuation rate due to side effects with
active treatment:
RR = 3.38 (95% CI, 1.98–5.76; p<0.001)
Biases, etc.: Studies involved only olanzapine, quetiapine,
and risperidone.
Table 4.3: RCTs of Augmentation with Atypical Antipsychotic Medications
Name
Mean ± SD Age (yr)
N
% Female
Berman,
2007
Placebo 44.2±10.9
64.2
176
Apiprazole 46.5±10.6
61.5
182
81.9% of active-treatment patients reported adverse effects.
Placebo
Followup Rate
Follow
-up
Time
%
Remissions
N
90.9
6 weeks
15.7
27
Apiprazole
%
Remissions
N
26.0
47
p
Study
Quality†
Biases*
<0. 05
5
None
87.9
†Study quality measured by Jadad scoring system (1 to 5 = low to high
*Biases: N: none; 1: sample attrition >15%; 2: sample selection bias; 3: detection bias (e.g., measurement error, ITT analysis, power); 4: study procedure biases (e.g., blinding, randomization)
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Table 4.4: RCTs of Third-Line Treatments for Depression
Mean ± SD Age (yr)
N
Name
% Female
Followup Rate
Followup Time
Mirtazapine
% Remissions
Fava,
44.9±11.9
46.8
NR
14
2006
235
weeks
Adverse effects were similar among treatment groups. No placebo control group included.
Mean ± SD Age (yr)
N
Name
% Female
Followup Rate
Followup Time
N
12.3
14
Lithium
% Remissions
N
Nortriptyline
% Remissions
N
p
Study
Quality†
Biases*
24
NS
1
3,4
Triiodothyronine
% Remissions
N
p
Study
Quality†
Biases*
19.8
Nierenberg,
42.0±2.0
58.5
NR
9.6 weeks
15.9
11
24.7
18
NS
1
2006
142
Fewer side effects were seen with triiodothyronine. No placebo control group included.
NR, not reported; NS, not significant
†Study quality measured by Jadad scoring system
*Biases: N: none; 1: sample attrition >15%; 2: sample selection bias; 3: detection bias (e.g., measurement error, ITT analysis, power); 4: study procedure biases (e.g., blinding, randomization)
3, 4
Table 4.5
Study
Schatzberg
(2005)
Inclusion & Exclusion
Criteria
Inclusion:
Adult outpatients in a current
Major Depressive Disorder
episode and scoring 20+ on
the HAM-D
Medication
(Nefazodone) or
psychotherapy
(CBASP) is
Exclusion:
effective when the Organic mental syndromes,
other is not
psychotic disorders, panic
disorder, PTSD, substance
abuse, eating disorders,
suicidality, medical
contraindications to
antidepressants, unstable
general medical disorders,
nonresponse to nefazodone,
recent treatment with
benzodiazepines, fluoxetine,
MAO-I, ECT, neuroleptics;
psychotherapy outside trial
Age
18-75
Limitations / Biases
Intervention and dose
N and Final N
Duration
No placebo control; no
nonresponder control
group continuing in
previous (initial) therapy.
24 weeks
681 patients randomized into
acute phase of nefazodone (N
= 226), CBASP (N = 228) or
combination therapy (N = 227).
Treatments only switched
for nonresponders able to
complete acute trial.
After 12 weeks, nonresponders
of nefazodone (N = 73) were
switched to CBASP and
nonresponders of CBASP (N =
83) were switched to
nefazodone.
Excluded patients with
greater levels of comorbid
conditions.
Nonresponders who
entered crossover trial
may not have been
comparable since they
were not initially
randomized.
Outcome
HAM-D score of
nonresponders to
nefazodone or CBASP
12 weeks after they
switched to the other
treatment.
Results
p
value
NNT
Both groups improved from
baseline of crossover to
endpoint.
In the intention-to-treat
analysis, patients who
switched from nefazodone
to CBASP showed
significantly greater
improvement than those
who had switched from
CBASP to nefazodone.
0.03
In the completer analysis,
there was no significant
between-group difference.
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Table 4.6
Study
Parker, Brotchie, &
Parker (2005) Is
combination
olanzapine and
antidepressant
medication
associated with a
more rapid
response trajectory
than
antidepressant
alone?
Inclusion &
Exclusion Criteria
Inclusion:
Male and female
outpatients with a first or
new episode of DSM-IV
nonpsychotic Major
Depression.
Age
Mean
age
49
Limitations /
Biases
Small number of
subjects.
Intervention and dose
N and Final N
Patients (N = 20) randomized into
one of two groups:
Duration
2 weeks
Outcome
HAM-D scores at 2
weeks.
Rx1: antidepressant plus
olanzapine (N = 10)
Rx2: antidepressant plus placebo
(N = 10) [After two weeks, Rx2
nonresponders (N = 4) were given
late olanzapine augmentation.]
Exclusion:
Antidepressant in
preceding two weeks,
ECT in previous one
month.
Results
p
value
NNT
Nonsignificant HAM-D improvement:
Endpoint
Baseline
(Day 14)
Rx1
20.5
8.4
Rx2
23.6
13.5
0.06
Four nonresponders of antidepressant
plus placebo who were given olanzapine
at 2 weeks, showed distinctive
improvement from baseline at day 21.
Endpoint
Baseline
(Day 21)
Rx2
25.2
3.0
Table 4.7
Study
Perry, et al.
(2004) Pindolol
augmentation in
depressed
patients resistant
to selective
serotonin
reuptake
inhibitors: a
double-blind, RCT
Inclusion &
Exclusion Criteria
Inclusion:
Male and female
outpatients with Major
Depression (per DSM IV
criteria) and minimum
HAM-D baseline score of
25.
Age
Limitations /
Biases
18-75 Type II error.
Inconsistent dosing in
acute phase.
Confounding patient
characteristics.
Exclusion:
Neuroleptics, psychosis,
substance abuse,
pregnancy,
contraindications to beta
blockers, reactive airway
disease, diabetes,
significant medical illness.
Intervention and dose
N and Final N
Duration
Patients initially received at least 20 3 weeks
mg fluoxetine, 20mg paroxetine, or
50mg sertraline per day for a
minimum of 6 weeks prior to study.
Forty-two patients who failed to
respond sufficiently to acute trial of
SSRIs were continued on SSRI
treatment and randomly assigned to
one of the following groups for 3
weeks:
Outcome
Primary outcome
measure was change
in HAM-D score from
baseline to the end of
week 3.
Results
NNT
No significant differences in
antidepressant response
between the two groups:
Partial response rates for
pindolol (19%) and control (24%)
were comparable at three weeks.
Pindolol and control groups
demonstrated mean decreases in
HAM-D scores of 6.5 and 9.7,
respectively, at three weeks.
Rx1
pindolol 2.5mg tid (N = 21)
Rx2
placebo tid (N = 17)
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p
value
Table 4.8
Study
Kauffmann (2004)
Slow right
prefrontal
transcranial
magnetic
stimulation as a
treatment for
medicationresistant
depression: a
double-blind,
placebocontrolled study
Inclusion &
Exclusion Criteria
Inclusion:
Eleven females, one male
(mean age 52) with Major
Depression (per DSM-IV
criteria) who failed to
respond to at least two
standard antidepressants
given at adequate doses
for at least 8 weeks.
Exclusion:
Pre-existing neurological
and/or cardiac diseases.
Age
18+
Limitations / Biases
Small number of subjects.
Short duration (10 days).
Limited evidence.
Effectiveness of blinding
not assessed.
Control group stimulation
similar to treatment group
stimulation.
Intervention and
dose
N and Final N
Patients randomly
assigned to one of two
groups:
Rx1:
Right transcranial
magnetic stimulation
(rTMS), N = 7
Rx2:
"sham" rTMS, N = 5
Duration
10 days
Outcome
Results
Primary outcome
measure was HAM-D
score after 10 days.
NNT
Mean HAM-D score for Rx1 decreased
significantly from 21.86 to
11.29.(p<.02)
< 0.02
Mean HAM-D score for Rx2 group
decreased from 18.20 to 11.80 (not
significant). (p>.09)
> 0.09
On follow-up, Rx1 relapsed after 2-3
months, whereas Rx2 relapsed after 2
weeks.
Unadjusted differences in
baseline HAM-D scores:
Active group 21.9, control
group 18.2.
Group x time interaction not
assessed.
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Table 4.9
Study
Rumi (2005)
Transcranial
magnetic
stimulation
accelerates the
antidepressant
effect of
amitriptyline in
severe
depression: a
double-blind,
placebo-controlled
study.
Inclusion &
Exclusion Criteria
Age
Inclusion:
Mean
Outpatient adults with
age 39
severe nonpsychotic
Major Depressive Disorder
(DSM-IV) and minimum
baseline score of at least
22 on HAM-D
Limitations / Biases
Efficacy of blinding not
assessed.
Short-term study.
Longer-term difference in
response and remission
rates not assessed.
Exclusion:
Neurological conditions,
personality disorders,
suicide risk, severe
uncontrolled organic
disease, substance abuse,
abnormal lab tests,
pacemaker, history of
seizure, major head
trauma, risk factors for
TMS procedure.
Intervention and
dose
N and Final N
Duration
Seven days prior to
4 weeks
treatment, all patients (N =
46) were started on
amitriptyline which were
maintained during the 4week trial.
Patients (N = 46) were
randomized into one of
two groups:
Rx1:
rTMS (N = 22) - 5
sessions a week for four
weeks.
Rx2:
sham rTMS (N = 24) - 5
sessions a week for four
weeks.
Outcome
Results
Primary outcome
measures were HAM-D
and MADRS scores, CGI
changes, and VAS at
four weeks.
NNT
Overall response ratio (HAM-D
decrease ≥ 50%) was significantly
higher in rTMS group than in sham
group (95% and 46% respectively).
< 0.001
Remission (HAM-D ≤ 7) was
significantly higher in rTMS group than
in sham group (54% and 12%
respectively).
< 0.002
Similar findings were observed for
MADRS and CGI scales, and
subjective assessments through VAS.
Neck pain and burning, and burning in
scalp was significantly predominant in
rTMS group.
The need for clonazepam was
significantly smaller in rTMS group
than in sham group (p<0.001).
< 0.001
Clonazepam was allowed
for sedative purposes; its
use was monitored
throughout the trial.
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Table 4.10
Study,
Total n
Hirschfeld, M.
2002 (RCT, open-label
trial)
Follow-up: 12 weeks
Treatment Groups Size & Drug
Rx1: nefazodone at 200 mg/day (in 2
divided doses) during the first week and
increased to 300 mg/day during week two,
dose adjustments were made thereafter in
weekly increments of 100 mg/day up to 600
mg/day.
Initial n: 681
Final n: Not stated
Rx2: Cognitive Behavioral Analysis System
of Psychotherapy (CBASP) drawing on
techniques from behavioral, cognitive, and
interpersonal forms of psychotherapy
Rx3: Combined nefazodone/CBASP
Study Population
Results
Patients met criteria for either chronic
Major Depressive Disorder, current Major
Depressive Disorder superimposed on
antecedent dysthymic disorder, or
recurrent MDD with incomplete
interepisode recovery (by definition,
these patients would have failed first-line
treatment).
Men and women between the ages of 18
and 75 (Mean of 43 ± 11)
65% female, 91% white,
43% married/cohabiting
Score of ≥ 20 on the 24-item Hamilton
Rating Scale for Depression (HAM-D)
© 2012 Kaiser Permanente Medical Care Program
HAM-D score analysis (numbers obtained from initial Keller
study)
p = 0.68 (Rx1 vs. Rx2) (no difference)
p ≤ 0.001 (Rx1 vs. Rx3) (in favor of combined treatment)
p ≤ 0.001 (Rx2 vs. Rx3) (in favor of combined treatment)
Comments
There was greater improvement in
psychosocial functioning and
general health when combined
treatment was used.
SF-36 general health without HAM-D
p = 0.22 (Rx2 vs. Rx1) (no difference)
p = 0.0003 (Rx3 vs. Rx1) (in favor of combined treatment)
p = 0.02 (Rx3 vs. Rx2) (in favor of combined treatment)
Combined treatment was
statistically superior to
psychotherapy or nefazodone
alone in reducing the HAM-D score
in patients with chronic Major
Depressive Disorder.
SF-36 social functioning with HAM-D as covariate:
p = 0.94 (Rx2 vs. Rx1) (no difference)
p = 0.02 (Rx3 vs. Rx1) (in favor of combined treatment)
p = 0.02 (Rx3 vs. Rx2) (in favor of combined treatment)
Patients were not blind to
treatment received
No placebo control group
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Table 4.11
Study,
Total n
Treatment Groups Size &
Drug
Fava, M.
2002 (RCT,
double-blind)
Rx1: High-dose fluoxetine
(40 – 60 mg/day)
(n = 33)
Follow-up: 4
weeks
Rx2: fluoxetine (20 mg/day)
plus desipramine
(25 – 50 mg/day) (n = 34)
Initial n: 101
Final n: 88
Rx3: fluoxetine (20 mg/day)
plus lithium
(300 – 600 mg/day) (n = 34)
Study Population
Outpatients with Major
Depressive Disorder (52
men and 49 women,
between 18 and 65 years
old) who were either
partial responders or
nonresponders to eight
weeks of treatment with
fluoxetine 20 mg/day.
Initial HAM-D-17 score of
≥ 16
Results
Comments
Mean change in HAM-D-17 score (from visit 1-endpoint)for all patients
with partial response or nonresponse to fluoxetine
20 mg/day
Rx1: 5.1± 5.3
Rx2: 3.5 ± 5.6
Rx3: 3.6 ± 6.2
p = 0.4 (not significant)
Response rate % (at least 50% reduction in HAM-D score)
Rx1: 50%
Rx2: 33.3%
Rx3: 33.3%
p = 0.5 (not significant)
For patients who fail to respond to a trial of a standard dose
of fluoxetine (20 mg/day), there are no significant
differences in efficacy among patients whose fluoxetine
dose is raised to 40 to 60 mg/day, patients on fluoxetine
plus low-dose desipramine
(25 – 50 mg/day), and patients on fluoxetine plus low-dose
lithium (300 – 600 mg/day).
Patients who partially respond to eight weeks of fluoxetine
20 mg/day may respond more completely to higher doses
of fluoxetine (with a response rate of 50%), although the
difference in response rates across the three treatment
groups was not statistically significant.
Most common side effects:
Rx1: gastrointestinal distress (54.5%), headache (42.4%), dizziness
(30.3%), dry mouth (27.3%), sedation or fatigue (18.2%)
Rx2: dry mouth (55.9%), gastrointestinal distress (47.1%), dizziness
(35.3%), insomnia (32.4%), agitation (29.4%), sedation or fatigue
(26.5%)
Rx3: gastrointestinal distress (50.0%), dry mouth (38.2%), insomnia
(35.3%), sedation or fatigue (32.4%), headache (26.5%)
No placebo control group – does not allow comparison with
continuing initial dose of antidepressant for a longer period
of time, and does not exclude placebo response to
augmentation.
May have been underpowered.
There were no significant differences in dropout rates across the three
groups.
© 2012 Kaiser Permanente Medical Care Program
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Table 4.12
Study,
Total n
Treatment Groups Size
& Drug
Peet, M.
2002 (RCT,
double-blind)
Rx1: ethyl-eicosapentaenoate
1 g/d plus three placebo
capsule (n = 17)
Follow-up: 12
weeks
Rx2: ethyl-eicosapentaenoate
2 g/d plus two placebo
capsules (n = 18)
Initial n: 70
Final n: 60
Intention-to treat
Rx3: ethyl-eicosapentaenoate
3 g/d plus one placebo
capsule
(n = 17)
Study Population
Results
Comments
Patients of either sex, aged
18 to 70
Change in HDRS (17-item Hamilton Depression Rating Scale) score for the
intent -to- treat (ITT) population
(comparing active treatment with placebo)
HAM-D-17 score of 15 or
Rx1: 9.9, p = 0.02 (statistically significant)
more despite ongoing
Rx2: 5.8, p = 0.88 (no difference)
treatment with a standard
Rx3: 5.4, p = 0.44 (no difference)
antidepressant at an adequate Rx4: 5.1
dose
Change in Montgomery-Asberg Depression Rating Scale (MADRS) score for
ITT population (comparing active treatment with placebo)
Rx4: Liquid paraffin placebo,
four capsules
(n = 18)
Treatment with ethyl-eicosapentaenoate at a
dosage of 1 g/d, but not higher doses is effective
in treating depression in patients who remain
depressed despite adequate standard therapy
(suggests a possible therapeutic window effect).
Small n
Rx1: 11.2, p = 0.006 (statistically significant)
Rx2: 3.0, p = 0.41 (no difference)
Rx3: 8.5, p = 0.15 (no difference)
Rx4: 5.4
Change in Beck Depression Inventory (BDI) score for the intention-to- treat
(ITT) population (comparing active treatment with placebo)
Rx1: 12.5, p = 0.007 (statistically significant)
Rx2: 5.7, p = 0.99 (no difference)
Rx3: 9.3, p = 0.24 (no difference)
Rx4: 5.5
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Table 4.13
Study,
Total n
Treatment Groups Size &
Drug
Nemets, B.
2001 (RCT, double-blind)
Rx1: Ethyl- eicosapentaenoate
(E-EPA), 2 g/day
Follow-up: 4 weeks
Rx2: Placebo
Initial n = 20
Final n = 19
Study Population
Results
Comments
17 women and 3 men
(18 – 75 years old) with a current
diagnosis of Major Depressive Disorder
Change in mean Hamilton Depression Rating
Scale Score from baseline to week four
Rx1: 12.4
Rx2: 1.6
24-item Hamilton Depression Rating Scale p = not stated
of 18 or higher
No clinically relevant side effects were
Patients under standard antidepressant
reported.
treatment for at least three months except
for one.
Highly significant benefits of the addition of the
omega-3 fatty acids compared with placebo were
found by week 3 of treatment,
Small n
Table 4.14
Study,
Total n
Treatment Groups Size &
Drug
Perez, VS.
1999 (RCT, double-blind)
Rx1: 5-HT reuptake inhibitors
plus pindolol (2.5 mg tid) (n = 40)
Follow-up: 10 days
Rx2: 5-HT reuptake inhibitors
plus placebo (tid) (n = 40)
Initial n: 80
Final n: 78
Study Population
Results
Adults 18 to 65 years
Existence of a Major Depressive Disorder,
single or recurrent (DSM-IV) with a current
episode resistant to pharmacological
treatment
17-item Hamilton depression-rating scale
score of ≥ 16
All patients except 2 were outpatients.
© 2012 Kaiser Permanente Medical Care Program
Comments
Change in HAM-D score from day 0 to day 10
Rx1: 2.2 ± 4.4
Rx2: 3.7 ± 5.9
Difference not significant, p value not given
The study does not support the hypothesis that
the addition of pindolol results in a rapid
augmentation of the effects of SSRIs in depressed
patients resistant to initial treatment with
antidepressants.
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5.
Length of Treatment With Antidepressants In Patients With MDD
Problem Formulation 5
Clinical Question:
Intended Use of
the Guideline:
Population:
Health Problem:
Health Intervention:
Practitioners:
Setting:
Health Outcomes
(associated with the
intervention):
How long should adults with MDD continue taking antidepressant
medication?
To assist primary care physicians and other health care professionals
in treating adults with Major Depression.
All adult (age 19 and older) patients with Major Depression who
receive treatment with antidepressant medication with:
 One lifetime episode of MDD
 Two or more episodes of MDD
MDD
Continue antidepressant (SSRIs, TCAs, DAs, SNRIs, or NRIs)
treatment for appropriate length of time
Discontinue antidepressant treatment
KP primary care physicians, physician assistants, nurse practitioners,
pharmacists, and health educators
Outpatient office visit, emergency department, urgent care clinics
 Change in symptoms
 Quality of life
 Missed school/work days
© 2012 Kaiser Permanente Medical Care Program
 Office/UCC/ER visits
 Hospitalizations
 Mortality
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Search Strategy
Article Type
and Other
Limits:
Database:
Search Terms:
PubMed
("Depression"[MeSH] OR "Major
Only items
Depressive Disorder"[All Fields] AND with
(“systematic"[All Fields] OR
abstracts,
“systematic review"[All Fields] OR
Humans,
“meta-analysis"[All Fields]))
English, All
Adult: 19+
years
("depression/drug therapy"[MeSH] OR
PubMed
Only items
"depression/therapy"[MeSH] OR
with
"depressive disorder/drug therapy"[MeSH] abstracts,
OR "depressive disorder/prevention and
Humans,
control"[MeSH] OR "Antidepressive
Randomized
Agents/ administration and dosage"[MeSH]
Controlled
OR "depression recurrent"[All Fields] OR
"depression chronic"[All Fields] OR "Major Trial, English,
All Adult:
Depressive Disorder"[All Fields]) AND
("drug administration schedule"[MeSH] OR 19+ years
Search
Date
8/2005
to
9/2007
No.
Included
/ Total
Retrieved*
0/129
8/2005
to
9/2007
0/72
Systematic
Review,
Metaanalyses and
RCTs
December
6, 2004
N/A
Systematic
Reviews
Systematic
Reviews and
RCTs
Q4, 2005
0/131
January
2006
N/A
"Recurrence/prevention and
control"[MeSH] OR "Treatment
duration"[All Fields] OR "treatment
discontinuation"[All Fields] OR "treatment
continuation"[All Fields])
National
Depression
Institute
for
Clinical
Excellence
(NICE)
Cochrane Depression, Anxiety and Neurosis
Group
Clinical
Chapter: Depressive Disorders
Evidence,
Issue 14
*
Note: “No. Included” refers to studies that are relevant to the problem formulation and, therefore, are included
in this analysis of the evidence. “Total Retrieved” refers to the number of studies retrieved in the search,
regardless of relevance. Because individual studies can be captured in multiple databases, they may be counted
more than once in the number included. Systematic reviews and meta-analyses with search dates outside the
range of current searches were excluded.
© 2012 Kaiser Permanente Medical Care Program
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Database:
Search Terms:
("depression/drug therapy"[MeSH] OR
PubMed
"depression/therapy"[MeSH] OR
"depressive disorder/drug therapy"[MeSH]
OR "depressive disorder/prevention and
control"[MeSH] OR "Antidepressive
Agents/administration and dosage"[MeSH]
OR "depression recurrent"[All Fields] OR
"depression chronic"[All Fields] OR "Major
Depressive Disorder"[All Fields]) AND
("drug administration schedule"[MeSH] OR
"Recurrence/prevention and
control"[MeSH] OR "Treatment
duration"[All Fields] OR "treatment
discontinuation"[All Fields] OR "treatment
continuation"[All Fields]) AND
Randomized Controlled Trial[ptyp] AND
English[Lang] AND "adult"[MeSH Terms]
AND "humans"[MeSH Terms] AND
("2003/01/01"[PDAT] : "3000"[PDAT])
AND Randomized Controlled Trial[ptyp]
AND English[Lang] AND "adult"[MeSH
Terms] AND "humans"[MeSH Terms]
AND ("2003/01/01"[PDAT] :
"2005/08/01"[PDAT])
Cochrane
Clinical
Evidence
Article Type
and Other
Limits:
Randomized,
controlled
trials
Systematic
reviews
Systematic
reviews &
RCTs
Depression
Depression
© 2012 Kaiser Permanente Medical Care Program
Search
Date
01/01/03
08/01/05
No.
Included
/ Total
Retrieved*
3/81
03/05/03
0/295
09/22/03
1/86
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National Adult Depression Clincial Practice Guideline
Article Type
and Other
Limits:
Search
Date
Database:
Search Terms:
((((("depression"[MeSH Terms] OR
Randomized,
PubMed
1980
depression[Text Word]) AND ("drug
controlled
administration schedule"[MeSH Terms] OR trials , English,
9/2001
DRUG ADMINISTRATION
Randomized
01/01/1980
SCHEDULE[Text Word]))
Controlled
("depression/drug therapy"[MeSH] OR
Trial, All
04/01/2003
"depression/therapy"[MeSH] OR
"depressive disorder/drug therapy"[MeSH]
OR "depressive disorder/prevention and
control"[MeSH] OR "Antidepressive
Agents/administration and dosage"[MeSH]
OR "depression recurrent"[All Fields] OR
"depression refractory"[All Fields] OR
"depression chronic" [All Fields] OR
"depression first episode"[All Fields] OR
"Major Depressive Disorder"[All Fields])
AND ("drug administration
schedule"[MeSH] OR "treatment
protocols"[MeSH] OR
"Recurrence/prevention and
control"[MeSH] OR "Treatment
duration"[All Fields] OR "treatment
discontinuation"[All Fields] OR "treatment
continuation"[All Fields])
Adult: 19+
years, English,
Human
Meta-Analysis,
All Adult: 19+
years, English,
Human
Review, All
Adult: 19+
years, English,
Human
No.
Included
/ Total
Retrieved*
0/344
5/308
01/01/1980
04/01/2003
0/4
01/01/1980
04/01/2003
0/44
Some studies found and used in this guideline did not appear in PubMed search results due to the
way studies are indexed in PubMed. The Keller(135) study did not show up in our search results
due to the way PubMed indexing is done.
Other Information Sources:
 Evidence report on the Treatment of Depression-Newer Pharmacotherapies. AHRQ(2)
 The British Medical Journal(151)
© 2012 Kaiser Permanente Medical Care Program
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Evidence Tables
Table 5.1
Study
Keller, et al.
(2005) Relapse
prevention with
gepirone ER in
outpatients with
Major
Depression
Inclusion & Exclusion
Criteria
Inclusion:
Adults with primary diagnosis of
recurrent Major Depression (per
DSM-IV); screening and baseline
HAM-D score 20+.
Exclusion:
HAM-D score that decreased by >
20% between screening and
baseline, history of treatmentrefractory depression, pregnancy,
substance abuse, pre-trial
treatment with MAO-I (within 3
weeks), fluoxetine (within 5
weeks), other psychotropic agents
(within 2 weeks).
Age
Limitations /
Biases
Intervention and dose
– N and Final N
18-70 Limited external validity In acute phase, patients (N
and generalizability due = 420) were given opento exclusion of :
label gepirone ER for 8 or
12 weeks, depending on
a) patients with severe time to remission.
comorbidities
Patients who achieved
b) patients with prior
remission (N = 250) were
treatment resistance or randomized into a doublewho responded
blind continuation phase:
insufficiently to
gepirone open label
a) gepirone ER (N = 126)
treatment.
b) placebo (N = 124)
© 2012 Kaiser Permanente Medical Care Program
Duration
44 weeks
Outcome
Primary outcome measure
was number of patients
with relapse, defined as
HAM-D score 16+ at
endpoint (44 weeks).
Results
In continuation phase, there
was a statistically significant
lower percentage of overall
relapses in gepirone ER
(23%) group than in placebo
(34.7%). (p=0.024).
Differences were statistically
significant from week 24 to
week 44. (p<0.05)
p value
8.5
0.024
< 0.05
Gepirone well tolerated 3.2% in continuation phase
dropped out due to adverse
events.
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Table 5.2
Study
Montogomery, et
al. (2004),
Venlafaxine
versus placebo in
the preventive
treatment of
recurrent Major
Depression
Inclusion & Exclusion Criteria
Age
Inclusion:
18+
Adult outpatients with Major Depression
(per DSM III-R criteria) who had a history
of recurrent Major Depression (≥1
previous episode in the last 5 years with a
symptom free period > 6 months between
episodes) and symptoms of depression for
> 1 month before study entry.
Exclusion:
Recent MI; history of drug or alcohol
dependence, hepatic or renal disease,
seizure disorder, psychotic disorder,
bipolar disorder, hypersensitivity to
venlafaxine; pregnancy; concomitant
psychiatric disorders
Limitations / Biases
Disproportionate
contribution of number of
participants (53 from
Europe, remaining from
USA).
Some investigators might
have inadvertently been
delivering psychotherapy,
in some way.
Short taper period for
those who switched to
placebo.
Intervention and
dose
N and Final N
Duration
Phase 1 Open label
12 months
treatment (N = 495): 100200mg/day venlafaxine for
6 months
Phase 2 Maintenance (N
= 225): Those who
responded to treatment in
Phase 1 were randomized
into one of two groups - a)
venlafaxine continuation
100-200mg/day (N = 109)
or b) placebo (N = 116) for 12 months.
© 2012 Kaiser Permanente Medical Care Program
Outcome
Primary outcome
was number of
patients
experiencing
recurrence of Major
Depression in the 12
months after a
successful Phase 2.
Results
22% cumulative probability of
recurrence in venlafaxinetreated patients after 12
months compared with 55%
for placebo group.
< 0.001
< 0.001
21% venlafaxine-treated
patients discontinued
treatment because of lack of
efficacy, compared with 48%
placebo-treated patients.
For use within Kaiser Permanente only.
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value
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Table 5.3
Study
Rapaport, Bose
& Zheng (2004),
Escitalopram
continuation
treatment
prevents relapse
of depressive
episodes
Inclusion & Exclusion
Criteria
Inclusion:
Adults diagnosed with Major
Depressive Disorder who had
completed open label phase.
Exclusion:
Principal Axis I disorder (other than
MDD), history of schizophrenia or
any other psychotic disorder;
suicidality, concomitant
psychotropic medication,
pregnancy.
Limitations /
Biases
Age
18-81 Two different phases,
each with separate
randomization.
Exclusion of patients
with comorbid
diagnoses (may not be
representative of
patients in routine
practice)
Impact of lead-in
treatment on subject
outcomes.
Intervention and dose
– N and Final N
Duration
Phase 1 Open label
treatment (N = 502): 10-20
mg/day escitalopram, 2040mg/day citalopram, or
placebo for 8 weeks.
36 weeks
Outcome
The primary efficacy
parameter was time to
relapse from the start of
the double-blind
treatment.
Phase 2 Double-blind (N =
274): Those who
responded to treatment in
Phase 1 were randomized
into one of two groups - a)
escitalopram (N = 181) or b)
placebo (N = 93) for 36
weeks.
Results
NNT
Time to relapse was
significantly longer and
cumulative rate of relapse was
significantly lower in
escitalopram group (26%
escitalopram vs. 40%
placebo) through 36 weeks.
p value
0.013
8
Continuing treatment with
escitalopram significantly
decreased percentage of
patients meeting DSM-IV
criteria for Major Depressive
Disorder: Escitalopram 23%
vs. Control 35%.
Table 5.4
Study,
Total n
Weihs, K.L.
2002 (RCT, double-blind)
Follow-up: 44 weeks (11 months)
Initial N: 816
Initial N (continuation phase) : 417
Final N: 103
Treatment Groups Size & Drug
All patients were treated for an initial 8weeks (acute phase), open- label phase in
which they received bupropion SR (150 mg
to 300 mg/day). Patients who responded to
the treatment and continued to meet the
selection criteria, entered a 44-week
randomized, double-blind, placebo
controlled continuation phase.
Rx1: bupropion SR, 300 mg/day
(n = 207)
Rx2: Placebo (n = 210)
Study Population
Men and women of at least 18
years old with moderate to
severe, recurrent Major
Depression based on
Diagnostic and Statistical
Manual-IV (DSM-IV) criteria
Minimum score of 18 on the 21item Hamilton Depression Scale
(HAMD)
Patient’s current episode must
have been preceded by at least
one other episode within the last
60 months.
© 2012 Kaiser Permanente Medical Care Program
Results
Time to depression relapse (time from randomization to
intervention)
Rx1: 44 weeks
Rx2: 24 weeks
p = 0.003 (log-rank test) favoring continuation treatment
Comments
Treatment with bupropion
SR for up to 44 weeks
decreases the risk of
depression relapse.
Survival estimates indicated 52% of placebo treated patients and
37% of bupropion patients would have become depressed by the
end of the study (p = 0.004 favoring bupropion).
By the end of one year treatment, the odds of placebo-treated
patients requiring treatment intervention for a relapse of
depression were 1.83 times greater that those of bupropion SRtreated patients.
For use within Kaiser Permanente only.
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Table 5.5
Study,
Total n
Reimherr, F.W.
1998 (RCT, double-blind)
Follow-up: 50 weeks
after acute phase
Initial N: 839
Initial N : (continuation
phase) = 395
Final N: Not given
Treatment Groups Size & Drug
Study phases:
Baseline:
A one week (5 to 9 day) medication-free baseline phase
Open label acute phase:
12 to 14 weeks of fluoxetine,
20 mg/day
Continuation phase (Randomized double-blind allocation)
Rx1: 14 weeks of continuation therapy with fluoxetine followed by 38 weeks
placebo(n = 97)
Study Population
Male and female
outpatients 18 to 65 years
of age who met the DSMIII-R criteria for Major
Depression with a
duration of at least one
month
All patients had a modified
17-item Hamilton
Depression Rating Scale
score of at least 16.
Rx2: 38 weeks of continuation therapy with fluoxetine followed by 12 weeks
placebo (n = 100)
Results
Relapse rate% (Kaplan-Meier estimates)
After 12 weeks of continuation treatment:
Rx1: 26.4%
Rx 4: 48.6%
p < 0.001 (favoring continuation treatment)
After 26 weeks of continuation treatment:
Rx2: 9.0%
Rx4: 23.2%
p < 0.001 (favoring continuation treatment)
After 50 weeks of continuation treatment:
Rx3: 10.7%
Rx4: 16.2%
p = 0.54 (no statistical difference)
RX3: 50 weeks of continuation therapy with fluoxetine (n = 102)
RX4: 50 weeks of placebo (no continuation phase)
(n = 96)
Relapse rates were calculated during 12 week periods after each double-blind
transfer from fluoxetine to placebo (weeks 12, 26, and 50).
© 2012 Kaiser Permanente Medical Care Program
Comments
The study shows significantly
lower relapse rates for
fluoxetine-treated patients
compared with placebo-treated
patients for at least 26 weeks
after 12 weeks of successful
acute treatment (38 weeks of
treatment in total).
There was no statistical
difference
(p = 0.54) in the relapse rate
between the fluoxetine group
(10.7%) and placebo (16.2%)
after 50 weeks of continuation
treatment (possibly due to lack
of statistical power due to
patient attrition, as only 53
patients were included in this
analysis).
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Table 5.6
Study,
Total n
Hochstrasser, B.
2001 (RCT, double- blind)
Follow-up: 48 to 77 weeks
Initial N: 264 (maintenance phase)
Final N: Not given
Intention-to-treat analysis
Treatment Groups
Size & Drug
Rx1 citalopram,
dose range 20 to 60 mg
(n = 132)
Rx2 placebo (n = 132)
Study Population
Results
Patients 18 to 65 years of age (inand out-patients) with recurrent
unipolar Major Depression (DSMIV), a Montgomery – Asberg
Depression Rating Scale score of ≥
Patients were treated with 22 and two or more previous
citalopram (20 to 60 mg)
depressive episodes, one within the
for 6-9 weeks, acute
past five years.
phase (n = 427), if
responding, continued for Intent- to-treat population consisted
16 weeks (continuation
of 29% males and 71% females
phase) (n = 327) before
randomized to doubleblind maintenance
treatment with citalopram
or placebo for 48 to 77
weeks.
Time from randomization to recurrence of a new depressive episode
(using Kaplan-Meier estimates) :
Time difference was significant, favoring citalopram group
p < 0.0001
Comments
Time to recurrence was
longer in patients taking
citalopram than in patients
taking placebo (p < 0.001)
Rx1: 0.22 recurrences/person year at risk
Rx2: 0.76 recurrences/person year at risk
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Table 5.7
Study,
Total n
Gilaberte, I.
2001 (RCT, double-blind)
Follow-up: 48 weeks of maintenance
treatment
Initial N: 253
Initial N (maintenance phase): 140
Final N: 78
Intention-to-treat analysis
Treatment Groups Size
& Drug
All patients completed 32
weeks of open-label
treatment phase consisting
of both an acute (8 weeks)
and a continuation period
(6 months).
Maintenance phase
Rx1: fluoxetine, 20 mg/day
(n = 70)
Rx2: placebo
(n = 70)
Study Population
Results
Male and female outpatients, 18 to
65 years of age, who met DSM-IIIR criteria for unipolar Major
Depression and had at least one
previous major depressive episode
in the last 5 years.
Score of at least 18 on the 17-item
Hamilton Rating Scale for
depression (HAM-D-17) and at
least 4 on the Clinical Global
Impression (CGI) severity scale.
Comments
Recurrence Rate (%)
Long-term maintenance treatment with
fluoxetine appeared to be effective in the
prevention of recurrent depression.
Rx1: 20%
Rx2: 40%
p = 0.010
Mean HAM-D-17 score at the end of maintenance phase:
Mean number of previous episodes for
fluoxetine group were 2.3 ± 1.2, and for
the placebo group 2.6 ± 1.5.
Rx1: 6.5 ± 8.6
Rx2: 9.9 ± 9.4
p = 0.027
The symptom-free period was significantly longer for patients
treated with Fluoxetine versus placebo (295 days vs. 192
days; Kaplan-Meier estimates, log-rank test, p = 0.002)
© 2012 Kaiser Permanente Medical Care Program
For use within Kaiser Permanente only.
237
02/12
National Adult Depression Clincial Practice Guideline
Table 5.8
Study,
Total n
Treatment Groups Size
& Drug
Kocsis, J.H.
1996 (RCT, double-blind)
Follow-up: 16 weeks for continuation
phase
24 months for maintenance phase
Initial N: 129
Initial N (maintenance phase): 53
Final N: Not given in both cases
Intention-to-treat analysis
All patients treated with
desipramine hydrochloride
during the acute phase (10
weeks) and continuation
phase (16 weeks), dose
range 50 to 325 mg/d).
Maintenance phase
Rx1 desipramine (n = 28)
Rx2 Tapered by 25% per
week in the first month to
placebo (n = 25)
Study Population
Results
Out patients who met DSM-III
diagnostic criteria for “pure”
dysthymia (40%), chronic Major
Depression (10%) and dysthymia
with current Major Depression
(50%)
88% white, 6% black,
4% Hispanic, 4% Asians
Mean age 36 to 37, 51 to 64%
female.
Comments
Only 41% of patients initially enrolled entered
maintenance phase treatment
Relapse rates (%), maintenance phase
Rx1: 15% (11% in abstract)
Rx2: 52%
ARR = 37%, NNT = 3
p = 0.01 favoring maintenance treatment
(p listed as 0.004 in abstract)
Long-term maintenance treatment with desipramine
appeared to be effective in the prevention or
postponement of relapse of depression in patients
who responded to desipramine during the acute
and continuation phases.
Most placebo relapses occurred during the first 6
months of maintenance therapy.
40% of patients studied did not have MDD,
although results did not differ by subgroup. The
three subtypes of chronic depression responded
similarly to desipramine treatment in the acute,
continuation, and maintenance phases.
Small sample size for maintenance phase
Table 5.9
Study,
Total n
Keller, M.B.
1998(RCT, double-blind)
Follow-up: 76 weeks of
maintenance phase
Initial N: 426
Initial N (maintenance phase):
161
Final N: 59
Treatment Groups Size
& Drug
Patients completed 12 weeks
of treatment (acute phase)
and 4 months of continuation
phase treatment with
sertraline 50 to 200 mg/d
Maintenance phase
Rx1 sertraline hydrochloride,
daily dose of 50 to 200 mg
(n = 77)
Rx2 placebo
(n = 84)
Intention-to-treat analysis
Study Population
Outpatients meeting a structured
clinical interview diagnosis of
Chronic Major Depression (of at
least 2 years in duration) or
Dysthymic Disorder with a
concurrent diagnosis of Major
Depression (double depression)
based on DSM-III-R.
Minimum baseline severity of 18
on the 24-item Hamilton
Depression Scale (HAM-D)
Results
Rx2 n (%)
Rx1 n (%)
Experienced
19 (23)
5 (6)
recurrence by strict protocol criteria
Comments
Log-Rank P
0.002
Long-term maintenance treatment with sertraline
protects against recurrence or reemergence of
depression and considerably extends the time in
remission for these high-risk patients.
Experienced
42 (50)
20 (26)
0.001
depression reemergence by Consensus assessment
Showed
50 (60)
26 (34)
0.001
first symptoms of reemergence of depression by consensus
assessment.
Strict protocol criteria: requiring 3 weeks of treatment and a
confirmatory second evaluation one week later by an
independent senior investigator
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238
02/12
National Adult Depression Clincial Practice Guideline
6.
Follow-Up For Patients In The Acute Phase (First Three Months)
of Treatment For MDD
Problem Formulation 6
Clinical Question:
Intended Use of
the Guideline:
Population:
Health Problem:
To assist primary care physicians and other health care professionals in
treating adults with Major Depression.
All adult (age 19 and older) patients in acute phase treatment of Major
Depression
MDD
Health
Intervention:
Follow-up* in the first 12 weeks of treatment (“acute phase”) for
patients diagnosed with MDD:
 Follow-up within four weeks and again at eight to twelve
weeks
 Three times in the first 12 weeks (HEDIS measure)
 Other follow-up intervals
 No follow-up
Practitioners:
KP primary care physicians, physician assistants, nurse practitioners,
pharmacists, and health educators
Setting:
Health Outcomes
(associated with
the intervention):
*
What is the recommended follow-up for patients in the first three
months of treatment for MDD?
Outpatient office visit, emergency department, urgent care clinics




Change in symptoms
Quality of life
Missed school/work days
Adherence
 Office/UCC/ER visits
 Hospitalizations
 Mortality
Follow-up contact may include in-person visits, phone calls or email between patient and clinician, or phone
calls/email between patient and a care manager.
© 2012 Kaiser Permanente Medical Care Program
For use within Kaiser Permanente only.
239
02/12
National Adult Depression Clincial Practice Guideline
Search Strategy
Article Type
and Other
Limits:
Database:
Search Terms:
PubMed
("Depression"[MeSH] OR "Major
Only items
Depressive Disorder"[All Fields] AND with abstracts,
(“systematic"[All Fields] OR
Humans,
“systematic review"[All Fields] OR
English, All
“meta-analysis"[All Fields]))
Adult: 19+
years
PubMed
(((((((("depression/drug
Only items
effects"[MESH] OR "depression/drug with abstracts,
therapy"[MESH]) OR
Humans,
"depression/therapy"[MESH]) OR
Randomized
"depression"[All Fields] OR "Major
Controlled
Depressive Disorder"[All Fields])
Trial, English,
AND ((("office visits"[MESH] OR
All Adult: 19+
"office visits"[text word]) OR
years
"telephone"[text word]) OR
"visits"[text word]))
Depression, Anxiety and Neurosis
Systematic
Cochrane
Group
Reviews
Clinical
Systematic
Evidence, Chapter: Depressive Disorders
Reviews and
Issue 14
RCTs
PubMed
(((((((("depression/drug effects"
Randomized,
[MESH] OR "depression/drug
controlled
therapy"[MESH]) OR "depression/
trials
therapy"[MESH]) OR "depression"
[All Fields] OR "Major Depressive
Disorder"[All Fields]) AND ((("office
visits"[MESH] OR "office visits"[text
word]) OR "telephone"[text word])
OR "visits"[text word])) AND
English[Lang]) AND "adult"[MeSH
Terms]) AND "hominidae"[MeSH
Terms])
*
Search
Date
8/2005
to
9/2007
No.
Included
/ Total
Retrieved*
0/129
8/2005
to
9/2007
0/87
Q4, 2005
0/131
January
2006
N/A
01/01/03
08/10/05
1/20
Note: “No. Included” refers to studies that are relevant to the problem formulation and, therefore, are included
in this analysis of the evidence. “Total Retrieved” refers to the number of studies retrieved in the search,
regardless of relevance. Because individual studies can be captured in multiple databases, they may be counted
more than once in the number included. Systematic reviews and meta-analyses with search dates outside the
range of current searches were excluded.
© 2012 Kaiser Permanente Medical Care Program
For use within Kaiser Permanente only.
240
02/12
National Adult Depression Clincial Practice Guideline
Database:
Search Terms:
Cochrane
Depression
Clinical
Evidence
Depression
PubMed
(((("depression"[MeSH Terms] OR
DEPRESSION[Text Word]) OR
"depressive disorder"[MeSH Terms])
OR depressive disorder[Text Word])
AND ("office visits"[MeSH Terms]
OR OFFICE VISIT[Text Word]))
(((((((("depression/drug
effects"[MESH] OR "depression/drug
therapy"[MESH]) OR
"depression/therapy"[MESH]) OR
"depression" [All Fields] OR"Major
Depressive Disorder"[All Fields])
AND ((("office visits"[MESH] OR
"office visits"[text word]) OR
"telephone"[text word]) OR
"visits"[text word]))
Article Type
and Other
Search
Limits:
Date
Systematic
03/05/03
reviews
Systematic
03/05/03
reviews and
RCTs
All publication
1980
types, All
adults 19+
04/25/2001
years, English,
Human
All publication
types, All
adults 19+
years, English,
Human
01/01/01
04/01/03
No.
Included
/ Total
Retrieved*
0/295
0/80
0/58
0/246
Some studies found and used in this guideline did not appear in PubMed search results due to the
way studies are indexed in PubMed.
© 2012 Kaiser Permanente Medical Care Program
For use within Kaiser Permanente only.
241
02/12
National Adult Depression Clincial Practice Guideline
Evidence Table
Table 6.1
Study
Swindle, et al.
(2003),
Integrating
clinical nurse
specialists into
the treatment of
primary care
patients with
depression.
Inclusion &
Exclusion Criteria
Age
Inclusion: diagnosis of Mean
Major Depression,
age 56
dysthymia or partially
remitted Major
Depression; ≥ 2
General Medicine
Clinics visits past one
year, telephone access,
informed consent
Exclusion:
Incompetent for
interview, nursing home
residence, active
suicidality, seen in
VAMC (Veterans Affairs
Medical Center) mental
health program,
substance abuse,
history of bipolar
disorder, terminal
illness.
Limitations / Biases
Intervention and dose
N and Final N
CNS's often disagreed with the
PRIME-MD diagnosis and did
not believe treatment was
appropriate or necessary for
many of the subjects (affecting
the fidelity of the intervention).
Duration
Control firm (N = 134):
12 months
Diagnosis of depression
documented in chart.
Intervention firm (N = 134):
At initial visit, Clinical Nurse
Specialist (CNS) would
create an initial treatment
Subjects of study were veterans plan based on medical record
(96% men) with medically
and responses to PRIMEcomplex issues.
MD. Components of the
treatment plan could include
Unit of randomization was the
medication, cognitive
firm and not the participant.
behavioral therapy, and or
referral to Mental Health.
No true control group (all
Monitoring through telephone
clinicians received educational and/or in person contacts
program).
was to occur at two weeks,
one month, and two months
Post hoc rather than a priori
after initial visit.
outcome assessment.
Outcome
Primary outcomes
assessed at 3 and 12
months were
depressive symptoms
and patient satisfaction.
Results
NNT
p value
No significant effects of the CNS
intervention on overall depressive
symptoms at 3 months .
0.43
No significant effects of the CNS
intervention on overall depressive
symptoms at 12 months .
0.51
Post hoc, within group analyses
of BDI scores revealed that
intervention group patients with
only Major Depression improved
significantly at 3 and 12 months.
Differences between intervention
and control groups in patient
satisfaction were small and not
significant.
Lacked power to detect
differences between
intervention and control for
patients with Major Depressive
Disorder.
Data on usual care patient
follow-up not provided.
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242
02/12
National Adult Depression Clincial Practice Guideline
7.
Follow-Up For Patients In The Continuation Phase
(Months Four to 12) of Treatment For MDD
Problem Formulation 7
Clinical Question:
Intended Use of
the Guideline:
To assist primary care physicians and other health care professionals in
treating adults with Major Depression.
Population:
All adult (age 19 and older) patients in continuation phase treatment of
Major Depression
Health Problem:
MDD
Health
Intervention:
Follow-up* for patients during months four to 12 of treatment
(“Continuation Phase”) for Major Depression:
 Follow-up at five to six months
 Additional follow-up visits
 Other follow-up intervals
 No follow-up
Practitioners:
KP primary care physicians, physician assistants, nurse practitioners,
pharmacists, and health educators
Setting:
Health Outcomes
(associated with
the intervention):
*
What is the recommended follow-up for patients in remission during
months four to 12 of treatment for MDD?
Outpatient office visit, emergency department, urgent care clinics




Change in symptoms
Quality of life
Missed school/work days
Adherence
 Office/UCC/ER visits
 Hospitalizations
 Mortality
Follow-up contact may include in-person visits, phone calls or email between patient and clinician, or phone
calls/email between patient and a care manager.
© 2012 Kaiser Permanente Medical Care Program
For use within Kaiser Permanente only.
243
02/12
National Adult Depression Clincial Practice Guideline
Search Strategy
Database:
PubMed
PubMed
PubMed
PubMed
Cochrane
Clinical
Evidence,
Issue 14
*
No.
Included
/ Total
Retrieved*
Article Type and
Other Limits:
Search
Date
("Depression"[MeSH] OR "Major
Depressive Disorder"[All Fields]
AND (“systematic"[All Fields] OR
“systematic review"[All Fields] OR
“meta-analysis"[All Fields]))
(((("depression/drug effects"[MESH]
OR "depression/drug therapy"
[MESH]) OR "depression/therapy"
[MESH]) OR "depression"[All
Fields] OR "Major Depressive
Disorder"[All Fields]) AND
((("office visits"[MESH] OR
"office visits"[text word]) OR
"telephone"[text word]) OR
"visits"[text word]))
(((("depression"[MeSH Terms] OR
DEPRESSION[Text Word]) OR
"depressive disorder"[MeSH Terms])
OR depressive disorder[Text Word])
AND ("office visits"[MeSH Terms]
OR OFFICE VISIT[Text Word]))
"follow up" AND ("telephone" OR
"office visit" or “remission”) AND
("depressive disorder" [MeSH
Terms])
Only items with
abstracts,
Humans, English,
All Adult: 19+
years
Only items with
abstracts,
Humans,
Randomized
Controlled Trial,
English, All
Adult: 19+ years
8/2005
to
9/2007
0/129
8/2005
to
10/2007
0/88
Only items with
abstracts, Humans,
Randomized
Controlled Trial,
English, All Adult:
19+ years
8/2005
to
10/2007
0/31
Only items with
abstracts, Humans,
Randomized
Controlled Trial,
English, All Adult:
19+ years
8/2005
to
10/2007
0/29
Depression, Anxiety and Neurosis
Group
Chapter: Depressive Disorders
Systematic
Reviews
Systematic
Reviews and
RCTs
Q4, 2005
0/131
January
2006
N/A
Search Terms:
Note: “No. Included” refers to studies that are relevant to the problem formulation and, therefore, are included
in this analysis of the evidence. “Total Retrieved” refers to the number of studies retrieved in the search,
regardless of relevance. Because individual studies can be captured in multiple databases, they may be counted
more than once in the number included. Systematic reviews and meta-analyses with search dates outside the
range of current searches were excluded.
© 2012 Kaiser Permanente Medical Care Program
For use within Kaiser Permanente only.
244
02/12
National Adult Depression Clincial Practice Guideline
Article Type and Search
Other Limits:
Date
Database:
Search Terms:
(((((((("depression/drug effects"[MESH] Randomized,
PubMed
01/01/03
OR "depression/drug therapy"[MESH]) controlled trials
OR "depression/ therapy"[MESH]) OR
08/10/05
No.
Included
/ Total
Retrieved*
0/20
"depression"[All Fields] OR "Major
Depressive Disorder"[All Fields]) AND
((("office visits"[MESH] OR "office
visits"[text word]) OR "telephone"[text
word]) OR "visits"[text word])) AND
English[Lang]) AND "adult"[MeSH
Terms]) AND "hominidae"[MeSH
Terms]) AND ("2001/01/01"[PDAT] :
"2003/04/01"[PDAT])) AND
"2003/07/23 13.27"[MHDA] :
"2005/08/10 15.01"[MHDA]
Cochrane
Clinical
Evidence
PubMed
Systematic
reviews
Systematic
Depression
reviews and
RCTs
(((("depression"[MeSH Terms] OR
All publication
DEPRESSION[Text Word]) OR
types, All adults
"depressive disorder"[MeSH Terms]) 19+ years,
OR depressive disorder[Text Word]) English, Human
AND ("office visits"[MeSH Terms]
OR OFFICE VISIT[Text Word]))
(((((((("depression/drug
All publication
types, All adults
effects"[MESH] OR
"depression/drug therapy"[MESH]) 19+ years,
OR "depression/therapy"
English, Human
[MESH])OR "depression" [All
Fields] OR "Major Depressive
Disorder"[All Fields]) AND
((("office visits"[MESH] OR
"office visits"[text word]) OR
"telephone"[text word]) OR
"visits"[text word]))
Depression
03/05/03
0/295
03/05/03
1/80
1980
04/25/01
0/5
01/01/01
04/01/03
0/246
Some studies found and used in this guideline did not appear in PubMed search results due to the
way studies are indexed in PubMed.
© 2012 Kaiser Permanente Medical Care Program
For use within Kaiser Permanente only.
245
02/12
National Adult Depression Clincial Practice Guideline
Evidence Table
Table 7.1
Study
Swindle, et al.
(2003),
Integrating
clinical nurse
specialists into
the treatment of
primary care
patients with
depression.
Inclusion &
Exclusion Criteria
Age
Inclusion: diagnosis of Mean
Major Depression,
age 56
dysthymia or partially
remitted Major
Depression; ≥ 2
General Medicine
Clinics visits past one
year, telephone access,
informed consent
Exclusion:
Incompetent for
interview, nursing home
residence, active
suicidality, seen in
VAMC (Veterans Affairs
Medical Center) mental
health program,
substance abuse,
history of bipolar
disorder, terminal
illness.
Limitations / Biases
Intervention and dose
N and Final N
CNS's often disagreed with the
PRIME-MD diagnosis and did
not believe treatment was
appropriate or necessary for
many of the subjects (affecting
the fidelity of the intervention).
Duration
Control firm (N = 134):
12 months
Diagnosis of depression
documented in chart.
Intervention firm (N = 134):
At initial visit, Clinical Nurse
Specialist (CNS) would
create an initial treatment
Subjects of study were veterans plan based on medical record
(96% men) with medically
and responses to PRIMEcomplex issues.
MD. Components of the
treatment plan could include
Unit of randomization was the
medication, cognitive
firm and not the participant.
behavioral therapy, and or
referral to Mental Health.
No true control group (all
Monitoring through telephone
clinicians received educational and/or in person contacts
program).
was to occur at two weeks,
one month, and two months
Post hoc rather than a priori
after initial visit.
outcome assessment.
Outcome
Primary outcomes
assessed at 3 and 12
months were
depressive symptoms
and patient satisfaction.
Results
NNT
p value
No significant effects of the CNS
intervention on overall depressive
symptoms at 3 months .
0.43
No significant effects of the CNS
intervention on overall depressive
symptoms at 12 months .
0.51
Post hoc, within group analyses
of BDI scores revealed that
intervention group patients with
only Major Depression improved
significantly at 3 and 12 months.
Differences between intervention
and control groups in patient
satisfaction were small and not
significant.
Lacked power to detect
differences between
intervention and control for
patients with Major Depressive
Disorder.
Data on usual care patient
follow-up not provided.
© 2012 Kaiser Permanente Medical Care Program
For use within Kaiser Permanente only.
246
02/12
National Adult Depression Clincial Practice Guideline
8.
Follow-Up For Patients In Maintenance Phase
(Beyond 12 Months) Treatment Of MDD
Problem Formulation 8
Clinical Question:
What is the recommended follow-up for patients in remission who need
ongoing treatment for MDD beyond 12 months?
Intended Use of
the Guideline:
To assist primary care physicians and other health care professionals in
treating adults with Major Depression.
Population:
All adult (age 19 and older) patients in maintenance phase treatment of
Major Depression
Health Problem:
Health
Intervention:
Practitioners:
Setting:
Health Outcomes
(associated with
the intervention):
*
MDD
Frequency of follow-up* for patients with MDD who need ongoing
treatment beyond 12 months
(“maintenance phase”):
 Annual follow-up
 Other follow-up intervals
 No follow-up
KP primary care physicians, physician assistants, nurse practitioners,
pharmacists, and health educators
Outpatient office visit, emergency department, urgent care clinics




Change in symptoms
Quality of life
Missed school/work days
Adherence
 Office/UCC/ER visits
 Hospitalizations
 Mortality
Follow-up contact may include in-person visits, phone calls or email between patient and clinician, or phone
calls/email between patient and a care manager. The use of email between patients and providers is relatively
new, and has not been a widely utilized means of communication to date. However, it is being increasingly
advocated as part of a patient-centered, more efficient (“less visit dependent”) model of care. At least one
member of the GDT uses this modality regularly and deems it effective for follow-up contacts.
© 2012 Kaiser Permanente Medical Care Program
For use within Kaiser Permanente only.
247
02/12
National Adult Depression Clincial Practice Guideline
Search Strategy
Database:
Search Terms:
PubMed
("Depression"[MeSH] OR "Major
Depressive Disorder"[All Fields]
AND (“systematic"[All Fields] OR
“systematic review"[All Fields] OR
“meta-analysis"[All Fields]))
(((("depression/drug effects"
PubMed
PubMed
[MESH] OR "depression/drug
therapy"[MESH]) OR "depression/
therapy"[MESH]) OR "depression"
[All Fields] OR "Major Depressive
Disorder"[All Fields]) AND ((("office
visits"[MESH] OR "office visits"[text
word]) OR "telephone"[text word]) OR
"visits"[text word]))
(((("depression"[MeSH Terms] OR
DEPRESSION[Text Word]) OR
"depressive disorder"[MeSH Terms])
OR depressive disorder[Text Word])
AND ("office visits"[MeSH Terms] OR
OFFICE VISIT[Text Word]))
PubMed
"follow up" AND ("telephone" OR
"office visit" or “remission”) AND
("depressive disorder" [MeSH
Terms])
Cochrane
Depression, Anxiety and Neurosis
Group
Chapter: Depressive Disorders
Clinical
Evidence,
Issue 14
Article Type and
Other Limits:
Only items with
abstracts,
Humans, English,
All Adult: 19+
years
Only items with
abstracts,
Humans,
Randomized
Controlled Trial,
English, All
Adult: 19+ years
Search
Date
8/2005
to
9/2007
No.
Included
/ Total
Retrieved*
0/129
8/2005
to
10/2007
0/88
Only items with
abstracts, Humans,
Randomized
Controlled Trial,
English, All Adult:
19+ years
Only items with
abstracts, Humans,
Randomized
Controlled Trial,
English, All Adult:
19+ years
8/2005
to
10/2007
0/31
8/2005
to
10/2007
0/29
Systematic
Reviews
Systematic
Reviews and
RCTs
Q4, 2005
0/131
January
2006
N/A
* Note: “No. Included” refers to studies that are relevant to the problem formulation and, therefore, are included
in this analysis of the evidence. “Total Retrieved” refers to the number of studies retrieved in the search,
regardless of relevance. Because individual studies can be captured in multiple databases, they may be counted
more than once in the number included. Systematic reviews and meta-analyses with search dates outside the
range of current searches were excluded.
© 2012 Kaiser Permanente Medical Care Program
For use within Kaiser Permanente only.
248
02/12
National Adult Depression Clincial Practice Guideline
Evidence Table
Table 8.1
Study
Swindle, et al.
(2003),
Integrating
clinical nurse
specialists into
the treatment of
primary care
patients with
depression.
Inclusion &
Exclusion Criteria
Age
Inclusion: diagnosis of Mean
Major Depression,
age 56
dysthymia or partially
remitted Major
Depression; ≥ 2
General Medicine
Clinics visits past one
year, telephone access,
informed consent
Exclusion:
Incompetent for
interview, nursing home
residence, active
suicidality, seen in
VAMC (Veterans Affairs
Medical Center) mental
health program,
substance abuse,
history of bipolar
disorder, terminal
illness.
Limitations / Biases
Intervention and dose
N and Final N
CNS's often disagreed with the
PRIME-MD diagnosis and did
not believe treatment was
appropriate or necessary for
many of the subjects (affecting
the fidelity of the intervention).
Duration
Control firm (N = 134):
12 months
Diagnosis of depression
documented in chart.
Intervention firm (N = 134):
At initial visit, Clinical Nurse
Specialist (CNS) would
create an initial treatment
Subjects of study were veterans plan based on medical record
(96% men) with medically
and responses to PRIMEcomplex issues.
MD. Components of the
treatment plan could include
Unit of randomization was the
medication, cognitive
firm and not the participant.
behavioral therapy, and or
referral to Mental Health.
No true control group (all
Monitoring through telephone
clinicians received educational and/or in person contacts
program).
was to occur at two weeks,
one month, and two months
Post hoc rather than a priori
after initial visit.
outcome assessment.
Outcome
Primary outcomes
assessed at 3 and 12
months were
depressive symptoms
and patient satisfaction.
Results
NNT
p value
No significant effects of the CNS
intervention on overall depressive
symptoms at 3 months .
0.43
No significant effects of the CNS
intervention on overall depressive
symptoms at 12 months .
0.51
Post hoc, within group analyses
of BDI scores revealed that
intervention group patients with
only Major Depression improved
significantly at 3 and 12 months.
Differences between intervention
and control groups in patient
satisfaction were small and not
significant.
Lacked power to detect
differences between
intervention and control for
patients with Major Depressive
Disorder.
Data on usual care patient
follow-up not provided.
© 2012 Kaiser Permanente Medical Care Program
For use within Kaiser Permanente only.
249
02/12
National Adult Depression Clincial Practice Guideline
9.
Discontinuation of Antidepressants In Patients With MDD
Problem Formulation 9
Clinical Question:
How should antidepressants be discontinued in patients with MDD?
Intended Use of
the Guideline:
To assist primary care physicians and other health care professionals
in treating adults with Major Depression.
Population:
Health Problem:
Health
Intervention:
Practitioners:
Setting:
Health Outcomes
(associated with the
intervention):
Side Effects
Associated With
the Intervention
All adult (age 19 and older) patients with Major Depression
MDD


Gradual tapering of antidepressants
Stopping antidepressants without tapering
KP primary care physicians, physician assistants, nurse practitioners,
pharmacists, and health educators
Outpatient office visit, emergency department, urgent care clinics
 Change in symptoms
 Quality of life
 Missed school/work days
 Office/UCC/ER visits
 Hospitalizations
 Mortality
 Medication withdrawal symptoms
© 2012 Kaiser Permanente Medical Care Program
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Search Strategy
Article Type
and Other
Limits:
Database:
Search Terms:
("Depression"[MeSH] OR "Major
PubMed
PubMed
PubMed
Cochrane
Clinical
Evidence,
Issue 14
PubMed
*
Depressive Disorder"[All Fields] AND
(“systematic"[All Fields] OR “systematic
review"[All Fields] OR “meta-analysis"[All
Fields]))
(("depression/drug effects"[MeSH] OR
"depression/drug therapy"[MeSH]) OR
"depressive disorder/drug therapy"[MeSH])
OR "Major Depressive Disorder"[All
Fields] AND ("discontinuation" OR
"withdrawal" OR "tapering")
Only items with
abstracts,
Humans, English,
All Adult: 19+
years
Search
Date
8/2005
to
9/2007
No.
Included
/ Total
Retrieved*
0/129
Randomized
Controlled Trial,
All Adult: 19+
years, English,
Human
01/2005
to
10/2007
0/37
("antidepressive agents"[MeSH]) AND Randomized,
("discontinuation" OR "withdrawal" OR controlled trial,
All Adult: 19+
"tapering")
01/2005
to
10/2007
0/40
Depression, Anxiety and Neurosis
Group
Chapter: Depressive Disorders
Q4, 2005
0/131
January
2006
N/A
01/01/03
08/01/05
1/77
years English,
Human
Systematic
Reviews
(("depression/drug effects"[MeSH] OR
"depression/drug therapy"[MeSH]) OR
"depressive disorder/ drug therapy"[MeSH]) OR
"Major Depressive Disorder"[All Fields] AND
(("antidepressive agents/adverse effects"[MeSH]
OR "serotonin uptake inhibitors/adverse
effects"[MeSH]) OR "substance withdrawal
syndrome"[MeSH]) AND English[Lang] AND
"adult"[MeSH Terms] AND "humans"[MeSH
Terms] AND ("2003/01/01"[PDAT] :
"3000"[PDAT]) AND Randomized Controlled
Trial[ptyp] AND English[Lang] AND
"adult"[MeSH Terms] AND "humans"[MeSH
Terms] AND ("2003/01/01"[PDAT] :
"2005/08/01"[PDAT])
Systematic
Reviews and
RCTs
Randomized,
controlled trials
Note: “No. Included” refers to studies that are relevant to the problem formulation and, therefore, are included
in this analysis of the evidence. “Total Retrieved” refers to the number of studies retrieved in the search,
regardless of relevance. Because individual studies can be captured in multiple databases, they may be counted
more than once in the number included. Systematic reviews and meta-analyses with search dates outside the
range of current searches were excluded.
© 2012 Kaiser Permanente Medical Care Program
For use within Kaiser Permanente only.
251
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Database:
Search Terms:
Cochrane
Depression
Clinical
Evidence
Depression
PubMed
((((((("depression"[MeSH Terms] OR
depression[Text Word]) OR "depressive
disorder"[MeSH Terms]) OR depressive
disorder[Text Word]) AND ("drug
administration schedule"[MeSH Terms] OR
DRUG ADMINISTRATION SCHEDULE
[Text Word])) AND Randomized Controlled
Trial[ptyp]) AND English[Lang]) AND
("1980"[PDat] : "3000"[PDat]))
(("depression/drug effects"[MeSH] OR
"depression/drug therapy"
[MeSH]) OR "depressive disorder/
drug therapy"[MeSH]) OR "Major
Depressive Disorder"[All Fields]) AND
(("antidepressive agents/adverse
effects"[MeSH] OR "serotonin uptake
inhibitors/adverse effects"[MeSH]) OR
"substance withdrawal syndrome"[MeSH]))
Article Type
and Other
Limits:
Systematic
reviews
Systematic
reviews and
RCTs
Clinical trials,
All adults 19+
years, English
All publication
types, All
adults 19+
years, English,
Human
Search
Date
03/05/03
No.
Included
/ Total
Retrieved*
0/295
09/22/03
0/86
1980
04/01/01
2/347
01/01/01
04/01/03
1/286
Some studies found and used in this guideline did not appear in PubMed search results due to the
way studies are indexed in PubMed.
© 2012 Kaiser Permanente Medical Care Program
For use within Kaiser Permanente only.
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Evidence Tables
Table 9.1
Study
Sunder, et al.
(2004),
Postpartum
Depression
Recurrence
Versus
Discontinuation
Syndrome:
Observations
from a
Randomized
Controlled Trial
Inclusion &
Exclusion Criteria
Twenty two pregnant
women (mean age 32)
who had recovered
from at least one prior
episode of Postpartum
Major Depressive
Disorder (PMDD)
Age
Mean
age 32
Limitations /
Biases
Postpartum women
only.
Only 11 out of 22
patients initially treated
for postpartum MDD
entered the tapering
phase:
Intervention and dose –
N and Final N
Sertraline (N = 14) or placebo (N = 8)
administered for 17 weeks post birth:
25mg/day for first four days,
50mg/day through first four weeks,
75mg/day through week 17.
Intervention tapered weeks 18-20:
50 mg/day in week 18, 25 mg/day
week 19, 25 mg/day week 20.
Discontinued after week 20. One
year follow-up phase began after
RCT; assessments for depression
every two months.
© 2012 Kaiser Permanente Medical Care Program
Duration
20 weeks
Outcome
Results
Depression symptoms
No significant difference
assessed every two months between sertraline and
in follow-up phase.
placebo treated groups on
sum of ASE-derived
symptoms in taper phase.
For use within Kaiser Permanente only.
253
p
value
NNT
0.96
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Table 9.2
Study,
Total n
Judge, R.
2002 (RCT, double-blind)
Follow-up: Not given
Initial N: 150
Treatment Groups Size & Drug
At visit one all patients received blinded
drug equivalent to their current daily
maintenance dose (fluoxetine 20-60 mg
or paroxetine 20-50 mg)
Rx1: fluoxetine (n = 75)
Rx2: paroxetine (n = 75)
Final N: 141
These patients were then randomized to:
active therapy at visit 2,
placebo at visit 3,
original active therapy at visit 4
placebo at visit 2,
active therapy at visit 3 and the rest of
the study
Periods of treatment interruption lasted
between 3-5 days.
Study Population
Male or female outpatient aged ≥ 18
Diagnosis of unipolar depressive
disorders for which the current effective
maintenance therapy with fluoxetine or
paroxetine was prescribed
Results
Comments
Mean change following treatment
interruption:
Mean change ± SD for Discontinuation
Emergent Signs and Symptoms (DESS),
Montgomery-Asberg Depression Rating Rx1: -0.2 ± 2.5
Rx2: 2.2 ± 5.5
Scale (MADRS) score of 12 or less
p = 0.001
Current continuous maintenance
treatment for depression (fluoxetine 20 Mean change ± SD for
Montgomery-Asberg Depression Rating
to 60 mg/day or paroxetine 20 to
50mg/day) lasting more than 4 months Scale (MADRS)
and less than 24 months
Rx1: 0.2 ± 2.9
Rx2: 1.8 ± 5.0
All white, 77% female
p = 0.021
Mean change ± SD for
Clinical Global Impressions-Severity
(CGI-severity scores)
Rx1: 0.0 ± 0.5
Rx2: 0.3 ± 0.8
p = 0.034
© 2012 Kaiser Permanente Medical Care Program
Comparison between treatment groups following
treatment interruption indicates paroxetine-treated
patients had significantly greater increases in
MADRS and CGI- severity than did fluoxetinetreated patients. The deterioration from baseline
within the paroxetine treatment group was also
significant for both MADRS (p = 0.010) and CGISeverity scores (p = 0.001).
Eighteen interruption-emergent symptoms were
reported by significantly more paroxetine-treated
patients than fluoxetine-treated patients
Did not examine for treatment withdrawal side
effects beyond 5 days of discontinuation, when side
effects of the longer half life medication fluoxetine
might be expected to emerge.
No evaluation of side effects between low and
higher doses of fluoxetine.
Industry funded (Eli Lilly, maker of fluoxetine).
For use within Kaiser Permanente only.
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10.
Treatment Preferences For MDD In Different Ethnic Groups
Problem Formulation 10
Clinical Question:
Do adult patients from different ethnic groups have a preference among
treatment options for MDD?
Intended Use of
the Guideline:
To assist primary care physicians and other health care professionals in
treating adults with Major Depression.
Population:
Health Problem:
Health
Intervention:
Practitioners:
Setting:
Health Outcomes
(associated with the
intervention):
Side Effects
Associated With
the Intervention:
Adults (age 19 and older) patients from diverse ethnic backgrounds who
have Major Depression
MDD
 Antidepressant treatment (SSRIs, TCAs, DAs, SNRIs, NRIs)
 Psychotherapy
(Interpersonal Therapy, Cognitive Behavioral Therapy,
Problem-Solving Therapy)
 Combination of antidepressants & psychotherapy
 Cultural healers
 Traditional/herbal remedies
 Clergy
 No treatment
KP primary care physicians, physician assistants, nurse practitioners,
pharmacists, and health educators
Outpatient office visit, emergency department, urgent care clinics
 Change in symptoms
 Quality of life
 Missed school/work days






Sexual problems
Drowsiness
Headache
Nausea
Insomnia
Agitation/
nervousness
 Dry mouth
 Seizures
 Noncompliance
© 2012 Kaiser Permanente Medical Care Program




Office/UCC/ER visits
Hospitalizations
Mortality
Patient satisfaction
 Patient dissatisfaction
 Elevated blood
pressure
 Constipation
 Diarrhea
 Abdominal pain
 Dizziness
 Blurred vision
 Weight gain
 GI bleeding
 Falls
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Search Strategy
Database:
Search Terms:
PubMed
("Depression"[MeSH] OR "Major
Depressive Disorder"[All Fields] AND
(“systematic"[All Fields] OR “systematic
review"[All Fields] OR “meta-analysis"[All
Fields]))
Article
Type and
Other
Limits:
Only items
with
abstracts,
Humans,
English, All
Adult: 19+
years
Search
Date
8/2005
to
9/2007
No.
Included
/ Total
Retrieved*
0/129
PubMed
((("depression/drug therapy"[Mesh Terms] OR
"depressive disorder/ drug therapy"[Mesh Terms])OR
"Major Depressive Disorder"[All Fields]) AND
((((((("cultural diversity"[MeSH Terms] OR "cultural
diversity"[Text Word]) OR "culture"[MeSH Terms]
OR "ethnic groups"[MeSH Terms]) OR "ethnic
groups"[Text Word]) OR "Asians"[text word]) OR
"Blacks"[Text Word]) OR "Hispanics"[Text word])
OR "social class"[MeSH Terms] OR "health
knowledge, attitudes, practice"[MeSH Terms]))
Only items
with
abstracts,
Randomized
Controlled
Trials,
Humans,
English, All
Adult: 19+
years
8/2005
to
9/2007
0/129
Cochrane
Depression, Anxiety and Neurosis Group
Systematic
Reviews
Q4, 2005
0/131
Clinical
Evidence,
Issue 14
Chapter: Depressive Disorders
Systematic
Reviews and
RCTs
January
2006
N/A
PubMed
((("depression/drug therapy"[Mesh Terms] OR
All
"depressive disorder/ drug therapy"[Mesh Terms])OR
"Major Depressive Disorder"[All Fields]) AND
((((((("cultural diversity"[MeSH Terms] OR "cultural
diversity"[Text Word]) OR "culture"[MeSH Terms]
OR "ethnic groups"[MeSH Terms]) OR "ethnic
groups"[Text Word]) OR "Asians"[text word]) OR
"Blacks"[Text Word]) OR "Hispanics"[Text word])
OR "social class"[MeSH Terms] OR "health
knowledge, attitudes, practice"[MeSH Terms])) AND
English[Lang] AND "adult"[MeSH Terms] AND
"humans"[MeSH Terms] AND
("2003/01/01"[PDAT] : "3000"[PDAT]) AND
English[Lang] AND "adult"[MeSH Terms] AND
"humans"[MeSH Terms] AND
("2003/01/01"[PDAT] : "2005/08/01"[PDAT])
01/01/03
08/01/05
1/74
*
Note: “No. Included” refers to studies that are relevant to the problem formulation and, therefore, are included
in this analysis of the evidence. “Total Retrieved” refers to the number of studies retrieved in the search,
regardless of relevance. Because individual studies can be captured in multiple databases, they may be counted
more than once in the number included. Systematic reviews and meta-analyses with search dates outside the
range of current searches were excluded.
© 2012 Kaiser Permanente Medical Care Program
For use within Kaiser Permanente only.
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National Adult Depression Clincial Practice Guideline
Database:
Search Terms:
Cochrane
Depression
Clinical
Evidence
Depression
PubMed
(("depression"[MeSH Terms] OR
DEPRESSION[Text Word]) AND
((("therapy"[Subheading]OR"therapeutics"
[MeSH Terms]) OR TREATMENT[Text
Word]) AND PREFERENCE[All Fields]))
PsychInfo Major
Depression/Preferences/Blacks/Asians/Hisp
anics/American Indians
PubMed
[All Fields]) AND ((((((("cultural diversity"
[MeSH Terms] OR "cultural diversity"[Text
Word]) OR "culture" [MeSH Terms]OR
"ethnic groups"[MeSH Terms]) OR "ethnic
groups"[Text Word]) OR "Asians"[text
word]) OR "Blacks"[Text Word]) OR
"Hispanics"[Text word])OR "social class"
[MeSH Terms] OR "knowledge, attitudes,
practice"[MeSH Terms]))
Article
Type and
Other
Limits:
Systematic
reviews
Systematic
reviews
and RCTs
Clinical
trials, All
adults 19+
years,
English,
Human
No.
Included
Search
/ Total
Date
Retrieved*
03/05/03
0/295
Systematic
reviews
and RCTs
All Adult:
19+ years
English,
Human
03/05/03
0/80
1998
3/2001
2/170
1985
04/1/03
01/01/01
04/01/03
0/43
0/9
Some studies found and used in this guideline did not appear in PubMed search results due to the
way studies are indexed in PubMed. The Cooper(168) study did not show up in our search results
due to the way PubMed indexing is done.
Other Information Source:
 Evidence report on the Treatment of Depression-Newer Pharmacotherapies. AHRQ.(2)
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Evidence Table
Table 10.1
Study
Dwight-Johnson, et al.
(2004), Using conjoint
analysis to assess
depression treatment
preferences among lowincome Latinos
Inclusion & Exclusion
Age
Criteria
Inclusion:
English and Spanish
speaking patients with
depression or dysthymia
age 18 and older seen as
outpatients in general
medicine and women's
clinics
Exclusion:
Suicidality, history of bipolar
or psychotic disorder,
evidence of gross cognitive
impairment.
18+
Intervention and
dose
N and Final N
Limitations /
Biases
Small sample.
N/A
Duration
N/A
Low response rate.
Most participants were
women (95%), and
most were Latino from
Mexico and El Salvador
(93%).
Outcome
Conjoint analysis survey
administered to 42
participants to assess:
1) Treatment choice
(counseling,
antidepressants, or
combination)
2) Treatment format
(individual or group)
Most completed the
survey in Spanish
(86%)
3) Treatment location
(primary care or mental
health clinic)
No comparison group.
4) Barrier reduction
strategies including system
navigation (help making
appointments vs. no help),
reducing transportation
barriers (bus pass,
telephone appointments, or
no assistance); and
educational interventions
(individual education
session, group education
session, pamphlets, or
videos)
© 2012 Kaiser Permanente Medical Care Program
Results
p value
Study patients expressed:
Preference for individual over
group treatment. (p<0.001)
< 0.001
Preference for combination
therapy over counseling
(p=0.009)
0.009
Preference for combination
therapy over medication
alone.
< 0.0010
No comparison for preference
of psychotherapy alone vs.
medication alone.
No significant preference for
treatment setting (p=0.833)
0.833
Helpful barrier reduction
strategies included:
written educational
information
< 0.001
telephone appointment
= 0.001
bus pass
< 0.001
help making appointments
< 0.001
For use within Kaiser Permanente only.
258
NNT
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National Adult Depression Clincial Practice Guideline
11.
Patient Self-Management Strategies For Improving Symptoms of MDD
Problem Formulation 11
Clinical
Question:
Population:
Health
Intervention:
Most
Important
Health
Outcomes:
What patient self-management strategies are effective in improving the
symptoms of MDD?
All adult (age 19 and over) patients in maintenance phase treatment of
Major Depression
 Exercise/physical activity
 Bibliotherapy
 Community resources
 Music therapy
 Internet resources
 Computer- or internet-based
 Support groups/befriending
self-study materials
 Light therapy
 No patient self-directed
 Life review therapy
intervention
 Change in symptoms
 Office/UCC/ER visits
 Quality of life
 Hospitalizations
 Missed school/work days
 Mortality
 Adherence to treatment plan
© 2012 Kaiser Permanente Medical Care Program
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Search Strategy
Database:
Article Type
and Other
Limits:
Search Terms:
Cochrane Depression
Systematic
Reviews
N/A
Clinical
Evidence
Depression
PubMed
("Depression"[MeSH] OR "Major
Depressive Disorder"[All Fields]
AND (“systematic"[All Fields] OR
“systematic review"[All Fields] OR
“meta-analysis"[All Fields]))
PubMed
Cochrane
*
("depression" [MeSH] OR
"depressive disorder" [MeSH] OR
"Major Depressive Disorder" [all
fields]) AND ("self care" [MeSH] OR
"self efficacy" [MeSH] OR "patient
participation" [MeSH] OR "choice
behavior" [MeSH] OR
"bibliotherapy" [MeSH] OR
"befriending" [all fields] OR
"behavioral activation" [all fields] OR
"exercise" [Mesh] OR "community
resources" [all fields] OR "self-help
groups" [MeSH] OR
"Internet"[MeSH])
Depression, Anxiety and Neurosis
Group
Systematic
Reviews and
RCTs; Adults
Only items with
abstracts,
Humans,
English, All
Adult: 19+ years
Only items with
abstracts,
Humans,
Randomized
Controlled Trial,
English, All
Adult: 19+ years
Systematic
Reviews
Search
Date
No.
Included
/ Total
Retrieved*
2005
to
2007
9/2007
to
9/14/2009
1/2006 9/2009
0/134
8/2005
to
9/2007
9/2007
to
9/14/2009
8/2005
to
9/2007
0/129
9/2007 to
9/2009
1/84
Q4, 2005
0/131
0/70
0/2
2/135
1/75
Note: “No. Included” refers to studies that are relevant to the problem formulation and, therefore, are included
in this analysis of the evidence. “Total Retrieved” refers to the number of studies retrieved in the search,
regardless of relevance. Because individual studies can be captured in multiple databases, they may be counted
more than once in the number included. Systematic reviews and meta-analyses with search dates outside the
range of current searches were excluded.
© 2012 Kaiser Permanente Medical Care Program
For use within Kaiser Permanente only.
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Article Type
and Other
Search
Limits:
Date
Database:
Search Terms:
Clinical
Chapter: Depressive Disorders
Systematic
January
Evidence
Reviews and
2006
RCTs
PubMed
("depression"[MeSH] OR "depressive All Adult: 19+
01/01/03
disorder"[MeSH] OR "Major
years, English,
Depressive Disorder"[all fields])
Randomized
08/01/05
AND ("self care"[MeSH] OR "self
Controlled Trial,
efficacy"[MeSH] OR "patient
Humans
participation"[MeSH] OR "choice
behavior"[MeSH] OR
"bibliotherapy"[MeSH] OR
"befriending"[all fields] OR
"exercise"[Mesh] OR "community
resources"[all fields] OR "self-help
groups"[MeSH] OR
"Internet"[MeSH]) AND Randomized
Controlled Trial[ptyp] AND
English[Lang] AND "adult"[MeSH
Terms] AND "humans"[MeSH
Terms] AND ("2003/01/01"[PDAT] :
"2005/08/01"[PDAT])
Systematic
Cochrane Depression
03/05/03
reviews
Systematic
Clinical
Depression
03/05/03
reviews and
Evidence
RCTs
PubMed
("depression" [MeSH] OR
All publication 01/01/1965
"depressive disorder" [MeSH] OR
types, All adults
"Major Depressive Disorder" [all
19+ years,
04/01/2003
fields]) AND ("self care" [MeSH] OR English, Human
"self efficacy" [MeSH] OR "patient
participation" [MeSH] OR "choice
behavior" [MeSH] OR
"bibliotherapy" [MeSH] OR
"befriending" [all fields] OR
"behavioral activation" [all fields] OR
"exercise" [Mesh] OR "community
resources" [all fields] OR "self-help
groups" [MeSH] OR
"Internet"[MeSH])
© 2012 Kaiser Permanente Medical Care Program
No.
Included
/ Total
Retrieved*
N/A
4/62
0/295
1/80
9/655
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Evidence Tables
Table 11.1: Included Studies of Patient-Self-Management Strategies for Improving Depression Symptoms
Study
Inclusion &
Exclusion Criteria
Limitations /
Biases
Age
Intervention and
dose
N and Final N
Duration
Outcome
Results
NNT
P/ 2 value
SELF-HELP MATERIALS
Salkovskis et al
(2006)
Inclusion: depressive
disorder; recently
prescribed
A randomized
antidepressant
controlled trial of the medication; aged 17–
use of self-help
70 years.
materials in addition Exclusion: difficulty
to standard general reading English;
severe (lifepractice treatment
threatening) medical
of depression
illness, history of
compared to
standard treatment psychosis or bipolar
disorder, current
alone.
alcohol or substance
dependency, and
taking antidepressants
for > 4 weeks.
Mean
Small sample size
age: 40.2
±11.9
Majority were women
39.2±13.3
Possible selection bias
%
Female:
83.0% for
self-help
vs. 78.3%
for
treatment
as usual
Self-help materials
(SH, N = 50)
26 weeks
Treatment as usual
(TAU, N = 46)
Beck
Depression
Inventory (BDI)
score
Compliance: 76%
Follow-up rate: 85%
NA
Baseline values:
SH: 27.1±10.5
TAU: 27.5±9.8
Follow-up values:
SH: 14.3±12.5
TAU: 12.6±9.6
Absolute effect:
1.7
P >0.5
EXERCISE
Craft et al (2007)
32 low-income,
minority women
Intervention study of volunteers from
exercise for
Boston’s center for
depressive
Excellence in Women’s
symptoms in
Health.
women.
Inclusion: English
speaking; aged
N initial: 32
between 18-55; DSMN Final: not
IV criteria for MDD,
reported
dysthymia, or
depressive disorder not
otherwise specified as
diagnosed and scoring
>9 on BDI-II; sedentary
Mean
age: 40.4
+ 10.6
Female:
100%
Race:
68.8%
black,
18.7%
white, and
12.5%
Latino.
No control group
Short duration and
follow-up
Small sample size
Low power
No blinding
Some women were also
under other treatment
for depression.
Possible selection bias.
Participants stratified
by current depression
treatment (no txt,
medication, therapy,
medication and
therapy) and
randomized into one of
two groups:
Clinic-based exercise
(N = 16): provided
feedback and
information on
exercise; 4-week clinicbased training for 2
times/wk + once/wk at
© 2012 Kaiser Permanente Medical Care Program
3 months
Outcome
measures were
changes in
BDI-II (Beck
Depression
Inventory),
BMI, % fat, and
cardiovascular
fitness.
46.9% of all participants
experienced a > 50%
reduction in depressive
symptoms.
NA
Overall effect size for
exercise on depressive
symptoms were large in
both groups between preand post-intervention (d= 0.97 vs. -1.3 for homeand clinic-based,
respectively).
At 3-months follow-up,
there were no significant
For use within Kaiser Permanente only.
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National Adult Depression Clincial Practice Guideline
Study
Inclusion &
Exclusion Criteria
lifestyle; and average
or below average
fitness level by
exercise testing.
Limitations /
Biases
Age
Low generalizability.
Intervention and
dose
N and Final N
Duration
home; followed by 8wks transitioned to
home-based phase.
Results
NNT
difference between the
two groups on BDI-II
depression score, selfreported physical activity,
BMI, % body fat, and
cardiovascular fitness.
Home-based exercise
(N = 16): feedback and
info on exercise and
one instructional
session.
Exclusion: CHD;
diabetes; mental health
diagnosis; and
contraindication to
exercise.
Outcome
P/ 2 value
<0.05
At 3-months, clinic-based
group walked further each
day than home-based
according to pedometer
readings.
A home-based program
can increased physical
activity and reduce
depressive symptoms
similar to clinic-based
program.
Dunn (2005),
Exercise treatment
for depression:
efficacy and dose
response
Inclusion:
Sedentary men and
women with mild
(HAM-D 12-16) to
moderate (HAM-D 1725) MDD. (75%
women, 75% white);
aged 20-45
Exclusion:
Not receiving any other
treatment for
depression; ≥160%
over ideal weight, ≥21
drinks per week,
suicidal risk, suicide
attempt last two years,
hospitalization or
psychiatric disorder
last five years,
substance abuse,
Participants not blinded
Mean
to treatment
age:
35.9 + 6.4 assignment.
Participants required to
exercise under
supervision; might have
compromised external
validity.
Sample size small
compared with
pharmacologic
treatment studies.
Participants
randomized into one of
five groups:
LD/3: Low dose
exercise
(7 kcal/kg/week) three
times per week.
(N = 16)
LD/5: Low dose
exercise
(7 kcal/kg/week) five
times per week.
(N = 18)
PHD/3: Public health
dose
(17 kcal/kg/week) three
times per week. (N =
17)
© 2012 Kaiser Permanente Medical Care Program
12 weeks
HAM-D score
Adjusted mean HAM-D
after 12 weeks. scores at 12 weeks were
reduced 47% from
baseline for PHD, a
significant difference
compared with
30% for LD
29% for control
The LD condition was not
significantly different from
the control condition.
NNT* for reduction of
HAM-D at 12 wks
compared to
participant’s baseline:
PHD vs. LD:
5.9
PHD vs. Cntrl:
5.6
0.38
LD vs. Cntrl:
100
The 3 day/week condition
was not significantly
different from the 5
day/week condition.
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Inclusion &
Exclusion Criteria
Limitations /
Biases
Age
inability to exercise,
planned or current
pregnancy.
Intervention and
dose
N and Final N
Duration
Outcome
Results
NNT
P/ 2 value
PHD/5: Public health
dose
(17 kcal/kg/week) five
times per week. (N =
16)
Placebo control: 3
days/week of stretching
flexibility exercise for
15-20 minutes per
session.
(N = 13)
Mather, A.S.
2002 (RCT)
Out-patients 53 years and older
Preponderance of
with a diagnosis of depression
women in the exercise
Score of at least 10 on the Geriatric group
Effects of exercise
Depression Scale (GDS)
on depressive
Actual HRSD pre and
symptoms in older
Have been taking a therapeutic
post scores were not
adults with poorly
dose of antidepressant therapy for given
responsive
at least 6 weeks
depressive disorder: No ongoing structured
Short term
randomized
psychotherapy
controlled trial.
No regular exercise more than
Definition of threshold
twice weekly
for response (30%
Initial N: 86
16% male, 84% female
reduction) is lower than
Final N: 86
usual 50% seen in most
studies
Intention-to-treat
analysis
Singh, N.A.
2001 (RCT)
Age 60 and older with a BDI score
of >12
Diagnosis of either unipolar major
The efficacy of
or minor depression or dysthymia
exercise as a long- according to DSM-IV diagnostic
term antidepressant criteria
in elderly subjects: a Excluded if suicidal, currently
randomized,
seeing a psychiatrist or had been
Rx1: Exercise group (n
= 43)
Follow-up:
10 weeks
Rx2: Nonexercise
social control (health
education talks) (n =
43)
Change in 17item Hamilton
Rating Scale
for Depression
(HRSD) from
baseline at 10
weeks (%)
All exercise session
lasted for 45 minutes
and comprised
predominantly weightbearing exercise; 2
sessions per week
Phase I (weeks 1-10)
Rx1: Supervised
Population elderly
exercise in laboratory
Rx2: Control group
Final difference between (health education
BDI scores between
lectures)
groups may not be
clinically significant.
Phase II (weeks 11-20)
© 2012 Kaiser Permanente Medical Care Program
264
Rx1: 55%
Rx2: 33%
NNT* for >30%
reduction in HRSD
score from baseline:
Rx1 vs. Rx2:
4.5
p = 0.05
(favoring
exercise group)
Response was defined as
a ≥ 30% reduction in
HRSD score from
baseline
This RCT found that 10
weeks of twice-weekly
exercise was associated
with a modest reduction in
depression symptoms in a
group of older people with
depression.
All patients continued
to take antidepressant
therapy throughout the
trial
Small sample size
Change in 17-item
Hamilton Rating Scale for
Depression (HRSD) from
baseline at 10 weeks (%)
Follow-up:
20 weeks ,
with followup at 26
months
BDI score
BDI score at 20 weeks
Rx1: Decreased from
21± 2.0 to 9.2 ± 2.8
Rx2 : Decreased from
18.28 ± 1.8 to 11.0 ± 2.36
NNT* for participants
classified as nondepressed (BDI<9) at
20 wks:
p= 0.036
(favoring
exercise)
BDI score after 26 months Exercise vs. Control:
Rx1: Decreased from
2.7
p= 0.036
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National Adult Depression Clincial Practice Guideline
Study
controlled trial.
Initial N: 32
Final N: 29
Inclusion &
Exclusion Criteria
Age
on antidepressant drugs within the
last three months
Subjects participating in aerobic
exercise more than twice a week in
the month prior to enrollment were
also excluded
37% male, 63% female
Mean age: 71 + 2
Limitations /
Biases
Intervention and
dose
N and Final N
Duration
Outcome
Rx1: Unsupervised
exercise at home,
laboratory or health
club setting (N = 15) ,
18±2 weight lifting
Response occurred over exercise sessions
time even in control
Rx2: Control group (N
group
= 14)
The effect of
exercise on
depressive
symptoms in the
moderately
depressed elderly.
Elderly outpatients with a mean age Elderly patients
of 72.5 years
BDI score of 12-24
Short-term results
Small n
Initial N: 30
Final N: 30
Rx1: Exercise, walking
between 20- 40
minutes, three times a
week
Rx2: Social Contact ,
two home visits (20 40 minutes) each week
by an undergraduate
psychology student
Rx3: Wait-list (control
group)
NNT
21± 2.0 to 13 ± 2.2
Rx2: Decreased from
18.4 ± 1.7 to 14.4 ± 2.2
No long-term difference
between groups if
exercise not continued
P/ 2 value
(favoring
exercise group)
The relative improvements
in depression scores in
the exercisers were 1.5 to
2.5 times greater than
those in the controls at the
end of Phase II.
Phase III (Months 6-26)
Rx1: No study
requirements
Rx2: No study
requirements
McNeil, J.K.
1991 (RCT)
Results
The exercise group
showed significantly
reduced depression
compared with control
group at both 20 weeks
and 26-month follow-up.
Follow-up:
6 weeks
Total and
psychosocial
subscale of the
Beck
Depression
Inventory.
BDI score (total)
NA
Rx1: decreased from 16.6
to 11.1
Rx2: decreased from 16.0
to 11.8
Rx3 : decreased from 15.2
to 14.7
BDI score (somatic
symptoms)
Rx1: decreased from 7.7
to 5.3
Rx2: decreased from 6.9
to 6.0
Rx3 : decreased from 6.8
to 6.4
p < 0.05
(favoring
exercise or
social contact)
p < 0.5 (favoring
exercise)
Exercise and social
contact both resulted in
significant reductions in
both total and the
psychosocial subscale of
the Beck Depression
Inventory. The exercise
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National Adult Depression Clincial Practice Guideline
Study
Inclusion &
Exclusion Criteria
Limitations /
Biases
Age
Intervention and
dose
N and Final N
Duration
Outcome
Results
NNT
P/ 2 value
condition, however,
resulted in decreased
somatic symptoms of the
BDI.
North, T.C.
1990 (Metaanalysis)
Depressed patients 11 to 55 years
with a mean of 31.8 ±12.4
20 studies were all males,
Effect of exercise on
depression.
16 studies were all females.
# studies included in effect of
exercise on depressioN = 80
# studies included in effect of age =
63
# of studies included for the effect
of gender = 36
There are a lot of
differences in the study
designs of the studies
used in this metaanalysis. That includes
differences in the mode
of exercise, length of the
exercise programs and
types of control groups).
Rx1: exercise (aerobic
endurance and
muscular strength)
varying in number of
sessions
Rx2: comparison
groups (control, leisure
activity, and
psychotherapy)
Meta-analysis excludes
older patients
Follow-up: Exercise
Varied from scores
4 weeks to
24 weeks
with
majorities of
studies
being
between 5 12 weeks
The overall Effect Size of NA
the studies included was –
0.53 ± 0.85. That
indicates that patients in
exercise groups (Rx1)
decreased their scores an
average of 0.53 of a
standard deviation unit
more than subjects in
comparison groups (Rx2).
A significant, negative
correlational relationship
was found between mean
age and ES. The negative
relationship suggests that
the older the subjects, the
greater the decrease in
depression with exercise.
The ESs for males and
females were not
significantly different,
suggesting that exercise
had an equally beneficial
effect in improving
symptoms of depression
in both genders.
p < 0.001
(p < 0.05)
(p > 0.05)
The overall results
indicated that exercise
has a beneficial effect on
improving symptoms of
depression.
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Study
Inclusion &
Exclusion Criteria
Limitations /
Biases
Age
Intervention and
dose
N and Final N
Duration
Outcome
Results
NNT
P/ 2 value
COMPUTER / INTERNET
Meyer et al. (2009)
Participants were
recruited via internet
Follow-up: 6 months depression forum in
Germany.
N initial: 396
N at 9 weeks: 216
Inclusion/ exclusion:
N at 18 weeks: 146 provided consent,
N at 6 months: 99
above 18 years, and
completed at least half
of baseline depression
questionnaire.
Female: 76%
Race: Not reported
Many of the
participants were
incapacitated in terms
of symptom severity
and social dysfunction.
Over half of the sample
was currently
unemployed, more
than half reported
currently being in
treatment (medication
and/or psychotherapy),
and 85% stated they
had been feeling
depressed for several
months (29%) or even
several years (56%).
Mean
age:
34.76 +
11.6
No placebo-control
group
Short duration and
follow-up
Participants were not
clinically diagnosed with
MDD
High attrition rate (at
least 55% at 9 weeks)
Some participants were
also under other
treatment for
depression.
Internet program as
Duration:
add-on to usual care (N 6 months
= 320): Consisted of 10
content modules
representing different
psychotherapeutic
approaches.
Wait-list control plus
usual care (N = 76):
No internet access until
9 weeks after the
treatment group has
completed.
Possible selection bias
– participants were more
experienced/comfortabl
e with
internet/computer;
heterogeneous sample
of users.
Low generalizability.
Outcome
Change in depression
measures were scale:
changes in the  Using last-observationadapted
carried forward ITT
German BDI
analysis, those in the
(Beck
internet program
Depression
demonstrated a
Inventory), and
reduction of 3.11 BDI
work and social
points (d=0.29) vs. no
adjustment
change observed in
scale (WSA).
participants assigned to
wait-list controls (BDI
change: -0.04).
 between-groups effect
size at 9 weeks, using
this ITT sample, was
Cohen’s d = .30.
 In completers, effect
size was reported at
Cohen’s d = .64 (CI
95% = 0.33 - 0.94).
Change in work and
social scale:
 Similarly, ITT analysis
found small decrease in
internet group (d=0.17),
versus no significant
change.
 Between-group effect
size at T1 was Cohen’s
d = .36.
 Follow-up:
 Improvements in
depression symptoms
were maintained at 6months follow-up for
completers (d=0.74).
NNT* clinical significant
improvement/recovered
(change of at least 8.46
points on BDI, with
posttest score of
<14.29):
, p<0.001
Internet vs. wait-list
controls:
4.3
NS (0.96)
p<0.001
25.4% vs. 1.9% of those
in the internet group and
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Inclusion &
Exclusion Criteria
Limitations /
Biases
Age
Intervention and
dose
N and Final N
Duration
Outcome
Results
NNT
P/ 2 value
the wait-list control
reached the criteria of
clinical significant
improvement/recovered
(change of at least 8.46
points on BDI, with
posttest score of <14.29).
Users who engaged more
often and intensively with
the program were more
likely to complete the
follow-up assessment and
to benefit from the
program.
Clarke, et al. (2005)
Overcoming
Depression on the
Internet (ODIN) (2):
A Randomized
Trial of a Self-Help
Depression Skills
Program With
Reminders
Inclusion:
Kaiser Permanente
Northwest HMO adults
with either 1)
depression – received
depression medication
or psychotherapy, and
had a chart diagnosis,
or 2) no previous
depression diagnosis,
but age and gender
matched to the first
group
Exclusion:
None stated.
18+
Subjects lost to followimplied,
up were older, more
not stated depressed, and less
likely to be in the control
group.
Low enrollment (255
patients out of over
12,000 initially eligible)
and completion (57% in
intervention group vs.
80% in usual care)
rates.
Only one self-reported
measure of depression.
Brief follow-up period –
16 weeks.
Rx1 Treatment as
16 weeks
usual without access to
the internet site.(N =
100)
Rx2 Access to
depression internet site
(www.believebetter.org
) with postcard
reminders (N = 75)
Rx3 Access to
depression internet site
with brief telephone
reminders delivered by
nonclinician study staff
(N = 80)
All participants were
permitted to obtain any
physical or mental
health services during
the study.
Primary
outcome
measure was
score on
Center for
Epidemiological
Studies (CESD) self-report
questionnaire
at 5, 10, and 16
weeks after
enrollment
Control and intervention
groups had statistically
equivalent baseline
depression (CES-D) and
SF-12 scores.
NNT* for patients who
moved over time from
the “disordered” to the
“non disordered” CESD ranges:
In the intention-to-treat
analysis, intervention
participants (Rx2 and
Rx3) reported greater
reductions in CES-D
depression scores
compared with the control
group (Rx1)
Rx3 vs. Rx1 = 5
Baseline
Rx1 28.0
Rx2 31.3
Rx3 30.3
© 2012 Kaiser Permanente Medical Care Program
16 weeks
22.3
18.2
19.0
Intervention had a greater
effect on those who were
more severely depressed
at baseline.
Baseline
0.02
16 weeks
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Inclusion &
Exclusion Criteria
Limitations /
Biases
Age
Intervention and
dose
N and Final N
Duration
Outcome
Results
Rx1 35.4
Rx2 35.2
Rx3 36.2
NNT
P/ 2 value
26.7
19.7
20.1
No significant difference
between treatment groups
with regard to outcome
measures.
Christensen,
Griffiths, & Jorm
(2004) Delivering
interventions for
depression by using
the internet: a
randomized
controlled trial
Men and women from
the community of
Canberra, Australia.
Participants had
scored 22 or higher on
the Kessler scale and
were not being
clinically treated by a
psychologist or
psychiatrist.
18-52
Short follow-up time (six
weeks) does not offer
information about the
sustainability of internet
interventions.
High drop-out rate for
MoodGYM.
525 participants were
randomized into one of
three groups:
Internet "Blue Pages"
(N = 165): provided
depression literacy,
offering evidencebased information on
depression and its
treatment.
No information on
whether or not patients
were concurrently taking
antidepressants.
Internet "Mood GYM"
(N = 182): offered
cognitive behavioral
therapy for the
prevention of
depression.
Control "Attention
placebo" (N = 178):
weekly contact with a
lay interviewer to
discuss lifestyle factors
such as exercise,
education, and health
habits.
© 2012 Kaiser Permanente Medical Care Program
6 weeks
Primary
outcome was
score on
Center for
Epidemiological
Studies (CES)
scale.
In Intent to treat analysis,
CES score improvement
(in points) was:
Blue Pages 3.9
MoodGYM 4.2
Control 1.0
NA
In Completer analysis,
CES score improvement
(in points) was:
Blue Pages 4.9
Mood Gym 5.8
Control 1.2
Therefore, in both
analyses:
MoodGYM was
significantly more effective
than control. (p<0.05)
Blue Pages was
significantly more effective
than control. (p<0.05)
MoodGYM was slightly
(but not significantly) more
effective than Blue Pages.
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< 0.05
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Clarke, G.
2002 (RCT)
Overcoming
depression on the
Internet (ODIN): a
randomized
controlled trial of an
Internet depression
skills intervention
program.
Initial N: 299
Final N: 177
Inclusion &
Exclusion Criteria
Limitations /
Biases
Age
Combination of depressed and
nondepressed cases
High attrition rate (41%)
Heterogeneous sample.
Rx1: Mean age of 43.3, with an SD
of 12.2, 73.6% females
Over three-quarter of
sample was female.
Rx2: Mean age of 44.4 with an SD
of 12.4, 77.4% females
Intervention and
dose
N and Final N
Rx1: Access to
Depression Internet
site (n = 144),
depression cases
(n = 107)
Rx2: Usual Care only
(n = 155), depression
cases (n = 116)
Duration
Follow-up:
32 weeks
Outcome
Change in
CES-D score
Much of the internet
site content was
adapted from group
CBT psychotherapy
manuals
Intention-to treat
analysis
Results
Change in CES-D score
(baseline to week 32
Depressed cases only:
mean(SD)
Rx1: 30.7(12.9) to
22.2(12.8)
Rx2: 31.3(11.5) to
25.2(14.2)
NNT
P/ 2 value
NA
p = 0.12
Stratified analyses by high
vs. low baseline CES-D
scores, gender, and age
greater or less than 45 all
showed no statistically
significant between group
differences.
The study found no
differences between the
control and experimental
conditions on self-reported
depression (CES-D) over
the study period,
indicating a lack of
treatment effect.
LIGHT THERAPY
Martiny, et al.
(2005) Adjunctive
bright light in
nonseasonal Major
Depression: results
from clinician-rated
depression scales
Inclusion:
Adults, 18 and older,
fulfilling diagnostic
criteria for Major
Depression according
to the DSM-IV; HAMD
score ≥13.
Exclusion:
Seasonal Depression
(SAD); fulfillment of
seasonal pattern
specifier; psychotic
disorder; organic brain
18+
No follow-up to
determine lasting
effects.
Unequal duration of
treatments (30 vs. 60
minutes).
Percentage of patients
in ongoing treatment
with antidepressants at
inclusion or who had
stopped treatment within
the last month before
All patients received a
fixed dose of 50mg
sertraline daily.
Increments or dose
reductions, oxazepam,
and mianserin were
allowed as necessary.
Rx2 showed a significantly
greater decrease in HAMD scores at five weeks.
Baseline 5 weeks
Rx1
22.1
11.6
Rx2
22.4
9.0
NNT* for response
(50% or greater
reduction of
baseline scores on the
HAM-D6) at 5 wks:
Patients were
randomized into one of
two groups:
Response rates at 5
weeks:
Rx1: 38.9%
Rx2: 70.8%
Bright vs. Dim light:
3.1
Rx1: Red dim light (50
lux, 30 minutes daily),
Remission rates at 5
weeks:
© 2012 Kaiser Permanente Medical Care Program
5 weeks
Primary
outcome
measure was
change in
HAMD-17
score from
baseline to
endpoint.
For use within Kaiser Permanente only.
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0.006
0.015
02/12
National Adult Depression Clincial Practice Guideline
Study
Inclusion &
Exclusion Criteria
Limitations /
Biases
Age
disorder; mental
retardation, alcohol or
drug abuse;
pregnancy; history of
light-induced migraine
or epilepsy; retinal
blindness or severe
cataract; glaucoma;
retinal diseases;
ongoing treatment with
antipsychotics; suicidal
ideation; severe
agitation; score of <13
on HAMD.
inclusion was noticeably
higher in bright light
group (46% vs. 30%).
This difference was
determined not to be
statistically significant,
but no analysis of
difference (p value)
reported.
Intervention and
dose
N and Final N
Duration
Outcome
N = 54
Results
NNT
P/ 2 value
Rx1: 18.5%
Rx2: 41.7%
Rx2: Bright white light
(10,000 lux, 60 minutes
daily), N = 48
LIFE REVIEW THERAPY
Serrano & Latorre
(2004), Life review
therapy using
autobiographical
retrieval practice for
older adults with
depressive
symptomatology
Volunteer clients (men 65-93
and women of Social
Services in Almansa,
Spain. All participants
receiving one hour of
social services per day,
five days per week.
Participants had to
have clinically
significant symptoms of
depression (CED-D
>16), no evidence of
dementia, and could
not be receiving
pharmacological
treatment for
depression. Patients
were 70% women.
No placebo control
where participants
received same amount
of attention, but without
intervention.
Prompting questions
during intervention
targeted primarily
positive memories.
No follow-up to indicate
maintenance of
changes.
Small sample size.
Not all participants had
MDD (although many
had significant
depressive symptoms).
Participants were
randomized into two
groups:
Experimental Group (N
= 20): given life review
therapy while
continuing with social
services. Life review
therapy consisted of
autobiographical
retrieval practice
focusing on a particular
period (childhood,
adolescence,
adulthood, summary)
each week for four
consecutive weeks.
Control group (N = 23):
social services as
usual.
Limited to older
population receiving
social services, in Spain.
8 weeks
Primary
outcome
measures were
scores on CESD, LSIA, and
BHS.
Secondary
outcome was
change in
specificity of
memories from
pretest to
posttest.
Significant Time x Group
effect indicated
experimental group
improvements in CES-D,
LSIA, and BHS.
Mean CES-D change
10.25 for treatment group
vs. 0 for control group.
NNT* for improvement < 0.0001
in CES-D to below
major depression
among those with CESD diagnosed
depression:
Experimental vs.
control:
NNT = 5
Experimental group
showed significant
increase in recall of
specific memories.
< 0.001
0.01
This was found to be a
significant predictor of
posttest hopelessness
0.03
This was also found to be
a significant predictor of
posttest life satisfaction.
0.06
There was a trend in the
same direction for posttest
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Inclusion &
Exclusion Criteria
Limitations /
Biases
Age
Intervention and
dose
N and Final N
Duration
Outcome
Results
NNT
P/ 2 value
CES-D.
BIBLIOTHERAPY
Smith, N.M.
1997(Observational)
Mean age Small sample size
of 41.6
±10.0
No control group
Initial N: 50
Final N: Not given
Observational study of
bibliotherapy only; no
comparative group.
Follow-up:
3-year
HRSD and BDI
scores
Sensitivity analysis not
included to account for
patients who completed
the initial study but did
not participate in the
follow-up (some of
whom may have
relapsed)
Follow-up analysis
revealed a significant
decrease in HRSD and
BDI scores from
pretreatment to follow-up
NA
p <0.05 each
p>0.05 each
No changes from post
treatment to follow-up
Treatment gains were
maintained over the 3year follow-up period and
participants were less
depressed than when they
began the program.
Study suggests that there
maybe long-range
benefits to participants in
structured, minimalcontact bibliotherapy
programs for depression.
Jamison, C.
1995 (RCT)
The outcome of
cognitive
bibliotherapy with
depressed adults.
Initial N: 80
Final N: 65
Mean age of 40 years
Score of 10 or greater on the
Hamilton Rating Scale for
Depression 21-item version (HRSD)
Score of 10 or greater on the 21item Beck Depression Inventory
(BDI)
Met the DSM-III-R criteria for a mild
or moderate Major Depression
Rx1: 30% females, 10% males
Rx2: 37% females, 3% males
Participants and
Treatment phase (4
researchers not-blinded. weeks)
Rx1: Cognitive
bibliotherapy (n = 33)
Wait-list control showed
marked symptom
Rx2: Waiting list
improvement in f/u
(control group)
phase
(n = 39)
Follow-up phase (3
months)
Rx1: Cognitive
bibliotherapy (n = 31)
Rx2: Waiting list
(control group)
© 2012 Kaiser Permanente Medical Care Program
Follow-up:
4 weeks of
treatment
and 3
months of
follow-up
HRSD and BDI
scores
Treatment phase
HRSD score
Rx1: decreased from 20.2
to 9.9
Rx2: decreased from 19.6
to 19.0
BDI score
Rx1: decreased from 21.9
to 9.2
Rx2: decreased from 20.9
to 19.5
NNT* of clinical
improvement at 3months follow-up (BDI
cutoff < 11; HRSD
cutoff < 12):
BDI:
2.17
p < 0.05;
favoring
bibliotherapy
HRSD:
1.7
Follow-up phase
HRSD score
Rx1: decreased from 10.0
For use within Kaiser Permanente only.
272
p < 0.05;
favoring
bibliotherapy
p < 0.05
(favoring
treatment) when
starting from
baseline
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National Adult Depression Clincial Practice Guideline
Study
Inclusion &
Exclusion Criteria
Limitations /
Biases
Age
Intervention and
dose
N and Final N
Duration
Outcome
(n = 34)
Results
NNT
to 9.2
Rx2: decreased from 18.7
to 10.0
P/ 2 value
p < 0.05
(favoring
treatment) when
starting from
baseline.
BDI score
Rx1: decreased from 9.6
to 7.7
Rx2: decreased from 18.9
to 11.1
Study suggests that
cognitive bibliotherapy for
depression is an effective
treatment for depression.
Scogin, F.
1990
Two-year follow-up
of bibliotherapy for
depression in older
adults.
60 years and older, mean of 67.2
No male participants
Mean age: 67.2 + 6.9 years
No control group
Race: 3 Black, 27 White
Small sample size
Gender: 30 female, 0 male
Sensitivity analysis not
included to account for
patients who completed
the initial study but did
not participate in the
follow-up (some of
whom may have
relapsed)
those who had not (n =
14)
Only included older
adults
Rx1: Behavioral
bibliotherapy (n = 23),
reading a copy of
Control Your
Depression
(Lewinsohn, et al.
1986) book
Initial N: 30
Final N: Not given
Scogin, F.
1989 (RCT, doubleblind)
Comparative
efficacy of cognitive
and behavioral
bibliotherapy for
mildly and
moderately
depressed older
adults.
60 years and older
Score of 10 or higher on the
Hamilton Rating Scale for
Depression (HRSD)
Predominantly female
Small sample size
Score of 8 or higher on the Mental
Status Questionnaire
Rx1: Behavioral and
cognitive bibliotherapy
(n = 22)
those who had read (n
= 16)
HRSD scores
HRSD score change from
post -treatment to 2-year
follow-up
NA
Rx1: 8.1 to 7.4, no
significant effect for time
p < 1.00
Structured bibliotherapy’s
effect for mild to
moderate depression in
older adults is maintained
2 years after treatment
Unknown how often
participants referred to
materials over time
Short follow-up
Not being on psychotropic
medication or, if so, then stabilized
Follow-up:
2-year
Rx2: Cognitive
bibliotherapy (n = 22),
reading a copy of
© 2012 Kaiser Permanente Medical Care Program
Follow-up:
Initial study
4 weeks of
treatment
and a 6month
follow-up
HRSD Score
changes
HRSD Score changes
from time 1 to 2 to 3
Rx1: 17.8 to 9.7 to 9.1
Rx2: 16.3 to 7.5 to 8.9
Rx3: 16.4 to 15.9 to 7.2
No significant differences
between Rx1 and Rx2.
NNT* for clinical
improvement from
bibliotherapy (scores
outside range of
dysfunctional
population):
2.13
Treatment gains were
For use within Kaiser Permanente only.
273
(Rx2 vs. Rx3) p
< 0.05, favoring
cognitive
bibliotherapy
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National Adult Depression Clincial Practice Guideline
Study
Inclusion &
Exclusion Criteria
Age
Limitations /
Biases
on the medication
Initial N: 67
Final N: 44
Scogin, 1990 (RCT,
double-blind)
Intervention and
dose
N and Final N
Duration
Outcome
Believing Good (Burns,
1980) book
NNT
P/ 2 value
maintained 6 months after
treatment for Rx1 and
Rx2. There was no
control group for follow-up
after the delayed
treatment group received
treatment.
Not being in psychotherapy
57 females and 10 males
Results
Rx3 : Delayed
treatment (control
group) (n = 22)
The Rx1 and Rx2 were
assessed at:
Pre-treatment =Time 1
Immediately following
treatment = Time 2
6-month follow-up =
Time 3
This study supports the
efficacy of self-paced
bibliotherapy for mild to
moderate depression in
older adults.
The Rx3 participants
were assessed at time
1 and at 1 month
following time 2, at
which point their own
treatment began, and a
third time immediately
following treatment.
MUSIC THERAPY
Hanser, S.B
1994 (RCT)
Effects of a music
therapy strategy on
depressed older
adults.
Older adults (61 to 86 years old)
Small sample size
77% female
Diagnosis of major or minor
Predominantly female
depressive disorder, based on a
structured interview using the
Relative short follow-up
Schedule of Affective Disorders and
Schizophrenia
Initial N: 30
Final N: 28
Rx1: Home based
music therapy
(n = 10)
Follow-up:
8 weeks
Rx2: Self-administered
music therapy (n = 10)
Rx3: Wail-list control
group (n = 10)
Change in
Geriatric
Depression
Scale sore
Change in Geriatric Depression NA
Scale sore (pretest to posttest)
Rx1: 17.30 to 7.70
Rx2: 17.60 to 12.30
Rx3: 15.30 to 16.20
p < 0.05
(favoring the two
music therapy
groups)
Follow-up results at nine
months revealed no significant
differences on the GDS score
from post test results in all
three groups.
This study supports the use of
music therapy strategies with
older adults experiencing
symptoms of depression.
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National Adult Depression Clincial Practice Guideline
Study
Inclusion &
Exclusion Criteria
Limitations /
Biases
Age
Intervention and
dose
N and Final N
Duration
Outcome
Results
NNT
P/ 2 value
EXERCISE & LIGHT THERAPY
Leppamaki, et al.
(2004), Drop-out
and mood
improvement: a
randomized
controlled trial with
light exposure and
physical exercise.
120 Volunteers from
Occupational Health
Centers: men and
women free from prior
mental disorders and
with HAM-D ≥ 8.
26-63
Participants were not a
random sample of the
population.
Participants were
randomized into one of
three groups:
Participants did not
have a clinical diagnosis
of Major Depression;
they had varying
degrees of depressive
symptoms.
Aerobics training in
bright light (N = 40)
Unclear on how many
participants may have
had Seasonal Affective
Disorder.
8 weeks
Primary
outcome
measures were
changes in
HDRS, ATYP,
and SIGHSAD-SR
Aerobics in normal
lighting of gym (N = 38)
Based on HDRS, 42
The NNT for light was
responders (50%
3.8.
improvement); 83% of
these responders received
light therapy, which was
significant.
2= 0.02
Based on ATYP, 51
responders; 73% of these
responders received light
therapy.
Relaxation and
stretching in bright light
(N = 42)
2= 0.02
Based on SIGH-SAD-SR,
45 responders; 82% of
these responders received
light therapy, which was
significant
No placebo control
group.
No information on
whether patients were
using other treatments.
INTERNET AND TELEPHONE
Patten, S.B.
2003 (RCT)
Prevention of
depressive
symptoms through
the use of distance
technologies.
Initial N: 786
Final N: 764
Volunteers were
Mean age
screened for diagnosis 45.2 ±
of current Major
11.9
Depression by using
the Composite
International
Diagnostic Interview
(95% CIDI) and eligible
participants were
assigned to treatment
or control groups. No
other information were
provided.
Included predominantly
older women.
Possible selection bias
– participants may be
more comfortable with
the internet.
Gender: 90.1% female,
and 9.9% male
Rx1: Active group,
Follow-up:
using web and
3 months
telephone-based
program (n = 420)
Rx2: Control group (n =
366)
The preventive
intervention was an
interactive computer
program accessible
through the Web or by
interactive voice
telephone.
© 2012 Kaiser Permanente Medical Care Program
Changes in
depression
rating scale
(CES-D)
% of patients exceeding
Center for Epidemiological
Studies Depression rating
scale (CES-D) score of
more than 15
Rx1: 37.4% (baseline
35.7%)
Rx2: 34.1% (baseline
33.3%)
Difference statistically not
significant.
NNT* for reduction in
CES-D score of >15:
Rx1 vs. Rx2:
111
The study did not find any
significant differences
between the groups.
For use within Kaiser Permanente only.
275
NS (p not
stated)
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National Adult Depression Clincial Practice Guideline
12.
Behavioral Health Education Classes For Adults With MDD
(Cognitive Behavioral Skills or Problem-Solving Classes)
Problem Formulation 12
Clinical Question:
Intended Use of
the Guideline:
Population:
Health Problem:
Are behavioral health education classes (cognitive behavioral skills
or problem-solving classes) effective in improving the symptoms of
MDD? If so, are they recommended for adults with MDD?
To assist primary care physicians and other health care professionals
in treating adults with Major Depression.
All adult (age 19 and over) patients with Major Depression
MDD
Health
Intervention:
Multi-Session behavioral health education classes:
 Cognitive behavioral skills for managing depression
 Problem-solving
 No behavioral health education classes
Practitioners:
KP primary care physicians, physician assistants, nurse practitioners,
pharmacists, health educators, and social workers
Setting:
Health Outcomes
(associated with the
intervention):
Outpatient office visit, emergency department, urgent care clinics,
health education, social work




Change in symptoms
Quality of life
Missed school/work days
Adherence to treatment plan





Office/UCC/ER visits
Hospitalizations
Mortality
Relapse prevention
Patient satisfaction
Note: Behavioral Health Education Classes (BHE) differ in content, structure, and scheduling
from protocolized psychotherapy delivered to patients with specifically defined diagnoses
in a specialty behavioral health setting. BHE delivers a specific educational curriculum
(as opposed to a structured, tailored psychotherapeutic intervention) focusing on coping and
self-care skills, targets patients with mild to moderate depressive symptoms (including patients
without Major Depression), and excludes patients with more severe Major Depression.
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National Adult Depression Clincial Practice Guideline
Search Strategy
Article Type
and Other
Limits:
Database:
Search Terms:
("Depression"[MeSH] OR "Major
PubMed
Pubmed
Cochrane
Clinical
Evidence,
Issue 14
PubMed
*
Depressive Disorder"[All Fields] AND
(“systematic"[All Fields] OR “systematic
review"[All Fields] OR “metaanalysis"[All Fields]))
("depression"[MeSH] OR "depressive
disorder"[MeSH] OR "Depressive
disorder/therapy"[MeSH] OR "Major
Depressive Disorder"[all fields]) AND
("health education"[MeSH] OR "patient
education"[MeSH] OR "behavior
therapy/methods"[MeSH] OR "patient
satisfaction"[MeSH] OR
"cognition"[MeSH] AND
"psychoeducation"[all fields] OR
"behavioral classes"[all fields])
Depression, Anxiety and Neurosis
Group
Chapter: Depressive Disorders
("depression"[MeSH] OR "depressive
disorder"[MeSH] OR "Depressive
disorder/therapy"[MeSH] OR "Major
Depressive Disorder"[all fields]) AND
("health education"[MeSH] OR "patient
education"[MeSH] OR "behavior
therapy/methods"[MeSH] OR "patient
satisfaction"[MeSH] OR
"cognition"[MeSH] AND
"psychoeducation"[all fields] OR
"behavioral classes"[all fields]) AND
English[Lang] AND "adult"[MeSH
Terms] AND "humans"[MeSH Terms]
AND ("2003/01/01"[PDAT] :
"2005/08/01"[PDAT])
Only items with
abstracts,
Humans, English,
All Adult: 19+
years
Search
Date
8/2005
to
9/2007
No.
Included
/ Total
Retrieved*
0/129
Only items with
abstracts,
Humans,
Randomized
Controlled
Trial, English,
All Adult: 19+
years
8/2005
to
9/2007
0/0
Systematic
Reviews
Systematic
Reviews and
RCTs
All publication
types, All
adults 19+
years, English,
Human
Q4, 2005
0/131
January
2006
N/A
01/01/03
08/01/05
0/4
Note: “No. Included” refers to studies that are relevant to the problem formulation and, therefore, are included
in this analysis of the evidence. “Total Retrieved” refers to the number of studies retrieved in the search,
regardless of relevance. Because individual studies can be captured in multiple databases, they may be counted
more than once in the number included. Systematic reviews and meta-analyses with search dates outside the
range of current searches were excluded.
© 2012 Kaiser Permanente Medical Care Program
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277
02/12
National Adult Depression Clincial Practice Guideline
Database:
Cochrane
Clinical
Evidence
PubMed
Article Type
and Other
Limits:
Systematic
reviews
Search Terms:
Depression
Systematic
reviews and
RCTs
Depression
("depression" [MeSH] OR "depressive
disorder" [MeSH] OR "Depressive
disorder/therapy" [MeSH] OR "Major
Depressive Disorder" [all fields]) AND
("health education" [MeSH] OR "patient
education" [MeSH] OR "behavior
therapy/methods" [MeSH] OR "patient
satisfaction" [MeSH] OR "cognition"
[MeSH], "psychoeducation" [all fields]
OR "psychosocial classes" [all fields] OR
"behavioral classes" [all fields])
Search
Date
03/05/03
No.
Included
/ Total
Retrieved*
0/295
03/05/03
0/80
All publication 01/01/1965
types, All
adults 19+
04/01/2003
years, English,
Human
2/704
Some studies found and used in this guideline did not appear in PubMed search results due to the
way studies are indexed in PubMed.
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National Adult Depression Clincial Practice Guideline
Evidence Tables
Table 12.1
Study,
Total n
Brown, R.A.
1984 (RCT)
Treatment Groups Size & Drug
Rx1: Class (n = 25)
Rx2: Individual tutoring (n = 13)
Follow-up: One and 6 months
Rx3: Phone contact (N = 14)
Initial N: 63
Final N: Not Stated
(4.6% drop-out rate)
Rx4: Wait-list control (N = 11)
“Coping with Depression” course format
was standardized across the three
treatment conditions. It included a text,
Control Your Depression from which
reading assignments were made.
Course consisted of 12 sessions over an
8 week period plus a visit or phone
contact (Rx3 group) at one and 6 month
post treatment
Study Population
Adults 16-65 years old
70% female
All met Research Diagnostic Criteria
(RDC) for a current episode of unipolar
depression
Mean Beck Depression Inventory (BDI)
score of 22.2 (consistent with mild to
moderate Major Depression)
Unclear if patients with severe Major
Depression or chronic Major
Depression excluded.
Patients with concurrent substance
abuse excluded.
Results
Comments
Participants in the three treatment groups
improved more during the 8-week period
than did the wait-list control group, p<0.05
Proportions of individuals receiving concurrent
treatment for depression in each group not
specified
There were no statistically significant
differences among the three treatment
groups, when compared at 8weeks
(treatment duration) and one and 6 months
follow-up sessions
Difference in response between those receiving
concurrent treatment and those not receiving
other treatment for depression not specified
Among the participants in the three
treatment groups, only 25% still met the
criteria for depression at the 6-month
follow-up session
34 of 122 individuals chose not to participate in
the study, differences between enrolled and not
enrolled group not specified
Those with residual depression tended to
have depression onset at an earlier age
than those who responded
Patients receiving concurrent treatment
for depression were included
From an economic point of view, the class
condition was by far the most cost effective
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Table 12.2
Study,
Total n
Treatment Groups Size
& Drug
Dowrick, C.
2000 (RCT)
Rx1: Six individual sessions of
Problem-Solving treatment
delivered in a setting
Follow-up: 6 and 12 months convenient for the patient
(usually the patient’s home) by
Initial N: 452
behavioral health, allied
Final N: 212
health, or nursing personnel
(N = 128)
Intention-to-treat-analysis
Rx2: Eight group sessions (2.5
hours each) of a course on
prevention of depression
(n = 108)
Rx3: Control group (n = 189)
Study Population
Adults ages 18 to 65
Results
Comments
Mean difference in Beck Depression Inventory (BDI) score
Rx1 at 6 months =-2.63 (-4.95 to –0.32), p=0.026 (significant)
At 12 months =-1.00 (-3.31 to 1.31), p=0.398 (not significant)
Diagnosis of depressive disorder
(71%) according to DSM-IV,
dysthymia (16%) , adjustment
Rx2 at 6 months = –1.50 (-4.16 to 1.17), p=0.272 (not significant)
disorder (4%) or other depressive At 12 months = 1.11 (-1.30 to 3.52), p=0.901 (not significant)
disorders (9%)
There were significant improvements in SF36 scores (mental role, social
Suicidal patients and patients
function, and mental health) at 6 months for patients in the depression
with concurrent substance abuse prevention course (p=0.042, 0.048, and 0.028 respectively), when
excluded.
compared with baseline scores
Unclear if patients with severe
Major Depression who were not
suicidal were excluded or
included.
There were significant improvements in SF36 scores (mental role, social
function, and mental health) at 6 months for patients in the Problem-Solving
therapy group compared with controls at 6 months (p=0.030, 0.012, and
0.005 respectively).
Study concludes both Problem-Solving
treatment and the course on prevention
of depression reduces the severity and
duration of depressive disorders and
improves subjective mental and social
functioning.
Mixed population (patients with different
types of depression, not all Major
Depressive Disorder) with the results
not stratified by condition
The number of different individuals
delivering the Problem-Solving therapy
was not specified, the problem-solving
There was no significant differences in SF36 scores at 12 months
therapy protocol was not specified, and
the inter-provider variability of
At 6 months there was a 17% difference in numbers of depressed patients
adherence to the therapy protocol was
between participants assigned to Problem-Solving and controls (NNT = 6). not analyzed. Therefore, this may not
At 12 months there was no difference between Rx1 and Rx3
be directly comparable to the ProblemSolving therapy delivered by trained
At six months there was a 14% difference in numbers of depressed patients mental health personnel in traditional
between participants assigned to prevention of depression and controls
behavioral health settings.
(NNT = 7). At 12 months there was no difference between Rx2 and Rx3.
Unweighted (complete case analysis) odds ratio for
RX1 at 6 months : 0.51 (0.27 to 0.97)
RX1 at 12 months : 0.92 (0.48 to 1.77)
Rx2 at 6 months : 0.50 (0.21 to 1.15)
Rx2 at 12 months: 1.02 (0.46 to 2.23)
More patients completed Problem-Solving therapy ((63%) than the course
(44%) p = 0.006.
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280
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National Adult Depression Clincial Practice Guideline
Table 12.3
Study,
Total n
Brown, R.A.
1984 (RCT)
Treatment Groups Size & Drug
Rx1: Class (n = 25)
Rx2: Individual tutoring (n = 13)
Follow-up: One and 6 months
Rx3: Phone contact (N = 14)
Initial N: 63
Final N: Not Stated
(4.6% drop-out rate)
Rx4: Wait-list control (N = 11)
“Coping with Depression” course format
was standardized across the three
treatment conditions. It included a text,
Control Your Depression from which
reading assignments were made.
Course consisted of 12 sessions over an
8 week period plus a visit or phone
contact (Rx3 group) at one and 6 month
post treatment
Study Population
Adults 16-65 years old
70% female
All met Research Diagnostic Criteria
(RDC) for a current episode of unipolar
depression
Mean Beck Depression Inventory (BDI)
score of 22.2 (consistent with mild to
moderate Major Depression)
Unclear if patients with severe Major
Depression or chronic Major
Depression excluded.
Patients with concurrent substance
abuse excluded.
Results
Comments
Participants in the three treatment groups
improved more during the 8-week period
than did the wait-list control group, p<0.05
Proportions of individuals receiving concurrent
treatment for depression in each group not
specified
There were no statistically significant
differences among the three treatment
groups, when compared at 8weeks
(treatment duration) and one and 6 months
follow-up sessions
Difference in response between those receiving
concurrent treatment and those not receiving
other treatment for depression not specified
Among the participants in the three
treatment groups, only 25% still met the
criteria for depression at the 6-month
follow-up session
34 of 122 individuals chose not to participate in
the study, differences between enrolled and not
enrolled group not specified
Those with residual depression tended to
have depression onset at an earlier age
than those who responded
Patients receiving concurrent treatment
for depression were included
From an economic point of view, the class
condition was by far the most cost effective
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281
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National Adult Depression Clincial Practice Guideline
Table 12.4
Study,
Total n
Treatment Groups Size
& Drug
Dowrick, C.
2000 (RCT)
Rx1: Six individual sessions of
Problem-Solving treatment
delivered in a setting
Follow-up: 6 and 12 months convenient for the patient
(usually the patient’s home) by
Initial N: 452
behavioral health, allied
Final N: 212
health, or nursing personnel
(N = 128)
Intention-to-treat-analysis
Rx2: Eight group sessions (2.5
hours each) of a course on
prevention of depression
(n = 108)
Rx3: Control group (n = 189)
Study Population
Adults ages 18 to 65
Results
Comments
Mean difference in Beck Depression Inventory (BDI) score
Rx1 at 6 months =-2.63 (-4.95 to –0.32), p=0.026 (significant)
At 12 months =-1.00 (-3.31 to 1.31), p=0.398 (not significant)
Diagnosis of depressive disorder
(71%) according to DSM-IV,
dysthymia (16%) , adjustment
Rx2 at 6 months = –1.50 (-4.16 to 1.17), p=0.272 (not significant)
disorder (4%) or other depressive At 12 months = 1.11 (-1.30 to 3.52), p=0.901 (not significant)
disorders (9%)
There were significant improvements in SF36 scores (mental role, social
Suicidal patients and patients
function, and mental health) at 6 months for patients in the depression
with concurrent substance abuse prevention course (p=0.042, 0.048, and 0.028 respectively), when
excluded.
compared with baseline scores
Unclear if patients with severe
Major Depression who were not
suicidal were excluded or
included.
There were significant improvements in SF36 scores (mental role, social
function, and mental health) at 6 months for patients in the Problem-Solving
therapy group compared with controls at 6 months (p=0.030, 0.012, and
0.005 respectively).
Study concludes both Problem-Solving
treatment and the course on prevention
of depression reduces the severity and
duration of depressive disorders and
improves subjective mental and social
functioning.
Mixed population (patients with different
types of depression, not all Major
Depressive Disorder) with the results
not stratified by condition
The number of different individuals
delivering the Problem-Solving therapy
was not specified, the problem-solving
There was no significant differences in SF36 scores at 12 months
therapy protocol was not specified, and
the inter-provider variability of
At 6 months there was a 17% difference in numbers of depressed patients
adherence to the therapy protocol was
between participants assigned to Problem-Solving and controls (NNT = 6). not analyzed. Therefore, this may not
At 12 months there was no difference between Rx1 and Rx3
be directly comparable to the ProblemSolving therapy delivered by trained
At six months there was a 14% difference in numbers of depressed patients mental health personnel in traditional
between participants assigned to prevention of depression and controls
behavioral health settings.
(NNT = 7). At 12 months there was no difference between Rx2 and Rx3.
Unweighted (complete case analysis) odds ratio for
RX1 at 6 months : 0.51 (0.27 to 0.97)
RX1 at 12 months : 0.92 (0.48 to 1.77)
Rx2 at 6 months : 0.50 (0.21 to 1.15)
Rx2 at 12 months: 1.02 (0.46 to 2.23)
More patients completed Problem-Solving therapy ((63%) than the course
(44%) p = 0.006.
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National Adult Depression Clincial Practice Guideline
13.
Antidepressants To Avoid During Pregnancy or Breastfeeding
Problem Formulation 13
Clinical Question(s)
Population
Health Intervention(s)
Most Important Health
Outcomes
Which antidepressants should be avoided in women who are
pregnant or breastfeeding?
Patients diagnosed with MDD who may be pregnant or
breastfeeding
 Antidepressant treatment (SSRIs, TCAs, DAs, SNRIs,
NRIs)
 No treatment
 Hospitalizations
 Mortality
 Spontaneous abortion
 Congenital malformations
 Perinatal complications (mother and child)
 Long-term behavioral sequelae
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Search Strategy
Article Type
and Other
Limits:
N/A
Search
Date
Database:
Search Terms:
Cochrane
Depression
2005
Systematic
to
Reviews
9/2007
9/2007
to
10/01/2009
PubMed
("Depression"[MeSH] OR "Major
Only items with
8/2005
Depressive Disorder"[All Fields] AND
abstracts,
to
(“systematic"[All Fields] OR “systematic Humans,
9/2007
review"[All Fields] OR “metaEnglish, All
9/2007
analysis"[All Fields]))
Adult: 19+ years
to
10/01/2009
"depression"[MeSH Terms] OR
PubMed
Only items with
1966
DEPRESSION[Text Word]) OR "depressive
abstracts,
disorder"[MeSH Terms]) OR depressive
Humans,
9/2007
disorder[Text Word]) OR "Antidepressive
English, All
Agents"[Mesh] AND “neonate” OR “neonatal”
Adult: 19+ years
*
OR “pregnancy” OR “lactation” OR
“breastfeeding”
(((("depression"[MeSH Terms] OR
DEPRESSION[Text Word]) OR "depressive
disorder"[MeSH Terms]) OR depressive
disorder[Text Word]) OR "Antidepressive
Agents"[Mesh]) AND ((((((“neonate” OR
“neonatal”) OR “pregnancy”) OR “lactation”)
OR “breastfeeding”) OR "prenatal") OR
"antenatal")
Only items with
9/2007
abstracts,
to
Humans,
10/01/2009
English, All
Adult: 19+ years
Hand search
NA
9/2007
to
10/01/2009
No.
Included
/ Total
Retrieved*
0/134
0/58
0/129
5/137
8/262
5/483
1
Note: “No. Included” refers to studies that are relevant to the problem formulation and, therefore, are included
in this analysis of the evidence. “Total Retrieved” refers to the number of studies retrieved in the search,
regardless of relevance. Because individual studies can be captured in multiple databases, they may be counted
more than once in the number included.
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Evidence Tables
Table 13.1: Meta-Analyses of Antidepressants in Pregnancy
Studies
Total N
Hemels MEH 2005
(meta-analysis)
Study Population
Groups Size & Drug
Results
Comments
Observational cohort studies including pregnant
women on antidepressant therapy
1 study of trazodone or nefazodone
1 study of venflaxine
1 study of sertraline/paroxetine/fluvoxamine
2 studies of fluoxetine
1 study of TCA
Rate of spontaneous abortion in
women exposed to all
antidepressants was 12.4%,
compared with 8.7% in women not
exposed to antidepressants (RR =
1.45)
Nonsignificant differences
seen among drug classes.
Lattimore KA 2005
(meta-analysis)
Prospective cohort studies of second and third
trimester exposure to SSRIs.
# studies found: 194
# studies included: 9
1 study of paroxetine only
2 studies of fluoxetine only
Outcome
Prematurity
Low birth wt
SNU/NICU
Poor adaptation
OR (95% CI)
1.85 (0.79,
4.29
3.64 (1.01,
13.08)
3.30 (1.45,
7.54)
4.08 (1.20,
19.93)
# studies found: 156
# studies included: 6
Total N = 3567
Biases, etc.
Time of exposure to antidepressants varied, studies
may represent overlapping populations, no verification
made of spontaneous abortion versus elective
termination of pregnancy.
Heterogeneity: overall heterogeneity
was nonsignificant (used fixed-effects
model?)
NNT
29
31
7
9
Total N = 326
Heterogeneity: a nonlinear mixed
effect model was used in statistical
analysis due to the absence of
homogeneity
Moses-Kolko EL 2005
(meta-analysis)
# studies found: not reported
# studies included: 9
Total N = 1,111
Cohort studies of patients who had been exposed
to SSRIs in the final trimester of pregnancy that
included assessment of neonatal outcomes
compared with control groups who had early or
no exposure
Outcome
Neonatal behavioral syndrome
SNU/NICU
Respiratory difficulty
Seizure
Authors’ conclusions:
Maternal exposure to antidepressants is associated
with an increased risk of spontaneous abortion.
p
0.1295
0.0481
0.0192
0.0694
Authors’ conclusions:
SSRI exposure appears to increase the incidence of
prematurity, low birth weight, special-care nursery
admissions, and the diagnosis of poor neonatal
adaptation.
Biases, etc.
Some studies included smokers and women using
other psychotropic medications.
OR (95% CI)
3.0 (2.0-4.4)
2.6 (1.4-4.7)
2.3 (1.6-3.2)
4.1 (1.5-11.0)
Authors’ conclusions: There is an increased risk of
neonatal behavior syndrome and other CNS
symptoms following gestational exposure to SSRIs.
Biases, etc.
No information regarding heterogeneity of data,
1 study of paroxetine only
3 studies of fluoxetine only
What model used for MA?
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Table 13.2: Cohort and Case-Control Studies of Antidepressants in Pregnancy
Name
design
Sample
characteristics
Pedersen et
al (2009)
Not reported.
Information from all
live-born children in
Denmark between
1/11966 –
12/31/2005.
Cohort study
Exposure/
Outcome of
interest
EXPOSED
Cases
NONEXPOSED
N
Cases
N
OR/ RR
95% CI
pvalue
Study
Quality†
Fair
Exposure:
SSRI (Fluoxetine,
Citalopram,
Paroxetine,
Sertraline) during
1st trimester of
pregnancy
Biases*
3,4
Outcomes:
Birth defects
including major
and minor
malformations,
septal heart
defects, noncardiac
malformations
Sub-analyses included women with one or more redemptions for antidepressants: 3010 women redeemed one
or more SSRI, 265 for tricyclic antidepressants, and 150 for venlafaxine."
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Name
design
Andrade et al
(2009)
Case-control
study
Sample
characteristics
Females >15 years
who were admitted
between 1996 –
2000 for delivery.
EXPOSED
Exposure/
Outcome of
interest
Exposure:
Antidepressants
used (SSRIs,
tricylics,
miscellaneous)
during 3rd
trimester.
Cases
2
NONEXPOSED
N
1104
Cases
N
3
1104
OR/ RR
95% CI
RR = for antidepressants used:
0.67
RR = for SSRIs:
0.79
pvalue
0.06 – 5.82
Study
Quality†
Biases*
Poor
3,4
Poor
3,4
0.07 – 6.89
Exposure and
nonexposure
women were
Outcomes:
matched by age,
health plan, year of Infant persistent
pulmonary
admission.
hypertension
(PPHN).
Wichman et al Women presented
(2009)
at Mayo Clinic from
1993 – July 15,
Retrospective 2005..
cohort study
Exposure:
SSRI use
(fluoxetine,
paroxetine,
sertraline,
citalopram,
escitalopram,
venlafaxine)
during pregnancy.
Outcomes:
Congenital heart
disease (CHD)
and PPHN.
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Name
design
Toh et al
(2009)
Case-control
study
Jordan et al
(2008)
Retrospective
cohort study
Sample
characteristics
EXPOSED
Exposure/
Outcome of
interest
Women who gave
birth to
nonmalformed an
non-hypertensive
babies and who
participated in the
Slone
Epidemiology
Center Birth
Defects Study from
1998 – 2007
Exposure:
SSRI use during
pregnancy
Pregnant women
with psychiatric
illness in prenatal
clinic from Sept
2005 - Aug 2006.
Exposure:
SSRI use during
pregnancy
Cases
NONEXPOSED
N
Cases
OR/ RR
N
95% CI
pvalue
Study
Quality†
Biases*
Poor-Fair
3,4
Poor
3,4
Outcomes:
Gestational
hypertension and
preeclampsia
13
46
10
59
RR =
1.67**
NA
NA
Outcome:
Neonatal
Women not treated behavioral
with SSRI
syndrome (NBS)
considered controls – irritability,
jitteriness, hypoor hypertonia,
hyperreflexia,
oxygen
requirement,
apnea, flaring,
grunting,
retractions,
vomiting, poor
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Name
design
Sample
characteristics
EXPOSED
Exposure/
Outcome of
interest
Cases
NONEXPOSED
N
Cases
N
OR/ RR
95% CI
pvalue
Study
Quality†
Biases*
feeding or
hypoglycemia.
Ramos et al
(2008)
Case-control
study
Pregnant women
aged 15 – 45 in
Quebec; have at
least 1 diagnosis of
psychiatric disorder
before pregnancy.
Exposure:
Antidepressants
(SSRIs, citalopram,
fluoxetine,
fluvoxamine,
paroxetine and
sertraline; tricyclic
– amitriptyline,
clomipramine,
deipramine,
doxepin,
imipramine,
nortriptyline,
trimipramine; and
new
antidepressants –
bupropion,
mirtazapine,
moclobemide,
nefazodone,
trazodone,
venlafaxine)
during 1st
trimester of
pregnancy.
Fair
4
Poor
2,3,4
Outcome:
Major congenital
malformation.
Diav-Citrin et
al (2008)
Prospective
cohort study
Pregnant women
who contacted the
Israeli, Italy and
Germany
Teratology
Information Service
(TIS).
Exposure:
Paroxetine or
fluoxetine or nonteratogenic
exposure (e.g.,
antibiotics, oral
contraceptives,
Table 2. Pregnancy outcomes.
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Name
design
Sample
characteristics
EXPOSED
Exposure/
Outcome of
interest
Cases
NONEXPOSED
N
Cases
N
OR/ RR
95% CI
pvalue
Study
Quality†
etc.).
Outcome:
Major congenital
abnormalities (i.e.
structural
abnormalities with
medical, surgical
or cosmetic
consequences;
VSD,
neurodevelopmen
tal or functional
problems)
Table 3. Logistic regression analysis for miscarriage rate and cardiovascular anomalies.
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Biases*
Name
design
Sample
characteristics
Salkeld et al
(2008)
Women aged 16 –
46 years in Ontario
who received
government-funded
drug coverage 2
years prior to
delivery.
Nested casecontrol study
Cases were
matched with
controls in ratio
1:10
Exposure/
Outcome of
interest
EXPOSED
Cases
NONEXPOSED
N
Cases
N
OR/ RR
95% CI
pvalue
Study
Quality†
Poor
Exposure:
Antidepressant
(SSRIs –
fluoxetine,
fluvoxamine,
sertraline,
paroxetine, and
citalopram; and
non-SSRIs –
cyclic
antidepressants,
bupropion and
venlafaxine) use
in 3rd trimester.
Biases*
2,3,4
Outcomes:
Postpartum
hemorrhage
Kallen and
Olausson
(2008)
Prospective
cohort study
Swedish women in
Register who gave
birth between 1997
– 2005 to infants
diagnosed with
PPHN.
Poor – Fair 3,4
Exposure:
SSRI during
pregnancy.
Outcome:
PPHN
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Name
design
Oberlander et
al (2008)
Retrospective
cohort study
Sample
characteristics
Records of live
births between
4/1/97 – 3/31/2002
in British Colombia
from women
diagnosed with
depression. Data
derived from
hospital, pharmacy
and physician
billing registries.
Exposure/
Outcome of
interest
EXPOSED
Cases
NONEXPOSED
N
Cases
N
OR/ RR
95% CI
pvalue
Study
Quality†
Fair
Exposure:
1st trimester SSRI
(Citalopram,
Fluoxetine,
Fluvoxamine,
Paroxetine,
Sertraline, And
Venlafaxine)
and/or
benzodiazepines
(BZ). Poly drug
exposure was
defined as SSRI
and BZ were
dispensed for
same day during
1st trimester.
3
Outcome:
Major congenital
anomalies and
subset of
cardiovascular
defect (VSD and
ASD).
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Biases*
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Name
design
Sample
characteristics
Exposure/
Outcome of
interest
EXPOSED
Cases
NONEXPOSED
N
Cases
N
© 2012 Kaiser Permanente Medical Care Program
OR/ RR
95% CI
pvalue
For use within Kaiser Permanente only.
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Study
Quality†
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Biases*
Name
design
Sample
characteristics
Exposure/
Outcome of
interest
EXPOSED
Cases
NONEXPOSED
N
Cases
N
© 2012 Kaiser Permanente Medical Care Program
OR/ RR
95% CI
pvalue
For use within Kaiser Permanente only.
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Biases*
Name
design
Sample
characteristics
Maschi et al
(2008)
Women who called
the Drug and
Health Information
Center in Milan,
took
antidepressants
during pregnancy
and delivered
infants between
1995-2003.
Case-control
Cases were
matched for
maternal age and
gravidity to 6
randomly selected
controls
EXPOSED
Exposure/
Outcome of
interest
Exposure:
Antidepressants,
including
paroxetine (most
used drug),
fluoxetine,
amitriptyline, and
benzodiazepine.
Cases
14
NONEXPOSED
N
200
Cases
OR/ RR
N
50
1200
OR = 1.73*
95% CI
pvalue
NS
Study
Quality†
Poor - Fair
Outcome:
poor neonatal
adaptation –
respiratory
distress,
hypoglycemia,
jitteriness,
lethargy,
hypotonia,
weak/absent cry,
feeding
difficulties,
convulsions and
hyperbilirubinaemi
a
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Biases*
3
Name
design
Sample
characteristics
Chambers CD Study groups were
2006
age-matched
Case control
study
EXPOSED
Exposure/
Outcome of
interest
Exposure:
SSRI (which
SSRIs used in
studies?) during
2nd and 3rd
trimester
Cases
14
NONEXPOSED
N
377
Cases
OR/ RR
N
6
836
6.1
95% CI
2.2-16.8
pvalue
0.001
Study
Quality†
N/A
N/A
Outcome:
Pulmonary
Hypertension
†
Based on KP system for grading the strength of a body of evidence (refer to Appendix A).
* Biases: N: none; 1: sample attrition >15%; 2: sample selection bias; 3: detection bias (e.g., measurement error, ITT analysis, power); 4: study procedure biases
(e.g., blinding, randomization)
** Calculated based on provided data.
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Table 13.3: Meta-Analyses of Antidepressants in Lactation
Studies
Total N
Study Population
Groups Size & Drug
Rubin ET 2004
(meta-analysis)
All studies of breast milk or breastfeeding and
CNS-acting drugs
# studies found: 345
# studies included: 123, 17 studies of
antidepressants
The infant exposure level (%) was defined as
follows: [Drug concentration in milk (mg/mL)] x
[Daily milk intake (mL/kg/d)] x 100 / Maternal
dose (mg/kg/d).
Results
Comments
Average breast fed infant exposure levels were
less than 10% of the therapeutic dose of
antidepressant medications per kilogram of body
weight.
Authors’ conclusions:
CNS-acting drugs used by breast-feeding mothers do not
pose any risk to the infant
Biases, etc.
Most studies evaluated were case reports
Total N = 642 in antidepressant studies
Weissman AM 2004
(pooled analysis)
All studies of antidepressant levels in nursing
mother-infant pairs
# studies found: 67
# studies included: 57
Levels of most medications found in breast milk
were extremely generally less than 10% of the
average maternal level
Fluoxetine levels exceeded 10% of maternal
levels in 22% (N = 8) of infants studied.
Total N = 337 mothers, 237 infants
Citalopram levels exceeded 10% of maternal
levels in 17% (N = 2) of infants studied.
© 2012 Kaiser Permanente Medical Care Program
Authors’ conclusions:
Breastfeeding infants exposed to nortriptyline, paroxetine or
sertraline unlikely to develop detectable or elevated plasma
drug levels, while those exposed to fluoxetine appear to be
at higher risk, especially following prenatal exposure.
Citalopram was also noted to produce elevated plasma
drug levels in some infants.
Biases, etc.
Most studies evaluated were case reports. Most studies did
not include all the parameters studied. Maternal weight,
timing of maternal dosing, and use of other medications
was not recorded. Small n for fluoxetine and citalopram fetal
drug level evaluation.
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