the PowerPoint - Arkansas Psychiatric Society

Schizophrenia Prediction and
Prevention: What Do We
Puru Thapa, M.D., M.P.H.
Associate Professor
Department of Psychiatry, UAMS
Staff Psychiatrist, Arkansas State
Review definition, epidemiology and etiology of
Understand the concept of levels of preventions
Critically review the strategies of prevention in
schizophrenia and evidence
Consider future directions
Syndrome characterized by psychosis and
dysfunction and probably the most devastating
mental illness with great distress to the individual
and families with heavy costs and burden to
Treated with antipsychotics and psychosocial
support and rehab
Schizophrenia – DSM-5 Criteria
Two (or more) of the following, each present for
a significant portion of time during a 1-month
period (or less if successfully treated). At least
one of these must be (1), (2), or (3):
Disorganized speech
Disorganized or catatonic behavior
Negative symptoms
Social/occupational dysfunction
Schizophrenia – DSM-5 Criteria
Duration: continuous signs persist for at least
six months
Exclude schizoaffective or mood disorder
Exclude general medical condition or substance
Relationship to a pervasive developmental
Schizophrenia - Costs
Cost of Schizophrenia in the US in 2002
Direct Costs
30.3 billion dollars
Indirect Costs
32.4 billion dollars
Total Costs
62.7 billion dollars
Mental anguish/distress to individuals affected
and to families
Wu EQ and colleagues, J Clin Psych 2005;66:1122-1129
Schizophrenia - Epidemiology
Life time prevalence approximately 1%
Incidence estimated .01% to .02%
Risk slightly higher in males than females
Age of onset: males 15-25 years, females 25-35
Phases of Schizophrenia
Contributes to vulnerability to schizophrenia
Change from premorbid functioning and extends time
of onset of frank psychotic symptoms
Average length 2 – 5 years
Impairment in psychosocial functioning
Onset of frank psychotic symptoms
Acute phase, Early recovery phase (first 6 months
after acute treatment), Late recovery phase (6-18
Period following recovery from first episode up to 5
years is Critical Period for up to 80% relapse
Early prodromal symptoms non-specific: sleep
disturbance, anxiety, irritability, depressed mood, poor
concentration and fatigue, and behavioral symptoms,
such as deterioration in role functioning and social
Late prodromal symptoms: positive symptoms, such as
perceptual abnormalities, ideas of reference, and
suspiciousness – herald imminent onset of psychosis
Prodrome – really based on retrospective reconstruction
Schizophrenia - Etiology
Etiology unknown – can be conceptualized as a clinical
syndrome that is the “final common pathway of multiple
different etio-pathogenetic processes”. Similar to concept
of Congestive Heart Failure or Nephrotic Syndrome
Neurodevelopmental – factors during perinatal period,
Other factors: season of birth, paternal age, diet during
pregnancy, obstetrical complications, etc.
Stress-Diathesis Model of disease causation
Stress-Diathesis Model
Diathesis: Inherited vulnerability – bad genes
Stress: Environmental insult – physical,
emotional, environmental
This model offers our best explanation of
schizophrenia cause
Genetic predisposition
1 parent with schizophrenia
Both parents
Dizygotic twin of schizophrenia patient
Monozygotic twin
Intrauterine trauma? (physical, drugs, etc)
Later trauma or stress? Often the 1st psychotic break
happens during a stressful period such as going away
to college, military, etc.
Challenges in Prevention of Schizophrenia
Disorder with unclear etiology
No objective marker or test to diagnosis
Rare disease
Antecedent factors and prodromal symptoms are
not specific – high number of false positives
Predictive Value
Gold Standard
Test Results
True Positive (TP)
False Positive (FP)
a b
c d
False Negative (FN) True Negative (TN)
PPV = TP/(TP+FP) or a/(a+b) = 80/(80+100) = 44%
NPV = TN/(FN+TN) or d/(c+d) = 800/(800+20) = 98%
Epidemiology and Prevention
To identify high-risk subgroups in population
 Identification of high risk groups may identify
modifiable risk factors.
 Can direct preventive efforts at such groups –
such as screening programs for early
detection of disease
Levels of Prevention
Prevention of disease by altering susceptibility or
reducing exposure for susceptible individuals
e.g., immunization, exercise
Early detection and treatment of disease
e.g., breast cancer screening, screening for disease
(occult blood in stool for colon cancer)
Limitation of disability and rehabilitation
Alleviation of disability resulting from disease and
attempts to restore function (Post-stroke rehabilitation)
Prevention – can be population-based or high risk group
Primary Prevention of Schizophrenia
Limited understanding about etiology and
pathogenesis of schizophrenia
Long latency between primary insult and onset
of schizophrenia
Much research ongoing but not currently
Tertiary Prevention
Tertiary prevention – reducing the burden of
disease by optimizing treatment and
rehabilitation and reducing relapse
In Schizophrenia, with tertiary prevention if
remission rates increase, then prevalence may
fall with lower burden
Very important to address but disease has
already manifest
Secondary Prevention
Secondary prevention - modify course of illness by early
detection, intervention and possibly prevention
Potentially feasible through intervention at the prodromal
Aim is to reduce full transition from prodromal to
Interventions could
 Delay onset of illness
 Mitigate profile of illness to “milder” or “less disabling”
Hope is to reduce cost and burden of disease
 How
Do We Define the Population to
Target for Secondary Prevention?
Genetically Vulnerable Population
Research has focused on genetically vulnerable
 Unable to identify which individuals within
genetic high-risk group will eventually develop
schizophrenia with sufficient predictive value to
justify intervention
 Problem with this approach is that of low
sensitivity since nearly 80% of affected
individuals with schizophrenia have no 1st
degree relatives and nearly 60% have negative
family history
Factors Predicting Schizophrenia
Spectrum Outcomes in Offsprings of
Schizophrenia Patients
Maternal influenza during gestation
 Obstetrical complications
 Neurointegrative deficits in infancy
 Separation during first year of life
 Social, affective, and motor coordination deficits in early
 Social dysfunction in later childhood
 Attention deficits, neuribehavioral deficits and poor
motor coordination in preadolescence
 Teacher rated timidity and day dreaming behaviors at
age 15 years
 Absence of protective family environment
Prodromal Phase Focus of Intervention
Why Intervention in Prodromal Phase?
Neurobiological deficit processes associated with
severity and chronicity with schizophrenia are already
present at time of first episode
Evidence suggests early treatment can result in
significant reduction in morbidity and better quality of life
DUP – Duration of untreated psychosis is defined as time
between onset of first psychotic symptoms and first adequate
Average DUP is 1 – 2 years
Longer DUP associated with male gender, poor premorbid
functioning, insidious onset of psychosis, and presence of
negative symptoms
A review of 25 DUP studies showed two thirds of them had
better outcome on one or more measures for shorter DUP and
none showed better outcomes with longer DUP
Why Intervention in Prodromal Phase?
Treatment in prodrome may prevent or
delay onset
Important to treatment prodromal
symptoms themselves to relieve distress
for parents and families
Specialized Early Intervention Programs
PACE – Personal Assessment and Crisis Evaluation
clinic, Melbourne, Australia
RAP – Hillside Recognition and Prevention Program,
EDIE – Early Detection and Intervention Evaluation
Program, Manchester, UK
PRIME – Prevention through Risk Identification,
Management, and Education Program, Yale Univ, CT
CARE – Cognitive Assessment and Risk Evaluation
Clinic in San Diego, CA
Prevention Strategies
 Psychopharmacology
 Cognitive/Cognitive
 Case
Behavior Therapy
McGorry et al. Arch Gen Psychiatry.
Design: Single blind (researchers) randomized controlled
trial comparing two treatments in 59 patients (age 14-30
years) at “ultra-high risk”
Needs Based (focus on needs based supportive therapy re social,
family issues, case management) vs
Specific Preventive (Needs Based and low dose risperidone and
cognitive behavior therapy)
Outcome: progression to frank psychosis lasting a week
or more
Treatment duration 6 months. After this all patients were
offered Needs Based Intervention.
Assessment at baseline, 6 months, 12 months
Note: 43 of 59 (73%) did not progress to psychosis at 12 months
McGorry et al. Arch Gen Psychiatry.
Number Needed to Treat (NNT) = 4. (NNT = 13 for
antihypertensives to prevent stroke)
In other words, 4 ultra-high risk patients would need to
be treated to prevent 1 patient from progressing to
psychosis over a 6 month period
Conclusions: Specific pharmacotherapy and
psychotherapy reduces risk of early transition to
psychosis in these patients but unclear which modality
more contributory
Ethical dilemma: 73% did not transition to psychosis. Is
using AP justified?
Potential Benefits of Prepsychotic
McGorry et al. Arch Gen Psychiatry. 2002;59:921-928
Patients more easily engaged and can receive
treatments regardless of whether preventive treatment
may be ineffective or unnecessary
Those who progress to psychosis have developed a
level of trust enabling them to accept treatment, have
minimal DUP and reduced comorbidity
Psychosocial impact of psychosis may be diminished
and better chance to recover
McGlashan et al. Am J Psychiatry.
Design: Double blind randomized controlled trial
comparing two treatments in 59 patients (age 14-30
years) at “ultra-high risk”
Olanzapine (Dose 5-15 mg/d) N=31
Placebo N=29
Outcome: progression to frank psychosis
Treatment duration 1 year; a second year of follow-up
with no treatment
At one year, 16.1% of olanzapine and 37.9% of placebo converted to psychosis
(p=.08). Olanzapine group had more improvement in symptoms.
At two years, most were lost to follow-up; but of remaining no difference
McGlashan et al. Am J Psychiatry.
Treatment difference not significant
Olanzapine group had improvement in symptoms
Major side effect of olanzapine – GUESS?
Authors admit study had low power - they tried to recruit
more subjects but were not successful
Cornblatt et al. J Clin Psychiatry.
Design: Prospective naturalistic treatment study of
adolescents (mean age 15.8 years) considered to be
“prodromal” (i.e., prepsychotic)
Antidepressants (N=20)
Second generation antipsychotics (N=28)
Outcome: progression to frank psychosis defined as a
score of 6 in any 1 of 5 positive symptom scale of the
SOPS (Scale of Prodromal Symptoms) lasting 2 weeks or
Treatment duration at least 6 months (mean duration 30.5
Recognition and Prevention Program (RAP), Zucker
Hillside Hospital, NY
Cornblatt et al. J Clin Psychiatry.
12 of 48 subjects (25%) converted to psychosis
0 from the AD group (N=20)
12 (43%) from the AP group (N=28)
BUT, 11 of 12 converters were non-adherent to the AP
Cornblatt et al. J Clin Psychiatry.
Non-random assignment limits comparison of
AD with AP
But number of adolescents with prodromal
features did well on AD
True prevention or False Positive? Underscores
retrospective nature of prodrome and challenge
in prevention.
Van Os J, Delespaul P. Toward a world consensus on
prevention of schizophrenia. Dialogues in Clinical
Neuroscience. 2005; 7:53-67.
Unclear understanding of disease and lack of better early
identification of high risk individuals with lower false
positives. Promising research describing better
Stigma – especially relevant because of high degree of
false positives
Lack of resources
Primary prevention of schizophrenia continues to be
elusive because of our inadequate understanding of
etiology resulting in high degree of false positives
Selective intervention shows promise but use of
pharmacotherapy for prevention still not established
Have to consider issues of stigma and public awareness
and education
Lack of resources for preventive activity
Brown AS, McGrath JJ. The Prevention of Schizophrenia.
Schizophrenia Bulletin. 2011; 37(2):257-261.
Brown AS, Patterson PH. Maternal Infection and Schizophrenia:
Implications for Prevention. Schizophrenia Bulletin. 2011; 37(2):284290.
Cornblatt BA, Lencz T, Smith CW et al. Can antidepressants be used
to treat the schizophrenia prodrome? Results of a prospective,
naturalistic treatment study of adolescents. Journal of Clinical
Psychiatry. 2007; 68:546-557.
Cornblatt BA, Auther AM. Treating early Psychosis: who, what, and
when? Dialogues in Clinical Neuroscience. 2005; 7(1):39-49
Kirkbridge JB, Jones PB. The Prevention of Schizophrenia- What Can
We Learn From Eco-Epidemiology? Schizophrenia Bulletin. 2011;
Knapp M, Mangalore R, Simon J. The global costs of schizophrenia.
Schizophrenia Bulletin. 2004: 30(2):279-293.
Lee C, McGlashan TH, Woods SW. Prevention of Schizophrenia: Can
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McEvoy JP. The costs of schizophrenia. Journal of Clinical
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McGlashan TH, Zipursky RB, Perkins D et al. Randomized, doubleblind trial of olanzapine versus placebo in patients prodromally
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McGorry PD, Killackey E, Yung AR. Early intervention in psychotic
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McGorry PD, Yung AR, Phillips LJ et al. Randomized controlled trial
of interventions designed to reduce the risk of progression to first
episode psychosis in a clinical sample with subthreshold symptoms.
Archives of General Psychiatry. 2002; 59:921-928.
Tsuang MT, Stone WS, Auster TL. Prevention of schizophrenia.
Expert review of Neurotherapeutics. 2010; 10(7):1165-1174.
Van Os J, Delespaul P. Toward a world consensus on prevention of
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Wu EQ, Birnbaum HG, Shi L et al. The economic burden of
schizophrenia in the United States in 2002. Journal of Clinical
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