How to assess the suicidal risk of patients with epilepsy undergoing AED trials? Andres M Kanner, MD Professor of Neurological Sciences and Psychiatry, Rush Medical College Director, Laboratory of EEG and VideoVideo-EEGEEG-Telemetry, Associate Director, Rush Epilepsy Center, Rush University Medical Center, Chicago, IL. • In January 2008, the FDA issued an alert that all AEDs are associated with a 1.8-fold increased risk of suicidality (suicidal ideation and behavior) – Based on a meta-analysis of data from 199 randomized trials of 11 AEDs involving nearly 44,000 patients treated for epilepsy, psychiatric disorders, and other disorders Package Insert Label in all AEDs 5 WARNINGS AND PRECAUTIONS 5.1 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including XAED, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. The FDA Alert on Suicidality and AEDs: Fire or False Alarm? • Major limitations and caveats – Analysis based on spontaneous adverse event reports – The analysis grouped together all 11 drugs as one class despite major differences in MOA – Only topiramate and lamotrigine were associated with a statistically significant increased risk of suicidality – The analysis is likely confounded by multiple factors including diagnosis and history of suicidality Hesdorffer DC Kanner AM. Epilepsia. 2009;50:978-986. AEDs and Risk of Suicidality Study Database Events considered Gibbons cohort study (bipolar) PharMetrics medical claims Attempted suicide No drug Yes ↑ risk: TPM & CBZ ↓ risk: GBP, VPA, LTG, OXC Olesen cohort study Danish populationbased recordslinkage Completed suicide CBZ No ↑ risk vs CBZ: VPA, LTG, PB, LEV Patorno cohort study Insurance claims Completed suicide TPM CBZ Yes ↑ risk vs TPM: GBP, LTG, OXC, TGB, VPA Vancott matched case control study VA & Medicare Ideation and attempted suicide GPB Yes ↑ risk vs GPB: VPA, LTG, LEV ↓ risk vs GPB: PHT, PB, CBZ Hesdorffer DC et al. Epilepsy Curr. 2010;10:137-145. Referent standard Controlled for prior SB Result (relative risk) AEDs and Risk of Suicidality: v The results are inconsistent and contradictory both across studies and within studies v No clear or convincing evidence that all AEDs are associated with an increased risk of suicidality v The potential for bias is great v Indication for prescription of AEDs is an important confounding factor Ø Only prospective, randomized, controlled trials in a single indication that systematically collects and controls for all relevant variables can answer this question Hesdorffer DC et al. Epilepsy Currents. 2010;10:137-145. Family Psychiatric history Axis I Diagnosis Mood Disorders Anxiety Disorders Personality Disorders Psychotic Disorders Postictal Psychiatric Episodes Suicidality Type of seizure disorder AEDs Suicide and Epilepsy 11.5% Jones JE et al. Epilepsy Behav 4 (Suppl 3):S31-8, 2003 Suicide in RCT in Epilepsy Ryvlin et al., AED mtg. •N = 21,490 patients •Deaths, n = 33 •Suicides, n = 2 (6% of deaths) Epilepsy, Psychiatric Disorders and Suicide Rate Ratio No Epilepsy Epilepsy P value 1 2.4 (2.0 (2.0--2.8) Epilepsy + <0.0001 <0.0001 Affective Disorder 32.0 (20.8 (20.8--49.4) <0.0001 Anxiety Disorder 11.4 (4.16(4.16-31.4) <0.0001 Schizophrenia 12.5 (8.05 (8.05--22.7) <0.0001 Christensen et al. Lancet Neurology 6: 693–98, 2007 Lifetime Prevalence Tellez-Zenteno, JF et al., Epilepsia, 2007; 48:2336-2344 Psychiatric Disorder Controls (%) Epilepsy (%) Major Depressive Disorder 10.7 (10.2– (10.2–11.2) 17.4 (10.0– (10.0–24.9) Anxiety Disorder 11.2 (10.8– (10.8–11.7) 22.8 (14.8– (14.8–30.9) Mood/Anxiety Disorders 19.6 (19.0– (19.0–20.2) 34.2 (25.0– (25.0–43.3) Suicidal Ideation 13.3 (12.8– (12.8–13.8) 25.0 (17.4 (17.4– –32.5) Any Psychiatric Disorder 20.7 (19.5– (19.5–20.7) 35.5 (25.9 (25.9– –44.0) Screening instruments… Item 9 BDI-II Suicidal Ideation In the last two weeks: 0. I don’ t have any thoughts of killing myself 1. I have thoughts of Killing myself, but I would not carry them out. 2. I would like to kill myself 3. I would kill myself if I had the chance. Suicidality Module M.I.N.I. 1. Did you ever make a suicide attempt? YES NO In the past month did you: 2. 3. 4. 5. 6. Think you would be better off dead or wish you were dead? YES Want to harm yourself? YES Think about suicide? YES Have a suicide plan? YES Attempt suicide? YES YES in 1, or 2, or 3 = LOW RISK YES in 4 or 1 + 3 = MODERATE RISK YES in 5 or 6 or 1+4 = HIGH RISK NO NO NO NO NO Columbia--Suicide Severity Rating Scale (C Columbia (C--SSRS) Posner, Brent, Lucas, Gould, Stanley, Brown, Fisher, Zelazny, Burke, Oquendo, & Mann. Columbia--Suicide Severity Rating Scale (C Columbia (C--SSRS) Posner, Brent, Lucas, Gould, Stanley, Brown, Fisher, Zelazny, Burke, Oquendo, & Mann. Neurological Disorders Depression Inventory in Epilepsy (NDDI-E) For the statements below, please circle the number that best describes you over the last two weeks including today. Always or Often Sometimes Rarely Never Everything is a struggle 4 3 2 1 Frustrated 4 3 2 1 Nothing I do is right 4 3 2 1 Feel guilty 4 3 2 1 Difficulty finding pleasure 4 3 2 1 I’d be better off dead 4 3 2 1 A total score >15 is suggestive of a diagnosis of major depressive episode Patient Health Questionnaire Questionnaire--Generalized Anxiety Disorder Disorder--7 PHQPHQ-GADGAD-7 Please circle the number that best describes you over the last 2 weeks, including today Nearly every day More than half the days Several days Not at all A total score >10 is suggestive of a diagnosis of generalized anxiety disorder Feeling nervous, anxious or on edge 3 2 1 0 Not being able to stop or control worrying 3 2 1 0 Worrying too much about different things 3 2 1 0 Trouble relaxing 3 2 1 0 Being so restless that it is hard to sit still 3 2 1 0 Being easily annoyed or irritable 3 2 1 0 Feeling afraid as if something awful might happen 3 2 1 0 Some data… Quick screen of suicidal risk: Item 9 from BDI-II N = 187 0. I don’t have any thoughts of killing myself: n = 163 (87.3%) 1. I have thoughts of killing myself, but I would not carry them out: n = 22 (7.2%) 2. I would like to kill myself: n = 1 (0.5%). 3. I would kill myself if I had the chance: n = 1 (0.5%). Relation between suicidal ideation and psychiatric diagnosis: Item 9 of BDI-II and Suicidality Module of the MINI Crosstab Count corrected.compressed.09.29.08 Anxiety subsyndromic MDE disorders none BDI Suicidal Thoughts or Wishes I don't have any thoughts of killing myself. I have thoughts of killing myself, but I would not carry I would like to kill myself. I would kill myself if I had the chance. Total Mixed MDE+AD Total 99 23 6 24 11 163 3 3 4 3 9 22 0 0 0 0 1 1 0 0 0 1 0 1 102 26 10 28 21 187 Crosstab Count none MINI - Suicidality Total No Yes 97 6 103 corrected.compressed.09.29.08 Anxiety subsyndromic MDE disorders 24 4 23 2 6 5 26 10 28 Mixed MDE+AD 12 9 21 Total 160 28 188 Screening for Depression, Generalized Anxiety Disorder and Suicidality at the Rush Epilepsy Center vN = 655 consecutive English-speaking adults. vAge: > 18 year-old vGender: 54.5% women ØNDDI-E >15: 17.9% ØGAD-7 10: 20.4% ØBoth: 10.9% Feasibility: Easy Required time to complete instruments: 4 minutes Required time for discussion with patient: Depends on findings! Class I or II evidence: no Suicidality Module M.I.N.I*. n = 655 1. Did you ever make a suicide attempt? YES NO 7.3% NO NO NO NO NO 6.2% 3% 5.4% 1.5% 0.5% In the past month did you: 2. Think you would be better off dead or wish you were dead? 3. Want to harm yourself? 4. Think about suicide? 5. Have a suicide plan? 6. Attempt suicide? YES YES YES YES YES Total suicidal Ideation: 15.2% Kanner et al, Epilepsia 2009. Poster 2.152 Suicidal Risk based on MINI in an outpatient population of patients with epilepsy YES in 1, or 2, or 3 = LOW RISK YES in 4 or 1 + 3 = MODERATE RISK YES in 5 or 6 or 1+4 = HIGH RISK ØLow risk: 9.2% ØModerate risk: 3.6% ØHigh risk: 2.4% Kanner et al, Epilepsia 2009. Poster 2.152 Association between severity of suicidal risk and the presence of suspected diagnosis of MDE, GAD and MDE+GAD Association* between severity of suicidal risk and: v NDDI-E > 15: Ø x2 = 75.6, df = 3, p<0.0001 v GAD-7 > 10 Ø X2 = 77, df = 3, p<0.0001 v NDDI-E > 15 + GAD-7 > 10 Ø X2 = 69.3, df = 3, p<0.0001 *Kruskal Wallis Test Kanner et al, Epilepsia 2009. Poster 2.152 Change in Suicidality symptoms according to the M.I.N.I. between two consecutive visits n total = 115, symptomatic at visit 1, n = 25 (22%) Question: No Change Improved Worsened (Symptomatic) (De novo) 2. Think you would be better off dead or wish you were dead? 5 4 5 3. Want to harm yourself? 1 5 3 4. Think about suicide? 1 6 1 5. Have a suicide plan? 1 0 1 6. Attempt suicide? 0 2 0 17 10 Total 8 Study in progress… Aims of the Study (1) 1) To determine the proportion of individuals with epilepsy who endorse active suicidal thoughts within the last 6 months or suicidal behavior within the 2 years prior to enrollment. 2) To examine: the feasibility of assessing suicidal risks using various scales including: - the C-SSRS - the suicidality module of the MINI 3) To assess the capability of epilepsy centers to appropriately manage the information collected. 4) To determine how different rating scales for depression and generalized anxiety correlate with suicidal ideation and behavior as identified with the C-SSRS. Aims of the study (2 (2) v To assess the prevalence of depression, anxiety and suicidal thoughts and the feasibility of using the proposed psychiatric rating scales in future epilepsy clinical trials. v To provide an estimate of the proportion of patients with epilepsy who may be ineligible for future trials. v To determine how these two instruments correlate with screening instruments of depression and anxiety disorders: BDI-II NDDI-E PHQ-9 PHQ-GAD-7 Ø Ø Ø Ø Methods v Cross-sectional study enrolling 200 outpatients with treatment resistant partial epilepsy, receiving 1-3 AEDS from 8 epilepsy centers. v One visit or a visit and a telephone call, lasting 1-2 hours, during which the following tests will be administered: Ø The MINI International Neuropsychiatric Interview, a structured interview developed to identify current Axis I psychiatric diagnoses. Ø Columbia Suicide Severity Rating Scale (C-SSRS). Ø Suicidality module of the MINI (MINI 5.5.0). Ø Beck depression Inventory (BDI-II). Ø Neurologic Depression Disorders Inventory –Epilepsy (NDDIE). Ø Patient Health Questionnaire- Depression (PHQ-9). Ø The Patient Health Questionnaire –Generalized Anxiety Disorder-7 (PHQ-GAD7). Ø Adverse Event Profile (AEP). Methods (2) v Inclusion criteria: • Partial epilepsy, confirmed with EEG studies • Aged 18 to 70 years-old • Proficient in English • Having a minimum of a 4th grade reading level • Having been on stable doses and type of AEDs for the previous two months. • At least 1 seizure/month for the past 6 months. v Exclusion criteria: • Non-epileptic seizures with or without comorbid epileptic seizures Conclusions v The screening of suicidal risk must include an instrument to identify: Ø Past suicidal attempts. Ø Current suicidal ideation. Ø Current depressive episodes. Ø Current anxiety disorder. v The ideal instrument to screen for suicidal risk in patients with epilepsy has yet to be identified.
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