Andrew C. Leon, Ph.D. Weill Cornell Medical College New York City, New York

1. Two Propensity Score-Based Strategies for a Longitudinal Observational Evaluation of Psychotropic Medications and Suicide Risk Andrew C. Leon, Ph.D. Weill Cornell Medical College New York City, New York

2. A Tribute to Andrew C. Leon (1951-2012) Scholar * Professor of Biostatistics in Psychiatry and Professor of Public Health at Weill Medical College of Cornell University * Numerous articles in Biostatistics & Mental Health on dynamic propensity models, study design, power & sample size Colleague * Associate Editor Statistics in Medicine * FDA Psychopharmacologic Drug Advisory Committee * Congressional Committee of Veterans Affairs hearing “Exploring the Relationship Between Medication and Veteran Suicide” * International Society for CNS Clinical Trials and Methodology (ISCTM) - The Andrew C. Leon Distinguished Career Award Great Friend * Always positive and FUN to be with * Jazz lover * Diehard Cleveland Indians fan

3. Disclosures (past 12 months) • Independent Data and Safety Monitoring Boards: • Merck, Pfizer and Sunovion. • Consultant/Advisor:  FDA, NIMH and MedAvante • Equity: MedAvante

4. Outline • 2 Case Studies: FDA Warnings of Suicidality with • Antidepressants • Antiepileptic Drugs • Limitations of RCT Results • Approaches to Observational Analyses • 2 Applications: Observational Studies of Treatment Emergent Suicidality Leon AC, Demirtas H, Li C, Hedeker D. Statistics in Medicine (in press)

5. FDA Psychopharmacologic Drugs Advisory Committee: Antidepressants and Suicidality FDA PDAC - December, 2006: Adult Data – 372 RCTs • N=99,839 (8 deaths: 5 Investigational, 2 PLA, 1 Comparator) • N=77,382 with MDD & other psych dx -- 295 RCTs • PDAC voted 6-2 in favor of warning, but with caveat: • Warn that untreated depression is a known risk • May, 2007: FDA Black Box extended to young adults

6. Excerpt from the Revised Labeling for Antidepressant Use in Children, Adolescents, and Adults (US FDA, 2007) Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder and other psychiatric disorders. Anyone considering the use of [Insert established name] or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. … Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. **Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior.

7. Limitations of FDA Results FDA results do not generalize to most patients treated with antidepressants: • Data from 4-6 week RCTs. Depression often chronic or recurrent. • Majority of Ss with major depression are excluded from RCTs: comorbidity, polypharmacy, recently or currently suicidal or psychotic

8. Objective To examine the risk of suicide attempts or suicide deaths associated with antidepressants in a study more representative of patients treated with antidepressants.

9. Application: NIMH Collaborative Depression Study • Recruited 955 Ss with affective disorders starting in 1978. • Five academic medical centers • Boston, Chicago, Iowa City, NYC & St. Louis • Semi-annual or annual assessments ≤27 years follow-up • Katz and Klerman, 1979

10. Hypothesis Based on the FDA findings … Hypothesis: Elevation in the risk of suicide attempts and suicide deaths when participants received an antidepressant compared with when they did not receive an antidepressant

11. Longitudinal Observational Study • Non-randomized treatment assignment • Multiple intervals of drug exposure per participant

12. Reduce Selection Bias • Propensity score, e(x): conditional probability of assignment to a particular treatment given observed covariates (Rosenbaum and Rubin, 1983) Propensity score: e(x)=pr(T=1|X=x) where X = covariates T=1 if receiving treatment T=0 if no treatment

13. Longitudinal Propensity Score e(xij) = pr(Tij =1 |X=xij) for subject i, observation j Incorporates within-subject variation in: • treatment • propensity for treatment Leon and Hedeker (2007), Stat Med

14. Safety Model: Time until Suicidality • Mixed-effects grouped time survival model (Hedeker et al, 2000) • Complementary log-log function (prop. hazards model) • Pijt=P(tij < t = 1-exp(-exp(t+x’ij + i)) • Where • Pijt = probability of failure up to and including time t • i denotes subject; j obs w/in subject • t = time • t= overall intercept • x = covariates - either b/t or w/in subject •  i= subject-specific random effect, assumed to follow a normal distribution

15. Unit of Analysis Antidepressant exposure interval, defined as a period of consecutive weeks duringwhich antidepressant exposure remained unchanged (AD+ or AD-). N=757 subjects with 6716 exposure intervals AD- : 3433 AD+: 3283

16. Propensity Model Gender, marital status, SES, Education, Site Depressive symptoms at intake Age at start of exposure interval Number affective episodes Psychopathology 8 wks prior to interval Psychopathology trajectory - prior 8 weeks (ie, worsening, stable, or improving) Suicide attempt from study intake to start of interval Supermix (Hedeker et al, 2008) for propensity and safety

17. Safety Analyses – Quintile Stratified

18. Pooled Results across Quintiles: Antidepressants Convey a Protective Effect 1) 370 suicide attempts; 17 suicide deaths 2) 321 suicide attempts; 9 suicide deaths Leon et al., 2011 J Clinical Psychiatry

19. FDA Warning: Antiepileptics (2008) All patients who are currently taking or starting on any antiepilepticdrugfor any indication should be monitored for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression * Not a boxed warning

20. Application: NIMH Collaborative Depression Study Antiepileptic exposure intervals Included AED approved for bipolar disorder Excluded intervals with other AED and antidepressants N=199 subjects with Bipolar I disorder with 1077 exposure intervals

21. Hypothesis Based on the FDA findings … Hypothesis: Elevation in the risk of suicide attempts and suicide deaths when participants received an antiepileptic compared with when they did not receive an antiepileptic

22. Unit of Analysis Antiepileptic exposure interval, defined as a period of consecutive weeks duringwhich antiepileptic exposure classification remained unchanged (AED+ or AED-).

23. Propensity Model Gender, marital status, SES, Site Age - start of exposure interval Antipsychotics prior to interval Suicide attempt from study intake to start of interval Severity of mania 8 wks prior to interval Severity of hypomania 8 wks prior to interval Psychopathology trajectory (worsening, stable, improving) % followup in episode prior to interval

24. Safety Analyses – Quintile Stratified Leon et al., 2012 Am J Psychiatry

25. Propensity Score Matching:Longitudinal AED Exposed and Unexposed Intervals *Matched set includes ≥1 exposed and ≥1 unexposed Full matching (as opposed to pairwise matching) Optimal matching (as opposed to greedy matching) Caliper=.10 (propensity sd units) Optmatch package in R (Hansen and Fredrickson, 2011) • Austin P. Analysis of Observational Health Care Data Using SAS. Faries et al (Ed)

26. Safety Model: Time until Suicidality • Mixed-effects grouped time survival model. (Hedeker et al., 2000) • Complementary log-log function • Pijkt=P(tij < t = 1-exp(-exp(t+x’ij + i + φk ))) • Where • k denotes matched sets • t = intercept • x = covariates •  = random subject-specific intercept • φ k = random matched set intercept • Proc GLIMMIX with person-period data

27. Results: No evidence of elevated Risk for AEDs 1) 52 suicide attempts; 1 suicide death 2) 9 suicide attempts; 2 suicide deaths

28. Summary • Longitudinal observational safety analyses must adjust for baseline treatment group differences • Propensity quintile stratified safety analyses feasible with very large data sets • Propensity matched safety analyses feasible with smaller data sets • Results of each complement those of RCTs

29. Acknowledgements • Hakan Demirtas, PhD • Donald Hedeker, PhD • Charles Li, MA

30. References • Rosenbaum P, Rubin DB. The central role of the propensity score in observational studies for causal effects. Biometrika 1983; 70:41-55. • Leon AC, Demirtas H, Li C, Hedeker D. Two Propensity Score-Based Strategies ... Statistics in Medicine (in press) • Leon AC, Hedeker D, Teres JJ. Bias Reduction in Effectiveness Analyses … Statistics in Medicine 2007; 26:110-123. • Leon AC, Solomon DA, Li C, Fiedorowicz JG, Coryell WH, Endicott J, Keller MB. Antidepressants and Risks of Suicide and Suicide… Journal of Clinical Psychiatry 2011; 72:580-586. • Leon AC, Solomon DA, Li C, Fiedorowicz JG, Coryell WH, Endicott J, Keller MB. Antiepileptic Drugs for Bipolar Disorder and the Risk …. American J Psychiatry 2012