1. 1 Recent Observational Studies of Antidepressants (ADs) and Suicidal Behavior Diane K. Wysowski, Ph.D. Office of Drug Safety FDA

2. 2 Selected Recent Studies of ADs and Suicidal Behavior Ecological studies Patient-level controlled observational studies: -case-control design -retrospective cohort design

3. 3 Ecological Studies Increasing AD use and decreasing suicide rates Correlation does not necessarily imply causality Numerous factors may be coincidental, not causal

4. 4 Ecological Studies Increased RR of suicide with ADs in children/adolescents may coexist with decreased suicide rate To better examine causality, need patient-level controlled studies (observational or trials)

5. 5 Pt.-Level Controlled Observational Studies--the Jick et al Study Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behavior. JAMA 2004;292:338-343. Matched case-control design based on patient Rxs/diagnoses in U.K.’s GPRD for 1993-1999

6. 6 Jick’s Case-Control Study Subjects: 10 through 69 years old Exposures: amitriptyline, fluoxetine, paroxetine, dothiepin (reference group) Cases: -nonfatal suicidal behavior (ideation or attempts) n = 555 -suicides n = 17 Controls: n = 2,062 -without suicidal behavior

7. 7 Jick’s Case-Control Study Range of RRs for nonfatal suicide behavior = 0.83-1.29 for ADs studied (compared to dothiepin) None statistically significant Paroxetine--RR=1.29 (95% CI: 0.97-1.70)--borderline stat. signif.

8. 8 Jick’s Case-Control Study Similar results for 10-19 year olds No statistically significant assn. between each AD and completed suicide No statistically significant assn. between stopping AD and nonfatal suicidal behavior

9. 9 Jick’s Case-Control Study RR of nonfatal suicidal behavior/suicide highest for pts. first prescribed AD within 1 to 9 days (versus ≥90 days) before the suicidal behavior (index date): RR nonfatal suicidal behavior = 4.07 (95% CI: 2.89-5.74) RR suicide = 38.0 (95% CI: 6.2-231)

10. 10 Jick’s Case-Control Study- Limitations Results as good as GPRD data-- ?missing data,?ascertainment, ?misclassification,?biases by AD No interviews of cases/controls-- ? AD compliance No unexposed group

11. 11 Jick’s Case-Control Study- Limitations Suicidal ideation--more subjective diagnosis than attempts or suicide Study of mostly adults Exclusions--any hx of 11 neuropsychiatric diagnoses-- ?representativeness of patients

12. 12 Pt.-Level Controlled Observational Studies–-the Valuck et al Poster Valuck RJ, Libby AM, Sills MR, et al. Antidepressant use and risk of suicide attempt in adolescents with major depressive disorder. ISPOR meeting, Poster, May, 2004 Retrospective cohort study--paid claims data, 1995 thru 3/03 ( PharmMetrics Integrated Outcomes Database of 70 managed health plans)

13. 13 Pt.-Level Controlled Observational Studies–-the Valuck Poster Identified ~16,000 adolescents aged 12-18 yrs. with first major depressive disorder (MDD) diagnosis Classified by no ADs, SSRIs, TCAs, other ADs

14. 14 Valuck’s Cohort Study (Poster) Cox proportional hazards model to evaluate multivariate relationship between AD use and time to suicide attempt 78% had no AD filled in 6 months after MDD diagnosis 15% had SSRIs filled within 30 days of MDD diagnosis

15. 15 Valuck’s Cohort Study (Poster) 209 (1.3%) made at least one suicide attempt after first MDD diagnosis AD treatment with any class of drugs did not increase risk of suicide attempt

16. 16 Valuck’s Cohort Study (Poster) AD <6 mos. (versus ≥ 6 mos.) associated with increased risk of suicide attempt: 1-55 days: Hazards Ratio = 2.94 (95% CI: 1.35-6.40) 56-179 days: Hazards Ratio = 3.25 (95% CI: 1.81-5.86)

17. 17 Valuck’s--Cohort Study (Poster) Independently at greater risk of suicide attempt: females psychotherapy within 90 days of MDD diagnosis substance abuse, schizophrenia, or another mental health disorder more chronic diseases and residents of Midwest and West

18. 18 Valuck’s Expanded Cohort Study Expanded Study--being reviewed for publication ~24,000 eligible patients with new MDD diagnosis

19. 19 Valuck’s Expanded Cohort Study Added propensity matching adjustment (to control for predictors of treatment /achieve more balance among exposure groups) No. suicide attempters = 346 (~1.4%)

20. 20 Valuck’s Expanded Cohort Study Hazard Ratios (HR) for Suicide Attempts: -SSRIs: HR = 1.58 (95% CI: 0.89- 2.82) -Tricyclics: HR = not estimable -Other ADs: HR = 1.03 (95% CI: 0.43-2.44)

21. 21 Valuck’s Expanded Cohort Study Multiple ADs (concurrent/sequential): HR =1.43 (95% CI: 0.70-2.89) Risk declined with ≥6 mos. (versus <8 wks.) AD use HR =0.34 (95% CI: 0.21-0.55)

22. 22 Valuck’s Cohort Studies-Limitations Results as good as claims data-- ?missing data, ?ascertainment, ?misclassification, ?biases by AD group No interviews of patients--?AD compliance

23. 23 Valuck’s Cohort Studies-Limitations No data on outcome of attempts (deaths) or on outright suicides No data on individual ADs Differences in results between poster and expanded study--prob. due to size

24. 24 Conclusions Studies do not completely rule out possible increased risk of suicidal behavior with AD use--although most risks not statistically significant Increased risk of suicidal events statistically significantly closer to diagnosis and onset of AD Rx

25. 25 Conclusions No data on characteristics of poor responders to ADs (those who don’t improve or worsen) All studies have limitations More definitive studies (e.g., randomized controlled trials— larger, longer) are needed