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Recent Observational Studies of Antidepressants (ADs) and Suicidal Behavior

Recent Observational Studies of Antidepressants (ADs) and Suicidal Behavior . Diane K. Wysowski, Ph.D. Office of Drug Safety FDA . Selected Recent Studies of ADs and Suicidal Behavior. Ecological studies Patient-level controlled observational studies: -case-control design

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Recent Observational Studies of Antidepressants (ADs) and Suicidal Behavior

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

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

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

  4. Ecological Studies • IncreasedRR 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Valuck’s Expanded Cohort Study • Expanded Study--being reviewed for publication • ~24,000 eligible patients with new MDD diagnosis

  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. 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. 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. 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. 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. 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. 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

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