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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

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
Selected Recent Studies of ADs and Suicidal Behavior
  • Ecological studies
  • Patient-level controlled observational studies:

-case-control design

-retrospective cohort design

ecological studies
Ecological Studies
  • IncreasingAD use and decreasing suicide rates
  • Correlation does not necessarily imply causality
  • Numerous factors may be coincidental, not causal
ecological studies1
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)
pt level controlled observational studies the jick et al study
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
jick s case control study
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

jick s case control study1
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.
jick s case control study2
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
jick s case control study3
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)

jick s case control study limitations
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
jick s case control study limitations1
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
pt level controlled observational studies the valuck et al poster
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)
pt level controlled observational studies the valuck poster
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
valuck s cohort study poster
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
valuck s cohort study poster1
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
valuck s cohort study poster2
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)
valuck s cohort study poster3
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
valuck s expanded cohort study
Valuck’s Expanded Cohort Study
  • Expanded Study--being reviewed for publication
  • ~24,000 eligible patients with new MDD diagnosis
valuck s expanded cohort study1
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%)
valuck s expanded cohort study2
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)

valuck s expanded cohort study3
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)

valuck s cohort studies limitations
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
valuck s cohort studies limitations1
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
conclusions
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
conclusions1
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