Evidence-Based Reviews

Safe use of SSRIs in young adults: How strong is evidence for new suicide warning?

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References

An independent meta-analysis by Bridge et al12 examined the pediatric trial data used in the FDA meta-analysis plus 7 additional studies. Its findings differ in 2 important ways from those of the FDA review:

  • Antidepressants—including others besides fluoxetine—showed efficacy in treating anxiety disorders and depression in children and adolescents.
  • The frequency of suicide-related adverse events (no trial patients committed suicide) was approximately 3% on active medication—25% lower than the FDA estimated rate—and 2% on placebo, similar to the FDA estimate.
The number needed to treat (NNT)— number of patients who must be treated to get a therapeutic response that would not have happened with placebo—ranged from 3 to 10. The number needed to harm (NNH)—number of patients who must be treated for 1 suicidal ideation/nonfatal attempt to occur that would not have happened with placebo—ranged from 112 to 200. The authors interpreted this as “indicating a favorable overall risk-to-benefit profile for antidepressants in the treatment of pediatric [major depressive disorder], [obsessive-compulsive disorder] (OCD), and non-OCD anxiety disorders.”12 These findings appear to support the efficacy of antidepressants in pediatric patients and a favorable risk-benefit ratio.

Antidepressants and suicide risk, 1985 to 2007

19851990199119992003200420062007
Case reports suggest link between suicide and SSRI useFDA analysis finds no association between SSRIs and increased suicide risk UK agency warns of suicide-related events in children treated with paroxetine and venlafaxineFDA conducts meta-analysis, requires black-box warnings of risk of suicidality in youth taking antidepressantsFDA meta-analysis finds age-dependent effect of antidepressants on suicidality risk in adultsFDA expands warning of increased suicidality risk with antidepressants to adults age
Antidepressant prescriptions quadruple; age-adjusted suicide rate drops 22.5% for women and 12.8% for menPediatric depression diagnoses and antidepressant prescriptions decline; suicides increase 11%Bridge et al meta-analysis finds 25% lower rate of suicide-related events in youth than the FDA found

What about adults?

Overall effect. A subsequent FDA meta-analysis of antidepressant clinical trial data in adults13 found 8 suicides in 372 trials totaling nearly 100,000 persons. All occurred in the 295 trials with psychiatric indications. Among these psychiatric trials, 59% had a suicidal behavior/ideation event in either the test-drug or placebo arm, and 41% had none. Eleven antidepressants were included in the meta-analysis:

  • 6 SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline)
  • 2 SNRIs (duloxetine and venlafaxine)
  • 3 others (bupropion, mirtazapine, and nefazodone).
Overall, antidepressants showed a protective (antisuicidal) effect in adults as compared with placebo (odds ratio 0.85 [95% CI: 0.71 to 1.02, P=0.08]), with no difference in effect between SSRIs and non-SSRIs.

Age-specific findings. When the FDA analysis was stratified by age, however, antidepressants’ benefit appeared greater for patients age ≥25 than for those age 18 to 24. The data suggested:

  • elevated suicidality risk among adults age
  • neutral or possibly protective effect for adults age 25 to 64
  • protective effect in adults age ≥65 ( Table 1 ).13
Table 1

FDA meta-analysis: Suicide rates by age in antidepressant trials

Age group (yr)Suicide rate (%)(test drug/placebo)Suicide attempt rate (%)(test drug/placebo)
18 to 240.03/0.000.55/0.27
25 to 300.00/0.030.23/0.11
31 to 640.01/0.000.13/0.15
≥650.00/0.040.03/0.25
Source: Reference 13
For 18-to 24-year-olds, the suicide rate was 0.03% (~1/4,000) in these mostly 8- to 12-week trials, and the suicide attempt rate was 0.55% (~1/200). For comparison, the lifetime prevalence of suicide was 2.2% to 8.6%—depending partly on illness severity—in a meta-analysis of patients with mood disorders.14

The odds ratio for suicidal behavior (preparatory acts, attempt, or suicide) for subacts, attempt, or suicide) for subjects age 18 to 24 on test drug vs placebo was 2.31 (95% CI: 1.02, 5.64) [event rate/sample: 23/3810 vs 8/2604]. NNH was 333, which means 333 adults in this age group would need to be treated with an antidepressant for 1 to experience a suicidal behavior event that would not have happened with placebo.

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