Evidence-Based Reviews

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

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Pediatric suicide rates increased in 2003-04 after the black-box warning, which has now been extended to patients age 18 to 24.


 

References

CASE: Life is 'not worth it'

Mr. B, age 20, has taken a semester leave from college because of gradually worsening depressed mood. Over the past 2 months he has lost interest in jogging and playing piano—which he usually enjoys. He reports reduced libido, middle insomnia, loss of appetite, feeling as if his head is “full of cotton,” trouble concentrating, and waking in the morning with a sense of dread. His anxiety dissipates during the day, but he continues to feel sad and sometimes weepy, which is unusual for him.

Mr. B reports feeling hopeless at times and has had vague thoughts about life being “not worth it if I continue to feel like this” but denies specific suicide plans. Your initial impression is that Mr. B is in the midst of a major depressive episode and that a selective serotonin reuptake inhibitor (SSRI) is indicated. As you finish taking his history, you run through your mind the pros and cons of the recommendation you will make to him.

Do SSRIs raise or lower the risk for suicidal behavior in young adults such as Mr. B? The answer is complicated and goes beyond an “either/or” question, as the FDA acknowledged in May 2007 when it:

  • extended the black-box warning of increased suicidality risk with antidepressants to cover adults age 18 to 24 as well as children and adolescents
  • included language in the warning about the benefits of treating depression and the suicide risk associated with untreated depression, given concerns about declining antidepressant prescriptions and rising suicides among youth.1
  • To help you make informed decisions when treating depression in adults, this article reviews the studies leading up to and following the FDA’s meta-analysis of antidepressant trial data in patients age 18 and older. Our goal is to provide a framework for clinical treatment of adults age 18 to 24 and those age ≥25.

Box

FDA’s pediatric suicidality analysis: What the data showed

The FDA meta-analysis designed to investigate a reported association between antidepressants and suicidality in children and adolescents found contradictory results:

  • Pooled adverse event data from 24 pediatric antidepressant trials totaling >4,400 patients showed a higher risk of suicidal ideation or behavior (no suicides occurred) with antidepressants (4%) vs placebo (2%).
  • Systematically collected suicide-related item scores from 17 of the trials showed no evidence that antidepressants worsen suicidality or cause it to emerge.

One interpretation of these findings is that antidepressants’ effect on suicidality is small and therefore subject to measurement error.

Another is ascertainment bias; any side effect associated with active medication encourages discussion with the clinician and may distort the frequency of reported adverse events.

The FDA meta-analysis also found:

  • Relative risk for suicidality ranged 10-fold among agents, from 0.9 with fluoxetine to 8.8 with venlafaxine.
  • Most suicide-related events occurred in subjects having the highest baseline levels of suicidality.
  • Hostility and agitation emerged with SSRI use, particularly during the first month of treatment.
  • Patient age, sex, or history of suicide attempt/ideation did not affect the results.

Source: Reference 7

First hints of suicidality

SSRIs revolutionized depression treatment. From 1985 to 1999, annual U.S. antidepressant prescriptions quadrupled, with SSRIs accounting for 70% of the increase (see “Antidepressants and suicide risk, 1985 to 2007”). At the same time, the age-adjusted suicide rate:

  • dropped 22.5% for women (who account for twice as many antidepressant prescriptions as men)
  • dropped 12.8% for men (without change in the rank order of suicide methods).2
For many patients, increased antidepressant use improved treatment of major depressive and other antidepressant-responsive disorders. In 1990, however, case reports suggested SSRIs might cause suicidal thoughts or behavior.3 Hypothesized mechanisms included increased aggression4 and akathisia.5 An FDA review found no proof, and a meta-analysis of data from 17 double-blind, randomized, controlled trials found no association between fluoxetine and suicidal thoughts or behavior.6

The debate rekindled in June 2003 when the British Committee on Safety of Medicines warned against using paroxetine or venlafaxine in children. After conducting its own meta-analysis, the FDA in 2004 ordered a black-box warning about suicidality and the use of antidepressants in children and adolescents ( Box ).7

After the pediatric ‘black box.’ Antidepressant prescriptions for children and adolescents declined in the years 2003 to 2004, as did diagnosis of pediatric depression.8-10 Antidepressant prescribing also showed signs of shifting from general practitioners to psychiatrists.8 At the same time, the suicide rate among youth age 11 In patients age >60, SSRI prescriptions continued to rise and suicide rates fell,9 a pattern of change consistent with antidepressants protecting against suicide.

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