Evidence-Based Reviews

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

Current Psychiatry. 2007 November;6(11):27-43

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

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References

1. Kuehn BM. FDA panel seeks to balance risks in warnings for antidepressants. J Am Med Assoc 2007;297:573-4.

2. Grunebaum MF, Ellis SP, Li S, et al. Antidepressants and suicide risk in the United States, 1985-1999. J Clin Psychiatry 2004;65(11):1456-62.

3. Teicher MH, Glod C, Cole JO. Emergence of intense suicidal preoccupation during fluoxetine treatment. Am J Psychiatry 1990;147:207-10.

4. King RA, Riddle MA, Chappell PB, et al. Emergence of self-destructive phenomena in children and adolescents during fluoxetine treatment. J Am Acad Child Adolesc Psychiatry 1991;30(2):179-86.

5. Rothschild AJ, Locke CA. Reexposure to fluoxetine after serious suicide attempts by three patients: the role of akathisia. J Clin Psychiatry 1991;52:491-3.

6. Beasley CM, Dornseif BE, Bosomworth JC, et al. Fluoxetine and suicide: a meta-analysis of controlled trials of treatment for depression. BMJ 1991;303:685-92.

7. Hammad TA. Review and evaluation of clinical data. Food and Drug Administration. August 16, 2004. Available at: http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-10-TAB08-Hammads-Review.pdf. Accessed September 19, 2007.

8. Nemeroff CB, Kalali A, Keller MB, et al. Impact of publicity concerning pediatric suicidality data on physician practice patterns in the United States. Arch Gen Psychiatry 2007;64(4):466-72.

9. Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry 2007;164:1356-63.

10. Libby AM, Brent DA, Morrato EH, et al. Decline in treatment of pediatric depression after FDA advisory on risk of suicidality with SSRIs. Am J Psychiatry 2007;164(6):884-91.

11. US. Department of Health and Human Services. Centers for Disease Control and Prevention. Fatal injury reports. Web-based injury statistics query and reporting system. Available at: http://www.cdc.gov/NCIPC/wisqars. Accessed July 16, 2007.

12. Bridge JA, Iyengar S, Salary CB, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA 2007;297:1683-96.

13. Levenson M, Holland C. Statistical evaluation of suicidality in adults treated with antidepressants. In: Laughren TP. Memorandum: overview for December 13 meeting of PsychopharmacologicDrugs Advisory Committee (PDAC). Center for Drug Evaluation and Research, US Food and Drug Administration. November 16, 2006. Available at: http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf. Accessed October 11, 2007.

14. Bostwick JM, Pankratz VS. Affective disorders and suicide risk: a reexamination. Am J Psychiatry 2000;157(12):1925-32.

15. Lafuente-Lafuente C, Mouly S, Longas-Tejero MA, et al. Antiarrhythmic drugs for maintaining sinus rhythm after cardioversion of atrial fibrillation: a systematic review of randomized controlled trials. Arch Intern Med 2006;166(7):719-28.

16. Khan A, Khan S, Kolts R, Brown WA. Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. Am J Psychiatry 2003;160:790-2.

17. Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. J Am Med Assoc 2004;292(3):338-43.

18. Martinez C, Rietbrock S, Wise L, et al. Antidepressant treatment and the risk of fatal and non-fatal self harm in first episode depression: nested case-control study. BMJ 2005;330(7488):389.-

19. Gunnell D, Saperia J, Ashby D. Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomised controlled trials submitted to the MHRA’s safety review. BMJ 2005;330(7488):385-9.

20. Fergusson D, Doucette S, Glass KC, et al. Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials. BMJ 2005;330(7488):396.-

21. Juurlink DN, Mamdani MM, Kopp A, Redelmeier DA. The risk of suicide with selective serotonin reuptake inhibitors in the elderly. Am J Psychiatry 2006;163(5):813-21.

22. Isacsson G, Holmgren P, Ahlner J. Selective serotonin reuptake inhibitor antidepressants and the risk of suicide: a controlled forensic database study of 14,857 suicides. Acta Psychiatr Scand. 2005;111(4):286-90.

23. Simon GE, Savarino J, Operskalski B, Wang PS. Suicide risk during antidepressant treatment. Am J Psychiatry 2006;163(1):41-7.

24. Gibbons RD, Brown CH, Hur K, et al. Relationship between antidepressants and suicide attempts: an analysis of the Veterans Health Administration data sets. Am J Psychiatry 2007;164(7):1044-9.

25. Simon GE, Savarino J. Suicide attempts among patients starting depression treatment with medications or psychotherapy. Am J Psychiatry 2007;164(7):1029-34.

26. Mann JJ, Apter A, Bertolote J, et al. Suicide prevention strategies: a systematic review. JAMA 2005;294(16):2064-74.

27. Rich CL, Isacsson G. Suicide and antidepressants in South Alabama: evidence for improved treatment of depression. J Affect Disord 1997;45:135-42.

28. Isacsson G, Bergman U, Rich CL. Antidepressants, depression and suicide: an analysis of the San Diego study. J Affect Disord 1994;32:277-86.

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30. Gibbons RD, Hur K, Bhaumik DK, Mann JJ. The relationship between antidepressant medication use and rate of suicide. Arch Gen Psychiatry 2005;62(2):165-72.

31. Hall WD, Mant A, Mitchell PB, et al. Association between antidepressant prescribing and suicide in Australia, 1991-2000: trend analysis. BMJ 2003;326(7397):1008-11.

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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.

Clinical Point

In 2003 to 2004, after the ‘black-box’ warning, pediatric antidepressant prescriptions declined and suicide rates increased 11%

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:

Clinical Point

FDA’s meta-analysis of suicide risk in adults found 8 suicides in 372 antidepressant trials totalling nearly 100,000 persons

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.