Published 11 August 2009, doi:10.1136/bmj.b3066
Cite this as: BMJ 2009;339:b3066

Editorials

Risk of suicidal behaviour in adults taking antidepressants

Increased risk is probably restricted to younger people and varies greatly between individual medicines

Antidepressant drugs currently carry warnings of the possibility of increased suicidal ideation and behaviour during treatment, especially in younger patients. In the linked meta-analysis (doi:10.1136/bmj.b2880), Stone and colleagues report on the possible link between the risk of suicide and antidepressants using data on individual patients from placebo controlled trials.¹ This analysis of 372 placebo controlled antidepressant trials and nearly 100 000 patients found that the association between antidepressant drugs and the incidence of reported suicidal behaviour is strongly related to age. The risk was raised in people under 25, not affected in those aged 25-64, and reduced in those aged 65 and older. The analysis also found differences in risk between drugs.

This analysis is not new—it was published fully on the Food and Drug Administration (FDA) website more than two years ago.² It was widely covered at the time in the international medical press and led to warnings being included on datasheets.^{3 4 5 6} Because the analysis has not been updated since the initial publication and the present report selectively reports the full analysis, it raises the question of why it is being published in the BMJ now, more than two years later. Its objective is to make a summary of these important results more widely available in a way similar to the publication in the BMJ of summaries of Cochrane reviews.

Other meta-analyses had already been performed, but this analysis was a methodological advance because it used individual patient data from the trials, and suicidal events were reclassified according to a common system to increase the reliability of the results.^{7 8}

Nonetheless, important limitations remain because of the characteristics of the primary trials. A standard exclusion in placebo controlled trials of antidepressant drugs is that severely ill patients, especially those who are actively suicidal, are not enrolled. This probably leads to very low numbers of completed suicides in these trials. If such trials aim to provide evidence of the clinical effects of the investigational drug, then this exclusion is as clinically illogical as excluding patients with a high risk of mortality in trials in oncology or cardiology. It makes it impossible to estimate the potential benefits of a reduction in baseline suicidality.⁹ Furthermore, the low event rate of completed suicide means that retrospective analyses have to broaden the definition of suicide beyond completed suicides to gain sufficient statistical power. Regardless of how much effort is put into developing standardised reclassifications, the fundamental uncertainty about the validity and meaning of a composite outcome that was not prespecified in the primary trials remains.

The review procedures showed some lack of transparency, as sometimes happens in analyses conducted by regulatory authorities.¹⁰ It is unclear why optimal methods of meta-analysis of systematic review—for example, prior pre-review and publication of the protocol, unselective reporting of the outcomes—were not used. One way of ensuring adherence to currently optimal guidelines for systematic reviews would have been to conduct the analysis under the auspices of the Cochrane Collaboration. Although meta-analyses of individual patient data could usefully look at important clinical outcomes other than suicidality, the Cochrane database still contains few meta-analyses of individual patient data. Could it be that companies are willing to release individual patient data only when required to by regulatory agencies who grant the marketing authorisations of drugs? If that is the reality, then the true collaboration between regulators and other agencies which seems to be the FDA’s new aim could be a powerful approach to synthesising clinical knowledge.¹¹ In particular, the age related decrease in risk for suicide, which seems to be inversely paralleled by increasing efficacy with age, could be investigated further with individual patient data from these trials.⁵

Finally, we should consider these results alongside other recent evidence on antidepressants in major depression. Although this report focuses on age related differences in the risk of suicidal behaviour, individual drugs seem to show some important differences. The odds of suicidal behaviour on sertraline, for example, is around half that on placebo. In comparison, citalopram and escitalopram seem to increase the risk of suicidal events. Unfortunately, the analysis did not include indirect comparisons (which would have been possible by virtue of the common placebo comparator) when comparing drugs, so that any conclusions about the differential effects of treatments must be made with caution. Nonetheless, it is becoming apparent that antidepressants vary in both their efficacy and adverse effects. A recent multiple treatments meta-analysis that compared the efficacy and acceptability of antidepressants showed meaningful differences between drugs.¹² That analysis found sertraline and escitalopram to have the best balance of short term efficacy and tolerability. Taking the results of the analyses together reinforces the view that sertraline has a highly favourable profile in terms of efficacy, acceptability, and safety. Although different mechanisms might lead to clinical relief of symptoms and increased suicidality (perhaps via increased agitation), a more likely mechanism for the effects of sertraline is that it is simply better tolerated and more likely to be effective, hence reducing both depressive symptoms and suicidality.

Cite this as: BMJ 2009;339:b3066

¹ University of Oxford, Warneford Hospital, Oxford OX3 7JX, ² Department of Medicine and Public Health, Section of Psychiatry and Clinical Psychology, University of Verona, Policlinico GB Rossi, 37134 Verona, Italy

Research, doi:10.1136/bmj.b2880

---

Competing interests: None declared.

Provenance and peer review: Commissioned; not externally peer reviewed.

References

1. Stone MB, Laughren T, Jones ML, Levenson M, Holland PC, Hughes A, et al. Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. BMJ 2009;339:b2880.[Abstract/Free Full Text]
2. Laughren TP. Briefing document for December 13 meeting of Psychopharmacologic Drugs Advisory Committee. 2006. www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-fda.pdf.
3. Friedman RA, Leon AC. Expanding the black box—depression, antidepressants, and the risk of suicide. N Engl J Med 2007;356:2343-6.[Free Full Text]
4. Kuehn BM. FDA panel seeks to balance risks in warnings for antidepressants. JAMA 2007;297:573-4.[Free Full Text]
5. Barbui C, Cipriani A, Geddes JR. Antidepressants and suicide symptoms: compelling new insights from the FDA’s analysis of individual patient level data. Evid Based Ment Health 2008;11:34-5.[Free Full Text]
6. Leon AC. The revised warning for antidepressants and suicidality: unveiling the black box of statistical analyses. Am J Psychiatry 2007;164:1786-9.[Free Full Text]
7. 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;330:385.[Abstract/Free Full Text]
8. Fergusson D, Doucette S, Glass KC, Shapiro S, Healy D, Hebert P, et al. Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials. BMJ 2005;330:396.[Abstract/Free Full Text]
9. Cipriani A, Barbui C, Geddes JR. Suicide, depression, and antidepressants. BMJ 2005;330:373-4.[Free Full Text]
10. Vitry A, Lexchin J, Sasich L, Dupin-Spriet T, Reed T, Bertele V, et al. Provision of information on regulatory authorities’ websites. Intern Med J 2008;38:559-67.[CrossRef][Web of Science][Medline]
11. Hamburg MA, Sharfstein JM. The FDA as a public health agency. N Engl J Med 2009;360:2493-5.[Free Full Text]
12. Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 2009;373:746-58.[CrossRef][Web of Science][Medline]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    StumbleUpon    Technorati    What's this?

Relevant Articles

Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration

Marc Stone, Thomas Laughren, M Lisa Jones, Mark Levenson, P Chris Holland, Alice Hughes, Tarek A Hammad, Robert Temple, and George Rochester
BMJ 2009 339: b2880. [Abstract] [Full Text] [PDF]

Suicide, depression, and antidepressants

Andrea Cipriani, Corrado Barbui, and John R Geddes
BMJ 2005 330: 373-374. [Extract] [Full Text] [PDF]

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

David Gunnell, Julia Saperia, and Deborah Ashby
BMJ 2005 330: 385. [Abstract] [Full Text] [PDF]

Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials

Dean Fergusson, Steve Doucette, Kathleen Cranley Glass, Stan Shapiro, David Healy, Paul Hebert, and Brian Hutton
BMJ 2005 330: 396. [Abstract] [Full Text] [PDF]

This article has been cited by other articles:

• Barbui, C., Cipriani, A., Furukawa, T. A, Salanti, G., Higgins, J. P T, Churchill, R., Watanabe, N., Nakagawa, A., Omori, I. M, Geddes, J. R (2009). Making the best use of available evidence: the case of new generation antidepressants: A response to: Are all antidepressants equal?. Evid. Based Ment. Health 12: 101-104 [Full text]  

Rapid Responses:

Read all Rapid Responses

Risk of Suicidality with SSRIs - Where do we go from here?

Malcolm VandenBurg
bmj.com, 22 Aug 2009 [Full text]

Online poll

Find out more on doc2doc >>