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BMJ. 2007 May 12; 334(7601): 974.
PMCID: PMC1867891

Depression is the real killer, not antidepressants, say commentators

On 2 May the US Food and Drug Administration ordered that all antidepressants must carry an expanded black box warning about an increased risk of suicidal symptoms in young adults aged between 18 and 24 years. But the requirement poses a problem for doctors, says an article published online in the New England Journal of Medicine on 7 May.

“Whether the new warning will do more good than harm is not clear,” write Richard Friedman and Andrew Leon, both of Weill Cornell Medical College, New York (http://content.nejm.org, doi: 10.1056/NEJMp078015). “The real killer in this story is untreated depression, and the possible risk from antidepressant treatment is dwarfed by that from the disease. But clinicians still need to tell their depressed patients that some people who take antidepressants have an increase in suicidal symptoms, especially early in treatment, and they need to follow their patients very closely during the first four to six weeks of treatment.”

The new warning states that there is no evidence of the drugs increasing the risk of suicidal symptoms among adults older than 24 years and that the risk is actually lower in adults aged 65 or older. It further states that “depression and other serious psychiatric disorders are themselves associated with increases in the risk of suicide,” making it the first black box warning to note that a disease itself carries risk and implying that not using the drug being warned about also carries a risk.

The warning was developed in the wake of an often contentious meeting of the FDA's psychopharmacological drugs advisory committee in December 2006 about the controversial link between antidepressant use and risk of suicide, says the article. Clinicians have known for years of this risk, which can occur during the first weeks of treatment when patients become energised and agitated and thus more likely to act on pre-existing suicidal impulses.

“But because suicidal thinking, feeling, and behavior are core symptoms of depression, there is no way to know whether suicidal symptoms that develop during treatment are due to the underlying illness or the medication,” says the article.

The FDA used the best available data in trying to disentangle the effects of treatment from those of the illness itself. It compared the prevalence of suicidal symptoms among patients taking antidepressants with that among people taking a placebo in a comprehensive meta-analysis of an enormous set of data from 99 839 participants in 372 randomised clinical trials of antidepressants conducted by 12 drug companies in the past two decades.

The primary analyses were restricted to participants in those trials that specifically concerned psychiatric disorders, write the authors. Among these were eight deaths from suicide: five among the 39 729 participants assigned to the drug under investigation, two among the 27 164 taking a placebo, and one among the 10 489 taking an active comparator.

In addition, 501 participants had suicidal feelings or thoughts or made unsuccessful attempts at suicide: 243 of those receiving the drug under investigation, 194 in the placebo group, and 64 in an active comparator group. When the analysis combined all adult age groups, no increased risk of suicidal behaviour or ideation was found. However, in age stratified analyses, the risk in patients aged 18-24 years was higher, albeit not significantly (odds ratio 1.6 (95% confidence interval 0.9 to 2.7)).

The committee gave two reasons for recommending expansion of the black box warning to include the risk to the 18-24 years age group. Firstly, the threshold for threats to safety is generally lower than that for efficiency, and the data did not provide strong evidence for an absence of risk.

But secondly—and more importantly—the trend across the age groups towards an association between antidepressant use and suicidality was convincing, particularly when taken together with earlier analyses of data on adolescents from randomised controlled trials. Furthermore, the data set was larger than any previously assembled to study suicidality or interventions for a psychiatric disorder, and the results of independent analyses by two groups of FDA reviewers, which used different statistical methods, were virtually identical.

The new black box warning is clearly an attempt to balance the small risk posed by antidepressants against their well documented benefits, the authors write.


Articles from The BMJ are provided here courtesy of BMJ Group