Antidepressant Use, Suicide Risk in Adults Strongly Linked to Younger Age

Caroline Cassels

August 13, 2009

August 13, 2009 — An expanded version of an analysis first published by the US Food and Drug Administration (FDA) on its Web site in 2007 shows that there is an increased risk for suicidal behavior associated with antidepressant use in individuals younger than 25 years but that this risk largely diminishes in middle age, culminating in a protective effect in old age.

Published online August 12 in the British Medical Journal, the analysis by Marc Stone, MD, and colleagues from the FDA found increased odds of suicidal behavior or ideation of 62% and more than a 2-fold increased risk for suicidal behavior alone in individuals younger than 25 years. In adults aged 25 to 64 years, there was little effect, but in individuals aged 65 years and older, antidepressant use was associated with a 63% decreased risk for suicidal behavior or ideation.

When age was modeled as a continuous variable, the odds ratio for suicidal behavior or ideation declined at a rate of 2.6% per year of age, and the odds ratio for suicidal behavior declined at a rate of 4.6% per year of age, the authors report.

"We saw an increase in [suicidality] in the [patients younger than 25 years of age], but we did not see this effect in middle-aged people, and in fact we observed a net reduction in older patients," Dr. Stone told Medscape Psychiatry.

Anecdotal Evidence

According to Dr. Stone, there is a long-standing hypothesis based largely on anecdotal evidence that depressed patients can develop suicidal behaviors during the recovery process and that this applies regardless of whether patients receive treatment with antidepressants or psychotherapy or recover spontaneously.

The introduction and subsequent widespread use of selective serotonin reuptake inhibitors as an effective treatment for depression resulted in such anecdotal reports becoming more prominent.

Several studies looking at this issue in adults found no link between antidepressant medications and suicidal thoughts or behaviors, including an independent FDA analysis of completed suicide from placebo-controlled, short-term trials of antidepressants in adults. However, the authors note that the strength of this conclusion was tempered by the low numbers of completed suicides in the trials.

In 2003, concerns that antidepressants may contribute to increased suicidality among children and adolescents led to an FDA analysis of the data from randomized placebo-controlled trials. This analysis revealed a relative risk of 1.95 for suicidal behavior or ideation for those treated with antidepressants vs placebo and led to the addition of a boxed warning to antidepressant labeling in 2005.

Worth a Second Look

On the basis of these findings in young patients, the FDA decided to take a second look at the adult literature for similar effects. Eight manufacturers of antidepressant medications provided data on suicidal thinking and behavior from published and unpublished randomized trials on antidepressants in adults.

In all, the investigators reviewed data from 372 placebo-controlled trials involving 99, 231 adults. The study's main outcome measures included suicidal behavior — defined as completed suicide, attempted suicide, or preparatory acts — and suicidal ideation.

The median age among study participants was 42 years; 63.1% were women. Indications for treatment included major depression (45.6%), other depression (4.6%), other psychiatric disorders (27.6%), and nonpsychiatric disorders (22.2%).

The study showed that there were 8 completed suicides, 134 suicide attempts, 10 patients who made preparations without attempting suicide, and 378 patients who had suicidal thoughts but did not act on them.

"Risk of suicidality associated with use of antidepressants is strongly age dependent. Compared with placebo the increased risk for suicidality and suicidal behavior among adults under 25 approaches that seen in children and adolescents.

"The net effect seems to be neutral on suicidal behavior but possibly protective for suicidal ideation in adults aged 25 to 64 and to reduce the risk of both suicidality and suicidal behavior in those aged ≥ 65," the authors conclude.

Uncertainty Remains

In an accompanying editorial, John Richard Geddes, MD, a professor of epidemiological psychiatry, University of Oxford, United Kingdom, and colleagues at the University of Verona, Italy, point out that because of the nature of primary trials, "fundamental uncertainty" about the study's findings remains.

"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," the editorialists write.

Although Dr. Stone said he thought the editorial by Dr. Geddes and colleagues was generally thoughtful, he added that the editorialists appear to view the issue as therapeutic — that is, whether antidepressants can reduce suicide risk.

"Our perspective is one of adverse events: Separate from any therapeutic benefit that the drugs may have in reducing the risk of suicide, some people, particularly younger individuals, may experience an adverse reaction manifested as suicidal thoughts or behavior," Dr. Stone told Medscape Psychiatry.

BMJ. Published online August 12, 2009.

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