Do antidepressants take more lives than they save?

Antidepressants may increase the risk of death, according to a Canadian study.

The study, published in Psychotherapy and Psychosomatics, found that the effect of antidepressant use on all-cause mortality depends on cardiovascular health.

A McMaster University-led team of researchers reviewed studies involving hundreds of thousands of patients in a meta-analysis. These studies estimated the risk of death from any cause associated with using antidepressants, and usually followed large cohorts of participants taking antidepressants over time and compared them to people not taking antidepressants, while controlling for other important demographic and health-related variables. When researchers statistically pooled these estimates together, they were able to determine the overall net effect of using antidepressants on mortality.

The study was completed because the researchers suspected that the way antidepressants work could have adverse long-term effects on health, based on some previous theoretical work, says author Paul Andrews, an associate professor at McMaster University, Hamilton, Ontario, Canada, who led the research team.

“Antidepressants disrupt the functioning of monoamines-biochemicals such as serotonin and dopamine-and these monoamines have important functions not only in the brain, but all over the body,” he says.

“For example, serotonin affects growth, reproduction, digestion, immune function, and many other processes, and it is found in almost every major organ,” Andrews says. “Disrupting the functioning of serotonin can therefore have different adverse effects, which can contribute to a risk of death in many different ways. We completed the study to test the hypothesis that interfering with the functioning of monoamines by using antidepressants can increase the risk of death from any cause.”

Study findings

The study found that antidepressant users had a 33% higher chance of death than non-users. Antidepressant users also had a 14% higher risk of cardiovascular events, such as strokes and heart attacks.

Maslej

“Taking antidepressants does not appear to affect the risk of death from any cause for individuals who have pre-existing cardiovascular conditions,” says McMaster researcher and co-author Marta Maslej. “However, in general population samples [i.e., individuals with no specified cardiovascular illness], using antidepressants is associated with a 33% increased risk of death from any cause. To put this finding into context, if unmedicated depression leads to eight deaths per 1,000 person-years, antidepressant use is estimated to cause an additional 2.64 deaths per 1,000 person-years.”

The study findings cast doubt on widely-held assumptions that antidepressants are relatively safe, and that they save lives by reducing depression-related mortality, Maslej says.

“In our meta-analysis, we only included studies that attempted to isolate the effects of antidepressant use on mortality by controlling for a variety of important variables, including depression,” she says. “Because general population samples taking antidepressants were still at an increased risk of death, relative to those not taking antidepressants, our findings suggest that the risk of death associated with using antidepressants may be greater than the risk of death associated with unmedicated depression. In other words, antidepressants could take more lives than they save.”

Next: More proof

Adding to the literature

Andrews believes that this study adds to a body of literature that scientifically tests whether antidepressant medications are safe and effective. 

“First, as a background point, clinicians have long known that most episodes of depression eventually resolve on their own, even without treatment,” Andrews says. “For instance, it is estimated that 20% to 35% of people will remit in a period of four to 20 weeks-this is usually the length of a single clinical trial-and in one year, it’s 53%.”

Second, research has consistently found that antidepressant medications are only modestly more effective than placebo in reducing depressive symptoms, Andrews says. Roughly 80% of the symptom reducing response to antidepressants can be attributed to placebo.

“Third, a related issue is what happens after you have gotten better on a treatment and decide to stop the treatment,” he says. “Research indicates that if you get better on an antidepressant, you have a much higher risk of relapse than if you got better on either placebo or on cognitive behavioral therapy.”

“Our study suggests that the risk of death associated with using antidepressants is greater than the risk of death associated with unmedicated depression, which contrasts previously held views that antidepressants lessen depression-related mortality by alleviating depressive symptoms” Andrews says.

Not all bad

However, the news about antidepressants is not all bad.

“Because commonly-used antidepressants-like SSRIs-have anti-clotting properties, they may normalize clotting processes in individuals where these processes are abnormally activated, like people with heart disease, diabetes, kidney disease and COPD," Andrews says. "In other words, because they reduce blood clotting, antidepressants may be beneficial for treating cardiovascular diseases, thereby offsetting their effects on mortality. This mechanism is speculative, and more empirical research is required to understand why antidepressants do not seem to affect mortality in these samples.”

A final point is that the reseachers found no evidence that newer or second-generation antidepressants (i.e., SSRI/SNRIs) are safer than older or first-generation antidepressants (i.e., TCAs). "The finding that SSRI/SNRIs and TCAs have similar effects on mortality is not consistent with widely-held views that TCAs are more harmful [perhaps because of their cardiotoxic side effects]," says Andrews. "However,  SSRI/SNRIs and TCAs interfere with the functioning of important and evolutionarily ancient biochemicals (regardless of whether they selectively target serotonin, norepinephrine, or dopamine), and so it is perhaps not too surprising that their effects on all-cause mortality do not differ from one another."