Antidepressants, Suicide Risk, and the FDA Black Box Warning

Do antidepressants increase the risk of suicide? There are certainly people out there who are very vocal in insisting that they do. However, as is so often the case, the loudmouths don’t tend to be especially well informed.

The FDA black box warning

Since 2004, the  U.S. Food and Drug Administration (FDA) has required a “black box label” (the most serious warning label they have) on antidepressants warning of an increased risk of suicidality in children and adolescents.

The FDA makes these types of decisions after considering the recommendations of its expert advisory committees. In the case of this particular warning, 8 out of 23 members of the advisory committee recommended against the black box warning.

This all came about after the FDA conducted a series of meta-analyses, which grouped together data from 372 clinical trials involving over 100,000 pediatric and adolescent participants. The number-crunching they did on all of the pooled data showed an increased risk of suicidality in participants receiving antidepressants compared to placebo. The rate of suicidal thinking was 4% in those that took antidepressants, and 2% in those that got a placebo; there were no suicide fatalities in those clinical trials. Various researchers have since raised concerns about the soundness of the FDA’s methodology in conducting the meta-analyses.

At the same time, FDA meta-analyses showed that there was no increase in suicidality associated with antidepressants for adults 24 years and older. Antidepressants had a clear protective effect for adults 65 years and older.

Aftermath of applying the warning label

Since the warning was put in place, there’s been a decrease in antidepressant prescribing for children and adolescents, but there’s also been a decrease in the rate of new depression diagnoses, and no increase in the use of other forms of treatment. If an unintended consequence of the black box labelling is that more people are going undiagnosed and untreated, that’s a problem.

While the FDA didn’t apply the warning to the use of antidepressants in adults, and there was no research to support doing so, sometimes people do erroneously extrapolate the information that way.

Akathisia, antidepressants, and suicide risk

There has been some media attention in recent years to antidepressants possibly increasing suicidality as a result of akathisia. Akathisia involves physical restlessness, which can be quite distressing. It’s more commonly associated with antipsychotic use, particularly older antipsychotic medication.

While akathisia is reasonably common as a side effect of antipsychotics, and several medication strategies have been identified to manage it if a change in antipsychotic isn’t the preferred option, akathisia as a result of antidepressants is rare. This difference likely results because antipsychotics directly affect D2 dopamine receptors, which can trigger akathisia, whereas the mechanism by which antidepressants can produce the same effect is more indirect.

A 2018 paper in the Oxford Journal of Neuropsychopharmacology found that among 219,635 hospitalized adult patients taking antidepressants, 83 patients had “suicidal adverse drug reactions”. Most of the reactions occurred shortly after starting or increasing the dose of an antidepressant. Restlessness was documented in 42 of these patients. There were 34 attempted and 5 completed suicides. Overall, the researchers concluded that suicidality as an adverse drug reaction is rare, and restlessness and impulsiveness could be considered early warning signs.

Other factors to consider

There’s another factor that could come into play with starting on antidepressants. It’s well-known that when depressed people with suicidal ideation start to respond to treatment and feel a little better, that’s a high-risk time. Often energy starts to improve before mood does, so if someone has recently started medication, their mood could still be very low, but they may have regained enough energy and motivation that they’re more likely to follow through on suicidal thoughts.

The biggest issue, though, is the risk of suicide due to untreated depression. Even if antidepressant-related akathisia is a risk, you can’t compare that to a presumed baseline risk of zero for someone not taking antidepressants. People with depression who don’t get treatment are at serious risk of dying, and antidepressants are more effective than placebo at treating depression.

Am I suggesting that medications are the right choice for every person all of the time? Absolutely not.  Decisions regarding any form of treatment for any health condition should always be based on an individual weighing of pros and cons. Making decisions about one’s health based on misinformation and assumptions, though, is not doing anyone any good.

I think what’s far more useful than vilifying antidepressants is ensuring adequate and responsive follow-up for anyone starting on medications. That’s an onus on the health care system, but as patients, we also have a responsibility to communicate significant reactions to our health care providers.

Depriving people of treatment, though, isn’t the answer to anything.

Overview

References

• Friedman, R.A. (2014). Antidepressants’ black-box warning – 10 years later. New England Journal of Medicine, 371, 1666-1668.
• Lenzer, J. (2004). FDA panel urges “black box” warning for antidepressants. BMJ, 329(7469), 702.
• Stübner, S., et al. (2018). Suicidal ideation and suicidal behavior as rare adverse events of antidepressan medication: Current report from the AMSP multicenter drug safety surveillance project. International Journal of Neuropsychopharmacology, 21(9), 814-821.

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Ashley L. Peterson

BScPharm BSN MPN

Ashley is a former mental health nurse and pharmacist and the author of four books.