Suicide Issues

Still, for advocates of esketamine, the more people with hard to treat depression who can start treatment with the new intranasal spray formulation, the better.

For this camp, increasing access for veterans has a particular advantage—possible reduction in veteran suicides. A proof-of-concept study published in the American Journal of Psychiatry last year showed esketamine rapidly and dramatically reduced the risk of suicide in suicidal, depressed patients.

The study compared esketamine to placebo in 68 acutely suicidal patients. Esketamine resolved suicide risk in 21.2% of those patients in four hours and in 40% within 24 hours compared to 9.7% and 6.5% of those who received a placebo, respectively.3

Experts who urge greater caution with the drug also cite suicide risk, however. Three participants committed suicide in the esketamine arm of one of the studies provided by the manufacturer on which the U.S. Food and Drug Administration based its approval. None died in the placebo arm. The study evaluated drug relapse and discontinuation following 16 weeks of treatment with esketamine plus an antidepressant, tapering to once every two weeks, before transitioning to antidepressant plus placebo or continued treatment with esketamine plus the antidepressant.4

The three suicides occurred between four and 20 days after the participants received their last dose of esketamine. Two of the individuals had not demonstrated signs of suicidal activity at baseline or at their last visit.

“This suggests a protracted withdrawal reaction, as has been reported with opioids, and one that is different from the more physical withdrawal symptoms seen acutely with opioids,” said Alan Schatzberg, MD, director of the Stanford Mood Disorders Center and professor of psychiatry and behavioral sciences at Stanford University School of Medicine in a commentary in the June issue of the American Journal of Psychiatry.5

In its briefing document on esketamine, the FDA addressed the suicides and three other deaths in esketamine arms of clinical trials saying, “it is difficult to consider these deaths as drug-related” because of the small number of cases, severity of participants’ illness and inconsistent pattern in the suicides.

Schatzberg called the FDA conclusion “misguided,” as “discontinuation reactions can certainly be due to the drug, even though patients are not taking them at that time” and because it failed to factor in the drug’s known abuse potential.

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