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How do you know when a new drug is safe? Well, “safe” is a broad term, but it does reflect what we clinicians must decide. Is the benefit worth the risk? That’s risk in all its facets, from side effects to short-term physiologic risks like QT prolongation, to long-term risks like tardive dyskinesia.
Hi! Jim Phelps here for the Psychopharmacology Institute. In this Quick Take, we’ll examine the safety of a new drug using a review of adverse events of esketamine based on postmarketing data. Our goal is to answer the question: How risky is esketamine after the 2 months or so which are covered in clinical trials?
Of course, we needn’t bother to look at risk unless efficacy is clearly established, especially for a new and expensive treatment. One source is a meta-analysis of 5 randomized trials by Papakostas and colleagues, which found an effect size of 0.36 for patients with major depression. This was on esketamine as an adjunct to patients’ previous antidepressant regimens. Remember that an effect size of 0.5 is medium and 1.0 is large, so 0.3 to 0.4 is small to small–medium, right at the lower limit of what might be expected to be noticeable clinically.
In my view, we can almost stop there, at a relatively low efficacy for a new and expensive drug. But, as you know, excitement about ketamine and esketamine is high. In the U.S., there are standalone ketamine clinics all over the place. Hanging over all this is the question: What happens a few months or a year or so down the road? This brings us to this study of postmarketing adverse events by Chiara Gastaldon and colleagues. Unfortunately, the database they used, the FDA’s Adverse Events Reporting System, doesn’t really address long-term issues like withdrawal after months of use or other indications of physiologic dependence. It merely allows us to examine what people on the medication are reporting, which is 2,300 side effects described by 960 people. Of course, there is confounding by indication, meaning that experiences reported could be arising from the depression for which the esketamine is being prescribed, not from the esketamine.
One way to control for that is to compare the rate of a particular adverse event to the rate of that event being reported for other treatments. In this study, a direct comparator was venlafaxine. And the results? Well, I’ll confess I spent quite a while looking at the supplement which describes their methods in detail, and I still wasn’t able to figure out the meaning of the odds ratios that they report except that, well, no surprise, dissociation is far more common with esketamine than with venlafaxine. What else? Well, I’ll tell you what the authors emphasize in their discussion.
First, they detect what I’d regard as side effects that didn’t emerge in the randomized trials. These don’t strike me as reasons not to use esketamine but more as flags to recognize when you see them, that they’re likely coming from the esketamine. That includes ataxia, akathisia, panic, and paranoia, but the authors also detected increased rates of “self-injurious ideation” and “mania” relative to venlafaxine. Venlafaxine is thought to be more likely to induce mania than other antidepressants, so if esketamine is more likely to do so, this is a serious concern and would certainly suggest that we hold back on using esketamine in patients with bipolar depression.
The authors express concern about finding descriptions of euphoric mood in these adverse events reports and suggest that this points in the direction of high abuse potential. Finally, the relative risk of reporting suicidal ideation was 5 to 9 times higher for esketamine than for venlafaxine. As the authors put it, this is “an extremely serious concern that cannot be ignored.” Well, that’s a bit odd. Increased suicidal ideation? Like ketamine, esketamine was found in a recent meta-analysis to lower suicidal ideation, but that’s in the hours after administration. Is there some sort of rebound increase in suicidal ideation, or are patients simply seeing a return of their baseline ideation after initial improvement, and then misattributing that to esketamine? Not clear.
In conclusion, as the authors say, this study shows that the esketamine safety profile in the real world population might be slightly different from that described in regulatory trials. They also remind us that patients for whom we prescribe exciting new treatments may be more likely to feel hopeless if the treatment doesn’t work right away. So, overall, their message is clear: Caution, caution.
Abstract
Post-Marketing Safety Concerns with Esketamine: A Disproportionality Analysis of Spontaneous Reports Submitted to the FDA Adverse Event Reporting System
Chiara Gastaldon, Emanuel Raschi, John M Kane, Corrado Barbui, Georgios Schoretsanitis
Introduction: Esketamine nasal spray received approval for treatment-resistant depression in March 2019.
Objective: Using the FDA Adverse Event Reporting System (FAERS) database (March 2019-March 2020), we analysed esketamine-related adverse events (AEs) to detect and characterize relevant safety signals.
Methods: We used the consolidated case/non-case approach to estimate the reporting odds ratio (ROR) and information component (IC) with relevant confidence intervals (95% CI) for esketamine-related AEs with ≥4 counts. Comparisons between serious and non-serious AEs were performed using non-parametric tests.nals for suicidal and self-injurious ideation, but not suicide attempt and completed suicide, remained when comparing esketamine to venlafaxine. Females and patients receiving antidepressant polypharmacy, co-medication with mood stabilizers, antipsychotics, benzodiazepines, or somatic medications were more likely to suffer from serious versus non-serious AEs (χ2 = 125.29, p < 0.001, χ2 = 9.08, p = 0.003, χ2 = 8.14, p = 0.004, χ2 = 19.48, p < 0.001, χ2 = 25.62, p < 0.001, and χ2 = 16.79, p < 0.001, respectively).
Conclusions: Esketamine may carry a clear potential for serious AEs, which deserves urgent clarification by means of further prospective studies.
Results: The FAERS database contained 962 cases of esketamine-related AEs, with signals detected for several AEs, such as dissociation (ROR = 1,612.64, 95% CI = 1,354.63, 1,919.79; IC = 8.19, 95% CI = 7.96, 8.35), sedation (ROR = 238.46, 95% CI = 202.98, 280.15; IC = 7, 95% CI = 6.75, 7.18), feeling drunk (ROR = 96.17, 95% CI = 61.42, 150.57; IC = 4.84, 95% CI = 4.09, 5.36), suicidal ideation (ROR = 24.03, 95% CI = 18.72, 30.84; IC = 4.31, 95% CI = 3.9, 4.61), and completed suicide (ROR = 5.75, 95% CI = 3.18, 10.41; IC = 2.25, 95% CI = 1.23, 2.94). Sig
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Reference
Gastaldon, C., Raschi, E., Kane, J., Barbui, C., & Schoretsanitis, G. (2020). Post-marketing safety concerns with esketamine: A Disproportionality analysis of spontaneous reports submitted to the FDA adverse event reporting system. Psychotherapy and Psychosomatics, 90(1), 41-48.
Related References
Papakostas, G. I., Salloum, N. C., Hock, R. S., Jha, M. K., Murrough, J. W., Mathew, S. J., Iosifescu, D. V., & Fava, M. (2020). Efficacy of esketamine augmentation in major depressive disorder. The Journal of Clinical Psychiatry, 81(4).
