A new systematic review and meta-analysis raised significant questions about the clinical efficacy of esketamine nasal spray for treatment-resistant depression and suicidal ideation. It highlighted modest effect sizes and challenged the basis for FDA approval of the ketamine-derived medication.

According to a comprehensive analysis published in the American Journal of Psychiatry, the current evidence for esketamine shows "marginal effect sizes after the first week, the lack of controlled long-term efficacy data, and negligible evidence for efficacy against suicidality."

The systematic review, conducted by Fountoulakis et al. of the Aristotle University of Thessaloniki and Stanford University School of Medicine, examined 87 reports, including 11 randomized placebo-controlled trials, that covered the entirety of published literature through March 2024. The analysis specifically focused on short-term outcomes (up to 4 weeks) for depressive symptoms and suicidality.

"The phase III program failed to prove that patients should be continued on esketamine beyond a few days, a considerably shorter duration than the recommended induction course of biweekly treatments for 4 weeks," Sanjay J. Mathew, MD, and Nicholas Murphy, PhD, of the Menninger Department of Psychiatry and Behavioral Sciences at Baylor College of Medicine in Houston noted in their editorial response to the review.

The FDA's 2019 approval of esketamine—the (S)-enantiomer of racemic ketamine—was based on an unconventional approach that relied primarily on a randomized withdrawal maintenance-of-effect trial rather than the traditional requirement of two similarly conducted short-term efficacy studies. Only one of three short-term efficacy studies met its primary endpoint.

Further complicating the approval process, FDA reviewers raised concerns that "the positive results could have been driven by a single outlier site in Poland, where a 100% relapse rate was reported in the placebo arm (compared to a 33% relapse rate at all other study sites)."

Regarding esketamine's second FDA-approved indication for depressive symptoms in major depressive disorder with acute suicidal ideation, the editorial highlighted that "none of the seven trials reporting on suicidal ideation around week 4 were positive." While studies showed rapid effects 2 to 4 hours after administration, there remains "no evidence that esketamine nasal spray (or ketamine) actually reduces the risk of suicide attempts or suicide."

The review also raised concerns about potential withdrawal effects. The researchers hypothesized that "unexplained suicide attempts were due to a discontinuation-related opioid reaction, with accumulating evidence that the antidepressant efficacy of ketamine (and esketamine) is linked to changes in opioid receptor signaling."

Postapproval surveillance data from the FDA Adverse Event Reporting System shows mixed results, with "no increase in the reporting odds ratio for suicide attempt but increases in suicidal ideation and 'depression suicidal.'"

Since its FDA approval, esketamine prescriptions "have nearly doubled since the beginning of 2023 in the United States, and more than 2,800 clinics now offer the treatment." The medication is currently administered under a Risk Evaluation and Mitigation Strategy, which requires in-clinic self-administration and at least 2 hours of monitoring after doses are taken.

The largest comparative study to date showed esketamine nasal spray plus an SSRI/SNRI was superior to extended-release quetiapine plus an SSRI/SNRI for remission at week 8 (27.1% vs. 17.6%) and no relapse through week 32 following remission (21.7% vs. 14.1%). However, the editorial researchers noted that "the difference was relatively small (a 2.8-point advantage on the Montgomery-Åsberg Depression Rating Scale at week 8 and 2.2 points at week 32)."

Addressing future research needs, the editorial emphasized the importance of studying how esketamine compares with newer adjunctive medications with more favorable side effect profiles, as well as neuromodulation treatments such as electroconvulsive therapy.

"Given the many uncertainties of these treatments, a 'less is more' perspective may be clinically prudent," Mathew and Murphy concluded.

Disclosures can be found in the editorial.