Review data published in the Cochrane Database of Systematic Reviews suggest that ketamine and esketamine are effective options for the short-term treatment of major depressive disorder. However, the certainty of evidence varied widely across the trials reviewed.

Investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Embase, and PsycINFO databases from inception through July 2020 for randomized clinical trials of glutamate receptor modulators for the treatment of depression. Eligible trials enrolled adults and compared glutamate receptor modulators with placebo, other active psychotropic drugs, or electroconvulsive therapy (ECT).Three review authors independently identified studies, assessed trial quality, and extracted data. The primary outcomes were treatment response rate and adverse events. Risk of bias was assessed using the Cochrane tool; certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria.

The review included 64 studies with a pooled cohort of 5299 patients. The majority of studies (75%) were placebo controlled. Most studies limited enrollment to patients with moderate to severe depression or treatment-resistant depression. Studied drugs included ketamine (n=31 trials), esketamine (9), memantine (5), lanicemine (4), D-cycloserine (2), Org26576 (2), riluzole (2), atomoxetine (1), basimglurant (1), citicoline (1), CP-101,606 (1), decoglurant (1), MK-0657 (1), N-acetylcysteine (1), rapastinel (1), and sarcosine (1). Ketamine was administered as a single dose in most associated trials, while esketamine had an established dosing regimen, such as twice a week for 4 weeks. Ketamine was most often administered intravenously, while esketamine was given intranasally.


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Per the results of 7 studies with a combined cohort of 185 patients, ketamine was associated with increased response and remission rates at 24 hours following administration vs placebo (odds ratio [OR], 3.94; 95% CI, 1.54-10.10). Ketamine was also associated with reduced depression rating scale scores in 8 studies. However, the evidence for both of these associations was of low certainty. Study attrition rates were not different between placebo and ketamine groups. Two trials compared ketamine with midazolam for the treatment of depression. Compared with midazolam, ketamine had an improved 24-hour remission rate (OR, 2.21; 95% CI, 0.67-7.21), although the difference was not statistically significant.

Esketamine was similarly associated with increased 24-hour remission rates compared with placebo, as determined by the results of 5 studies with 894 participants (OR, 2.74; 95% CI, 1.71-4.40). The evidence for this association was of moderate certainty. According to additional moderate-certainty evidence from 4 studies, esketamine was associated with decreased depression rating scale scores at 24 hours compared with placebo (standard mean difference [SMD]: -0.31; 95% CI, -0.45 to -0.17). Trial drop-out was not increased among esketamine recipients compared with the placebo arm.

Very little data were available for the efficacy of the remaining glutamate receptor modulators. Risk of bias was low or unclear across most studies, while data certainty ranged from low to moderate. Overall, the evidence points to the probable efficacy of ketamine and esketamine over placebo at 24 hours following administration. However, the long-term effects of these treatments remain unclear. “Long term non-inferiority [randomized controlled trials] comparing repeated ketamine and esketamine, and rigorous real-world monitoring are needed to establish comprehensive data on safety and efficacy,” authors concluded.

Disclosure: Two study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference

Dean RL, Hurducas C, Hawton K, et al. Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder. Cochrane Database Syst Rev. 2021;9(9):CD011612. doi:10.1002/14651858