Analyzing ten studies — five more than the 2015 Cochrane Review — researchers found little benefit to the use of ketamine and other glutamate receptor modulators for depression in bipolar disorder. The analysis was published in the Cochrane Database of Systemic Reviews.

Emerging evidence shows glutamatergic system dysfunction may play a role in bipolar depression. However, no clearly established biomarkers have been found. Limited data show lamotrigine may affect glutamate release, while ketamine, a glutamate NMDA receptor, may relieve bipolar depression symptoms. The researchers conducted an update of a 2015 Cochrane Review to obtain more current information about ketamine and other glutamate receptor modulators in bipolar depression.

The researchers included double- or single-blind randomized controlled trials comparing ketamine, memantine, cytidine, N-acetylcysteine, and riluzole with other active psychotropic drugs or saline placebo in people with bipolar depression. They also considered the first period in cross-over trials. After applying all additional criteria, the researchers were left with the five studies from the 2015 systematic review and five additional studies.

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Analyzing the two ketamine studies, the researchers found one intravenous dose to be more effective than a placebo at 24 hours (odds ratio (OR) 11.61, 95% (CI) 1.25 to 107.74; P = 0.03, IN = 0%, 2 studies, 33 participants, number needed to treat for an additional beneficial outcome (NNTB) = 3,95% CI 2 to 10).

The researchers found no difference between memantine and placebo at 1 and 2 weeks and a “marginal” benefit of memantine compared with placebo at 4 weeks. The N-acetylcysteine and cytidine studies also showed no difference in response rate compared with the placebo.

The researchers admit the review was based on a limited number of studies, participants, and predefined outcomes. The intervention of focus, ketamine, and data were only available on 33 participants and 5 of 33 predefined outcomes. The researchers also reported that they could not confirm the certainty of the studies nor the level of bias.

Nevertheless, this review provides very limited evidence for an antidepressant effect of acute administration of ketamine (as an add-on therapy to mood stabilizers) compared with placebo in the treatment of bipolar depression, the researchers conclude.

“The effect of ketamine was found to have a quick onset, which may be promising for clinical practice, but the effect was not long-lasting. An important clinical implication for ketamine in bipolar depression would be in cases where a rapid response is crucial, for instance in patients at high risk of self-harm or suicide (Smith 2018)1. However, the studies included in this review did not report adequate data about such important outcomes.”


Dean RL, Marquardt T, Hurducas C, Spyridi S, Barnes A, et al. Ketamine and other glutamate receptor modulators for depression in adults with bipolar disorder. Cochrane Database of Systematic Reviews. Published October 8, 2021. doi: 10.1002/14651858.CD011611.pub3.1. Smith KA, Cipriani A, Hawton KE. Modelling suicide in bipolar disorders: Limitations and opportunities. Bipolar Disord. 2018;20(6):566-567. doi:10.1111/bdi.12683