A systematic review of 64 randomized controlled trials (5299 participants) examined glutamate receptor modulators for unipolar major depression. Ketamine and esketamine may reduce depressive symptoms more than placebo within 24 hours, but the evidence for ketamine is very uncertain, while esketamine shows moderate-certainty evidence for increased remission. No difference in dropout rates was found between these drugs and placebo. Evidence for other glutamate modulators (memantine, lanicemine, etc.) is very limited. The authors call for long-term trials and real-world monitoring to establish safety and efficacy.
A Cochrane review of ten randomized controlled trials (647 participants) examined glutamate receptor modulators for bipolar depression. Only ketamine appeared more effective than placebo for response rate 24 hours after a single intravenous dose, but evidence was low-certainty and limited to two small trials. Ketamine did not show better remission rates than placebo. Evidence for other modulators—memantine, cytidine, N-acetylcysteine, and riluzole—was insufficient or showed no benefit. The review concludes that while ketamine may have a rapid, transient antidepressant effect, the evidence is too uncertain to draw reliable conclusions, and more rigorous studies are needed.