Although the molecular action of pharmacotherapeutic treatment for major depressive disorder (MDD) is immediate, it may take weeks for the therapy to be effective. Evidence suggests that ketamine, an arylcycloalkylamine-derived NMDA receptor antagonist, produces rapid-onset antidepressant action in patients with MDD. Twenty-nine studies have evaluated the antidepressant effects of ketamine with response rates from 25–100% and time to attainment of response typically within hours; however, there were no comparators to control for the subjective effects of ketamine in these studies which may indicate an enhanced placebo effect. In animal studies, the acute administration of ketamine consistently produced an anti-depressant like effect of rapid onset in rodent models with depression, although this is not definitive for clinical antidepressant activity.

The mechanism of action is unknown but it is proposed that it is due to the targeting of sites including the AMPA receptor, neurotrophins, MTOR, GSK-3, GABA, and others. Because ketamine can cause psychotomimetic disturbances similar to PCP (phencyclidine) such as visual and auditory hallucinations, sedation and possible sleep disturbances, diarrhea, and impairment of certain types of memory, it is not likely to be a first-line medication for most MDD patients but continues to be recognized as a potential treatment with rapid-onset antidepressant effects.

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