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What is the mechanism of Ketamine's rapid‐onset antidepressant effect? A concise overview of the surprisingly large number of possibilities

Abundant clinical data now confirm that ketamine produces a remarkable rapid‐onset antidepressant effect – hours or days – in contrast to the delayed onset (typically weeks) of current antidepressant drugs. This surprising and revolutionary finding may lead to the development of life‐saving pharmacotherapy for depressive illness by reducing the high suicide risk associated with the delayed onset of effect of current drugs. As ketamine has serious self‐limiting drawbacks that restrict its widespread use for this purpose, a safer alternative is needed. Our objective is to review the proposed mechanism(s) of ketamine's rapid‐onset antidepressant action for new insights into the physiological basis of depressive illness that may lead to new and novel targets for antidepressant drug discovery.