The rapid-onset antidepressant effect of ketamine: More surprises?

An effective rapid-onset treatment for major depressive disorder could save lives. Extensive preclinical and clinical data demonstrate such an action of ketamine. However, the presumptive mechanism of action, inhibition of NMDA (N-methyl-D-aspartate) receptors, has recently been challenged. Elucidation of the mechanism is important clinically for drug discovery and for understanding the (patho)physiology of depression.

The best-known pharmacologic property of ketamine is non-competitive inhibition of the NMDA subtype of glutamate receptor. Although other mechanisms have been postulated, this action has been assumed the major one that accounts for ketamine's antidepressant effect. However, a ketamine metabolite and a different mechanism have now been claimed to be necessary and sufficient for the effect.

A metabolite has been proposed to be responsible for the antidepressant action of ketamine, via activation of non-NMDA receptors. It will be important to determine which of the competing views is correct.