La kétamine est un antagoniste non compétitif des récepteurs NMDA utilisé depuis sa synthèse dans les années soixante comme agent anesthésique. Depuis quelques années, un nombre grandissant de publications met en évidence l’effet antidépresseur spectaculaire de la kétamine à faible posologie. Son profil d’efficacité, rapide en quelques heures, sa puissance avec une efficacité chez des patients présentant des dépressions résistantes aux thérapeutiques médicamenteuses conventionnelles et son mode d’action différent de la modulation monoaminergique des antidépresseurs conventionnels conduisent à repenser la physiopathologie de la dépression et son traitement.

Depression is a frequent disease with a significant medico-economic impact. Conventional antidepressants have a delayed action and are ineffective in one third of cases. Discovery of ketamine's antidepressant effects these last years opens new perspectives for treatment-resistant depression.

This article reviews the discovery of the antidepressant effect of ketamine, the current state of knowledge on its use and the mechanisms underlying these properties.

Many studies now show a robust and rapid but transient antidepressant effect of a subanesthesic dose of ketamine in patients with treatment-resistant depression. To maintain the initial benefits, limited published data pinpoint the interest of repeated administrations of ketamine while relay with glutamatergic modulators seem to be inefficient as well as the combination with electroconvulsive therapy. Ketamine's mechanisms of action are strongly explored. Evidences indicate that ketamine antagonism of the NMDA receptor with a subsequent activation of AMPA receptor are mandatory for the antidepressant effect. Intracellular signalling pathways play a key role. An anti-inflammatory effect of ketamine would also be at stake.

The demonstration of ketamine antidepressant effects is a major discovery in psychopharmacology. If studies are still required to evaluate efficacy and safety of ketamine, especially in the long-term exposure and if data remains too limited to use ketamine in routine practice, the discovery of the potent antidepressant effect of ketamine strongly stimulates research for a better understanding of the pathophysiology of depression and for new therapeutic strategies, particularly in the field of modulation of the glutamate pathway in depressive disorders.