Antidepressant actions of ketamine: from molecular mechanisms to clinical practice

Introduction

Major depressive disorder remains a leading cause of disability, and commonly used antidepressant drugs that target monoamine systems typically take several weeks to produce clinical benefit and fail in about one-third of patients. There is therefore a substantial unmet need for treatments with a rapid onset of action, particularly for people with treatment-resistant depression and those at increased risk of suicide. Clinical reports that low doses of the NMDA receptor antagonist ketamine can produce antidepressant effects within hours, and antisuicidal effects in the short term, generated intense interest because they suggested a fundamentally different mechanism from conventional monoaminergic antidepressants. Monteggia and colleagues set out to review preclinical and clinical evidence on ketamine’s antidepressant actions with emphasis on synaptic and intracellular mechanisms that might explain its rapid and relatively durable behavioural effects. The review also surveys clinical developments aimed at prolonging ketamine’s benefit, developing alternative NMDA-modulating agents with fewer psychotomimetic effects, and identifying potential biomarkers of response. The aim is to link mechanistic insights with translational and clinical strategies for next-generation rapid-acting antidepressants.