SUMMARYWhat is known and objective: The current pharmacotherapeutic treatment of major depressive disorder (MDD) generally takes weeks to be effective. As the molecular action of these drugs is immediate, the mechanistic basis for this lag is unclear. A drug that has a more rapid onset of action would be a major therapeutic advance and also be a useful comparator to provide valuable mechanistic insight into the disorder and its treatment. Comment: Recent evidence suggests that ketamine produces rapid-onset antidepressant action. Important questions are as follows: is it specific or coincidental to other effects; is there a dose-response relationship; and is the mechanism related to that of current antidepressants. NMDA receptor antagonism is unlikely the explanation for ketamine's antidepressant action. What is new and conclusion: It is not an exaggeration to state that the new findings, if validated, might produce a revolution in understanding and treating depressive disorders. WHAT IS KNOWN AND OBJECTIVERecent evidence strongly suggests that ketamine produces a rapidonset antidepressant effect in humans with major depressive disorder (MDD). [1][2][3] This commentary focuses on the evidence for the efficacy of ketamine as a rapid-onset antidepressant and the implications of its mechanism of action for yielding insight into the biochemical basis of MDD.MDD is a serious neuropsychological disorder associated with significant morbidity and mortality (suicide). The reported lifetime prevalence of MDD varies widely by country (generally within the range 8-12%). 4 Estimates for the United States are higher, closer to 17%. Worldwide, approximately 300 million people are affected. 5 A diagnosis of MDD is about twice as common in women (8-10%) as in men (3-5%), 6,7 but it is not certain whether this represents a physiological difference or a reporting difference. 8 A first depressive episode is most likely to occur between the ages of 30 and 40 years 9 , and the aetiology is multifactorial, involving biological and psychosocial contributions. Some evidence links it to short alleles of the 5-HT (5-hydroxytryptamine, serotonin) transporter gene SLC6A4 10 located on human chromosome 17 (17q11Á1-q12). 11 The three modalities most commonly used currently for the management of MDD are psychotherapy, pharmacotherapy and ECT (electroconvulsive therapy). Combinations of them are also used effectively. 12 But none provide complete efficacy in all patients. Among the most studied forms of psychotherapy for depression are cognitive behavioural therapy (CBT) 13 and variations of this approach. 14 Studies report good results of CBT for certain patients and symptoms, 15 and it appears to be beneficial in preventing relapse when used as part of a comprehensive treatment plan. 16 A significant drawback is that the suicide attempt rate remains higher than baseline for weeks or even months after initiation of therapy. 17 The efficacy of antidepressant pharmacotherapy 18,19 has been reported to be somewhat superior to that of psychother...