Ketamine’s Legacy: New Targets for the Development of Rapid onset Antidepressant Drugs

Major depressive disorder is a common, recurrent and disabling psychiatric disorder associated with significant morbidity and mortality. For half a century, the field of neuro psychopharmacology of depression has been dominated by the monoaminergic hypothesis, especially regarding the development of antidepressant drugs. However, the mono aminergic antidepressants have significant limitations: these drugs present a delayed onset of action (weeks to months), and a considerable fraction of patients do not respond to treatment even after several therapeutic attempts. In the last decade, compelling clinical evidence has demonstrated that a single sub anesthetic dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist, ketamine, can induce a significant improvement of depressive symptoms within hours, even in situations of treatment-resistant depression. Furthermore, preclinical studies aiming to elucidate the biological mechanisms underpinning the antidepressant action of ketamine opened new perspectives into the neurobiology of depression and consequently to the emergence of important targets for the development of new antidepressant drugs. Ketamine seems to be the prototype for a new generation of antidepressants that can impact the clinical management of depression exerting their therapeutic effects within hours. Here, we are presenting some evidence regarding the efficacy, safety, and tolerability of ketamine. We also included a summary of the mechanisms underlying the rapid antidepressant effects of ketamine, and discussion of the contributions of these mechanisms for nextgeneration rapid-acting antidepressants: the called “legacy of ketamine”.