Ketamine: Promising Path or False Prophecy in the Development of Novel Therapeutics for Mood Disorders?

Introduction

Sanacora and Schatzberg frame ketamine as a treatment that has challenged conventional views of antidepressant therapy by producing rapid-onset antidepressant and anxiolytic effects, including in patients with treatment-resistant depression. Earlier research has shown that most approved antidepressants require weeks to exert clinically meaningful effects and act primarily on monoaminergic systems; ketamine’s apparent ability to induce fast, robust, but temporally limited improvements has therefore reinvigorated interest in novel mechanisms of action for mood disorder therapeutics. This Circumspectives piece sets out to evaluate what is known and uncertain about ketamine’s antidepressant effects. Sanacora presents evidence and interpretation that emphasise NMDAR antagonism and downstream glutamatergic modulation as key mechanisms, whereas Schatzberg offers a countervailing view that other mechanisms (including opioid, sigma and monoaminergic effects) may be critical and that an exclusive focus on NMDAR antagonism risks misdirecting drug development. Together the authors review preclinical and clinical data, highlight methodological challenges in the field, and discuss implications for future therapeutic development and safety evaluation.