Ketamine for Treatment-Resistant Mood Disorders

Strong evidence supports the rapid, although temporary, antidepressant effects of a single intravenous ketamine infusion for treatment-resistant major depressive disorder (MDD) and bipolar depression. Although ketamine has diverse effects on brain neurotransmitters, current theories have implicated N-methyl-d-aspartate antagonist effects at the presynaptic interneuron in mediating its antidepressant effects. Intravenous ketamine administration for treatment-resistant depression (TRD) is generally safe and well tolerated when administered by trained professionals. Repeated intravenous ketamine infusions as an off-label treatment for TRD are increasingly available for clinical use, although their safety and effectiveness are not well characterized. Intranasal administration of esketamine—the (S)-enantiomer of racemic ketamine—recently completed phase 3 multicenter trials; a Food and Drug Administration application for its use in TRD is expected. Relatively little is known about the longer term side effects of ketamine for TRD. Concerns have been raised about its dissociative side effects, risk of abuse, and potential excitotoxic neuronal injury at higher doses and with repeated use. Treatment guidelines are needed to standardize ketamine use in psychiatric disorders. Ketamine research is transforming our understanding of the pathophysiology of mood disorders and leading the way toward developing new, rapid-acting interventions for TRD.