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Racemic ketamine, a derivative of phencyclidine, has been used as a dissociative anesthetic since 1970. In 2000, the first randomized controlled trial showed a rapid relief of depressive symptoms. Since then, intravenous ketamine and intranasal S-ketamine have been validated for the treatment of depression and suicidal ideation following dose-response and double-blind placebo-controlled clinical trials. In clinical practice, after dose titration and with repeated treatments, patients may experience approximately 2–3 weeks of symptomatic relief from depression. Areas covered in this narrative review include mechanism of action, dosing, safety, and tolerability. Some attention is paid to the possibility of R-ketamine as a future antidepressant. We recommend further investigation into treatment dosing and frequency strategies as well as approaches that prolong the therapeutic effects. The current fixed dosing of esketamine for obese individuals may be insufficient. Additional investigation into co-administration with somatic and neuromodulation treatments needs investigation. Finally, continuing to monitor research subjects and patients long-term for the emergence of adverse effects on cognition or other organ systems is critical.

Key considerations for the use of ketamine and esketamine for the treatment of depression: focusing on administration, safety, and tolerability