Ketamine

Ketamine is a phencyclidine derivative that functions primarily as an antagonist of the N-methyl-D-aspartate receptor and has been in clinical use since 1970. ^{[1] [2]} Best characterized for its dissociative anesthetic properties, ketamine also exerts analgesic, anti-inflammatory, and antidepressant actions. ^[2] Ketamine is a racemic mixture composed of equal amounts of (S)-ketamine and (R)-ketamine, and its S-enantiomer esketamine received FDA approval for treatment-resistant depression in 2019. ^{[3] [4]}

A single sub-anesthetic dose of ketamine induces rapid and sustained antidepressant actions, with effects appearing within hours of administration. ^{[5] [3]} Proposed antidepressant mechanisms include inhibition of N-methyl-D-aspartate receptors and downstream changes in synaptic plasticity involving brain-derived neurotrophic factor and mTOR signaling. ^[5] An emerging view is that metabolism of ketamine is a crucial step in its mechanism, since the metabolite (2R,6R)-hydroxynorketamine shows antidepressant potential in preclinical studies while being devoid of ketamine's dissociative properties and abuse potential. ^[6]

Intravenous ketamine and intranasal esketamine, co-administered with an antidepressant, are established as efficacious in the management of treatment-resistant depression. ^{[7] [8]} Intranasal esketamine has regulatory approval in the United States and European Union, while intravenous ketamine is often administered off-label as an antidepressant with no standard operating procedures. ^[9] A systematic review and meta-analysis of 24 trials representing 1877 participants found intravenous ketamine appeared more efficacious than intranasal esketamine for the treatment of depression. ^[10] A real-world systematic review and meta-analysis reported that about 45% of treatment-resistant depression patients responded and 30% remitted with ketamine, though the effect varied considerably among patients. ^[11] A separate meta-analysis of esketamine found its efficacy as an add-on to antidepressants was modest in treatment-resistant depression and absent against suicidality itself. ^[12]

Possible adverse effects of ketamine and esketamine include psychiatric, cardiovascular, neurologic and genitourinary effects, and the potential for abuse. ^[9] The most common side effects are generally transient, mild and self-limited and include dissociation, nausea, headache, and elevated heart rate and blood pressure. ^[13] Esketamine was approved under a Risk Evaluation and Mitigation Strategy that requires administration under medical supervision. ^[4] A systematic review of side effects concluded that assessment of long-term use and safety after repeated dosing is limited, recommending large-scale trials with long-term follow-up. ^[14]