Esketamine, an NMDA receptor antagonist, is approved as a nasal spray for treatment-resistant major depression and for rapid symptom reduction in psychiatric emergencies. In the US it is also approved as a monotherapy for treatment-resistant depression. Acute treatment often causes dissociative effects, but a link between these initial symptoms and later therapeutic response is not sufficiently proven. A key methodological problem is functional unblinding, where characteristic side effects reveal group assignment. Proponents of ketamine-augmented psychotherapy suggest that ketamine-induced synaptic plasticity opens a 'therapeutic window' for psychotherapy, but current research methods cannot adequately test causal relationships due to unblinding and general limitations of psychotherapy studies.
Ketamine, administered intravenously at subnarcotic doses, has emerged as a rapid-acting treatment for treatment-resistant depression. This historical overview traces its development, compares it with the newer esketamine nasal spray, and discusses future prospects. Intravenous ketamine infusions have shown efficacy in rapidly reducing depressive symptoms, while esketamine, a derivative, offers a more convenient nasal route but may have different efficacy and safety profiles. The article highlights the need for further research to optimize dosing, duration of effect, and long-term outcomes, as well as to understand the mechanisms underlying ketamine's antidepressant action.