Beyond Monoamines: Ketamine, Esketamine, and Classic Psychedelics in the Treatment of Depression

Summary

Major depressive disorder is a common and burdensome condition, and many patients do not fully recover after standard antidepressant treatment, prompting interest in rapid-acting interventions that target brain pathways beyond serotonin, norepinephrine, and dopamine. This review examines ketamine, esketamine, and classic psychedelics for depression, especially treatment-resistant depression. Ketamine and esketamine have the strongest evidence, with ketamine showing rapid antidepressant and anti-suicidal effects, and intranasal esketamine being the first NMDA receptor antagonist approved for treatment-resistant depression. Psilocybin-assisted therapy has shown promising results but remains investigational and requires a structured therapeutic framework. Evidence for LSD, DMT, and mescaline is preliminary. These treatments highlight the roles of glutamatergic modulation, serotonergic mechanisms, and neuroplasticity. Key unresolved issues include maintaining effects over time, identifying which patients benefit most, and safe delivery outside specialized settings.

Study at a glance

Abstract

Major depressive disorder is a highly burdensome psychiatric condition worldwide, and many patients do not achieve full remission after standard monoaminergic antidepressant treatment. This has contributed to growing interest in rapid-acting antidepressant interventionstargeting neurobiological pathways beyond traditional serotonin, norepinephrine, and dopamine mechanisms. This review summarizes currentevidence on ketamine, esketamine and classic psychedelics in depression, with particular emphasis on treatment-resistant depression,mechanisms of action, clinical efficacy and safety considerations. Ketamine and esketamine currently possess the strongest evidence base amongrapid-acting antidepressant interventions. Ketamine has demonstrated rapid antidepressant and anti-suicidal effects, while intranasal esketaminerepresents the first NMDA receptor antagonist approved specifically for treatment-resistant depression. Psilocybin-assisted therapy has shownpromising results in major depressive disorder and treatment-resistant depression, although it remains investigational and requires administrationwithin a structured psychotherapeutic framework. Evidence for LSD, DMT, mescaline and other emerging psychedelic compounds remainspreliminary and is derived mainly from small clinical trials, experimental studies or naturalistic observations. Overall, these treatments highlightthe relevance of glutamatergic modulation, serotonergic mechanisms, and neuroplasticity in depression. The main unresolved issues are whetherthese effects can be maintained over time, which patients are most likely to benefit, and how such treatments could be delivered safely outside highly specialized settings.