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Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review

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Ketamine and its enantiomer S-ketamine (esketamine) are promising candidates to produce a rapid-onset antidepressant effect in treatment-resistant depression. Ketamine causes continued blockade of the glutamate N-methyl-d-aspartate (NMDA) receptor, though this might not primarily mediate the antidepressant effect. Alternative hypotheses include selectivity for the NMDA receptor subtype containing the NMDA receptor subunit 2B (NR2B), inhibition of the phosphorylation of the eukaryotic elongation factor 2 (eEF2) kinase, increased expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrKB), and activation of the mammalian target of rapamycin (mTOR) signaling pathway, alongside other independent actions attributed to the ketamine metabolism to R-hydroxynorketamine (R-HNK). The enantiomer S-ketamine (esketamine) displays approximately fourfold greater affinity for the glutamate NMDA receptor in vitro than R-ketamine. Proof-of-concept single-dose and repeat-dose studies with intravenous ketamine show a significant antidepressant and probably antisuicidal effect in the short term, with response rates over 60% as early as 4.5 h after a single dose, with a sustained effect after 24 h, and over 40% after 7 days. This response can be further sustained over several weeks with repeated doses (two to three doses per week). Tolerability seems acceptable in the short term, with transient elevation of blood pressure and mild and transient dissociative and psychotomimetic effects. Intranasal esketamine has shown a comparable antidepressant effect, which has resulted in the US FDA granting the drug a “breakthrough therapy” designation, and theoretically it may offer an improved tolerability profile. However, major concerns remain regarding an effective protocol to maintain the clinical antidepressant effect of ketamine seen with acute administration and the safety of ketamine and esketamine in the long term, specifically related to potential neurocognitive and urologic toxicity, together with the potential induction of substance use disorders. Ketamine and esketamine are not currently approved treatments for depression, but the clinical use of ketamine is increasing in a variety of practice settings internationally.

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All authors made a substantial contribution to the conception, writing and structure of the review article. The first draft of the manuscript was prepared by PM (clinical aspects) and JJM (pharmacological aspects). All authors proofread the manuscript.

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Correspondence to P. Molero.

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No sources of funding were used to conduct this study or prepare this manuscript.

Conflict of interest

Three of the six authors are principal investigators or subinvestigators on several Janssen-supported studies of esketamine for depression. PM is supported by Clinica Universidad de Navarra and has received research grants from the Ministry of Education (Spain), the Government of Navarra (Spain), the Spanish Foundation of Psychiatry and Mental Health and Astrazeneca. Without any relevance to this work, PM declares that he is a clinical consultant for MedAvante-ProPhase and has received speaker honoraria from Scienta, AB-Biotics and Janssen. PM is the principal investigator at Clinica Universidad de Navarra of several studies supported by Janssen about the efficacy and safety of esketamine. JARQ is the principal investigator for Hospital Universitari Vall d’Hebron in several studies about the efficacy and safety of esketamine supported by Janssen-Cilag. ECS is cooperating as subinvestigator at Hospital Universitari Vall d’Hebron in several studies about the efficacy and safety of esketamine for the treatment of depression supported by Janssen-Cilag. LGR has been speaker and advisory board member for Janssen, Rovi, Servier, Lundbeck, Otsuka, Pfizer and Exeltis. RMS and JJM have no conflicts of interest.

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Molero, P., Ramos-Quiroga, J.A., Martin-Santos, R. et al. Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review. CNS Drugs 32, 411–420 (2018).

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