European neuropsychopharmacology : the journal of the European College of NeuropsychopharmacologyMar 3, 2023

Are ketamine and esketamine antidepressants that also help stabilize mood?

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 27, 2026

Abstract

Ketamine and esketamine may offer therapeutic benefits for Treatment-Resistant Depression (TRD) with various clinical profiles.

A high prevalence of bipolarity is noted in individuals with TRD.
Efficacy of ketamine/esketamine is observed in alleviating mixed features, anxiety, dysphoric mood, and bipolar traits.
The pharmacodynamic mechanisms of ketamine/esketamine are complex and extend beyond simply blocking NMDA receptors.
Further research is necessary to assess the effectiveness of esketamine nasal spray specifically for bipolar depression.
Bipolar characteristics may predict the response to ketamine/esketamine treatment.
Future applications could include using these substances as mood stabilizers in addition to their antidepressant effects.

Simplified

Ketamine and esketamine, the S-enantiomer of the racemic mixture, have recently generated considerable interest as potential therapeutic agents for Treatment-Resistant Depression (TRD), a complex disorder that includes various psychopathological dimensions and distinct clinical profiles (e.g., comorbid personality disorder, bipolar spectrum, dysthymic disorder). This perspective article provides a comprehensive overview of the action of ketamine/esketamine from a dimensional point of view, taking into account the high prevalence of bipolarity in TRD and the evidence of the efficacy of these substances on mixed features, anxiety, dysphoric mood, and, generally, bipolar traits. Additionally, the article underscores the complexity of the pharmacodynamic mechanisms of action of ketamine/esketamine, which goes beyond the non-competitive antagonism of NMDA-R. The need for further research and evidence is highlighted, mainly to evaluate the efficacy of esketamine nasal spray in bipolar depression, the presence of bipolar elements as a predictor of response, and the potential role of these substances as mood stabilizers. The article implies that, in the future, ketamine/esketamine could be used with fewer limitations, not only as antidepressants for the most severe form of depression but also as valuable tools to stabilize subjects with mixed symptoms or bipolar spectrum.

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Competing interests

Conflict of interest Giorgio Di Lorenzo has been a speaker and / or a consultant for Angelini, Livanova, Lundbeck, Neuraxpharm, Otsuka, and Recordati. Dr. Roger McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, Atai Life Sciences. Dr. Roger McIntyre is the CEO of Braxia Scientific Corp. Giovanni Martinotti has been a consultant and/or a speaker and/or has received research grants from Angelini, Doc Generici, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Servier, and Recordati. The remaining authors declare that the research was conducted without any commercial or financial relationship that could be construed as a potential conflict of interest.

PubMed

Are ketamine and esketamine antidepressants that also help stabilize mood?

Abstract

Full Text

Funding

Competing interests

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Abstract

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