Rethinking ketamine and esketamine action: Are they antidepressants with mood-stabilizing properties?
Giacomo d'Andrea, Mauro Pettorruso, Giorgio Di Lorenzo, Gianluca Mancusi, Roger S McIntyre, Giovanni Martinotti
European Neuropsychopharmacology May 2023 DOI: 10.1016/j.euroneuro.2023.02.010 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Interventions | Ketamine Esketamine |
| Topics | Esketamine Ketamine |
| Keywords | Bipolar depression Mood stabilizers Rapid-acting therapies Trd |
| Key points | Argues that ketamine and esketamine may be effective not only as antidepressants in severe treatment-resistant depression but also against mixed features, anxiety, dysphoric mood, and bipolar traits, and proposes that bipolar elements could predict response and that these substances might act as mood stabilizers. Contends that their pharmacodynamic action goes beyond non-competitive NMDA receptor antagonism and calls for further research, particularly on esketamine nasal spray in bipolar depression. |
Abstract
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.
Comparable studies
Other theoretical and historical papers on esketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Esketamine and Acceptance and Commitment Therapy (ACT) for Treatment-Resistant Depression: An Intervention-Development Framework and Treatment Manual | 2026 | Theoretical or philosophical paper | |
| Adjunctive dopaminergic enhancement of esketamine in treatment-resistant depression. | 2022 | Theoretical or philosophical paper | |
| Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling. | 2022 | Theoretical or philosophical paper |
Citations in the library
Cited by 26
- Predicting outcome with Intranasal Esketamine treatment: A machine-learning, three-month study in Treatment-Resistant Depression (ESK-LEARNING) Psychiatry Research July 29, 2023
- The Role of Ketamine in the Treatment of Bipolar Depression: A Scoping Review. Brain Sciences June 4, 2023
- Investigating the Effectiveness and Tolerability of Intranasal Esketamine Among Older Adults With Treatment-Resistant Depression (TRD): A Post-hoc Analysis from the REAL-ESK Study Group American Journal of Geriatric Psychiatry July 8, 2023
- Ketamine for bipolar depression: an updated systematic review Therapeutic Advances in Psychopharmacology 2023
- A comparison between psilocybin and esketamine in treatment-resistant depression using number needed to treat (NNT): A systematic review. Journal of Affective Disorders April 1, 2024
and 21 more in the library
Cites 14
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- Comparison of antidepressant and side effects in mice after intranasal administration of (R,S)-ketamine, (R)-ketamine, and (S)-ketamine. Pharmacology, Biochemistry, and Behavior June 1, 2019
- Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats. Psychopharmacology June 1, 2010
- Arketamine, a new rapid-acting antidepressant: A historical review and future directions Neuropharmacology August 14, 2022
- Treating bipolar depression with esketamine: Safety and effectiveness data from a naturalistic multicentric study on esketamine in bipolar versus unipolar treatment‐resistant depression Bipolar Disorders January 13, 2023
and 9 more in the library