New investigational agents for the treatment of major depressive disorder
Bartłomiej Pochwat, A. Krupa, M. Siwek, Bernadeta Szewczyk
Expert Opinion on Investigational Drugs August 17, 2022 DOI: 10.1080/13543784.2022.2113376 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Interventions | Ketamine psychedelics non-hallucinogenic serotonergic modulators metabotropic glutamate receptor ligands |
| Topics | Depression |
| Key findings | Argues that rapid, long-acting antidepressant effects require durable changes to dendritic spine architecture and density in mood-regulating brain regions, a mechanism attributed to ketamine and psychedelics. The authors suggest the hallucinatory effects of these compounds may be essential to their antidepressant action, while serotonergic modulators at 5-HT1A, 5-HT4, and 5-HT7 receptors show rapid antidepressant-like activity in behavioral studies without such effects. Combined therapy and metabotropic receptor ligands are proposed as alternative strategies. |
Abstract
ABSTRACT Introduction Pharmacotherapy of depression is characterized by the delayed onset of action, chronic treatment requirements, and insufficient effectiveness. Ketamine, with its rapid action and long-lasting effects, represents a breakthrough in the modern pharmacotherapy of depression. Areas covered The current review summarizes the latest findings on the mechanism of the antidepressant action of ketamine and its enantiomers and metabolites. Furthermore, the antidepressant potential of psychedelics, non-hallucinogenic serotonergic modulators, and metabotropic glutamate receptor ligands was discussed. Expert opinion Recent data indicated that to achieve fast and long-acting antidepressant-like effects, compounds must induce durable effects on the architecture and density of dendritic spines in brain regions engaged in mood regulation. Such mechanisms underlie the actions of ketamine and psychedelics. These compounds trigger hallucinations; however, it is thought that these effects might be essential for their antidepressant action. Behavioral studies with serotonergic modulators affecting 5-HT1A (biased agonists), 5-HT4 (agonists), and 5-HT-7 (antagonists) receptors exert rapid antidepressant-like activity, but they seem to be devoid of these effects. Another way to avoid psychomimetic effects and achieve the desired rapid antidepressant-like effects is combined therapy. In this respect, ligands of metabotropic receptors show some potential.
Comparable studies
Other narrative reviews on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synaptic Dysfunction in Depression: Potential Therapeutic Targets | 2012 | Review | |
| Mindfulness-Based Cognitive Therapy for Depression: A New Approach to Preventing Relapse | 2003 | Review | |
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| Sudarshan Kriya Yogic Breathing in the Treatment of Stress, Anxiety, and Depression: Part II—Clinical Applications and Guidelines | 2005 | Review |
Citations in the library
Cited by 7
- The Efficacy and Safety of Intranasal Formulations of Ketamine and Esketamine for the Treatment of Major Depressive Disorder: A Systematic Review Pharmaceutics December 22, 2023
- Trends in research on novel antidepressant treatments. Frontiers in Pharmacology 2025
- Drugs with glutamate-based mechanisms of action in psychiatry. Pharmacological Reports December 1, 2024
- Anhedonia and depression severity measures during ketamine administration in treatment-resistant depression. Frontiers in Psychiatry 2024
- Treatment-resistant depression and intranasal esketamine: Spanish consensus on theoretical aspects Frontiers in Psychiatry August 4, 2025
and 2 more in the library
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and 40 more in the library