Rapid onset brain plasticity at novel pharmacologic targets hypothetically drives innovations for rapid onset antidepressant actions.
Takesha Cooper, Michael David Seigler, Stephen M Stahl
Journal of Psychopharmacology March 1, 2023 DOI: 10.1177/02698811231158891 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Depression Neuroplasticity |
| Keywords | Pharmacology Plastogen |
| Citations | 18 |
| Key findings | Novel rapid-acting antidepressants from three distinct classes all act as plastogens, triggering neuroplasticity that correlates with their fast clinical effects. |
Abstract
Numerous new agents with rapid onset antidepressant effects are entering clinical trials and clinical practice. Studies focus on either first-line treatment of major depressive disorder or on patients whose major depressive disorder is resistant to prior antidepressant drugs. Novel agents target three very different central nervous system sites: as antagonists of N-methyl-d-aspartate (NMDA) glutamate receptors, as positive allosteric modulators (PAMs) of gamma amino butyric acid (GABA) A neurosteroid and benzodiazepine receptor sites, and as psychedelic agonists of serotonin 2A/2C receptors. Onset of antidepressant action is rapid, sometimes after only one dose whereas traditional agents for depression take several days to weeks to have an antidepressant effect. Although the direct molecular targets of these three classes of agents with rapid antidepressant onset are quite diverse and not clearly related to each other, analysis of the downstream effects of all these agents show that all are "plastogens," namely agents that trigger rapid onset of neuroplasticity that correlates with their rapid onset of antidepressant clinical action. The GABA A PAMs and some of the NMDA antagonists induce neuroplasticity without notable changes in mental status and can be designated "neuroplastogens." Some NMDA antagonists cause mental dissociation, and the psychedelics cause psychotomimetic/hallucinatory experiences and can be designated "psychoplastogens." A great debate exists whether psychoplastogens are effective because of their ability to acutely alter mental state, or whether these acute mental states are unwanted behavioral toxicity. The promise of numerous novel agents with rapid acting antidepressant action and neuroplasticity is set to transform the treatment of major depressive disorder.
Comparable studies
Other narrative reviews on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists | 2012 | Review | |
| Towards an understanding of psychedelic-induced neuroplasticity. Review of preclinical and clinical studies | 2023 | Review | |
| Buddha's Brain: Neuroplasticity and Meditation [In the Spotlight] | 2008 | Review | |
| Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics | 2021 | Review | |
| Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms | 2020 | Review |
Citations in the library
Cited by 11
- Demystifying the Antidepressant Mechanism of Action of Stinels, a Novel Class of Neuroplastogens: Positive Allosteric Modulators of the NMDA Receptor. Pharmaceuticals January 24, 2025
- Zalsupindole is a Nondissociative, Nonhallucinogenic Neuroplastogen with Therapeutic Effects Comparable to Ketamine and Psychedelics ACS Chemical Neuroscience October 13, 2025
- Should we skip the trip? Clinical implications of psychedelic-associated subjective effects and the potential role of non-hallucinogenic alternatives. General Hospital Psychiatry July 3, 2025
- Psychoplastogens: A Novel Therapeutic Approach for Neurological Diseases and Disorders. ACS Medicinal Chemistry Letters September 14, 2023
- Psychoplastogens to Reduce Persistent Cognitive Symptoms for Traumatic Brain Injury as a Chronic Condition Journal of Neurotrauma October 19, 2026
and 6 more in the library
Cites 17
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Global Street Food: la cocina de la calle Diseño interior 2009
- Ketamine: a paradigm shift for depression research and treatment Neuron March 1, 2019
and 12 more in the library