Synaptic priming: A framework for pharmacotherapy in depression.
Kyle A Brown, Musa I Ajibola, Gustavo C Medeiros, Todd D Gould
Neuron November 19, 2025 DOI: 10.1016/j.neuron.2025.09.010 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Depression Ketamine Neuroplasticity |
| Keywords | Bcm Bienenstock-cooper-munro Long-term potentiation Metaplasticity Metaplastogen Neuroplastogen Psychoplastogen Synaptic priming Synaptic psychiatry |
| Citations | 6 |
| Key findings | Rapid-acting antidepressants like ketamine prime synapses so that subsequent doses evoke stronger plasticity, a framework called primer pharmacology that can optimize therapeutic outcomes. |
Abstract
Recent antidepressant drug development focuses on a next generation of drugs to rapidly relieve symptoms. Yet, how ketamine, the prototype rapid-acting antidepressant, maintains symptom relief days after drug elimination, and how repeated doses sustain longer-lasting therapeutic effects, remains unclear. Derived from elements of metaplasticity (synaptic priming), this review discusses a framework in which rapid-acting antidepressants prime synapses such that subsequent doses evoke stronger plasticity. Within this framework, we describe how the indirect relationship between ketamine's pharmacokinetics and sustained antidepressant pharmacodynamics reveals a dosing model (primer pharmacology) that can be harnessed to fine-tune therapeutic outcomes. This review also explores how plasticity machinery engaged by antidepressant pharmacotherapies overlaps with priming induced by contextual conditions relevant to depression (e.g., stress and psychotherapy), suggesting innovative opportunities for treatment strategies with emerging primers (e.g., psychedelics such as psilocybin). The integration of synaptic priming with primer pharmacology reveals a model to guide clinical and translational work in psychiatry.
Comparable studies
Other narrative reviews on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| 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 | |
| Ketamine: a paradigm shift for depression research and treatment | 2019 | Review | |
| Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective | 2019 | Review | |
| Ketamine: A tale of two enantiomers | 2020 | Review | |
| Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor | 2021 | Review |
Citations in the library
Cited by 4
- Ketamine combined with psychotherapy for treatment-resistant depression: Real-world outcomes and the role of subjective experience. General Hospital Psychiatry 2026
- Enhancing plasticity to treat depression and other central nervous system diseases using event-driven pharmacology. Journal of Psychopharmacology July 13, 2026
- A time-sensitive plasticity distinguishes the rapid and sustained synaptic actions of ketamine from its (2R,6R)-hydroxynorketamine metabolite. Journal of Neuroscience February 3, 2026
- Ketamine preserves perineuronal nets in chronic stressed mice brain through the inhibition of microglia activation IBRO Neuroscience Reports July 26, 2026
Cites 93
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
and 88 more in the library