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Synaptic priming: A framework for pharmacotherapy in depression.

Kyle A Brown1, Musa I Ajibola1, Gustavo C Medeiros1

  • 1Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Neuron
|October 9, 2025
PubMed
Summary
This summary is machine-generated.

Ketamine and other rapid-acting antidepressants prime synapses, enhancing subsequent doses for sustained relief. This primer pharmacology model guides new antidepressant strategies, including psychedelics like psilocybin.

Keywords:
BCMBienenstock-Cooper-Munrodepressionketaminelong-term potentiationmetaplasticitymetaplastogenneuroplasticityneuroplastogenplastogenpsychoplastogensynaptic primingsynaptic psychiatry

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Area of Science:

  • Neuroscience
  • Psychiatry
  • Pharmacology

Background:

  • Current antidepressant development aims for rapid symptom relief.
  • The mechanism of sustained antidepressant effects after drug elimination, like with ketamine, is not fully understood.
  • Understanding how repeated doses enhance therapeutic effects is crucial.

Purpose of the Study:

  • To present a framework for understanding sustained antidepressant effects based on synaptic priming.
  • To explore ketamine's pharmacokinetics and pharmacodynamics in relation to a "primer pharmacology" dosing model.
  • To identify overlaps between antidepressant-induced plasticity and depression-related contextual factors for novel treatment strategies.

Main Methods:

  • Review of existing literature on metaplasticity, synaptic priming, and rapid-acting antidepressants.
  • Analysis of the relationship between ketamine's pharmacokinetic and pharmacodynamic properties.
  • Exploration of how plasticity mechanisms overlap with factors like stress and psychotherapy.

Main Results:

  • A framework is proposed where rapid-acting antidepressants "prime" synapses, making them more responsive to subsequent doses.
  • Ketamine's pharmacokinetic-pharmacodynamic relationship suggests a "primer pharmacology" model for optimized dosing.
  • Antidepressant-induced plasticity shares mechanisms with priming from contextual factors like stress and psychotherapy.

Conclusions:

  • Synaptic priming offers a model to explain sustained antidepressant effects.
  • Primer pharmacology, informed by ketamine's action, can guide clinical dosing strategies.
  • Integration with contextual priming factors, including psychedelics like psilocybin, presents innovative treatment opportunities.