Synaptic priming: A framework for pharmacotherapy in depression.

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.