Ketamine and Evolving Neuroplasticity

Ketamine has revolutionized the treatment of mood disorders by offering rapid antidepressant effects, particularly in individuals with treatment-resistant depression. Unlike traditional monoaminergic antidepressants, ketamine acts primarily through antagonism of the N-methyl-D-aspartate (NMDA) receptor, initiating a cascade of glutamatergic signaling that promotes synaptic plasticity, neurogenesis, and rapid symptom relief. However, while its mechanisms are increasingly understood, the temporal trajectory of these neuroplastic changes-and their behavioral correlates-remain poorly defined. This review synthesizes both preclinical and clinical evidence on the time-dependent effects of ketamine across molecular, cellular, and behavioral domains. Preclinical studies are examined to characterize rapid molecular and synaptic changes, including brain-derived neurotrophic factor (BDNF) signaling, activation of the mechanistic target of rapamycin (mTOR) pathway, and modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which collectively drive early phases of synaptic remodeling. In parallel, clinical studies are reviewed to evaluate how these biological processes correspond to changes in mood, motivation, cognition, and functional outcomes in patients, with particular emphasis on the timing of antidepressant response and durability of effects. Special attention is given to how ketamine-induced neuroplasticity unfolds over hours to days, and how this temporal progression links mechanistic findings from preclinical models with observed clinical recovery. By framing ketamine's action within a plasticity-centered model of antidepressant response, this review provides a novel perspective that integrates neuroscience and clinical psychiatry. It also identifies critical gaps in translational research and offers a roadmap for optimizing the therapeutic use of ketamine and future fast-acting antidepressants.