A systematic review of ketamine and esketamine-induced long-term potentiation and synaptic scaling: Do the molecular and synaptic plasticity effects inform dosing intervals?

Ketamine and esketamine exhibit rapid antidepressant effects in persons with treatment-resistant depression (TRD) and bipolar depression (TRBD). However, the synaptic mechanisms governing dose, frequency, and durability of response remain unclear. This review aims to evaluate the dosing parameters, including minimum dose and optimal dosing intervals, that reliably induce or maintain long-term potentiation (LTP) and/or synaptic scaling in humans and preclinical models. A systematic search (database inception to June 2025) was conducted on OVID and PubMed to identify preclinical and clinical studies reporting ketamine-induced clinical symptom changes alongside direct or indirect marker of LTP and/or synaptic scaling. Study selection, quality assessment, and data extraction were conducted by two independent reviewers. Sixty-one clinical and 17 preclinical studies met inclusion criteria. Most clinical studies enrolled persons with TRD, with fewer including TRBD or mixed TRD/TRBD samples. In TRD, a single 0.5 mg/kg intravenous ketamine infusion produced rapid but transient antidepressant effects, peaking at 24-hours and declining over 2-3 days. A similar temporal pattern was observed in TRBD. Early neurophysiological changes emerged within 3-8-hours, consolidated by 24-hours, and were sparsely detected beyond 3-days post-ketamine treatment. Consistent neurophysiological findings were observed in preclinical models. Across clinical trials, twice- versus thrice-weekly dosing yielded comparable four-week outcomes, and weekly maintenance significantly reduced relapse risk. Ketamine may open a plasticity window lasting approximately 2-3 days. Dosing intervals aligned with this window during an acute course of treatment, informed by rapid neurophysiological markers, may optimize antidepressant durability and response while minimizing drug exposure.