Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review

Major depressive disorder carries one of the highest global burdens of disability, yet a substantial proportion of patients fail to achieve remission with existing pharmacotherapies — including selective serotonin reuptake inhibitors and tricyclic antidepressants — which share a delayed therapeutic onset of weeks to months and clinically significant rates of non-response. This review examines the evidence for ketamine and other N-methyl-D-aspartate (NMDA) receptor antagonists as antidepressant agents, focusing on their capacity to produce rapid, robust symptomatic relief — including acute reductions in suicidal ideation — through mechanisms distinct from the classical monoaminergic pathway. The glutamatergic hypothesis of depression holds that disrupted NMDA and AMPA receptor signalling in prefrontal and limbic circuits underlies both the neurobiology of the disorder and the therapeutic cascade initiated by NMDA blockade. The synaptoplasticity model proposes that ketamine's antidepressant effects arise through downstream AMPA receptor activation, release of brain-derived neurotrophic factor, and mTOR-dependent synaptic protein synthesis — a mechanistic sequence that accounts for both the speed and the neuroplasticity-associated durability of the antidepressant response.

This paper is a narrative clinical review synthesising published trial data, mechanistic pharmacology, and pharmacokinetic findings on ketamine and related NMDA antagonists. The authors survey the evidence from early proof-of-concept studies through to single and multiple infusion protocols, and discuss alternative routes of administration including oral, intramuscular, sublingual, and intranasal formulations. No formal systematic search strategy or quality appraisal methodology is described; the review is structured thematically around pharmacological mechanism, clinical trial outcomes, and outstanding research questions relevant to future clinical development.

The landmark Berman et al. (2000) crossover trial — involving seven patients with treatment-resistant depression receiving a single subanesthetic intravenous infusion of ketamine (0.5 mg/kg) — is cited as establishing proof of concept, with approximately 71% of patients meeting response criteria within one day and 35% maintaining response at one week. Subsequent single-infusion trials replicated this rapid response pattern across larger and more heterogeneous samples. Multiple infusion protocols, typically comprising six infusions administered over two weeks, produced response rates of approximately 70.8% at twelve days, with a mean relapse time of approximately 18 days; around 30% of patients maintained response beyond one month. Intranasal esketamine is discussed as an FDA-approved maintenance formulation, and data on oral, intramuscular, and sublingual administration are summarised, with each route presenting trade-offs between bioavailability, onset speed, and clinical tolerability. Memantine and other partial NMDA antagonists are also reviewed as lower-abuse-potential alternatives, though their antidepressant efficacy has generally proven weaker and less consistent than that of ketamine.

Ketamine's rapid antidepressant action is framed as a paradigm-shifting finding that has reinvigorated interest in glutamatergic targets for depression. Several fundamental questions nonetheless remain unresolved: the optimal infusion schedule, the dose-response relationship, predictors of non-response, and the most appropriate maintenance strategy for patients who achieve an acute response. Dissociative and psychotomimetic side effects, together with abuse potential and the practical demands of intravenous administration, are recognised as significant barriers to widespread clinical deployment. The role of the subjective dissociative experience in mediating antidepressant effects is discussed as an open question, with evidence both supporting and challenging the view that dissociation is mechanistically necessary for efficacy. The authors also note that the short-lived nature of ketamine's antidepressant effects in most patients underscores the need for well-designed maintenance protocols and for the identification of biomarkers that predict durable response.

Ketamine and related NMDA antagonists represent a genuinely novel antidepressant mechanism with a speed and magnitude of effect not matched by conventional monoaminergic agents. The clinical evidence, while still maturing, supports their use in treatment-resistant and acutely suicidal patients for whom rapid relief is a clinical priority. Further research is needed to establish optimal dosing regimens, characterise long-term safety profiles, and determine which patients are most likely to derive sustained benefit from this class of agents.