Antidepressant actions of ketamine: from molecular mechanisms to clinical practice

Major depressive disorder remains a leading cause of disability, and commonly used antidepressant drugs that target monoamine systems typically take several weeks to produce clinical benefit and fail in about one-third of patients. There is therefore a substantial unmet need for treatments with a rapid onset of action, particularly for people with treatment-resistant depression and those at increased risk of suicide. Clinical reports that low doses of the NMDA receptor antagonist ketamine can produce antidepressant effects within hours, and antisuicidal effects in the short term, generated intense interest because they suggested a fundamentally different mechanism from conventional monoaminergic antidepressants. Monteggia and colleagues set out to review preclinical and clinical evidence on ketamine’s antidepressant actions with emphasis on synaptic and intracellular mechanisms that might explain its rapid and relatively durable behavioural effects. The review also surveys clinical developments aimed at prolonging ketamine’s benefit, developing alternative NMDA-modulating agents with fewer psychotomimetic effects, and identifying potential biomarkers of response. The aim is to link mechanistic insights with translational and clinical strategies for next-generation rapid-acting antidepressants.

The extracted text presents a narrative review rather than a systematic review or meta-analysis; no explicit methods section, search strategy, or prespecified inclusion criteria are reported in the provided text. Instead, the paper synthesises findings from basic neuroscience studies (molecular, cellular, and rodent behavioural work) together with clinical trials and biomarker studies to construct mechanistic and translational perspectives. The review focuses on: (1) mechanistic hypotheses derived from genetic, pharmacological and signalling studies in animal models and in vitro systems; (2) clinical trial data for ketamine and other NMDA receptor modulators (including dose/routing information and time course of antidepressant effects where reported); and (3) emerging approaches for maintaining response and identifying biomarkers. Where available, specific experimental manipulations (for example, gene knockouts and pharmacological inhibition of signalling proteins) and clinical trial parameters (agent, dose, sample size when given, and time to effect) are discussed, but no formal quality appraisal or meta-analytic pooling methods are described in the extracted text.

Clinical observations summarised in the review indicate that a single low intravenous dose of ketamine can produce a rapid antidepressant response within about two hours, with effects lasting up to two weeks in some patients; rapid antisuicidal effects have also been reported. Ketamine’s plasma half-life is approximately three hours, implying that sustained behavioural effects are not due to persistent receptor blockade but to downstream synaptic plasticity mechanisms. At the synaptic and neuronal level, two principal mechanistic hypotheses are presented. One posits disinhibition: ketamine blocks NMDA receptors on inhibitory interneurons, reducing their activity and thereby increasing excitatory network activity. However, genetic deletion of the obligatory NR1 subunit from interneurons did not abolish ketamine’s antidepressant-like effects in mouse models, arguing against this being the sole pathway. The alternative, more synapse-specific hypothesis proposes that low-dose ketamine blocks NMDA receptors that are active at rest (spontaneous neurotransmission). This blockade inhibits eukaryotic elongation factor 2 (eEF2) kinase, reducing eEF2 phosphorylation and desuppressing translation of proteins such as brain-derived neurotrophic factor (BDNF). Increased BDNF then promotes AMPA receptor insertion and downstream synaptic plasticity processes; pharmacological inhibition of eEF2 kinase alone produced rapid and long-lasting antidepressant-like effects in preclinical models. Importantly, ketamine failed to elicit antidepressant-like responses in mice lacking eEF2 kinase, BDNF, or the AMPA receptor subunit GluA2, supporting the necessity of this pathway. Differential actions of other NMDA antagonists are described. Memantine, a clinically tolerated noncompetitive NMDA antagonist, appears to have minimal effect on NMDA receptors under resting physiological magnesium levels and does not alter eEF2 phosphorylation or BDNF expression; consistent with this, memantine has not produced rapid antidepressant effects in treatment-resistant depressed patients. Conversely, selective NR2B antagonists showed some clinical promise: CP-101,606 produced antidepressant effects within five days in treatment-resistant major depression, and an oral NR2B antagonist (MK-0657; 4–8 mg/day) showed antidepressant properties by day 5 without psychotomimetic effects in a pilot trial. A low-trapping NMDAR antagonist, AZD6765 (150 mg i.v.), produced improvement in Montgomery–Åsberg Depression Rating Scale (MADRS) scores within 80 minutes in a 22-patient trial without psychotomimetic effects, but the benefit lasted only about two days; an independent study reproduced the AZD6765 signal. Regarding maintenance and relapse prevention, trials examining riluzole as a strategy to prolong ketamine’s antidepressant effect did not find benefit over a 4-week period in two studies. Other maintenance strategies under investigation include repeat ketamine dosing, traditional antidepressants, mood stabilisers (noting shared glycogen synthase kinase-3 inhibition with lithium), antipsychotics, electroconvulsive therapy and psychotherapy. Repeat-dose ketamine shows encouraging preliminary results but controlled long-term safety data are lacking. Biomarker research is at an early stage: possible clinical predictors include higher body mass index and a family history of alcohol use disorder being associated with greater short-term improvement in some analyses. Peripheral measures, genetics, neuroimaging, sleep and electrophysiology have all been explored as potential biomarkers, but the authors emphasise that replication is required.

Monteggia and colleagues interpret the collective evidence as indicating that ketamine’s rapid antidepressant effects represent a distinct and translationally important mechanism, one that can be dissociated from classical monoaminergic antidepressant actions. They highlight BDNF and downstream pathways such as mTOR as central mediators: blockade of resting NMDA receptor activity appears to desuppress protein synthesis via eEF2 kinase inhibition, increasing BDNF levels, triggering AMPA receptor insertion and activating mTOR-dependent synaptic plasticity mechanisms that plausibly underlie the sustained behavioural response. The authors note that BDNF is a shared requirement for both fast-acting and traditional antidepressants in preclinical models. The review situates clinical findings within this mechanistic framework and draws two practical lessons from non-ketamine NMDA antagonist trials: rapid antidepressant effects can be achieved without psychotomimetic side effects, but agents tested to date have generally produced less robust or less durable benefits than ketamine. Consequently, the authors underscore the need to delineate the precise synaptic circuits and molecular targets responsible for ketamine’s effects, with the goal of developing compounds that engage downstream effectors (for example, components of the eEF2–BDNF–mTOR pathway) while avoiding undesirable effects of NMDA receptor blockade. Several limitations and unanswered questions are acknowledged: the specific brain regions and circuits beyond the hippocampus and prefrontal cortex remain to be mapped, long-term safety and optimal maintenance strategies for ketamine require more evidence, and many candidate biomarkers need replication. Finally, the authors indicate that while ketamine shows potential benefit in treatment-resistant depression in community settings, definitive conclusions about its ultimate clinical utility await further safety, feasibility and mechanistic studies.

The review concludes that ketamine has reshaped thinking about antidepressant mechanisms by demonstrating that a rapid-onset antidepressant response is feasible and by pointing to glutamatergic synaptic plasticity processes as therapeutic targets. Ongoing preclinical work and clinical trials with different ketamine formulations, selective NR2B antagonists and other glutamatergic modulators are actively pursued to identify agents that retain efficacy but have improved tolerability. Clarifying the synaptic mechanisms underlying ketamine action is viewed as essential for discovering additional synaptic proteins and pathways that could be targeted to produce rapid antidepressant effects without the liabilities of direct NMDA receptor antagonism. The authors stress that more knowledge is needed on long-term safety, maintenance strategies and biomarkers before ketamine or related treatments can be fully integrated into clinical practice.