Ketamine: A tale of two enantiomers

Current antidepressant treatments are limited by delayed onset of action and a substantial proportion of patients who do not respond, risks that are particularly concerning for people with suicidal ideation. Early clinical and preclinical work has shown that the dissociative anaesthetic ketamine, an uncompetitive NMDA receptor antagonist, can produce rapid antidepressant and anti‑suicidal effects, often within hours and including in treatment‑resistant cases. Although ketamine's acute effects have been widely attributed to NMDA receptor antagonism with downstream glutamate surge and synaptic plasticity, evidence has accumulated that additional or alternative mechanisms, as well as actions of individual enantiomers and metabolites, may be important for both therapeutic and adverse effects. Jelen and colleagues set out to review clinical and preclinical findings on ketamine, its two enantiomers ((S)-ketamine and (R)-ketamine) and major metabolites, with particular emphasis on differences in pharmacology, antidepressant efficacy, side‑effect profiles and putative molecular and cellular mechanisms. The review aims to clarify where evidence converges or conflicts and to highlight outstanding questions and future directions for developing rapid‑acting antidepressants with improved safety profiles.

The extracted text presents a narrative review rather than a systematic review or meta‑analysis and does not report a formal Methods section describing literature search strategy, inclusion criteria or risk‑of‑bias assessment. Instead, the paper synthesises preclinical (rodent, cellular) and clinical (healthy volunteer, small open‑label, Phase II/III trials and imaging/pharmacology) studies addressing pharmacology, efficacy and mechanisms of racemic ketamine, (S)-ketamine, (R)-ketamine and selected metabolites such as hydroxynorketamine (HNK) and norketamine. Across sections the authors draw on experimental pharmacology (binding affinities, enzyme metabolism pathways), animal behavioural models (forced swim, chronic social defeat, learned helplessness), human clinical trials and pharmacokinetic/pharmacodynamic investigations (plasma metabolite levels, PET imaging). Where available, clinical trial designs and key dosing details are reported (for example IV infusions of 0.5 mg/kg over 40 minutes or intranasal fixed doses of (S)-ketamine), but the review does not provide a prespecified protocol for study identification or quantitative pooling of results. Because the paper integrates diverse types of evidence, the authors frequently contrast preclinical mechanisms with clinical observations and highlight inconsistencies between laboratories and between animal and human data. The extracted text does not specify formal analytic methods for the review synthesis.

Ketamine pharmacology and metabolism: Ketamine is a racemic (R,S)-mixture of (S)-ketamine (esketamine) and (R)-ketamine (arketamine). (S)-ketamine has approximately three to fourfold greater NMDA receptor binding affinity (Ki ≈ 0.30 μM) than (R)-ketamine (Ki ≈ 1.4 μM) and is generally more potent as an anaesthetic and analgesic. Both enantiomers are metabolised via cytochrome P450 enzymes to norketamine, dehydronorketamine, hydroxyketamines and hydroxynorketamines; (2R,6R)-HNK and (S)-norketamine are of particular interest as candidate active metabolites. Clinical efficacy and tolerability: A single sub‑anaesthetic IV infusion of racemic ketamine (0.5 mg/kg over 40 minutes) produces rapid antidepressant effects within hours, with benefits often persisting up to about one week. Repeated IV infusions (two to three times weekly) can sustain efficacy over short periods (for example 15 days in one RCT), but not all trials have shown positive effects; one small recent RCT of six infusions in severe TRD with chronic suicidality failed to find a difference, though it was likely underpowered. Intranasal (S)-ketamine, administered as an adjunct to an oral antidepressant, has produced positive findings in several Phase II/III trials and a large discontinuation trial (n=297) reported delayed relapse among those continuing intermittent (S)-ketamine; however, some trials were negative and questions about overall effectiveness, safety and abuse potential remain. Longitudinal open‑label data for intranasal (S)-ketamine report common dosing‑day adverse events including dizziness, dissociation, nausea and headache that are mostly mild to moderate and resolve the same day; dissociative symptoms tend to decline with repeated administrations. Data on long‑term safety and maintenance are much less extensive for racemic or (R)-ketamine. Evidence for (R)-ketamine: Preclinical studies often find (R)-ketamine to have more potent and longer‑lasting antidepressant‑like effects with fewer behavioural side‑effects and lower abuse liability than (S)-ketamine. In the first open‑label human pilot, seven TRD subjects received a single IV 0.5 mg/kg (R)-ketamine infusion; mean MADRS fell from 30.7 at baseline to 10.4 at day 1, with 71% responding at day 1 and 57% at day 7. Dissociation was minimal in that small sample, though most participants were taking antipsychotic medication, which may have confounded physiological and experiential effects. Larger clinical trials and Phase I safety work are underway. Mechanistic findings—NMDA antagonism, GABAergic disinhibition and AMPA activation: The classic model holds that NMDA receptor blockade on GABAergic interneurons disinhibits pyramidal cells, producing a cortical glutamate surge and subsequent AMPA receptor activation; preclinical blockade of AMPA receptors prevents ketamine’s antidepressant‑like effects. Some rodent data suggest the (R)‑enantiomer or its metabolite (2R,6R)-HNK produce antidepressant actions that do not require NMDA antagonism but do require AMPA receptor activation. However, reproducibility across laboratories is mixed and some work suggests unmetabolised (R)-ketamine may be responsible for antidepressant effects. BDNF–TrkB, mTORC1 and ERK signalling: Preclinical studies link ketamine’s rapid antidepressant‑like effects to increased BDNF synthesis and TrkB activation in hippocampus and medial prefrontal cortex, with downstream engagement of protein‑synthesis pathways. Early rodent work implicated rapid mTORC1 activation in synaptogenesis after (R,S)-ketamine and mTORC1 inhibition (intracortical rapamycin) blocked those effects. Later work indicates differential engagement by enantiomer: mTORC1 appears more important for (S)-ketamine and (S)-norketamine, whereas ERK signalling may be more relevant for (R)-ketamine. A human randomised double‑blind crossover trial unexpectedly found that oral rapamycin given before ketamine did not blunt acute antidepressant effects and rather prolonged them at two weeks, though peripheral dosing and differing follow‑up durations complicate translation. GSK‑3 and Gαs/cAMP pathways: In rodents, GSK‑3 inhibition is necessary for (R,S)-ketamine’s antidepressant effects and correlates with mTORC1 activation and AMPA receptor stabilisation; combining ketamine with lithium potentiated synaptic and behavioural responses preclinically. Clinical continuation of lithium after ketamine did not extend benefit at two weeks; in bipolar TRD, ketamine showed large effect sizes relative to placebo regardless of mood stabiliser, but no differential benefit tied clearly to GSK‑3 inhibition. Separately, ketamine and (2R,6R)-HNK induce translocation of Gαs from lipid rafts to non‑raft membrane regions in cell models, increasing cAMP and later BDNF expression, pointing to an NMDA‑independent pathway recognised as an antidepressant hallmark in preclinical work. Monoaminergic systems: Several lines of evidence implicate serotonergic mechanisms, including blockade of ketamine’s antidepressant‑like effects by 5‑HT depletion in animals, ketamine‑induced inhibition of SERT and increased cortical 5‑HT release via AMPA‑driven dorsal raphe activation. Enantiomer differences are reported: both (R) and (S) increase prefrontal 5‑HT in vivo, with (R)-ketamine producing a larger increase that appears less dependent on AMPA activation. Dopaminergic effects are more variable; (S)-ketamine appears to produce more robust striatal dopamine release in some imaging studies, which may relate to psychotomimetic effects, but several lines of evidence suggest ketamine’s antidepressant actions are not due to direct dopamine transporter or receptor binding and may instead reflect indirect glutamate‑driven activation of midbrain dopamine neurons. Lateral habenula and T‑type channels: Rodent studies indicate that NMDA receptor‑dependent bursting in the lateral habenula contributes to depressive phenotypes and that (R,S)-ketamine blocks this bursting, producing rapid antidepressant effects. T‑type calcium channel inhibitors produced rapid antidepressant‑like effects in some preclinical assays, but clinical and other preclinical results have been negative or inconsistent, and the relevance of lateral habenula inhibition beyond the acute phase (beyond 1 hour) or differences between enantiomers are unresolved. Opioid receptor involvement: Ketamine shows modest affinity for mu and kappa opioid receptors, with greater affinity for (S)-ketamine than (R)-ketamine. One small human study found naltrexone pre‑treatment attenuated ketamine’s antidepressant and anti‑suicidal effects, suggesting opioid system involvement, but this finding is contested by other human and rodent studies that did not observe blockade. Preclinical work suggests opioid signalling may be necessary but not sufficient for ketamine’s actions and could interact with glutamatergic, BDNF/ERK and monoaminergic pathways. Overall evidence on opioid dependence of ketamine’s antidepressant effect is mixed and methodologically limited.

Jelen and colleagues interpret the accumulated evidence as indicating that ketamine’s rapid antidepressant effects arise from a constellation of mechanisms rather than a single pathway. They emphasise that although NMDA receptor antagonism and subsequent AMPA receptor activation have prominent roles, alternative and NMDA‑independent mechanisms—differentially engaged by (S)-ketamine, (R)-ketamine and metabolites such as (2R,6R)-HNK and (S)-norketamine—are increasingly supported by preclinical data. The authors highlight that (R)-ketamine, despite lower NMDA affinity, has shown in many animal models greater potency, longer duration of antidepressant‑like effects and fewer behavioural side‑effects than (S)-ketamine, and an initial small human pilot yielded promising outcomes with minimal dissociation; nevertheless, large controlled clinical trials are required to confirm efficacy and safety. The review notes important inconsistencies and gaps: some labs have been unable to replicate findings regarding HNK metabolites; clinical metabolite correlations sometimes run counter to preclinical predictions; and route, dosing and pharmacokinetic factors complicate translation. The authors caution that several clinical findings are limited by small sample sizes, open‑label designs or concomitant medications that may confound effects. They also emphasise uncertainty about the role of the opioid system, given mixed human and animal data and methodological limitations in the trials that implicate opioids. For future research, the paper calls for rigorous Phase I/II studies, direct head‑to‑head comparisons of (R)-ketamine, (S)-ketamine and racemic ketamine, mechanistic human studies that measure target engagement and signalling pathways, and work to resolve discrepancies between preclinical and clinical results. The authors suggest exploring complementary or synergistic effects of enantiomers and metabolites, and investigating additional candidate systems such as transforming growth factor β1 and the brain–gut–microbiome axis. They stress that a deeper understanding of differential signalling underlying therapeutic and adverse effects will be essential for developing safer rapid‑acting antidepressants and for optimising maintenance strategies.

The discovery of rapid antidepressant effects of racemic ketamine has transformed antidepressant research and led to regulatory approval of intranasal (S)-ketamine for treatment‑resistant depression, albeit with ongoing concerns about efficacy, side‑effects and abuse potential. Preclinical and early clinical evidence suggest (R)-ketamine may offer more potent and longer‑lasting antidepressant effects with a potentially more favourable safety profile, but confirmatory clinical trials and mechanistic studies are needed. As the field progresses, disentangling the distinct and possibly complementary mechanisms of (S)-ketamine, (R)-ketamine and their metabolites will be crucial for developing future rapid‑acting antidepressants with improved safety and for designing maintenance treatments to sustain therapeutic responses.