Rapid-acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

Major depressive disorder (MDD) affects hundreds of millions worldwide and remains a leading cause of disability, with roughly 30% of patients refractory to current antidepressants and a clinically important delay of weeks to months before benefit. Bipolar depression is similarly difficult to treat, with poor responsiveness to conventional antidepressants and a high risk of switching to mania. These unmet needs have driven interest in rapidly acting treatments, particularly following accumulating evidence that the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid and, in some patients, sustained antidepressant and anti‑suicidal effects in treatment‑resistant MDD and bipolar disorder (BD). This paper by Hashimoto sets out to provide a historical overview of phencyclidine and ketamine, to review clinical and preclinical evidence on ketamine's antidepressant actions and adverse effects, and to discuss the antidepressant potential of ketamine's enantiomers and metabolites (notably (R)-ketamine, (S)-ketamine, norketamine and hydroxynorketamine). In addition, the author examines other candidate rapid‑acting antidepressants (other NMDAR antagonists and modulators, T‑type calcium channel inhibitors, Kir4.1 potassium channel inhibitors, negative modulators of GABAA α5 receptors and related agents) and surveys proposed molecular and cellular mechanisms that might underlie ketamine's effects. The review is presented as a narrative synthesis of clinical trials, preclinical studies and emerging biomarker and mechanistic work, with a focus on comparing efficacy, side‑effect profiles and potential mechanistic pathways among enantiomers and metabolites and on outlining future research directions and therapeutic opportunities.

The extracted text does not report a formal methods section or a structured literature search strategy; the paper is a narrative, historical and mechanistic review rather than a systematic review or meta‑analysis. Hashimoto draws on clinical trial reports, preclinical rodent and primate experiments, biomarker studies, pharmacokinetic and PET investigations, and recent regulatory and industry trial outcomes to assemble the overview. Content areas covered include: the clinical trial literature on ketamine and its enantiomers in MDD and BD (including route and dosing variations), preclinical comparisons of (R)- and (S)-ketamine in animal models of depression, pharmacology and metabolism (norketamine and hydroxynorketamine metabolites), candidate biomarkers (genetic, inflammatory, EEG and metabolomic measures), safety and neuropathological signals, and mechanistic hypotheses (AMPAR activation, mTORC1, BDNF‑TrkB, VEGF, HCN1, GSK‑3, opioid interactions, microRNA and gut microbiota). Where human clinical trials or translational studies are cited, key design features such as randomised, double‑blind, placebo‑controlled trials and use of active controls (e.g. midazolam) are referenced in the narrative, but no explicit inclusion/exclusion criteria, search dates or quality assessment methods are provided in the extracted text. When reporting preclinical findings, the review summarises results across different rodent paradigms (chronic social‑defeat stress, learned helplessness, repeated corticosterone, lipopolysaccharide models) and notes when experimental conditions (strain, dose, route, brain region injections) differ between studies, emphasising heterogeneity as a caveat to interpretation.

Clinical efficacy and dosing. Ketamine produces rapid antidepressant and anti‑suicidal effects in many treatment‑resistant MDD and BD patients. Early double‑blind, placebo‑controlled trials established fast onset (hours to days) after a single 0.5 mg/kg intravenous infusion, with reported response rates across studies of about 25%–85% at 24 hours and 14%–70% at 72 hours. Repeated infusions improve response durability: a six‑infusion regimen over 12 days yielded a 70.8% response rate in one study, and twice‑ or thrice‑weekly maintenance infusions have been used to sustain benefit. Routes other than intravenous (intramuscular, intranasal, oral, rectal, subcutaneous, sublingual) have been tested; intramuscular bioavailability is high (~93%) whereas oral bioavailability is low (17%–29%), which may explain slower onset and lower efficacy with oral dosing. Enantiomers and regulatory status. Ketamine is a racemic mixture of (R)- and (S)-enantiomers. (S)-ketamine (esketamine), which has higher NMDAR affinity, was developed clinically and—based on phase 2 and phase 3 trials with mixed outcomes—received US FDA approval as an intranasal formulation on 5 March 2019 for treatment‑resistant depression, subject to a Risk Evaluation and Mitigation Strategy. Phase 3 results were heterogeneous: only two of five pivotal trials were positive and some experts raised concerns about efficacy and abuse potential. Clinical trials of (R)-ketamine in depressed patients were not reported in the extracted text at the time of publication; a Phase I study of (R)-ketamine and (2R,6R)-HNK was noted as initiated in early 2019. Preclinical enantiomer comparisons and metabolites. Across multiple rodent models, (R)-ketamine generally produced more potent and longer‑lasting antidepressant‑like effects than (S)-ketamine and the racemate, and exhibited a lower propensity for psychotomimetic and locomotor side‑effects. Brain and blood levels of the two enantiomers after equivalent dosing were similar, suggesting efficacy differences are pharmacodynamic rather than pharmacokinetic. Ketamine is metabolised to norketamine and further to hydroxynorketamines (HNKs); Zanos et al. reported that generation of (2R,6R)-HNK was essential for (R,S)-ketamine's antidepressant effects in rodents, but Hashimoto summarises conflicting data. Some groups find (2R,6R)-HNK has antidepressant‑like activity and favourable oral bioavailability in several species, whereas others report (2R,6R)-HNK or (R)-norketamine lacked efficacy in several depression models in which (R)-ketamine was effective. Experiments using CYP inhibitors to block conversion of (R)-ketamine to (2R,6R)-HNK still produced antidepressant effects of (R)-ketamine, arguing that conversion to HNK is not strictly required in those models. Safety and adverse effects. Acute psychotomimetic effects and dissociation are well described after ketamine infusion; these effects typically dissipate within 60–120 minutes. (S)-ketamine causes more pronounced psychotomimetic reactions and increases dopamine release in primate striatum (PET evidence) compared with (R)-ketamine, which is associated with fewer acute behavioural perturbations in animal studies. Preclinical neuropathological concerns include NMDAR antagonist‑induced changes in retrosplenial cortex ('Olney's lesion') and induction of heat‑shock protein HSP‑70 with some NMDAR antagonists; in rodents, (R)-ketamine produced fewer such markers than (S)-ketamine. (S)-norketamine, a major metabolite of (S)-ketamine, produced antidepressant‑like effects in rodents but without the behavioural and biochemical abnormalities (rewarding effects, PPI deficits, γ‑oscillation increases, PV‑immunoreactivity reduction) seen with (S)-ketamine, suggesting a potentially improved safety profile. Biomarkers and predictors. Candidate predictors of ketamine response include genetic variation in BDNF (Val66Met), inflammatory markers (baseline interleukin‑6, changes in TNF‑α), bone‑turnover markers (OPG/RANKL ratio, osteopontin), metabolomics shifts (kynurenine decrease, increased arginine bioavailability), and electrophysiological measures (baseline and post‑infusion γ‑power in visual cortex). Results are preliminary and not consistently replicated; the author emphasises the need for larger studies to validate biomarkers. Brain regions and circuitry. Preclinical work implicates the medial prefrontal cortex and hippocampus (including dentate gyrus and CA3) as sites where ketamine restores synaptogenesis and BDNF–TrkB signalling. The nucleus accumbens (NAc) appears less central in some models, though ketamine modulates NAc long‑term potentiation and dopamine pathways in other paradigms. Recent rodent data suggest blockade of NMDAR‑dependent bursting in the lateral habenula (LHb) may underlie rapid antidepressant effects, but dose and locus differences across studies warrant further study. Other candidate drugs. Several non‑ketamine NMDAR antagonists and modulators have failed to reproduce ketamine's clinical efficacy despite promising preclinical profiles: memantine was ineffective in an 8‑week RCT; lanicemine failed in a large phase 2b/3 programme and development was discontinued; rapastinel showed preclinical efficacy and early clinical promise but did not meet primary endpoints in three pivotal phase 3 studies. Several other agents and combinations (AV‑101, NRX‑101, AXS‑05, AGN‑241751) were under clinical investigation with mixed or negative early results. Alternative mechanisms and targets. Preclinical exploration of low‑voltage T‑type calcium channel inhibitors (ethosuximide), Kir4.1 potassium channel modulation, negative allosteric modulators of α5 GABAA receptors (MRK‑016, L‑655,708), HCN1 channel inhibition, VEGF signalling, GSK‑3 phosphorylation, p11 (S100A10), microRNA changes and the gut microbiota have produced promising leads, but efficacy and translational relevance vary across models and remain to be established in humans.

Hashimoto frames the discovery of ketamine's rapid antidepressant and anti‑suicidal effects as a major, serendipitous advance in mood‑disorder research, responding to a clear unmet need for treatments that act quickly and are effective in treatment‑resistant MDD and bipolar depression. The review emphasises that while NMDAR antagonism was the starting hypothesis, accumulated evidence indicates that simple blockade of NMDARs does not fully account for ketamine's clinical efficacy, given the failure of several other NMDAR antagonists to reproduce ketamine's profile and the complex downstream signalling implicated in preclinical studies. The author interprets preclinical enantiomer data as supportive of (R)-ketamine being more potent and longer‑lasting than (S)-ketamine in multiple rodent depression models, and notes a more favourable side‑effect profile for the R‑enantiomer in animals. Hashimoto highlights that (S)-ketamine (esketamine) progressed to clinical development and regulatory approval (intranasal spray), but that mixed phase 3 results and safety considerations (dissociation, abuse potential) temper enthusiasm and warrant caution. The role of metabolites is presented as contested: Zanos and colleagues proposed (2R,6R)-HNK is essential for antidepressant effects, yet other preclinical data—including blockade of HNK formation and persistence of (R)-ketamine efficacy—argue against a single essential metabolite; the review presents these conflicting findings without resolution. Key mechanistic themes discussed by the author include AMPAR activation and subsequent synaptic potentiation, involvement of BDNF–TrkB and VEGF neurotrophic signalling, engagement of intracellular pathways such as mTORC1 and ERK (with mTORC1 data described as controversial), modulation of HCN1 and GSK‑3, and possible interactions with the opioid system. Hashimoto notes that some clinical findings (for example, a report that naltrexone attenuated ketamine's antidepressant effect) have provoked debate and require larger trials for clarification. The review also points to emerging areas such as miRNA regulation and gut‑brain axis involvement as promising but preliminary. Acknowledged limitations and uncertainties include heterogeneity across animal models, species and strains, differences in dosing and routes of administration, incomplete translation between preclinical and clinical findings, and variable quality and outcomes of clinical trials for ketamine and comparator drugs. The author stresses that many mechanistic claims remain provisional because of inconsistent replication and differences in experimental paradigms. Implications and next steps identified by Hashimoto are pragmatic and translational: conduct direct clinical comparisons of (R)-ketamine, (S)-ketamine and (2R,6R)-HNK in depressed patients; validate candidate biomarkers (genetic, inflammatory, EEG, metabolomic) in larger clinical cohorts to predict responders; pursue development of metabolites or enantiomers that retain efficacy with fewer adverse effects; and continue mechanistic research to identify molecular targets that could yield rapid‑acting antidepressants without ketamine's liabilities. Drug repurposing of enantiomers or metabolites derived from the racemate is highlighted as an attractive, cost‑sensible strategy given high attrition and expense in novel drug development.