Ketamine in neuropsychiatric disorders: an update

Abstract

The discovery of ketamine as a rapid-acting antidepressant led to a new era in the development of neuropsychiatric therapeutics, one characterized by an antidepressant response that occurred within hours or days rather than weeks or months. Considerable clinical research supports the use of—or further research with—subanesthetic-dose ketamine and its (S)-enantiomer esketamine in multiple neuropsychiatric disorders including depression, bipolar disorder, anxiety spectrum disorders, substance use disorders, and eating disorders, as well as for the management of chronic pain. In addition, ketamine often effectively targets symptom domains associated with multiple disorders, such as anxiety, anhedonia, and suicidal ideation. This manuscript: 1) reviews the literature on the pharmacology and hypothesized mechanisms of subanesthetic-dose ketamine in clinical research; 2) describes similarities and differences in the mechanism of action and antidepressant efficacy between racemic ketamine, its (S) and (R) enantiomers, and its hydroxynorketamine (HNK) metabolite; 3) discusses the day-to-day use of ketamine in the clinical setting; 4) provides an overview of ketamine use in other psychiatric disorders and depression-related comorbidities (e.g., suicidal ideation); and 5) provides insights into the mechanisms of ketamine and therapeutic response gleaned from the study of other novel therapeutics and neuroimaging modalities.

Introduction

Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist with rapid-acting therapeutic effects, has created a paradigm shift in the field of neuropsychopharmacology. First developed in 1962 as a shorter-acting sedative agent to replace phencyclidine, ketamine was quickly integrated into widespread use due to its broad safety profile [1]. Since its initial discovery, evidence has also suggested that ketamine may possess neuroprotective and anti-inflammatory effects, may decrease hyperalgesia, and may prevent septic and hypovolemic shock [2].

The investigation of another NMDAR antagonist, MK-801, as a putative antidepressant in the early 1990s led to a surge of interest surrounding the potential antidepressant effects of glutamatergic modulation [3]. Although the discovery of ketamine’s rapid-acting antidepressant actions is sometimes described as somewhat serendipitous, the seminal clinical study conducted by Berman and colleagues in 2000 [4] was in fact based on significant preclinical research. That study demonstrated that a subanesthetic dose of ketamine alleviated depressive symptoms within hours [4], a feat previously unheard of for the treatment of any neuropsychiatric disorder. Shortly thereafter, ketamine’s robust antidepressant effects were confirmed in treatment-resistant depression (TRD) and bipolar disorder (BD) [5–7], and this rapid-acting efficacy in TRD cemented its path to the clinic. Subsequently, ketamine was found to affect several diagnostic and therapeutic domains and brain circuitries; for instance, ketamine has been found to be effective for traditionally treatment-refractory symptoms such as suicidality, anxiety, and anhedonia, and to impact functional circuitries related to motivation [8, 9].

The antidepressant effects associated with a single ketamine administration last well beyond its half-life. These prolonged effects implicate the activation of multiple cellular signaling cascades that sustain its initially observed therapeutic effects, likely by immediately enhancing structural and functional plasticity effects relevant to antidepressant effects. The antidepressant effects of an acute dose of ketamine are typically thought to occur within hours, peak around 24 h then gradually decline over a period of 10–12 days [10]. Based on significant clinical evidence, the Food and Drug Administration (FDA) approved the use of intranasal esketamine (Spravato^TM)—the (S+) enantiomer of ketamine—for adults with TRD in 2019; in 2020, it was approved to treat adults with major depression and acute suicidal ideation or behavior. Esketamine has also been approved by the European Union for the same indications.

In addition to its known clinical side effects—including sedation, dizziness, dissociation, and psychotomimetic symptoms—ketamine also has a relatively long history of recreational substance misuse. While dependence rates are relatively low amongst recreational users, long-term unregulated use has been reported to lead to issues such as ulcerative cystitis and memory impairment [11]. In addition, rates of recreational ketamine use are increasing in countries such as the United Kingdom and Taiwan [12–14]. Due to these concerns, the use of esketamine as a therapeutic is limited under a Risk Evaluation and Mitigation Strategy (REMS), requiring supervision by certified providers for administration.

Although subanesthetic-dose ketamine was first studied for its antidepressant effects, its varied pharmacological actions suggested that it could also be effective in other neuropsychiatric disorders. This manuscript: explores the pharmacology and hypothesized mechanisms of subanesthetic-dose ketamine in clinical research; discusses the similarities and differences in the mechanism of action and antidepressant efficacy between racemic ketamine, its (S) and (R) enantiomers, and its hydroxynorketamine (HNK) metabolite; describes the day-to-day use of ketamine in the clinical setting; reviews ketamine use in other psychiatric disorders and depression-related comorbidities (note that neurological conditions such as Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease are excluded); and explores how the development of other novel therapeutics and neuroimaging modalities provides insights into the mechanisms of ketamine and therapeutic response.

Ketamine’s mechanism of action

As a phencyclidine derivative, ketamine is a highly water- and lipid-soluble agent that can rapidly cross the blood-brain barrier [15]. Like phencyclidine, ketamine binds to a site located deep within the NMDAR channel, necessitating the removal of the magnesium block before binding [16]. Ketamine then creates an open-channel block that prevents ions from traveling through the channel [17]. Ketamine is metabolized within minutes after administration by nitrogen-mediated demethylation to norketamine, mediated primarily by cytochrome P450 liver enzymes [18, 19]. Subsequent metabolism of norketamine to dehydronorketamine (DHNK) and hydroxynorketamine (HNK) also occurs rapidly, potentially contributing to its therapeutic effects (described below). The elimination rate of ketamine is nearly equal to that of liver blood flow, with a half-life of approximately two to three hours [20, 21]. Ketamine is a racemate made up of two enantiomers mirrored on a chiral center: (S+)-ketamine and (R-)-ketamine. Notable differences in metabolism exist between the two enantiomers: (S)-ketamine has a higher demethylation and clearance rate, as well as a wider distribution pattern than either (R)-ketamine or racemic (R,S)-ketamine [22]. In addition, steady-state concentrations of metabolites such as HNK are also impacted in a stereoselective manner, which could contribute to enantiomer-specific therapeutic effects [23].

Because ketamine is classified as a non-competitive NMDAR antagonist, preliminary preclinical and clinical research focused on the NMDAR-mediated mechanisms underlying its rapid-acting antidepressant actions. NMDARs play a unique role in excitatory transmission, functioning as “coincidence detectors”, whereby cellular depolarization and co-agonism by glutamate and glycine are necessary for the magnesium block to be removed and the channel to open [24]. NMDAR function is also extremely location- and composition-dependent; indeed, research suggests that synaptic NMDAR transmission promotes cell survival and that extra-synaptic NMDARs promote cell death through p38MAPK inhibition and activation, respectively [25].

Two main theories are thought to explain ketamine’s therapeutic actions: the theory of direct NMDAR inhibition and the disinhibition hypothesis [26]. The theory of direct NMDAR inhibition suggests that ketamine lessens tonic NMDAR activation by circulating glutamate, eventually decreasing the suppression of eukaryotic elongation factor 2 (eEF2) and promoting synaptic protein synthesis. The deactivation of eEF2 kinase, and resulting increase in eEF2 activation and brain-derived neurotrophic factor (BDNF) protein synthesis, has repeatedly been linked to ketamine’s rapid-acting antidepressant effects [27]. The disinhibition hypothesis suggests that ketamine preferentially antagonizes NMDARs, which are located on gamma aminobutyric acid (GABA)-ergic interneurons, due to a stronger affinity to GluN1/GluN2C subunits, causing the disinhibition of excitatory pyramidal neurons. Both theories converge on a downstream increase in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) transmission, which activates cellular signaling pathways proposed to be integral to ketamine’s rapid-acting therapeutic effects such as increases in BDNF expression and mechanistic target of rapamycin complex 1 (mTORC1) activation [28]. Ketamine also inhibits NMDAR-dependent bursting activity of lateral habenula neurons, reversing the increases in bursts and theta-band synchronization observed in depression [29].

However, the necessity of NMDAR inhibition for ketamine’s antidepressant effects remains unknown. For instance, recent research suggests that (R)-ketamine and the ketamine metabolite (2R,6R)-HNK may exert antidepressant-like effects by upregulating AMPAR transmission independent of NMDAR antagonism [30, 31]. In addition to glutamatergic modulation, ketamine is also an opioid (mu, kappa, delta) and dopamine receptor agonist, inhibits monoamine reuptake, and antagonizes muscarinic receptors [32]. Ketamine’s main hypothesized mechanisms of action are displayed in Fig. 1.

Fig. 1. Current hypothesized mechanisms of ketamine.

Ketamine’s rapid-acting antidepressant-like actions appear to be mediated primarily through NMDAR antagonism and AMPAR activity. Blockade of NMDARs by racemic ketamine and esketamine on GABAergic interneurons decreases the inhibition of pyramidal neurons, leading to increased glutamate release. This increased probability of glutamate release activates downstream mechanisms that activate mTORC1 signaling, leading to upregulation of synaptic density, PSD-95, and GluA1-containing AMPAR surface insertion. In addition, blockade of extrasynaptic NMDARs dephosphorylates eEF2, leading to increased BDNF translation and mTORC1 activity. Ketamine has also been hypothesized to bind to mu-opioid receptors, though the exact downstream mechanisms are unknown. Lastly, ketamine can block LHb bursting activity through NMDAR antagnosim on LHb neurons. Overall, these changes lead to improved E/I balance between glutamate and GABA in order to elicit therapeutic effects. Abbreviations: AMPAR α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, BDNF brain-derived neurotrophic factor, eEF2 eukaryotic elongation factor, E/I Excitatory/inhibitory, GABA γ-aminobutyric acid, GAD glutamate decarboxylase, Glu glutamate, HNK hydroxynorketamine, LHb lateral habenula, mGluR metabotropic glutamate receptor, mRNA messenger ribonucleic acid, mTORC1 mechanistic target of rapamycin complex 1, NMDAR N-methyl-D-aspartate receptor, PSD-95 post-synaptic density 95, TrkB tropomyosin receptor kinase B. Adapted with permission from [170].

Ketamine for neuropsychiatric disorders

Ketamine’s early success in rapidly and effectively targeting TRD spurred a surge of interest into its potential to treat other neuropsychiatric disorders, particularly those that are commonly comorbid with depression. With few exceptions, the evidence described below focuses on studies published in the last four years (2019–2023); Table 1 also summarizes recent clinical findings (2019–2023) across multiple neuropsychiatric disorders.

Table 1.

Clinical updates on ketamine (2019–2023).

Disorder	Dose and administration route	Study type	Results and reference
MDD/TRD	Racemic ketamine, with or without adjunctive treatment
	Repeated racemic ketamine (0.5 mg/kg), intravenous	Retrospective analysis, real-world effectiveness (n = 9016)	50% response rate, 30% remission rate. Initial responders had a 60% probability of maintaining response at eight weeks [58].
	Repeated racemic ketamine (0.5 mg/kg), intravenous	Case series, real-world effectiveness (n = 30)	Significant decrease in depressive symptoms for up to two weeks, transient increase in hypertension only during infusion period [60].
	Repeated racemic ketamine (0.5 mg/kg – 0.75 mg/kg) intravenous monotherapy or adjunct to antidepressants	Real-world effectiveness (n = 220)	No significant differences after the four-infusion protocol, except for greater decreases in suicidality with ketamine as monotherapy [54].
	Repeated/intermittent racemic ketamine (0.3 mg/kg) + ECT	RCT (n = 134)	Higher remission rates with ketamine-assisted ECT up to three months [50].
	Repeated/intermittent racemic ketamine (0.3 mg/kg) + ECT	RCT (n = 157)	No significant differences in remission rates, and greater cognitive impairment with ketamine-assisted ECT after ECT course was finished [51].
	Repeated racemic ketamine (0.5 mg/kg) + CBT	RCT (n = 28)	CBT in addition to ketamine generated a greater sustained antidepressant response up to 14 weeks after last ketamine infusion [57].
	Acute racemic ketamine + ASAT	RCT (n = 154)	Ketamine + ASAT group had significantly reduced MADRS scores over a 30-day period [56].
	Racemic ketamine versus esketamine
	Racemic ketamine (0.5 mg/kg) and esketamine (0.25 mg/kg), intravenous	RCT, non-inferiority trial (n = 63)	No significant differences at 24 h, though the racemic ketamine group had lower MADRS scores at seven days [37].
	Repeated racemic ketamine intravenous (0.5 mg/kg) and intranasal esketamine (varying doses)	Observational study (n = 62)	Number of treatments to remission was significantly smaller for intravenous racemic ketamine [38]. 3
	Racemic and esketamine, varying doses, intravenous	Meta-analysis	Racemic ketamine was associated with greater antidepressant response than esketamine and less dropout [36].
	Acute/repeated racemic ketamine, esketamine, varying doses and routes of administration	Meta-analysis, real-world effectiveness	Significant remission rates, but varied responses within patient populations [59].
	Esketamine
	Intranasal esketamine	Post-hoc analysis of Phase 3 trials (n = 928)	Increased incidence of adverse events in early-phase treatment that decreased with each subsequent treatment for up to 12 months [39].
	(R)-ketamine
	(R)-ketamine (0.5 mg/kg), intravenous	Open-label pilot (n = 7)	Significant antidepressant effects, little dissociation at 24 h [42].
	(R)-ketamine (0.5 mg/kg), intravenous	RCT, Phase 2a (n = 102)	No significant antidepressant effects at 24 h [43].
	(R)-ketamine (0.5 mg/kg), intravenous	RCT (n = 10)	No significant antidepressant effects at 24 h [44]
	Hydroxynorketamine (HNK)
	(2R,6R)-HNK, single ascending dose	Phase 1 clinical trial	Completed, results not yet published.
Treatment-resistant bipolar depression	Repeated adjunctive racemic ketamine (0.5 mg/kg), intravenous	Pilot study (n = 19)	Significantly reduced depressive symptoms and suicidal ideation for up to two weeks after last infusion [55].
	Repeated racemic ketamine (0.5 mg/kg), intravenous	Real-world effectiveness (n = 66)	Subsequent decreases in depressive symptoms after each infusion for up to two weeks [61].
Suicidal ideation	Acute racemic ketamine, varying doses, intravenous	Meta-analysis	Reduced suicidal ideation within one day and up to one week, partially independent of effects on mood [72].
	Acute racemic ketamine (0.5 mg/kg)	RCT (n = 18)	88% remission of suicidal ideation after ketamine treatment in the emergency department between 90 and 180 min after treatment [77].
	Two doses racemic ketamine (0.5 mg/kg), intravenous	RCT (n = 156)	Significantly decreased severe acute suicidal ideation at three days, but heterogeneity in results based on primary diagnosis [76].
	Acute/repeated ketamine/esketamine, varying doses and route of administration	Meta-analysis	Significant reductions in suicidal ideation at four hours to three days after infusion, but large heterogeneity between trials [74].
	Acute and repeated racemic ketamine, with maintenance infusions (0.5 mg/kg), intravenous	RCT (n = 37)	69% remission of suicidal ideation after repeated infusions that could be prolonged by maintenance infusions. Maximal effects were seen at seven days after infusion [83].
	Repeated racemic ketamine (0.5 mg/kg), intravenous	Pilot study (n = 86)	Reductions in suicidal ideation as early as four hours post-infusion; initial response predicted sustained response at 24 h after sixth infusion [80].
	Repeated racemic ketamine (0.5 mg/kg), intravenous	Pilot study (n = 111)	Ketamine treatment was associated with subjective and objective functional improvements for up to 26 days after first infusion [81].
	Repeated racemic ketamine (0.5 mg/kg), intravenous	Retrospective chart review (n = 424)	Significant reduction in self-harm and suicidal ideation within six weeks [82].
	Repeated racemic ketamine (0.5–0.75 mg/kg), intravenous	Retrospective analysis (n = 209)	Significant reductions in suicidal ideation in participants with TRD or BD after four infusions [86]
	Repeated racemic ketamine augmentation (0.5 mg/kg), intravenous	RCT (n = 26)	No significant differences between ketamine and placebo at 240 min or three months after infusion [87].
	Racemic ketamine (0.5 mg/kg, intravenous) + rapamycin pre-treatment	Secondary pilot analysis from an RCT (n = 14)	Rapamycin had no impact on ketamine-associated reductions in suicidal ideation for up to two weeks post-administration [92].
Anxiety spectrum disorders	Acute racemic ketamine (0.5 mg/kg), intravenous	RCT (n = 18)	Ketamine significantly reduced social anxiety up to two weeks after infusion [98].
	Racemic ketamine, varying dose and route of administration	Meta-analysis	Ketamine treatment was broadly effective at targeting anxiety spectrum disorders over multiple timepoints [95].
	Repeated racemic ketamine (0.5 mg/kg), intravenous	Retrospective analysis (n = 113)	Baseline anxiety, irritability, and agitation predicted better response to ketamine up to one week after last infusion [94].
	Maintenance racemic ketamine (1 mg/kg), subcutaneous.	Open-label pilot study (n = 20)	Ketamine led to increased social and/or work functioning over three months of weekly ketamine treatment [99].
	Extended-release oral racemic ketamine	Open-label pilot study (n = 7)	Decreased measures of anxiety within 96 h [97].
PTSD	Acute racemic ketamine (0.5 mg/kg), intravenous	RCT (n = 15)	Short-term decline in measures of attention, executive functioning, and verbal memory that resolved within 24 h [105].
	Repeated racemic ketamine (0.2 mg/kg or 0.5 mg/kg), intravenous	RCT (n = 158)	Ketamine had no significant effect on PTSD symptoms during treatment or up to four weeks after last infusion [104].
	Repeated racemic ketamine (0.5 mg/kg), intravenous	RCT (n = 30)	67% response rate to ketamine two weeks after first infusion [102].
	Repeated racemic ketamine, intravenous	Observational (n = 30)	Ketamine significantly decreased PTSD symptoms after six infusions [103].
PTSD + chronic pain	Acute racemic ketamine (0.5 mg/kg), intravenous	RCT (n = 41)	Significant improvement of PTSD and chronic pain symptoms within 24 h and lasting seven days [107].
OCD	Acute racemic ketamine (0.5 mg/kg), intravenous	RCT (n = 15)	Ketamine significantly improved Y-BOCS scores up to three weeks after infusion [114].
	Acute racemic ketamine (0.5 mg/kg), intravenous	RCT (n = 45)	Ketamine significantly improved OCD symptoms at one and seven days after infusion, an effect mediated by cognitive control [113].
	Repeated racemic ketamine (0.5 mg/kg), intravenous	Pilot study (n = 14)	Significant reductions in OCD-related symptoms in a subset of patients over two weeks [112].
	Repeated racemic ketamine (0.5 mg/kg), intravenous	RCT	Recruiting, NCT05577585
Anorexia Nervosa	Repeated racemic ketamine (0.5 mg/kg), intravenous + ketogenic diet	Pilot study (n = 5)	Significant improvements in ED-related thoughts and behaviors after 24 h [122].
	Repeated racemic ketamine (0.3 mg/kg–0.5 mg/kg), intramuscular and intravenous	Case series (n = 4)	Improved depressive symptoms, but only minor improvements in ED-related symptoms over 12 months [123].
Chronic pain	Acute racemic ketamine (0.25 or 0.5 mg/kg)	RCT (n = 103)	Both doses of ketamine reduced acute exacerbations of chronic pain, but no evidence of long-term pain control between 24 and 48 h [130].
	Acute racemic ketamine (0.3 mg/kg), intravenous	Retrospective analysis (n = 24)	Ketamine most effectively targeted pain immediately after infusion in patients with low baseline functional connectivity between the PFC and precuneus [133].
	Racemic ketamine (varying doses and routes of administration)	Observational (n = 257)	Pain intensity decreased significantly at one year [132].
	Racemic ketamine (varying doses), intravenous	Meta-analysis	Small effect at reducing pain up to two weeks after infusion [129].
	Repeated racemic ketamine (0.5 mg/kg) or ketamine + magnesium sulfate	RCT (n = 20)	No differences in daily pain intensity with ketamine over five weeks [131].
Chronic migraine	Racemic ketamine (0.1–0.2 mg/kg), intranasal	Retrospective analysis (n = 34)	Overall pain reduction in study was 66.1%, measured immediately after each infusion [137].
	Five-day infusion of racemic ketamine (increasing doses)	Pilot study (n = 6)	Pain decreased by discharge, but these improvements did not last four to six weeks post-discharge [135].
	Esketamine (varying doses), intranasal	Retrospective analysis (n = 169)	Headache intensity decreased and self-reported quality of life significantly increased over a one-year period [136].
Primary headache syndromes	Racemic ketamine (total 1 mg/kg), intranasal	RCT (n = 53)	Ketamine did not perform better than current standard therapy (metoclopramide) at 30 min after administration [138].
Alcohol use disorder	Acute racemic ketamine (350 ng/ml for 30 min), intravenous	RCT (n = 70)	Ketamine disrupted reward memories in hazardous drinkers, reducing long-term drinking patterns up to 10 days after administration [141].
	Acute racemic ketamine (0.71 mg/kg), intravenous	RCT (n = 40)	In combination with MET, ketamine increased abstinence, decreased the amount of drinking, and delayed relapse over 21 days after ketamine administration [143].
	Up to three infusions racemic ketamine (0.8 mg/kg), intravenous	Qualitative analysis, semi-structured interviews (n = 12)	Self-reported shift in perceived relationship with alcohol throughout six months of treatment [144].
	Repeated racemic ketamine (0.8 mg/kg), intravenous	RCT (n = 96)	Ketamine increased the number of abstinent days within six months post-treatment and had a greater effect in combination with therapy [142].
Cannabis use disorder	Racemic ketamine (0.71–1.41 mg/kg), intravenous (repeated for non-responders)	Pilot study (n = 8)	Significant decrease in frequency of cannabis use when administered in combination with mindfulness-based relapse prevention and MET up to three or more weeks after infusion [146]
Cocaine use disorder	Acute racemic ketamine	RCT (n = 55)	Ketamine significantly reduced cocaine use and time to relapse in combination with behavioral interventions for over two weeks [149].
Opioid use disorder + MDD	Repeated racemic ketamine (0.5 mg/kg), intravenous	Pilot study	Assess the impact of ketamine on methadone treatment retention, currently underway (NCT05051449)

ASAT automated self-association training, BD bipolar depression, CBT cognitive behavioral therapy, ECT electroconvulsive therapy, ED eating disorder, HNK hydroxynorketamine, MDD major depressive disorder, MET motivational enhancement therapy, PFC prefrontal cortex, RCT randomized, controlled trial, TRD treatment-resistant depression, Y-BOCS Yale-Brown Obsessive-Compulsive Scale.

Depression and bipolar disorder

Ketamine has repeatedly been shown to effectively reduce the symptoms of major depressive disorder (MDD) and BD. Because that literature has been extensively reviewed elsewhere [33–35], this review will instead focus on major novel lines of thought: ketamine’s enantiomers and metabolites in the treatment of depression, and the use of adjunctive ketamine in real-world settings.

As noted above, ketamine is a racemic mixture of two enantiomers: (R)-ketamine and (S)-ketamine. Although FDA approval was granted to esketamine, significant discussion continues regarding the comparative efficacy between racemic ketamine and its enantiomers; also, it is important to note that esketamine is approved for intranasal administration, although some of the studies described below have examined intravenous formulations. One meta-analysis found that racemic ketamine elicited a greater overall antidepressant response and had fewer dropouts across studies than esketamine [36]. Another recent comparison of intravenous esketamine (0.25 mg/kg) (n = 34) and racemic ketamine (0.5 mg/kg) (n = 29) found no significant differences in remission rates or safety profile at 24 h after an acute infusion, though there was a slight trend towards decreased MADRS scores and increased response rates in those who received racemic ketamine at 72 h and seven days [37]. Another study comparing intranasal esketamine with intravenous racemic ketamine (n = 62) also found no significant differences in rates of response and remission, though the number of treatments needed to achieve remission was significantly higher for intranasal esketamine [38]. This may be due to an increased incidence of adverse events in early-phase intranasal esketamine treatment; these decrease with subsequent treatments [39].

Although a direct comparison between racemic ketamine and (R)-ketamine has yet to be conducted, considerable preclinical research suggests that (R)-ketamine may have an improved antidepressant profile compared to (S)-ketamine [40]. Pharmacologically, (R)-ketamine may induce fewer adverse events than (S)-ketamine, given its lower binding affinity to NMDARs and cholinergic or alpha-1 adrenergic receptors, which are associated with side effects such as dissociation, tachycardia, hypertension, and palpitations [41]. Clinically, an initial open-label pilot trial found that (R)-ketamine exerted significant antidepressant effects in seven individuals with TRD and, furthermore, was associated with few dissociative symptoms [42]. Despite these promising initial results, the first large-scale, Phase 2a, proof-of-concept clinical trial (n = 102) (NCT05414422) found that (R)-ketamine (PCN-101) had no significant effect on baseline Montgomery-Asberg Depression Rating Scale (MADRS) scores at 24 h post-administration, though it had a generally positive safety profile [43]. Another recent, small, controlled trial (n = 10) obtained similar results [44], suggesting that larger clinical trials are needed to elucidate (R)-ketamine’s antidepressant potential.

Recently, significant attention has focused on the ketamine metabolite HNK, which was initially thought to be inactive. Preclinical research first suggested that metabolism to (2S,6S;2R,6R)-HNK was essential for ketamine’s antidepressant-like effects and that (2R,6R)-HNK could exert its own antidepressant effects in mice [45, 46]. However, an inverse relationship was observed between (2S,6S;2R,6R)-HNK concentration and antidepressant response at three and seven days post-infusion; lower rather than higher levels of (2S,6S;2R,6R)-HNK were associated with improved response [47]. Nevertheless, clinical studies are needed to confirm whether (2R,6R)-HNK has antidepressant effects; a Phase 1 trial is currently in the recruitment stage (NCT04711005), and a Phase 2 trial is planned. Norketamine has also been investigated to a lesser extent [48] but, to date, no clinical trials have assessed its effects in MDD or BD.

Low-dose ketamine could also be an effective adjunctive therapy when given in conjuction with other treatments that target depressive disorders. One salient example is electroconvulsive therapy (ECT), a gold-standard treatment for TRD that requires anesthesia for administration. Multiple studies have now tested the effects of adjunctive ketamine on ECT outcomes and found that ketamine most effectively improves ECT outcomes when it is administered together with another anesthetic; no significant effects were found with ketamine administration alone [49]. However, two studies (n = 134 and n = 157, respectively) found that intermittent low-dose ketamine (0.3 mg/kg, administered before each ECT treatment) improved cognitive functioning and reduced psychiatric complications after ECT [50, 51]. This suggests that low-dose concentrations of ketamine may reduce complications in patients also receiving ECT, though mixed results from meta-analyses of anesthetic-dose ketamine suggest that cautious interpretation is warranted [49, 52, 53].

Ketamine has also been examined as adjunctive therapy with other antidepressants. Interestingly, one study found that adjunctive ketamine performed worse on measures of suicidality than ketamine monotherapy, though no differences were observed on other measures of depression, anxiety, or functional impairment (n = 220) [54]. In contrast, repeated adjunctive ketamine infusions were found to be extremely effective in reducing both depressive symptoms and suicidal ideation in 19 individuals with treatment-resistant bipolar depression [55].

Ketamine has also been administered in conjunction with behavioral therapy. A large, randomized, controlled trial of 154 participants with TRD found that those who received an acute dose of ketamine (0.5 mg/kg) in conjunction with “automated self-association training” (ASAT) over four days had significantly reduced depression scores over a 30-day period; in contrast, the scores of those who received ketamine and a sham ASAT steadily increased over 30 days [56]. Another randomized trial (n = 28) found that cognitive behavioral therapy in addition to repeated ketamine infusions (six infusions over three weeks) generated greater sustained improvement than ketamine alone [57].

Ketamine/esketamine: daily clinical practice

While ketamine’s antidepressant efficacy has repeatedly been demonstrated in randomized, controlled trials, few reports have explored its impact in common clinical practice. One retrospective analysis found response and remission rates of ~50 and 30%, respectively, in community practice [58]. Interestingly, those who responded initially also had an approximately 60% probability of sustaining response at eight weeks without needing maintenance infusions. A recent meta-analysis [59] found that ketamine had substantial real-world effectiveness, with a mean response rate of 55.3% and a remission rate of 28.9%, but differences in remission rates varied across patient groups. In addition, no decreases in therapeutic efficacy were observed with repeated doses, suggesting that chronic ketamine administration could be useful in maintaining antidepressant effects. Another study found that ketamine significantly decreased depressive symptoms in 53 older adults, with a 27% remission rate after four infusions, but was associated with transient increases in hypertension [60]. Finally, another study found that ketamine demonstrated real-world effectiveness in treatment-resistant bipolar depression (n = 66), with subsequent decreases in depressive symptoms observed after each infusion [61].

With regard to esketamine in particular, clinical use was largely based on four positive Phase 3 efficacy studies [62–65] that informed the subsequent FDA approval of intranasal esketamine for TRD and suicidal ideation with intent, as described above. This approval stipulated that patients should receive a maintenance dose of an SSRI or a serotonin-norepinephrine reuptake inhibitor (SNRI) alongside intranasal ketamine as an augmentative treatment (twice per week for four weeks). After this, patients were to transition into a maintenance phase of weekly or biweekly esketamine.

In general, the side effect profile of intranasal esketamine is within the range of previously known intravenous formulations, with events such as dizziness, dissociation, and hypertension being most prominent. As previously noted, intranasal esketamine needs to be administered via a REMS strategy by certified healthcare professionals in specialized treatment centers. However, the COVID-19 pandemic highlighted the possibility of administering and monitoring therapeutics virtually. In this context, a recent, large, open-label effectiveness trial (n = 1247) found that sublingual ketamine monitored over telehealth applications was safe and effective for treating the symptoms of anxiety and depression [66]; 32.6% and 31.3% of participants were classified as remitted on the Patient Health Questionnaire 9 (PHQ-9) and the Generalized Anxiety Disorder 7-item Checklist (GAD-7), respectively. However, this finding and manner of practice remains to be confirmed in controlled efficacy and safety studies. Real-world effectiveness data on intranasal esketamine administered over a study period of six months (n = 66) found a response rate of 47.8% and a remission rate of 37% [67]. However, as noted above, long-term data on the misuse liability of ketamine as an antidepressant are scarce, suggesting that caution is still warranted; nevertheless, preclinical data did not suggest an induction of synaptic plasticity in the nucleus accumbens after repeated use, suggesting a decreased risk of misuse [68]. However, other mechanisms that increase misuse may be in play and should not be disregarded.

As daily clinical practice moves forward, it will be crucial to compare the efficacy of ketamine with other treatment modalities. For instance, one trial found that remission rates post-ketamine were inferior to those post-ECT [69], and a meta-analysis comparing ECT and ketamine obtained similar results, demonstrating an inferiority of ketamine to ECT [70]. A larger non-inferiority trial is currently underway, and results are pending (ELEKT-D; NCT03113968). However, a network meta-analysis found that ketamine was superior to other pharmacological treatments at two weeks after treatment initiation; at four, six, and eight weeks, quetiapine and risperidone augmentation were found to be the best and second best treatments, respectively [71]. Comparative data are not yet available for ketamine versus neuromodulatory treatments such as transcranial magnetic stimulation or deep brain stimulation.

Suicidal ideation

Significant research supports the use of ketamine to treat suicidal ideation in MDD and BD. Multiple meta-analyses and systematic reviews have demonstrated that ketamine significantly reduces suicidal ideation within one day and up to six weeks, an effect that appears to be at least partially independent of its effects on mood [72–75]. Altough initial research focused primarily on acute intravenous doses of ketamine, recent research has shifted towards analyzing the effects of repeated doses, different routes of administration, and the effects of ketamine in more naturalistic settings. Of particular interest has been the use of ketamine for acute treatment in emergency situations, with recent research demonstrating that ketamine significantly improved full remission rates for those presenting with severe acute suicidal ideation, though this effect differed based on primary diagnosis [76]. Previous research echoes these results, with multiple studies finding high rates of remission for suicidal ideation after a single ketamine infusion in patients hospitalized for acute suicidal ideation [77–79].

Clinical trials also indicate that repeated ketamine infusions can improve and maintain reductions in suicidal ideation [80–82]. One double-blind, crossover trial (n = 37) found that 69% of participants had complete remission of suicidal ideation after six ketamine infusions, an effect maintained with weekly maintenance infusions [83]. Improvements in working memory and serum tryptophan metabolites have also been associated with decreased suicidal ideation after repeated ketamine infusions [84, 85] (n = 59 and n = 73, respectively). Another study found that repeated ketamine infusions significantly reduced measures of suicidality in an outpatient cohort of 177 participants with MDD and 26 participants with BD [86]. Although a different study found that repeated ketamine infusions had no effect on severity of depressive symptoms or suicidal ideation, the 26 participants in that study had severe MDD with chronic suicidal ideation, suggesting that a higher ketamine dose or an increased number of infusions may have been necessary to see an effect [87].

Esketamine has also shown efficacy in reducing suicidal ideation in individuals with TRD. Clinical trials found that esketamine, in combination with an oral antidepressant, rapidly reduced suicidal thoughts compared to placebo in adults with TRD who were at imminent risk for suicide [65, 88, 89]. Indeed, this finding led the FDA to approve esketamine for depressed individuals with suicidal ideation. However, it should be noted that a recent systematic review found that intranasal esketamine did not perform better than placebo at reducing suicidal ideation [90], though this finding may have been confounded by the high placebo response rate that exists when assessing suicidal ideation [91].

To further understand the potential mechanisms underlying ketamine’s effects on suicidal ideation, a recent clinical study assessed the effect of pre-treatment with rapamycin (an mTORC1 inhibitor) on suicidal ideation. In a post-hoc analysis, one study (n = 14) found that rapamycin did not improve suicidal ideation measures after ketamine treatment [92], an effect that differed from its effect on depressive symptoms (n = 20) [93]. The difference in pre-treatment rapamycin’s impact suggests that ketamine may have mechanistically distinct impacts on suicidal ideation and depressive symptoms. Future research should further assess the maintenance of ketamine’s anti-suicidal effects through repeated dosages, the performance of ketamine in combination with behavioral interventions, and the distinct mechanisms underlying ketamine’s effects on suicidal ideation and behaviors.

Anxiety-related disorders

Most research in this area has focused on ketamine’s impact on anxiety symptoms in those with depression or comorbid anxiety disorders. One study found that repeat-dose ketamine rapidly improved anxiety, irritability, and agitation in 201 individuals with MDD or BD, and that participants with baseline anxiety, irritability, and agitation experienced a greater reduction in depressive symptoms and anxiety [94]. In addition, a recent systematic review and meta-analysis across all anxiety spectrum disorders found that ketamine was broadly effective for treatment-resistant anxiety disorders, particularly with repeated doses [95]. Another study found that repeated intramuscular administration of ketamine to 452 patients diagnosed with MDD, generalized anxiety disorder, or post-traumatic stress disorder (PTSD) reduced anxiety scores by 50% from baseline to last treatment; these anti-anxiety effects were maintained for over seven months after treatment [96]. Finally, another study found that an extended-release oral ketamine tablet gradually decreased depressive and anxiety symptoms in seven participants with TRD and anxiety within 96 h of administration [97].

In those diagnosed with social anxiety disorder (SAD), one randomized, placebo-controlled, crossover trial (n = 18) found that ketamine effectively decreased ratings of anxiety within three hours, an effect that was maintained for up to two days post-infusion [98]. Another study (n = 20) also found that maintenance ketamine doses were safe and effective in those diagnosed with treatment-refractory generalized and/or social anxiety disorders [99].

Post-traumatic stress disorder

Ketamine has also been assessed for the treatment of PTSD. Only two pharmacotherapies are currently approved for PTSD—sertraline and paroxetine—and both have high relapse rates [100]. Notably, single-dose intravenous ketamine rapidly reduced PTSD symptoms in a proof-of-concept trial (n = 22) [101]. Another study of repeat-dose ketamine (six infusions over two weeks, n = 30) found a response rate of 67% [102]. High-dose ketamine administered over six infusions (n = 30) also significantly decreased PTSD symptoms [103]. In contrast, a recent, randomized, placebo-controlled (saline), multicenter clinical trial found that repeat-dose ketamine (eight infusions, given twice per week) had no effect on PTSD-associated symptoms in 158 individuals with treatment-resistant PTSD, potentially due to a high placebo response; however, repeat-dose ketamine significantly decreased depressive symptoms [104]. Another study (n = 15) found that ketamine was associated with short-term attention deficits in participants with PTSD, but these effects appeared to be transient [105]. Despite these mixed results, ketamine may be uniquely effective in effectively targeting common comorbidities associated with PTSD, including MDD, chronic pain, and alcohol use disorder [106]. For example, one randomized, controlled trial (n = 40) found that ketamine successfully decreased symptoms of both chronic pain and PTSD, an effect that lasted seven days post-infusion [107].

Obsessive-compulsive disorder

Ketamine has also been investigated in obsessive-compulsive disorder (OCD). An early, randomized, controlled trial (n = 15) and a case report both found that ketamine effectively targeted the obsessions and compulsions characteristic of OCD, as measured by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) [108, 109]. This effect may have been mediated in part by decreasing NMDAR activity and mediating GABA receptors, which are thought to be associated with behavioral dysregulation in OCD [110, 111]. Another study (n = 14) found that multiple ketamine infusions effectively reduced symptoms in a subset of individuals with treatment-resistant OCD [112]. Furthermore, a recent, randomized, controlled trial (n = 45) found that ketamine significantly reduced OCD symptoms at one and seven days post-infusion, an effect that was mediated by measures of cognitive control [113]. Another randomized, controlled trial (n = 15) found significant long-term reductions in OCD symptoms for up to three weeks after an acute ketamine infusion [114]. However, not all studies support the use of ketamine to treat OCD. One open-label ketamine trial (n = 10) found that this agent had no effect on OCD symptoms, though it did improve depressive symptoms in some participants [115]; it should also be noted that two participants in that trial with similar neuropsychiatric histories experienced delayed-onset symptoms of anxiety, suicidal ideation, and dysphoria post-ketamine infusion [116]. Nevertheless, a recent systematic review supported ketamine use for the treatment of OCD, though results appeared to vary across studies and require further investigation [117]. Additional randomized, placebo-controlled trials are currently recruiting participants to assess the effects of ketamine on OCD symptoms (NCT05577585, NCT02624596).

Eating disorders

Eating disorders (ED) are highly prevalent neuropsychiatric disorders with severe physical and psychological symptom profiles [118]. Eating disorders often also present with concomitant disorders such as depression and anxiety and have the highest mortality rate of all psychiatric disorders [119, 120]. In an open-label pilot study, repeated ketamine infusions were used in conjunction with a ketogenic diet in five individuals who had recovered from anorexia nervosa but still had persistent ED-related thoughts and behaviors. Significant improvements were found across multiple measures on the Eating Disorder Examination Questionnaire and Clinical Impairment Assessment; importantly, these were found to last for up to six months [121]. A case series (n = 5) found significant improvements in anxiety and depression measures after ketamine-assisted psychotherapy in a residential ED treatment center, though there was no follow-up on ED symptoms [122]. Interestingly, a longitudinal case series (n = 4) found that intramuscular ketamine improved depressive symptoms in those diagnosed with a severe ED and comorbid TRD, though there were only minor changes in ED-related symptomology [123]. While few studies have been conducted to assess ketamine’s effects in ED, the initial promising results and the success of other glutamatergic agents for this indication encourage further exploration [124–126].

Chronic pain/migraine

Ketamine has been used for decades to treat chronic pain, particularly neuropathic pain, phantom limb pain, and fibromyalgia [127, 128]. However, it remains unclear why ketamine is effective, or which forms of chronic pain it may target most effectively. A meta-analysis of randomized, controlled trials assessing ketamine’s analgesic effects found that it was generally effective in targeting both neuropathic and non-neuropathic pain [129]. One study (n = 97) found that acute exacerbations of chronic pain were effectively managed by low-dose ketamine, but symptoms returned within 24–48 h [130]. As mentioned previously, ketamine was also effective in PTSD with comorbid chronic pain [107].

In a double-blind, randomized, controlled trial of 20 individuals with neuropathic pain, ketamine had no analgesic effects at five weeks post-infusion, suggesting that it may work more acutely [131]. However, a multicenter prospective trial (n = 256) found significant pain improvements at one-year follow-up [132]. Interestingly, the authors identified distinct pain trajectories and responses to ketamine for different forms of chronic pain, which could inform future clinical use of ketamine for pain management. Finally, a recent resting-state functional magnetic resonance imaging (fMRI) study (n = 24) determined that ketamine targeted chronic pain most effectively in participants with low baseline functional connectivity strength between the medial prefrontal cortex and precuneus [133].

The analgesic effects of ketamine have generated significant interest as a way to treat refractory chronic migraines, which are characterized by substantial disability and multiple treatment failures [134]. In an observational pilot study (n = 6), ketamine was slightly more effective than lidocaine for pain relief during hospitalization, although pain levels returned to baseline within six weeks [135]. A prospective study also found that intranasal ketamine effectively reduced headache intensity and improved quality of life in 169 participants with refractory chronic migraines [136]. A preliminary retrospective review (n = 34) also found that intranasal ketamine effectively reduced migraine pain in a pediatric population [137]. However, a randomized, controlled trial (n = 53) for primary headache syndromes found that ketamine did not perform better than current standard therapies [138]. A recent systematic review found similarly mixed results on the efficacy of ketamine for the treatment of migraines and primary headache disorders, emphasizing the need for further randomized controlled trials that compare ketamine to the current standard of care [139].

Substance and alcohol misuse

Alcohol and substance misuse are highly prevalent, and current treatments have long-term relapse rates, necessitating novel therapeutic approaches. Chronic alcohol use has been associated with changes in NMDAR function [140], suggesting that ketamine may be an effective mediator of withdrawal symptoms and relapse. Indeed, a recent, randomized, controlled trial found that ketamine effectively disrupted maladaptive reward memories in 70 hazardous drinkers who were actively recollecting an associated memory, reducing the potential reinforcing effects of the memory and long-term drinking patterns [141]. In a placebo-controlled, randomized trial (n = 96), ketamine increased the number of days of abstinence from alcohol in those diagnosed with severe alcohol use disorder, and this number was even greater when used in combination with psychotherapy [142]. Another study found that adjunctive ketamine administered with motivational enhancement therapy (n = 40) significantly increased the likelihood of abstinence, decreased the amount of drinking, and delayed relapse [143]. A qualitative analysis of semi-structured interviews in 12 participants with alcohol use disorder found that ketamine administration significantly shifted participants’ perceived relationship with alcohol [144]. A systematic review suggested that the evidence was not yet strong enough to make solid conclusions, but that the initial results were promising enough to prompt further exploration of ketamine’s long-term effects in alcohol use disorders [145].

Substance use disorders are often resistant to traditional pharmacotherapy and behavioral interventions. Glutamatergic dysregulation has been implicated across multiple substance use disorders, leading to interest in the putative therapeutic impact of ketamine. In a proof-of-concept study (n = 8), ketamine significantly decreased self-reported cannabis use in combination with motivational enhancement therapy and mindfulness-based relapse prevention [146]. Interestingly, a small, randomized, controlled trial (n = 8) found that an initial dose (0.41 mg/kg) of ketamine reduced cue-induced craving at 24 h post-infusion, and that cravings were further decreased with a subsequent ketamine infusion (0.71 mg/kg) [147]. Building on this work, another randomized, controlled trial of 20 participants with cocaine use disorder found that ketamine decreased cocaine self-administration by 67% after 24 h, though this effect disappeared after a few days [148]. Significant reductions in cocaine use were also observed after ketamine administration in a randomized, controlled trial (n = 55) of ketamine in combination with mindfulness-based behavioral interventions [149].

One major therapeutic focus for ketamine has been its potential to treat opioid use disorder, particularly in combination with other long-acting opioid agonists. A recent case study found that ketamine may work synergistically with buprenorphine on buprenorphine-precipitated opioid withdrawal due to its unique pharmacological profile that can reduce opioid withdrawal symptoms without direct mu-opioid receptor binding [150]. A pilot clinical trial is currently underway to assess the impact of ketamine on methadone treatment retention and depressive symptoms in opioid use disorder (NCT05051449). This area of research is also closely linked to ketamine’s analgesic effects. Given ketamine’s initial role as an anesthetic, clinicians have been investigating whether low-dose ketamine might be used instead of opioids to address acute pain in various settings, such as in patients with cancer or limb fractures [151]. Interestingly, one randomized, controlled trial (n = 129) found that ketamine reduced post-operative opioid consumption and pain ratings in opioid tolerant, but not opioid-naïve, patients [152]. However, a randomized trial on acute pain management after orthopedic surgery in 180 patients diagnosed with opioid use disorder found that repeated ketamine administration was not as effective as systemic lidocaine administration in reducing ratings of pain and restlessness or morphine use [153].

Caution in this area of research is also warranted as ketamine has been used as a recreational substance, though the misuse liability of ketamine after administration in clinical settings remains unknown [154]. For instance, preclinical evidence suggests that ketamine therapy may be associated with certain risks, such as increasing drug-dependence-related behaviors like self-administration, conditioned place preference, hyperlocomotion, and prepulse inhibition deficits [155–157]. However, work in mice found no drug-induced sensitization or drug-evoked synaptic plasticity for ketamine, suggesting lower misuse liablity than the comparative substance, cocaine [68]. Minimal clinical research supports these findings, suggesting that risks of dependency are extremely low when ketamine is administered in a medical setting [158–160]. Nevertheless, assessing the impact of repeated ketamine administration in an outpatient setting and in participants with a history of substance misuse or dependence may provide a more realistic look at dependency rates. Interestingly, recent research suggests that (R)-ketamine may present a lower liability risk than racemic or (S)-ketamine. Preclinically, (R)-ketamine does not induce conditioned place preference, deficits in prepulse inhibition, or hyperlocomotion [155–157]. Clinically, reported psychotomimetic effects have been more pronounced after administration of (S)-ketamine than (R)-ketamine [43], which could contribute to misuse liability. However, to the best of our knowledge, no formal assessments have been conducted to assess dependency after ketamine enantiomer-specific administration.

Pitfalls in current research

Despite the bulk of the novel evidence described above, rapid-acting antidepressants like ketamine are associated with some of the same issues that plague research with longer-acting antidepressants such as selective serotonin reuptake inhibitors (SSRIs). First, placebo response rates are high in depression and suicidality research, as well in trials with rapid-acting antidepressants [104]. This might be due to patients’ expectations of benefits in clinical trials with novel substances, behavioral conditioning in research settings, or the striking overlap in neuroanatomical substrates between affected brain regions in MDD and placebo response [161]. Strategies to mitigate placebo response include increasing study duration, randomizing the run-in period, and addressing functional blinding in rapid-acting antidepressant trials [162]. Second, outcome parameters such as the MADRS were designed to measure symptom changes in longer time periods (seven days) than rapid-acting agents, whose effects often manifest in 24 h or less, although validation of the MADRS for repetitive use within 24 h exists [163]. In this context, a task-force within the International Society for CNS Clinical Trials and Methodology to evaluate assessment methods and endpoints for rapid-acting antidepressants has been funded, and novel outcome parameters are expected to be developed. Third, data on safety and relapse rates during repetitive and prolonged use for rapid-acting antidepressants is only beginning to be established. In this regard, more data are currently available for ketamine/esketamine than for other rapid-acting agents (e.g., serotonergic psychedelics). Caution is also warranted when administering drugs with potent psychophysiological effects in uncontrolled medical settings (i.e. home use), since adverse events including dependency would be harder to assess.

Insights from other novel therapeutics

While ketamine evidently has great clinical utility, its direct therapeutic mechanisms are still unclear. However, the recent development and/or repurposing of other neuropsychopharmacological interventions provides important insight into how different aspects of ketamine’s unique pharmacology, such as NMDAR antagonism and AMPAR modulation, may contribute to symptom alleviation. In addition, the success of therapeutics with well-defined mechanisms of action can provide insight into how ketamine may target each neuropsychiatric disorder discussed above. It should be noted that other therapeutic interventions such as repeated transcranial magnetic stimulation, electroconvulsive therapy, and deep brain stimulation also warrant further attention but are beyond the scope of this review.

NMDAR modulators

Given that ketamine is a canonical NMDAR antagonist, preclinical and clinical research on various NMDAR antagonists quickly followed the discovery of ketamine’s rapid-acting therapeutic effects. Early work in this area, however, found that few NMDAR antagonists and modulators had clinical success, failing to replicate ketamine’s broad therapeutic profile and rapid onset of robust antidepressant effects. For example, non-specific NMDAR antagonists such as memantine had extremely varied results in clinical studies due to differences in patient population, dosing regimen, and concurrent antidepressant medications [164]. Lanicemine (AZD6765) initially demonstrated rapid-acting antidepressant effects in patients with TRD [165, 166], but these findings were not replicated in a Phase 2 trial [167]. Glycine site modulators such as GLYX-13, apimostinel, and 4-Chlorokynurenine (AV-101) experienced similar difficulties [168]. Following the failure of more generalized NMDAR antagonists and modulators as clinically effective antidepressants, NR2B-specific subunit antagonists such as traxoprodil (CP-101,606), MK-0657 (CERC-301), and eliprodil (EVT-101) were developed but suffered similar failures. Broadly, these agents demonstrated no significant antidepressant efficacy and an adverse events profile that led to the early terminations of some clinical trials in indications such as MDD, TRD, and Parkinson’s disease [169, 170].

Nevertheless, some other NMDAR antagonists and modulators have shown promise, including D-cycloserine, nitrous oxide, MIJ-821, REL-1017, and AXS-05. D-cycloserine, a glycine site modulator, has been assessed over the last decade in negative, positive, and cognitive symptom domains in schizophrenia with mixed results [171]. More recent research is investigating adjunctive D-cycloserine for indications such as OCD, PTSD, and MDD [172–174]. D-cycloserine has also been proposed as a method of maintaining clinical response after ketamine administration; one study of individuals with either MDD or bipolar depression (n = 32) found that although it was unable to differentiate from placebo in maintaining an antidepressant effect, it was superior in maintaining ketamine’s antisuicidal effects [175]. Another study found that D-cycloserine in combination with hydrocortisone facilitated fear extinction in 90 participants with PTSD [174].

Nitrous oxide inhibits NMDA currents in a dose-dependent manner, amongst other documented mechanisms [176]. Inhaled 50% nitrous oxide had significant and rapid-acting antidepressant effects in 20 individuals with TRD [177] and in a small cohort (n = 3) of participants with PTSD [178]. A proof-of-concept, randomized, controlled trial in 25 individuals with treatment-refractory BD found that nitrous oxide significantly decreased same-day ratings of depression severity, though there were no significant changes in MADRS scores at 24 h; in addition, baseline cerebral blood flow predicted MADRS reductions at 24 h post-nitrous oxide administration, a finding not observed in control groups [179]. In addition, a Phase 2 trial of 25 and 50% inhaled nitrous oxide for TRD (n = 24) found significant improvement in depressive symptoms in both nitrous oxide groups, with a significantly lower rate of adverse events in the 25% nitrous oxide group [180]. Multiple clinical trials are currently underway to assess the effects of nitrous oxide on suicidal ideation (NCT03736538), MDD and/or TRD (NCT05357040, NCT03932825), and OCD (NCT03826693).

MIJ-821 is an NR2B negative allosteric modulator that binds to and inhibits the activity of NMDARs, thereby inhibiting abnormal neurotransmission. A recent proof-of-concept, Phase 2a, randomized clinical trial compared two doses of intravenous MIJ-821 to ketamine in 70 adults with TRD and found that the antidepressant effects of MIJ-821 were comparable to those of ketamine, but that MIJ-821 had a safer pharmacological profile [181].

REL-1017 (esmethadone, d-methadone) is an NMDAR channel blocker that has demonstrated significant promise as a therapeutic. Preclinical research found that REL-1017 preferentially binds to the NR1-2D subunit [182]. An early Phase 1 clinical trial demonstrated significant increases in plasma BDNF after administration of esmethadone in six healthy volunteers [183], and Phase 2a, randomized, double-blind trials (n = 62 in both trials) found significant rapid and sustained (seven days) antidepressant effects in participants with TRD after repeated administration of REL-1017 [184, 185]. However, a recent Phase 3 trial to assess REL-1017 as monotherapy for MDD found no significant differences from placebo (NCT05081167). Other Phase 3 trials for MDD are currently recruiting participants (NCT04855747; NCT04855760).

Finally, in October 2022, the FDA approved Auvelity (AXS-05), an extended-release oral tablet containing dextromethorphan and buprenorphine for the treatment of MDD in adults. Although it does not act as rapidly as ketamine, Auvelity demonstrated a significant difference from placebo at one week and up until six weeks (n = 327) [186]. Auvelity is hypothesized to work via the NMDAR antagonism of dextromethorphan, which is prolonged by bupropion, a norepinephrine-dopamine reuptake inhibitor [187]. Dextromethorphan is also a sigma-1 agonist, implicating a novel mechanism of action in rapid-acting antidepressant effects. Auvelity has also received a fast-track designation from the FDA to treat Alzheimer’s disease, with multiple ongoing and completed clinical trials that have not yet posted results [188] (NCT05557409, NCT04947553, NCT04797715, NCT03226522). Thus, despite early failures in the development of other NMDAR modulators as rapid-acting antidepressants, several promising agents are currently under investigation.

mGluR2/3 antagonists

Metabotropic glutamate receptors (mGluRs) have repeatedly been implicated in the pathophysiology of depression, and mGluRs2/3 are known to mediate levels of glutamate and synaptic plasticity [189]. mGluR2/3 antagonists have also been preclinically successful at inducing rapid-acting antidepressant-like effects. In rodent brain slices, both ketamine and (2R,6R)-HNK augmented excitatory synaptic transmission, an effect mediated via the actions of mGluRs2/3 [46, 190–192]. In addition, an mGluR2/3 agonist-induced hypothermic assay demonstrated that racemic ketamine and (2R,6R)-HNK prevented the increases in body temperature induced by an mGluR2/3 orthostatic agonist (LY379628), implicating mGluR2/3 antagonism in ketamine’s antidepressant effects [193]. Administration of LY379628 before (2R,6R)-HNK also prevented the rescue of anhedonic-like behavior and shock-induced escape deficits. These findings were not replicated with other NMDAR antagonists or with 6,6-d2-(R,S)-ketamine [193].

Currently, mGluR2/3 antagonists and negative allosteric modulators (NAMs) are undergoing Phase 1 and Phase 2 clinical trials. TS-161, an mGluR2/3 antagonist, completed a Phase 1 evaluation of its safety profile, tolerability, and pharmacokinetics and was found to be safe and well-tolerated with high rates of conversion to its active metabolite and sufficient CSF penetration for pharmacological effects [194]; a Phase 2 trial is currently underway (NCT04821271). RO4995819 (decoglurant), an mGluR2/3 NAM, has also completed Phase 1 clinical trials and a Phase 2 trial in partially refractory MDD, but no significant differences were observed between decoglurant and placebo [195]. While there is no direct link between ketamine and mGluR2/3 antagonism, sub-effective ketamine administered in conjunction with LY341495 produced significant antidepressant-like effects in a preclinical model [196]. Co-administration of ketamine and an mGluR2/3 antagonist also sustained antidepressant-like responses in another animal model [197], which further supports mGluR2/3 antagonists as effective adjunctive therapies.

AMPAR modulators

As noted above, ketamine has repeatedly been shown to increase AMPAR activity and throughput, suggesting that increasing AMPAR signaling itself may facilitate rapid-acting therapeutic effects. Following this line of thinking, many companies began to develop AMPAR modulators [198]. AMPAkines, a series of AMPAR positive allosteric modulators (PAMs) that increase the amplitude and duration of AMPA currents and include CX516, CX546, CX614, CX691, and tulrampator, were assessed for indications such as TRD, cognitive decline, and Alzheimer’s disease, but later-stage clinical trials often failed to meet their primary endpoints [198].

Other AMPAR PAMs, such as S18986, LY392098, and mibampator, which are thought to function by reducing desensitization of the ion channel [199], have been tested since the early 2000s for their potential applications in depression, schizophrenia, Parkinson’s disease, and attention deficit hyperactivity disorder (ADHD) [200]. While AMPAR PAMs appeared to be well-tolerated in early-phase clinical trials, failures to improve cognition and mood have consistently been observed [201, 202]. The consistent failures of PAMs to pass Phase 2 clinical trials suggest that the unique efficacy of ketamine may not be mediated solely through AMPAR modulation. Despite these caveats, the unique structure and function of AMPARs allow for multiple approaches to mediate glutamatergic activity and could still hold great promise for developing novel therapeutics.

Insights from neuroimaging

Neuroimaging studies can provide a strong foundation to bridge preclinical and clinical research, allowing a non-invasive way to study changes in brain function. Techniques such as electroencephalography (EEG), magnetoencephalography (MEG), magnetic resonance spectroscopy (MRS), fMRI, and/or positron emission tomography (PET) allow for a macroscopic viewpoint of neurophysiological function. One of the hallmarks of most neuropsychiatric disorders is dysregulated neuroplasticity, which interrupts most facets of normal functioning, including normal cognitive, learning, and memory processes [203].

A key area of interest for elucidating ketamine’s underlying mechanisms of action has been measuring changes in gamma oscillations, as they are closely regulated by GABA_A modulation and AMPAR-mediated depolarization, making them a valuable measure of excitatory/inhibitory balance [204]. Gamma power has been found to be consistently increased after subanesthetic ketamine administration in participants with depression [205, 206].

Preclinical PET imaging also provides a valuable tool for translating scientific results, allowing for high-throughput hypothesis testing before recruiting human participants. Paralleling previous preclinical research, PET imaging studies found that increased 5-HT_1B receptor binding was associated with ketamine response in participants with TRD and correlated with depression symptom ratings at baseline [207]. Using [¹¹C]UCB-J, a radioligand that binds to synaptic vesicle protein 2A (SV2A) and can provide a proxy measure of synaptic connectivity in participants, a recent study found that lower SV2A density at baseline in healthy volunteers and participants with MDD and/or PTSD predicted increases in SV2A density after ketamine administration; these increases, in turn, were associated with fewer depressive symptoms [208].

Deficits in global brain connectivity have also been repeatedly implicated in MDD and can be assessed using resting-state fMRI. While initial studies found improved global brain connectivity post-ketamine administration [209], another study found similar baseline differences between healthy volunteers and individuals with MDD but did not replicate differences in global brain connectivity after ketamine versus placebo [210]. Another resting-state fMRI study found that ketamine increased frontostriatal connectivity in participants with TRD, an effect that was disrupted when ketamine was administered to healthy volunteers [9]. Furthermore, decreased hyperconnectivity of the subgenual anterior cingulate cortex and the default mode network, as assessed through resting-state fMRI, were found to be associated with treatment response after a 96-h ketamine infusion [211]. In another fMRI study, participants with TRD had lower activity in the right frontal cluster, anterior cingulate cortex, and insula after ketamine infusion when compared to healthy volunteers, and this pattern mirrored measurements from healthy volunteers after a placebo infusion [212], suggesting that ketamine normalized function. In contrast, a novel approach of combining EEG with fMRI suggested that increases in the subgenual anterior cingulate cortex after subanesthetic ketamine administration may be due to physiological noise; however, the study was conducted in healthy volunteers, and the results implicated a distinct time course for neural responses to ketamine that should be explored in future research [213].

Collectively, the evidence reviewed above suggests that neuroimaging provides a powerful translational tool for addressing the underlying mechanisms of ketamine and therapeutic response. Notably, differences between healthy volunteers and other participants—particularly those with TRD—should be considered when interpreting results, as most imaging research in this area identified disparate effects. For more detailed reviews on neuroimaging correlates associated with ketamine, we refer the interested reader to [214, 215].

Future directions and clinical implications

Most research to date has unsurprisingly focused on the antidepressant effects of ketamine. Over time, however, increasing evidence has suggested that ketamine is a promising treatment for BD, suicidal ideation, anxiety spectrum disorders, eating disorders, chronic pain, migraines, and substance use disorders. Given ketamine’s broad efficacy, future research in this area should further verify the utility of ketamine in lesser-studied disorders such as PTSD and OCD, as well as depression-related comorbidities and other neurological conditions. It should also be noted that while these initial results are certainly encouraging, the efficacy of ketamine for several of the neuropsychiatric conditions reviewed above is based on a small number of trials and participants, suggesting that larger, more rigorous trials are needed to confirm the findings. Likewise, many of the trials presented in Table 1 are pilot studies and case series, which are often uncontrolled or have small sample sizes, again underscoring the need to replicate results. In addition, variance in the dose used, the frequency of administration, and the duration of treatment can significantly impact results and should be considered carefully when designing studies or interpreting results.

As noted in our discussion of how novel therapeutics may provide insight into ketamine’s mechanisms and the development of more effective therapeutics, future studies in drug development are likely to uncover insights into target disorder-specific pathways. Preclinical research should further elucidate ketamine’s underlying mechanisms for each disorder separately, such as NMDAR antagonism, AMPAR modulation, or opioid system modulation. Disparities in dosing regimens and formulations (enantiomers, metabolites) should also be considered in a diagnosis-specific manner.

As the use of ketamine in daily clinical practice increases, decreasing the adverse events associated with ketamine and esketamine should be a priority, since such measures could increase treatment adherence and decrease patient discomfort in the long-term. Notably, initial research has suggested that adverse events occur less freqently with maintenance treatments of intranasal esketamine, but this should be assessed further. Another area of interest is (R)-ketamine. As noted above, preclinical and early phase clinical research found that (R)-ketamine may elicit fewer adverse effects than either racemic ketamine or esketamine, but its lack of efficacy in a large-scale clinical trial suggests that more potent NMDAR antagonism (associated with ketamine’s dissociative and psychotomimetic effects) or other mechanisms may be necessary for rapid-acting antidepressant effects. When longer-term data are available, it is essential to assess the misuse liability of ketamine when administered in a clinical setting, particularly for those at greater risk of substance use disorders. In addition, while intranasal esketamine is used adjunctively in daily clinical practice, few studies have yet examined drug-drug interactions between ketamine and monoaminergic-based therapeutics. Further characterization of ketamine in conjunction with different treatment strategies such as psychotherapy, rTMS, and ECT are also essential, particularly for cases that may not have initially responded to behavioral or neuromodulatory interventions.

Collectively, the evidence reviewed above demonstrates that ketamine has clinical efficacy across multiple neuropsychiatric disorders, and the FDA has approved the use of esketamine for MDD and acute suicidal crisis. The novel pharmacological mechanisms of action currently being studied open up a field of novel therapeutics with rapid-acting properties. While many of the involved neurobiological mechanisms remain unclear, the current evidence emphasizes the importance of both NMDAR and AMPAR mediation and the involvement of downstream cascades that mediate rapid changes in network plasticity. Importantly, the side-effect profiles of ketamine and esketamine as prototypes for rapid-acting substances are now well established, though long-term data on the risk of abuse and dependence remain scarce. However, under cautious use and medical supervision—as required by FDA approval and REMS strategy—reports of misuse and abuse of esketamine as an antidepressant have been extremely low.

The discovery of ketamine’s rapid-acting antidepressant properties and the field’s ongoing study of its underlying mechanisms of action have yielded valuable insights into novel antidepressant mechanisms. These insights, in turn, continue to broaden our understanding of the utility of this agent across multiple neuropsychiatric disorders, refine our view of the pathophysiology of MDD and related disorders, and are expected to yield crucial discoveries in the coming years.

Author contributions

All authors contributed equally to the conceptualization of the manuscript, literature search, generation of the figure and table, writing, and revision of this manuscript. All authors approved the final version of the paper.

Funding

Funding for this work was provided by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIAMH002857). Additional funding was provided by a NARSAD Young Investigator Award to BK. The NIMH and NARSAD had no further role in study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. The work was completed as part of the authors’ official duties as Government employees. The views expressed do not necessarily reflect the views of the NIH, the Department of Health and Human Services, or the United States Government.

Competing interests

CAZ is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. BK is now a full-time employee and shareholder of Jazz Pharmaceuticals. All other authors have no conflict of interest to disclose, financial or otherwise.