This review (2015) provides an overview of the antidepressant mechanism of ketamine, clinical studies with ketamine, and its use in shaping the development of next-generation treatments, which include better tolerated non-ketamine NMDA antagonists and other non-NMDA glutamatergic modulators.
Review: In the past decade the emergence of glutamate N-methyl-D-aspartate (NMDA) receptor blockers such as ketamine as fast-acting antidepressants fostered a major conceptual advance by demonstrating the possibility of a rapid antidepressant response. This discovery brings unique mechanistic insight into antidepressant action, as there is a substantial amount of basic knowledge on glutamatergic neurotransmission and how blockade of NMDA receptors may elicit plasticity. The combination of this basic knowledge base and the growing clinical findings will facilitate the development of novel fast acting antidepressants.
Major depressive disorder remains a leading cause of disability, and commonly used antidepressant drugs that target monoamine systems typically take several weeks to produce clinical benefit and fail in about one-third of patients. There is therefore a substantial unmet need for treatments with a rapid onset of action, particularly for people with treatment-resistant depression and those at increased risk of suicide. Clinical reports that low doses of the NMDA receptor antagonist ketamine can produce antidepressant effects within hours, and antisuicidal effects in the short term, generated intense interest because they suggested a fundamentally different mechanism from conventional monoaminergic antidepressants. Monteggia and colleagues set out to review preclinical and clinical evidence on ketamine’s antidepressant actions with emphasis on synaptic and intracellular mechanisms that might explain its rapid and relatively durable behavioural effects. The review also surveys clinical developments aimed at prolonging ketamine’s benefit, developing alternative NMDA-modulating agents with fewer psychotomimetic effects, and identifying potential biomarkers of response. The aim is to link mechanistic insights with translational and clinical strategies for next-generation rapid-acting antidepressants.
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The extracted text presents a narrative review rather than a systematic review or meta-analysis; no explicit methods section, search strategy, or prespecified inclusion criteria are reported in the provided text. Instead, the paper synthesises findings from basic neuroscience studies (molecular, cellular, and rodent behavioural work) together with clinical trials and biomarker studies to construct mechanistic and translational perspectives. The review focuses on: (1) mechanistic hypotheses derived from genetic, pharmacological and signalling studies in animal models and in vitro systems; (2) clinical trial data for ketamine and other NMDA receptor modulators (including dose/routing information and time course of antidepressant effects where reported); and (3) emerging approaches for maintaining response and identifying biomarkers. Where available, specific experimental manipulations (for example, gene knockouts and pharmacological inhibition of signalling proteins) and clinical trial parameters (agent, dose, sample size when given, and time to effect) are discussed, but no formal quality appraisal or meta-analytic pooling methods are described in the extracted text.
Clinical observations summarised in the review indicate that a single low intravenous dose of ketamine can produce a rapid antidepressant response within about two hours, with effects lasting up to two weeks in some patients; rapid antisuicidal effects have also been reported. Ketamine’s plasma half-life is approximately three hours, implying that sustained behavioural effects are not due to persistent receptor blockade but to downstream synaptic plasticity mechanisms. At the synaptic and neuronal level, two principal mechanistic hypotheses are presented. One posits disinhibition: ketamine blocks NMDA receptors on inhibitory interneurons, reducing their activity and thereby increasing excitatory network activity. However, genetic deletion of the obligatory NR1 subunit from interneurons did not abolish ketamine’s antidepressant-like effects in mouse models, arguing against this being the sole pathway. The alternative, more synapse-specific hypothesis proposes that low-dose ketamine blocks NMDA receptors that are active at rest (spontaneous neurotransmission). This blockade inhibits eukaryotic elongation factor 2 (eEF2) kinase, reducing eEF2 phosphorylation and desuppressing translation of proteins such as brain-derived neurotrophic factor (BDNF). Increased BDNF then promotes AMPA receptor insertion and downstream synaptic plasticity processes; pharmacological inhibition of eEF2 kinase alone produced rapid and long-lasting antidepressant-like effects in preclinical models. Importantly, ketamine failed to elicit antidepressant-like responses in mice lacking eEF2 kinase, BDNF, or the AMPA receptor subunit GluA2, supporting the necessity of this pathway. Differential actions of other NMDA antagonists are described. Memantine, a clinically tolerated noncompetitive NMDA antagonist, appears to have minimal effect on NMDA receptors under resting physiological magnesium levels and does not alter eEF2 phosphorylation or BDNF expression; consistent with this, memantine has not produced rapid antidepressant effects in treatment-resistant depressed patients. Conversely, selective NR2B antagonists showed some clinical promise: CP-101,606 produced antidepressant effects within five days in treatment-resistant major depression, and an oral NR2B antagonist (MK-0657; 4–8 mg/day) showed antidepressant properties by day 5 without psychotomimetic effects in a pilot trial. A low-trapping NMDAR antagonist, AZD6765 (150 mg i.v.), produced improvement in Montgomery–Åsberg Depression Rating Scale (MADRS) scores within 80 minutes in a 22-patient trial without psychotomimetic effects, but the benefit lasted only about two days; an independent study reproduced the AZD6765 signal. Regarding maintenance and relapse prevention, trials examining riluzole as a strategy to prolong ketamine’s antidepressant effect did not find benefit over a 4-week period in two studies. Other maintenance strategies under investigation include repeat ketamine dosing, traditional antidepressants, mood stabilisers (noting shared glycogen synthase kinase-3 inhibition with lithium), antipsychotics, electroconvulsive therapy and psychotherapy. Repeat-dose ketamine shows encouraging preliminary results but controlled long-term safety data are lacking. Biomarker research is at an early stage: possible clinical predictors include higher body mass index and a family history of alcohol use disorder being associated with greater short-term improvement in some analyses. Peripheral measures, genetics, neuroimaging, sleep and electrophysiology have all been explored as potential biomarkers, but the authors emphasise that replication is required.
Monteggia and colleagues interpret the collective evidence as indicating that ketamine’s rapid antidepressant effects represent a distinct and translationally important mechanism, one that can be dissociated from classical monoaminergic antidepressant actions. They highlight BDNF and downstream pathways such as mTOR as central mediators: blockade of resting NMDA receptor activity appears to desuppress protein synthesis via eEF2 kinase inhibition, increasing BDNF levels, triggering AMPA receptor insertion and activating mTOR-dependent synaptic plasticity mechanisms that plausibly underlie the sustained behavioural response. The authors note that BDNF is a shared requirement for both fast-acting and traditional antidepressants in preclinical models. The review situates clinical findings within this mechanistic framework and draws two practical lessons from non-ketamine NMDA antagonist trials: rapid antidepressant effects can be achieved without psychotomimetic side effects, but agents tested to date have generally produced less robust or less durable benefits than ketamine. Consequently, the authors underscore the need to delineate the precise synaptic circuits and molecular targets responsible for ketamine’s effects, with the goal of developing compounds that engage downstream effectors (for example, components of the eEF2–BDNF–mTOR pathway) while avoiding undesirable effects of NMDA receptor blockade. Several limitations and unanswered questions are acknowledged: the specific brain regions and circuits beyond the hippocampus and prefrontal cortex remain to be mapped, long-term safety and optimal maintenance strategies for ketamine require more evidence, and many candidate biomarkers need replication. Finally, the authors indicate that while ketamine shows potential benefit in treatment-resistant depression in community settings, definitive conclusions about its ultimate clinical utility await further safety, feasibility and mechanistic studies.
The review concludes that ketamine has reshaped thinking about antidepressant mechanisms by demonstrating that a rapid-onset antidepressant response is feasible and by pointing to glutamatergic synaptic plasticity processes as therapeutic targets. Ongoing preclinical work and clinical trials with different ketamine formulations, selective NR2B antagonists and other glutamatergic modulators are actively pursued to identify agents that retain efficacy but have improved tolerability. Clarifying the synaptic mechanisms underlying ketamine action is viewed as essential for discovering additional synaptic proteins and pathways that could be targeted to produce rapid antidepressant effects without the liabilities of direct NMDA receptor antagonism. The authors stress that more knowledge is needed on long-term safety, maintenance strategies and biomarkers before ketamine or related treatments can be fully integrated into clinical practice.
Major depressive disorder is a devastating mental disorder. Fortunately, there are treatment options of which antidepressant medications are most commonly used. Current antidepressant drugs target the monoamine system and typically require several weeks to mediate an antidepressant response, with the latest clinical findings suggesting they are not efficacious in at least one-third of patients. There is a critical unmet need for antidepressants with a rapid onset of action, particularly in patients who do not respond to traditional antidepressants of which many are at an increased risk of suicide. Therefore clinical data demonstrating that a low dose of ketamine, a noncompetitive glutamate N-methyl-Daspartate (NMDA) receptor antagonist, could mediate a rapid antidepressant response in patients with major depression [1 ,2 ,3 ] including treatment resistant depression [2 ,3 ] and bipolar depression [4,5] was met with great interest. These clinical data showed that ketamine could elicit a rapid antidepressant response within two hours with effects lasting up to two weeks in some patients. In addition, rapid antisuicidal effects have been reported with ketamine [2 ,5,6,7]. Ketamine has a halflife of approximately three hourssuggesting that it is not persistent blockade of NMDA receptors that mediate the antidepressant response but rather synaptic plasticity mechanisms of ketamine that are involved in the longer term behavioral effects.
It is relatively straightforward to envision how activation of NMDA receptors lead to synaptic and behavioral plasticity whereas how an NMDA receptor blocker can elicit plasticity is more difficult to account for using canonical activity dependent neuronal signaling pathways. The action of a blocker implies that there is an ongoing tonic activity of NMDA receptors that leads to certain signaling events, which in turn are suppressed by the blocker that either inhibits these signaling events and/or leads to desuppression of an alternative pathway. To explain this rather unusual behavioral effect of ketamine at the neuronal level, studies to date have focused on two possibilities. One hypothesis posits that NMDA receptors present on inhibitory interneurons are tonically active and thus drive inhibition onto excitatory networks. Blockade of these NMDA receptors leads to a decrease in the activity of these interneurons and ultimately to a decrease in inhibition that in turn 'disinhibits' excitatory networks. This form of regulation has been previously proposed for the action of high dose of ketamine and other NMDA receptor blockers as a glutamatergic theory of schizophrenia. Some studies on ketamine as an antidepressant have based their reasoning on this pathway as the potential link between NMDA receptor blockade and subsequent regulation of neuronal plasticity events. However, genetically deleting the obligatory NR1 subunit of the NMDA receptor from inhibitory interneurons does not alter ketamine antidepressant responses in mouse modelswhereas mice lacking the NMDA receptor NR2B subunit on excitatory cortical neurons do not produce an antidepressant response to ketamine. A alternative hypothesis has been proposed in light of recent studies showing that global suppression of inhibition as well as suppression of glutamate a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activity does not elicit a rapid antidepressant effect. The second hypothesis of how ketamine triggers an antidepressant response suggests a more synapse specific effect of ketamine as the underlying basis for its rapid behavioral effect. These studies suggest that low dose ketamine blocks NMDA receptors at rest resulting in specific effects on downstream intracellular signaling. This model proposes that blockade of spontaneous NMDA receptors results in inhibition of eukaryotic elongation factor (eEF2) kinase and a resulting decrease in phosphorylation of eEF2 that desuppresses protein translation resulting in an upregulation of brain-derived neurotrophic factor (BDNF) that triggers insertion of AMPA receptors and other traditional synaptic plasticity processes. These studies demonstrated that pharmacologically inhibiting the eEF2 kinase was sufficient to trigger a rapid and long lasting antidepressant response independent of blocking NMDA receptors. Importantly, ketamine did not elicit an antidepressant response in eEF2 kinase knockout, BDNF knockout or the AMPA receptor subunit, GluA2 knockout mice.
The validity of this second mechanism is bolstered by recent data delineating why the clinically better tolerated noncompetitive NMDA receptor antagonist, memantine, does not induce a rapid antidepressant response in treatment resistant depressed patients. Recent work has demonstrated that memantine has a negligible ability to block NMDA receptors under resting conditions in physiological levels of magnesium and does not initiate this specific intracellular pathway linked to spontaneous neurotransmission mediated activation of NMDA receptors. This differential effect of ketamine and memantine on blockade of NMDA receptors activated at rest extends to key signaling differences where memantine does not alter the levels of phosphorylation of eEF2 or subsequent expression of BDNF, key determinants of ketamine mediated antidepressant efficacy. These data further the previous work on the importance of NMDA receptor activity at rest and this specific intracellular signaling pathway on mediating the rapid antidepressant action of ketamine and start to provide crucial data on the requirements for NMDA receptor antagonist effects on neurotransmission to mediate the antidepressant response. A finding that has emerged from these studies is that BDNF appears to be a common denominator between fast-acting and classical antidepressants. Ketamine requires BDNF signaling to elicit an antidepressant effect, in that ketamine does not elicit an antidepressant response in inducible BDNF KO or conditional TrkB miceor in mice that have the BDNF Val66Met mutation. Previous data has demonstrated that traditional antidepressants also require BDNF in mediating an antidepressant effect in preclinical animal models. BDNF is a prevalent growth factor in the brain that can impact synaptic plasticity processes as well as neurotransmission. BDNF can bind to its high affinity receptor, TrkB, and activate several downstream transduction pathways that include mTOR as well as others. Recent data has shown that ketamine triggers activation of phosphorylation of mTOR in mediating an antidepressant response and that rapamycin blocks the ketamine behavioral effect 24 hours later. BDNF is one of the most potent endogenous activators of mTOR, an important integrator of downstream neuronal signaling, which can then impact synaptic mechanisms and may be involved in the long-term behavioral effects of ketamine. The finding that ketamine can trigger a rapid antidepressant response has provided a fresh perspective to the depression field. The idea that an antidepressant response can be generated in a manner distinct from monoamines suggests that there is more than one way to trigger an antidepressant response and that it is now feasible to develop antidepressants with a rapid antidepressant response. However, there are many unanswered questions that are important as we work toward the development of next generation antidepressants. There is a critical need to delineate the exact synaptic circuits involved in mediating an antidepressant response. The focus to date has been on the hippocampus and prefrontal cortex, two areas that appear critical for ketamine action but undoubtedly are not the only regions. It will also be important to identify a specific site of ketamine action that can be targeted by therapeutics. Further, it will also be critical to better understand the specific eEF2 kinase pathway in mediating an antidepressant response, as it may be possible to design compounds to target specific sites along this signaling pathway to bypass NMDA receptors and thus avoid undesirable effects of NMDA receptor blockade.
While exciting preclinical studies are underway to further delineate the mechanism of ketamine's rapid antidepressant effect, several other avenues are being explored clinically. Some of these paths include maintenance strategies of ketamine's response, developing NMDA receptor modulators with lower liability for producing psychotomimetic and dissociative side effects, and use of ketamine and other rapid acting agents in developing clinical and human biomarkers of treatment response. Regarding the first point, maintenance strategies being examined include the use of riluzole, an FDA-approved medication for the treatment of amyotrophic lateral sclerosis. Riluzole is a glutamate modulatorwith preliminary efficacy as monotherapy and adjunctive therapy in patients with treatment-resistant MDD. However, two studies did not find that riluzole prolonged the initial antidepressant effects of ketamine over the course of 4 weeks. Post-ketamine relapse prevention strategies being studied include traditional antidepressants, mood stabilizers (because both ketamine and lithium are glycogen synthase kinase-3 (GSK-3) inhibitors), antipsychotics, electroconvulsive therapy, and evidence based psychotherapy. In addition, repeat doses of ketamine are being attempted with encouraging resultsalthough controlled and longterm safety data is lacking. With regards to other NMDA antagonists, the NMDARs are tetrameric proteins comprising NR1 and NR2 subunits; four different NR2 subunits (NR2A-D) exist in the brain. A significant reduction in NR2A and NR2B subunit expression was found in the prefrontal cortex (PFC) of patients with MDD. In a previous study, it was found that the subunit selective NR2B receptor antagonist Ro25-6981 exerted antidepressant-like properties in mice. In a clinical study, Preskorn and colleagues found that a single i.v. infusion of the NR2B receptor antagonist CP-101,606 (Traxoprodil) produced antidepressant effects within five days in patients with TRD-MDD. Subsequently an oral formulation of a selective NR2B receptor antagonist (MK-0657; 4-8 mg/day) in a randomized, double-blind, placebo-controlled, pilot study in unmedicated patients with TRD-MDD was found to have antidepressant properties as early as day 5 in the treatment group compared to placebowith no psychotomimetic effect observed. More recently, a randomized, double-blind, placebo-controlled pilot study evaluating the potential rapid antidepressant efficacy and tolerability of a single i.v. infusion of the low-trapping NMDAR antagonist AZD6765 (150 mg) in 22 patients with TRD-MDD was conducted. Within 80 min, MADRS scores improved in subjects receiving AZD6765 compared with placebo and no psychotomimetic effect was found, but this improvement only lasted two days; the antidepressant efficacy of AZD6765 in TRD-MDD was independently demonstrated in a subsequent study. The studies with nonketamine NMDAR antagonists demonstrate two critical things. First, that rapid antidepressant effects can be attained without psychotomimetic effects. Second, that the antidepressant effects are not as robust and durable as those observed following ketamine, underscoring the need for additional studies with other glutamatergic modulators or downstream effectors of ketamine action. Predictive biomarkers are being studied with the goal of differentiating treatment responders and nonresponders to antidepressants. Until recently, these studies were limited to monoaminergic-based antidepressants and thus were likely to generate insights associated with only these treatments, which are known to have a lag of onset of action and are clinically ineffective for many patients; such studies also tend to be long, have high dropout rates, and are associated with risk of non-compliance. Rapid-onset antidepressants and novel targets offer a unique opportunity to study potential clinical and neurobiological biomarkers of treatment response within a limited time period. Clinical predictors of ketamine response in treatment-resistant depression are being examined. For example, greater improvement in depressive symptoms was associated with a higher body mass index at 230 min and day 1, and family history of alcohol use disorder in a first-degree relative at day 1 and day 7. A number of biomarkers have also been explored in the context of ketamine treatment including peripheral measures, genetics, neuroimaging, sleep, and electrophysiology of studies. Many of these are promising but are in need of replication.
In this review, we have provided an overview of the antidepressant mechanism of ketamine, clinical studies with ketamine, and its use in shaping the development of next generation treatments with rapid antidepressant efficacy. Although, considerable progress has been made within a relative short period of time toward this goal, much more knowledge is needed. Indeed, a number of avenues are being pursued including mechanistic preclinical studies, clinical trials with different formulations of ketamine as well as more selective and apparently better tolerated non-ketamine NMDA antagonists and other non-NMDA glutamatergic modulators. In this regard it will be critical to fully delineate the specific synaptic mechanisms underlying ketamine action as this information will likely uncover additional synaptic proteins that can be targeted to elicit a rapid antidepressant response. Finally, there appears to be a potential benefit to patients with ketamine in treatment-resistant depression in the community. However, further studies into ketamine's safety and feasibility are needed to determine its ultimate clinical utility.
Dr. Zarate is listed as a co-inventor on a patent application for the use of ketamine and its metabolites in major depression. Dr. Zarate has assigned his rights in the patent to the US government but will share a percentage of any royalties that may be received by the government.
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