Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression

This systematic review (2015) and meta-analysis (n=147) investigates ketamine and other N-methyl-d-aspartate (NMDA) receptor antagonists in the treatment of major depression. It highlighted the antidepressant efficacy of ketamine, and D-cycloserine and rapastinel for future glutamate-modulating strategies but also noted the ineffectiveness of other NMDA antagonists. It underlined the need for a greater understanding of ketamine’s mechanism of action.

Abstract

“Objective: The authors conducted a systematic review and meta-analysis of ketamine and other N-methyl-d-aspartate (NMDA) receptor antagonists in the treatment of major depression.

Method: Searches of MEDLINE, PsycINFO, and other databases were conducted for placebo-controlled, double-blind, randomized clinical trials of NMDA antagonists in the treatment of depression. Primary outcomes were rates of treatment response and transient remission of symptoms. Secondary outcomes included change in depression symptom severity and the frequency and severity of dissociative and psychotomimetic effects. Results for each NMDA antagonist were combined in meta-analyses, reporting odds ratios for dichotomous outcomes and standardized mean differences for continuous outcomes.

Results: Ketamine (seven trials encompassing 147 ketamine-treated participants) produced a rapid, yet transient, antidepressant effect, with odds ratios for response and transient remission of symptoms at 24 hours equaling 9.87 (4.37–22.29) and 14.47 (2.67–78.49), respectively, accompanied by brief psychotomimetic and dissociative effects. Ketamine augmentation of ECT (five trials encompassing 89 ketamine-treated participants) significantly reduced depressive symptoms following an initial treatment (Hedges’ g=0.933) but not at the conclusion of the ECT course. Other NMDA antagonists failed to consistently demonstrate efficacy; however, two partial agonists at the NMDA coagonist site, d-cycloserine and rapastinel, significantly reduced depressive symptoms without psychotomimetic or dissociative effects.

Conclusions: The antidepressant efficacy of ketamine, and perhaps D-cycloserine and rapastinel, holds promise for future glutamate-modulating strategies; however, the ineffectiveness of other NMDA antagonists suggests that any forthcoming advances will depend on improving our understanding of ketamine’s mechanism of action. The fleeting nature of ketamine’s therapeutic benefit, coupled with its potential for abuse and neurotoxicity, suggest that its use in the clinical setting warrants caution.“

Authors: D. Jeffrey Newport, Linda L. Carpenter, William M. McDonald, James B. Potash, Mauricio Tohen & Charles B. Nemeroff

Summary

Ketamine therapy has been celebrated as a breakthrough in antidepressant treatment, but it may have adverse sequelae.

Ketamine and other N-methyl-D-aspartate (NMDA) receptor antagonists have been shown to have promising antidepressant properties, but are less effective than existing antidepressants due to the brain’s adaptive response to sustained increases in monoaminergic neurotransmission produced by these agents.

Current antidepressants have unsatisfactory remission rates and delayed therapeutic response, and may not be effective in treating unremitted depression. However, promising results from clinical and preclinical antidepressant studies of NMDA receptor antagonists have generated considerable excitement.

Evidence for aberrant NMDA receptor-mediated glutamate neurotransmission was gathered nearly 20 years ago, and glutamatergic agents might hold antidepressant efficacy as far back as 50 years ago.

The NMDA receptor is a tetramer composed of two GluN1 subunits and two GluN2 subunits, and possesses both a ligand gate and a voltage gate, each of which must be opened to enable ion flow. The presence of NMDA receptors not only within the synapse but at extrasynaptic sites as well, implying a complex physiological regulation, is likely more complex and remains a focus of intense scrutiny.

Many compounds listed in the data supplement accompanying the online version of this article have been shown to have antidepressant effects, including ketamine, memantine, ifenprodil, and D-cycloserine.

The APA Council of Research Task Force on Novel Biomarkers and Treatments reviewed ketamine and other NMDA receptor antagonists for depression.

Search

We searched for peer-reviewed articles addressing treatment of major depression using ketamine, memantine, and other NMDA antagonists, and screened references of included studies and relevant reviews.

Data Extraction and Outcomes

All studies utilized the Montgomery-sberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D) to evaluate depression symptom severity. Dissociative, psychotomimetic, and hemodynamic effects were evaluated as secondary outcomes.

Meta-Analytic Calculations

Odds ratios were used for dichotomous measures, and adjusted mean differences were calculated for zero frequency cells. Standard deviations were calculated from other available data when possible.

RESULTS

A literature search yielded 581 citations. Twenty-four studies fulfilled the a priori criteria for inclusion in the meta-analysis.

Ketamine Studies

The search identified 12 reports of randomized clinical trials examining ketamine in the treatment of depression. The studies included participants who had failed a previous or current treatment for depression.

Ketamine produced a rapid antidepressant response in patients, peaking within one day of administration. The response rate remained significant when data were stratified by diagnosis, separating major depressive disorder and bipolar disorder.

After 2 weeks, the odds ratio for treatment response declined steadily, but remained statistically significant. The odds ratio for treatment response was statistically significant for major depressive disorder, but not for bipolar disorder.

The odds ratio for transient symptom remission followed a similar temporal pattern, with statistical significance achieved on day 1 but not day 7. Ketamine infusion was also reported to significantly outperform placebo in rapidly reducing suicidal ideation among patients with treatment-resistant depression.

Ketamine therapy produced psychotomimetic and dissociative side effects, with mean BPRS positive subscale scores 0.74 (95% CI50.46 – 1.01)points higher and Clinician-Administered Dissociative States Scale mean scores 23.75 (95% CI522.13 – 25.37) points higher, respectively, among those receiving ketamine therapy.

Ketamine’s long-recognized sympathomimetic properties were only reported in two of the seven ketamine trials. Both studies reported that blood pressure measures had returned to baseline within 4 hours of infusion.

Ketamine Augmentation of ECT

Ketamine use in conjunction with ECT was associated with a greater reduction in depressive symptoms after an initial ECT session, but not at the conclusion of the complete course of ECT.

Ketamine-ECT has been associated with higher rates of post-ECT disorientation and restlessness, as well as delirium and fear upon waking due to psychotic symptoms.

Ketamine augmentation with ECT did not cause cardiovascular effects in two of the five studies, but did cause blood pressure elevation in five subjects. Ketamine was eliminated by coadministration of propofol with ECT.

Memantine Studies

Memantine, like ketamine, acts as an antagonist by binding to the NMDA receptor at a site within the receptor ion channel. However, memantine did not outperform placebo in achieving a therapeutic response or in reducing depressive symptom severity in three randomized clinical trials.

Lanicemine (AZD6765) Studies

Lanicemine is an antidepressant that binds to the NMDA receptor and is administered through intravenous infusion. There are no published randomized clinical trials evaluating lanicemine treatment of depressive episodes of bipolar disorder.

Lanicemine failed to produce a statistically significant reduction in depressive symptoms at 1 day or 3 days following infusion, but serial administration over 3 weeks demonstrated significant improvement in rates of treatment response and symptom remission.

Lanicemine therapy was not associated with psychotomimetic or dissociative side effects.

Nitrous Oxide Study

Nitrous oxide (N20) is an NMDA antagonist that binds to a site within the ion channel. It was administered via inhalation for 1 hour.

In this study, N20 was associated with a significantly greater reduction in HAM-D scores than placebo at both 2 hours and 24 hours after inhalation.

The authors of the existing study report that the intervention was devoid of psychotomimetic and dissociative side effects.

Traxoprodil (CP-101,606) Study

Traxoprodil does not bind to the NMDA receptor at a channel site, but instead to an allosteric site outside the receptor ion channel on the GluN2B subunit. It was used to augment the antidepressant paroxetine in a sample that had failed to respond to paroxetine and had received a single blind placebo.

MK-0657 (CERC-301) Study

MK-0657 acts as an NMDA antagonist by binding to the receptor at an allosteric site on the GluN2B subunit.

D-Cycloserine Studies

D-cycloserine binds to the glycine coagonist binding site on the NMDA receptor and acts as a partial agonist, but a full agonist at glycine binding sites on GluN2C subunits.

The literature search identified two randomized clinical trials of D-cycloserine treatment of depression, both published by the same group. The studies used widely divergent oral D-cycloserine doses.

The higher-dose D-cycloserine trial (112) demonstrated a significantly greater reduction in depressive symptoms than the lower-dose trial (111), and a significantly greater likelihood of therapeutic response (54% versus 15%), although the difference in rate of symptom remission did not achieve statistical significance.

In the higher-dose D-cycloserine study, it was not associated with elevation of the HAM-D paranoia or depersonalization/derealization items.

Rapastinel (GLYX-13) Study

Rapastinel, like D-cycloserine, is a partial agonist at NMDA receptor glycine binding sites. It is unknown whether rapastinel possesses pharmacodynamic specificity that varies by the NMDA receptor subunit on which the glycine binding site resides.

Rapastinel reduced 17-item HAM-D scores more than placebo at all intervals except day 14. The low (1 mg/kg) and high (30 mg/kg) doses were not associated with significant greater 17-item HAM-D score reduction than placebo.

DISCUSSION

Ketamine is the most extensively studied NMDA antagonist, with 12 published randomized clinical trials, followed by lanicemine, memantine, and D-cycloserine. Ketamine is the only NMDA antagonist to date consistently demonstrating antidepressant efficacy across multiple trials.

Current data provide compelling evidence that ketamine infusion has antidepressant effects that are rapid and robust, albeit transient. Moreover, ketamine-associated side effects were predictive of improvement of depressive symptoms in some trials.

Ketamine’s prominent psychotomimetic and dissociative side effects may compromise efforts to blind study participants and investigators to treatment assignment, thereby leading to biased results. However, the uniform evidence of rapid antidepressant efficacy for ketamine across nearly all studies suggests otherwise.

Ketamine’s antidepressant effects cannot be sustained with serial infusions or transition to an alternative maintenance pharmacotherapy. In one case, 41 ketamine infusions failed to alleviate depression and the patient was referred for deep brain stimulation.

Ketamine’s antidepressant effect quickly dissipates and it produces prominent dissociative and psychotomimetic side effects. Ketamine’s use as an antidepressant in the clinical setting is supported by the current data.

Ketamine’s Mechanism of Action

Ketamine’s unique antidepressant properties may be due to distinctions in its pharmacodynamic activity within the NMDA receptor, or to the fact that other NMDA channel blockers have yet to replicate ketamine’s rapid antidepressant effects.

Ketamine and memantine both bind to the NMDA receptor at the channel binding site, but ketamine has a greater propensity for becoming trapped, once bound, within the channel than memantine.

Ketamine and memantine have different capacities to activate intracellular signaling pathways linked to synaptic plasticity. Ketamine has been more reliably associated with increased phosphorylation of eEF2, increased synthesis of brain-derived neurotrophic factor, and heightened activation of mammalian target of rapamycin than memantine.

Ketamine activates synaptic signaling proteins by antagonizing the NMDA receptor, but activation of glutamatergic AMPA receptors is also necessary for ketamine’s antidepressant effects.

Ketamine’s mechanism of action remains obscure, but it is likely that NMDA antagonism triggers presynaptic release of glutamate, which binds to AMPA receptors and induces synaptogenesis. Ketamine may be neuroprotective in some contexts but potentially neurotoxic in others.

Clinical Use of Ketamine

Ketamine infusion provides a rapid therapeutic response for many patients suffering with treatment-resistant depression. However, the available data do not support ketamine infusion as an ECT alternative for acute treatment of depression, and there are currently no data regarding the efficacy and safety of continuation or maintenance phase therapy.

Ketamine has been associated with neuronal apoptosis in the developing brain of rodents and rhesus monkeys, but has also been shown to inhibit inflammation in the context of a noxious stimulus such as pain. It is unclear if ketamine would have similar effects in adult humans.

Ketamine is seldom administered repeatedly over days and weeks as part of a general anesthetic regimen, but could potentially have a different safety profile when used as an intervention for depression.

Ketamine abuse is a widely recognized social problem in several countries, and widespread dissemination in the outpatient setting could readily produce physiological and psychological dependence on ketamine. Ketamine diversion for illicit use could rival or even surpass problems currently encountered with prescription opiates and sedative-hypnotics.

Future Research Directions

Among the other NMDA antagonists studied to date, high-dose D-cycloserine and rapastinel exhibit an inverted U-shape dose-response curve, suggesting that they behave as classic partial agonists within a low to moderate dose range but exhibit full agonist activity at especially high doses.