Ketamine and Other NMDA Antagonists : Early Clinical Trials and Possible Mechanisms in Depression
D. Jeffrey Newport, M.D., M.S., M.Div., Linda L. Carpenter, M.D., William M. McDonald, M.D., James B. Potash, M.D., M.P.H., Mauricio Tohen, M.D., Dr.P.H., M.B.A., Charles B. Nemeroff, M.D., Ph.D., The APA Council of Research Task Force on Novel Biomarkers and Treatments
American Journal of Psychiatry, 2015, 172, 950–966
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’g50.933) 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.
The emergence of intravenous ketamine therapy has been celebrated as perhaps “the most important breakthrough in antidepressant treatment in decades” (1). However, concern has been raised that off-label clinical utilization of ketamine as a pharmacotherapeutic agent is out pacing scientific scrutiny and may invite adverse sequelae that will exceed any accrued therapeutic benefit (2–4).
The flurry of interest in the antidepressant utility of ketamine and other N-methyl-D-aspartate (NMDA) receptor antagonists has been driven by a confluence of forces. First are the shortcomings of the current antidepressant armamentarium. The failings of existing antidepressants, which are largely thought to work primarily by enhancing monoamine neurotransmission, as well as the clear deficiencies of the underlying monoamine hypothesis of depression (5), arewell-documented. When used to treat depression, currently available antidepressants are hindered by a prolonged delay of onset of action and disappointing remission rates (6). Both weaknesses are likely attributable, at least in part, to the fact that current antidepressants work via indirect mechanism(s) of action. There is considerable evidence that the therapeutic activity of antidepressants is not mediated by their direct synaptic effects, on for example monoamine reuptake, but by the brain’s adaptive response to sustained increases in monoaminergic
neurotransmission produced by these agents, in a manner akin to the emergence of tolerance in the context of chronic use of habit-forming substances (7).Whatever the precise mechanism of action of currently available antidepressants truly is, their less than optimal efficacy has now been well established in largescale clinical trials such as the Sequenced Treatment Alternatives to Relieve Depression Study (8–13) and the International Study to Predict Optimized Treatment in Depression (14).
The concatenation of the unsatisfactory remission rates and the delayed therapeutic response plaguing current antidepressants highlight the important unfilled need for an improved antidepressant pharmacopoeia, especially in view of the mortality (e.g., suicide and risk for heart disease and other major medical disorders) and morbidity associated with unremitted depression (15–18). Such unmet needs may be overcome by identifying interventions that more directly address the underlying pathophysiology of depression. In fact, this assumption has been the driving force behindmuch of the effort to identify novel antidepressant compounds over the past decade. Unfortunately, the search for novel compounds has been remarkably unsuccessful in recent years, resulting in a stagnant developmental pipeline for new antidepressant agents (19–22). It is understandable, given this otherwise bleak picture, that promising results from clinical and preclinical antidepressant studies of NMDA receptor antagonists would generate considerable excitement.
Nearly 20 years ago, several lines of evidence pointed to aberrant NMDA receptor-mediated glutamate neurotransmission as a viable neurobiological substrate on which to base a novel intervention for depression. Evidence includes alterations in central NMDA receptor binding profiles of rodents exposed to chronic stress, a laboratory animal model of depression, and postmortem tissue from suicide victims, in addition to changes in NMDA receptor activity produced by chronic antidepressant exposure (23). Indeed, the evidence that glutamatergic agents might hold antidepressant efficacy dates as far back as 50 years ago (24–26).
The complex physiology of the NMDA receptor (Figure 1) offers numerous pharmacodynamic targets for intervention. A tetramer, composed of two GluN1 subunits and two GluN2 subunits, encompassing an ion channel that regulates neuronal influx of calcium (Ca11) in addition to sodium (Na1) influx and potassium(K1) efflux, the NMDA receptor is unique in that it possesses both a ligand gate and a voltage gate, each of which must be opened to enable ion flow. Furthermore, the ligand gate is opened only when concurrently activated by two ligandmolecules, a receptor agonist, glutamate, and a receptor coagonist, either glycine or D-serine, and the voltage gate is opened onlywhenneuronal depolarization is triggered elsewhere (e.g., via glutamate binding thea–amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid [AMPA] receptors, acetylcholine binding at a7 nicotinic receptors, etc.). Additional complexity is conferred by the presence of NMDA receptors not only within the synapse but at extrasynaptic sites as well. The origin of endogenous ligands at extrasynaptic NMDA receptors, thoughobscure,maybe avarietyof sources, including spillover of synaptic glutamate, glial release of glutamate, glycine, and D-serine, neuronal release of glycine and D-serine, and capillary extravasation of serum glycine (27), implying a complex physiological regulation. Moreover, activation of extrasynaptic NMDA receptors has been implicated in neuronal toxicity, whereas synaptic NMDA receptor activation has been credited with promoting neuronal survival (28). The respective roles of synaptic and extrasynaptic NMDA receptors in mediating synaptic plasticity and neuronal toxicity are likely more complex and remain a focus of intense scrutiny (27, 29, 30).
There is growing evidence of antidepressant effects of many of the compounds listed in the data supplement accompanying the online version of this article. For example, a series of preclinical antidepressant screening test studies have demonstrated antidepressant-like effects (e.g., decreased immobility timein the forced swimtest) for numerous NMDA receptor antagonists, including ketamine (31–35), memantine (36–38), ifenprodil (39), and D-cycloserine (39, 40). A plethora of open-label trials of ketamine reporting a 25%-78% reduction in depressive symptom severity have been published in recent years (41–72), including those demonstrating particular antidepressant efficacy among those with family histories of alcoholism(73–77), as well as positive openlabel studies of amantadine (78) and memantine (79). The objective of the present review by the APA Council of Research Task Force on Novel Biomarkers and Treatments was to conduct a systematic review and meta-analysis of the randomized clinical trials of ketamine and other NMDA receptor antagonists in the treatment of depression, critically examining findings for both the efficacy and adverse effects of these various agents.