Glutamate NMDA receptor modulators for the treatme

Authors: James W Murrough

Publish Date: 2015/03/11

Volume: 232, Issue: 8, Pages: 1497-1499

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Abstract

Several decades of research have provided evidence for disturbances within the glutamate system in patients with depressive disorders and have pointed towards the glutamate system as a target for treatment development for mood disorders Sanacora et al 2008 Skolnick et al 2009 In particular clinical studies showing a rapid antidepressant effect of the glutamate Nmethyldaspartate NMDA receptor NMDAR antagonist ketamine provide a critical proof of principle for targeting the NMDAR as a novel treatment approach for refractory forms of unipolar and bipolar depression Murrough and Charney 2010 Fifteen years have passed since the first clinical study of ketamine in depression was published Berman et al 2000 To date no agents targeting the NMDAR or other components of the glutamate system have gained regulatory approval for the treatment of depression During the past 15 years what has the field learnedThe original publication by Berman et al reported the rapid antidepressant effect of a single intravenous infusion of ketamine 05 mg/kg compared to saline using a randomized withinsubject crossover design Berman et al 2000 This finding was followed by a milestone publication by Zarate et al in 2006 demonstrating a rapid antidepressant effect of ketamine specifically in patients with treatmentresistant depression TRD in a larger sample Zarate et al 2006 This group went on to demonstrate the rapid antidepressant effect of ketamine in patients with bipolar depression Diazgranados et al 2010 Zarate et al 2012 Our group built on these findings conducting the largest study of singleadministration ketamine in TRD to date involving 73 patients randomized across two sites in a parallelarm design Murrough et al 2013a This study featured the anesthetic benzodiazepine agent midazolam as a “psychoactive control” condition designed to mitigate the threat of unblinding related to the acute psychoactive effects of ketamine Compared to midazolam ketamine was associated with a higher rate of antidepressant response at 24 h posttreatment 64 and 28  respectively odds ratio OR 218 Separately we demonstrated the feasibility and preliminary efficacy of repeated administrations of ketamine in patients with TRD administering up to six doses over 2 weeks aan het Rot et al 2010 Murrough et al 2013b New data on the effects of ketamine administered in an intranasal fashion in TRD is also promising Lapidus et al 2014 A recent metaanalysis included seven randomized controlled trials RCTs of ketamine in mood disorders involving a total of 183 subjects McGirr et al 2014 Relative to the comparator a single administration of ketamine was associated with higher odds of antidepressant response at 24 h 3 days and 7 days posttreatment OR 91 68 and 49 respectively number needed to treat NNT ranged from 3 to 4 A second metaanalysis published recently in Psychopharmacology included nine controlled studies of ketamine in mood disorders and likewise found that depression scores were significantly decreased in the ketamine groups compared to those in the control groups standardized mean difference of 099 95  CI 123–077 Fond et al 2014Given the accumulated data may we conclude that the therapeutic benefit of ketamine for depression has been established The question is more complex than it may first appear In particular it is instructive to draw a distinction between the question of pure efficacy demonstrated in a controlled environment and the larger questions of effectiveness in real world settings and the favorability or lack thereof of the treatment risktobenefit ratio The answer to the first question is of critical importance to the science of mood disorders and is a necessary prerequisite to begin to address the latter questions Taking the first question first the accumulated data does appear to confirm the rapid antidepressant efficacy of ketamine What are the implications of this discovery Foremost this fact provides the most robust evidence available linking the NMDAR and the glutamate system more broadly to the pathophysiology of depression This realization should prompt substantial research investment aimed at characterizing the role of the NMDAR in depression The discovery also provides the key rationale to pursue the NMDAR and its related molecular machinery as targets for novel treatment development efforts While government and nonprofit organizations are focused on the former the industry is appropriately focused on the latterOne question that has arisen regarding the antidepressant mechanism of action of ketamine is as follows To what extent is the efficacy of ketamine dependent on the NMDAR This is an empirical question that no doubt requires further study A preponderance of data however shows that the physiological properties of ketamine are mediated primarily by its function as a noncompetitive highaffinity NMDAR antagonist Hirota and Lambert 1996 Potter and Choudhury 2014 At binding affinities much lower than that of the NMDAR ketamine interacts with opioid and cholinergic receptors among others Hirota and Lambert 1996 Ketamine does have abuse liability and its actions at opioid receptors in particular merit additional consideration Although complex ketamine appears to function as an antagonist at mu receptors rather than an agonist such as morphine and an agonist at kappa receptors Smith et al 1985 Hustveit et al 1995 Of note the sedative effects of ketamine in humans are not reversed by naloxone Mikkelsen et al 1999 furthermore naltrexone potentiates rather than inhibits the perceptual effects of ketamine in humans Krystal et al 2006 The available evidence is consistent with the hypothesis that NMDAR antagonism rather effects at other receptors is the key to ketamine’s antidepressant mechanism of actionReturning to questions of effectiveness and safety we are on less surefooted ground The total number of subjects studied in RCTs of ketamine in depression is less than 200 and no studies have examined the effects of ketamine over a longer time interval than a few weeks Wan et al 2014 Importantly there is no safety or efficacy data concerning chronic ketamine treatment for depression This paucity of longerterm data dictates first that prescribing clinicians must proceed with great caution and second that largerscale studies of ketamine are needed straightaway in order to inform the risktobenefits analyses that are critical to patients providers and regulators The eagerness with which some patients and providers have embraced ketamine for the treatment of severe and refractory depression is a testament to the urgency of the needFollowing on the heels of ketamine several other NMDAR modulators are being investigated as candidate antidepressant agents Lapidus et al 2013 Sanacora and Schatzberg 2015 Despite some success several compounds have stalled during the drug development process The failure of the lowaffinity NMDAR antagonist memantine to separate from placebo in TRD was an early disappointment Another NMDA receptor antagonist lanicemine has yielded mixed results and its continued development for depression is uncertain Sanacora and Schatzberg 2015 Agents selective for the NR2B subunit of the NMDAR have shown promise in clinical trials although there have been setbacks as well The glycine site partial agonist dcycloserine DCS demonstrated antidepressant efficacy in TRD when administered at high doses at high doses DCS is believed to function as an NMDAR antagonist HerescoLevy et al 2013 Dextromethorphan is an antitussive NMDAR antagonist that is beginning to be examined for potential therapeutic effects in mood disorders Chen et al 2014 Kelly and Lieberman 2014 A particular bright spot on the horizon may be a pair of NMDAR modulators—GLYX13 and NRX1074—which are purported to show antidepressant efficacy in phase II studies although published data is not yet available Clearly the field has learned a considerable amount of information concerning NMDARs as treatment targets in depression Will we see NMDAR modulators come to market as approved therapies for depression Will we wait another 15 years for a breakthrough in depression treatment Will we wait longerIn the past 3 years Dr Murrough has served on advisory boards for Janssen Research and Development and Genentech has provided consultation services for ProPhase LLC and Impel Neuropharma and has received research support from Janssen and Avanir Pharmaceuticals he is named on a patent pending for neuropeptide Y as a treatment for mood and anxiety disorders he is named on a patent pending for lithium as a method to maintain the antidepressant response to ketamine Dr Dennis Charney Dean of Icahn School of Medicine at Mount Sinai and Icahn School of Medicine at Mount Sinai have been named on a use patent on ketamine for the treatment of depression The Icahn School of Medicine has entered into a licensing agreement for the use of ketamine as therapy for treatmentresistant depression Dr Charney and Icahn School of Medicine at Mount Sinai could potentially benefit if ketamine were to gain approval for the treatment of depression

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