Ketamine for depression

Inspired by discussions regarding a patient.

Murrough JW, Abdallah CG, Mathew SJ. Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov. 2017 Mar 17. doi:10.1038/nrd.2017.16. [Epub ahead of print]

Abstract

Major depressive disorder (MDD) is severely disabling, and current treatments have limited efficacy. The glutamate N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine was recently repurposed as a rapidly acting antidepressant, catalysing the vigorous investigation of glutamate-signalling modulators as novel therapeutic agents for depressive disorders. In this Review, we discuss the progress made in the development of such modulators for the treatment of depression, and examine recent preclinical and translational studies that have investigated the mechanisms of action of glutamate-targeting antidepressants. Fundamental questions remain regarding the future prospects of this line of drug development, including questions concerning safety and tolerability, efficacy, dose-response relationships and therapeutic mechanisms.

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From the article

The NMDAR-blocking agent ketamine — an anaesthetic that has been available for human use since the 1960s — was reported in 2000 to induce profound clinical improvements in the core symptoms of depression within several hours of treatment; this was an unexpected finding that was later hailed as “arguably the most important discovery [in mood disorders] in half a century”  Moreover, this discovery triggered vigorous research in both industry and academia to understand the role of glutamate signalling in depression pathophysiology and to develop novel treatments. Investigational drugs that target components of the glutamate system have begun to enter phase II and phase III trials. This Review evaluates the role of glutamate signalling in depression and discusses the potential of ketamine and other glutamate -signalling modulators as novel antidepressant agents. We critically review the limitations of existing studies of the clinical effects and hypothesized mechanisms of action of glutamate-based antidepressant candidates, and detail progress in this area. We evaluate evidence concerning the role of the NMDAR versus other molecular targets in the antidepressant mechanism of action of ketamine and other candidate glutamate modulators, and conclude with a discussion of the challenges of glutamate modulation for novel drug development and opportunities for new directions…

Nearly all clinical trials of parenteral ketamine in depression have used a dose of 0.5 mg per kg infused over 40 minutes. The US National Institute of Mental Health’s ketamine dose-finding study in TRD com-paring four dose regimens is expected to complete in 2017. A less well-studied but equally crucial component of dose optimization concerns dosing frequency, as some NMDAR modulators might be more optimally administered intermittently rather than  daily. A considerable design hurdle concerns the potential for elevated expectancy effects with parenteral drug administration that contribute to an exaggerated placebo response. All controlled ketamine trials to date have used inert saline as the placebo condition, with the exception of one that used midazolam to provide a plausible (though imperfect) psychoactive control condition. Studies of ketamine and NMDAR modulators with unwanted acute psychotomimetic and haemodynamic effects suffer a potential bias in the form of functional unblinding. Keeping efficacy raters masked to acute changes in haemodynamic parameters will be essential. One study of lanicemine found that neither clinicians nor patients were likely to correctly guess whether they were receiving the active drug or the inactive placebo1, suggesting that NMDAR modulators with less dramatic acute effects are less likely to compromise the blind. In addition, the standard outcome scales for conventional antidepressant trials may lack sensitivity for detecting rapid changes in mood, as these scales were developed to detect changes in depressive symptoms over a 7-day time frame. Whether shorter versions of these instruments are more likely to show sensitivity to changes in core components of depression for  rapid- onset antidepressant medications is under study.

Despite its favourable safety profile in well-controlled medical settings, there are important concerns regarding the toxicity of ketamine at high doses and for prolonged periods. Preclinical studies have documented neurotoxic effects of ketamine and NMDAR modulators when administered at high doses, or during specific developmental periods. Ketamine is recreationally abused as a club drug and is listed in Schedule 3 by the FDA (indicating that the drug has accepted medical uses but has the potential for abuse). In the United Kingdom, increasing restrictions have made it more cumbersome to conduct experimental research with ketamine, which was classified as Class B in 2014  (in the United Kingdom, controlled drugs are scheduled as Class A, B or C according to their potential for  harm, with Class A reserved for drugs deemed to be associated with the greatest harm).In an analysis of three clinical trials of ketamine for depression, we did not find evidence of negative psychological or medical sequelae, or substance abuse-related emergencies, although the patients included in this  analysis were exposed only to low doses and to short courses of the drug (no more than six infusions over 2 weeks). In addition to neuropsychiatric and cognitive effects, potential adverse effects of chronic exposure to ketamine include hypertension, tachycardia and cystitis. These data highlight the crucial role of dose and frequency in determining the safety or toxicity of ketamine. The large gaps in our current knowledge of the safety or efficacy of ketamine and of other NMDAR antagonists for the treatment of depression should dissuade  widespread clinical use until more data are obtained.