Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review

Abstract

Current pharmacotherapies for major depressive disorder (MDD) and bipolar depression (BDep) have a distinct lag of onset that can generate great distress and impairment in patients. Furthermore, as demonstrated by several real-world effectiveness trials, their efficacy is limited. All approved antidepressant medications for MDD primarily act through monoaminergic mechanisms, agonists or antagonists with varying affinities for serotonin, norepinephrine and dopamine. The glutamate system has received much attention in recent years as an avenue for developing novel therapeutics. A single subanesthetic dose infusion of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been shown to have rapid and potent antidepressant effects in treatment-resistant MDD and BDep. In a reverse translational framework, ketamine's clinical efficacy has inspired many preclinical studies to explore glutamatergic mechanisms of antidepressant action. These studies have revealed enhanced synaptic plasticity/synaptogenesis via numerous molecular and cellular mechanisms: release of local translational inhibition of brain-derived neurotrophic factor and secretion from dendritic spines, mammalian target of rapamycin activation and glycogen synthase kinase-3 inhibition. Current efforts are focused on extending ketamine's antidepressant efficacy, uncovering the neurobiological mechanisms responsible for ketamine's antidepressant activity in biologically enriched subgroups, and identifying treatment response biomarkers to personalize antidepressant selection. Other NMDA receptor antagonists have been studied both preclinically and clinically, which have revealed relatively modest antidepressant effects compared with ketamine but potentially other favorable characteristics, for example, decreased dissociative or psychotomimetic effects; therefore, there is great interest in developing novel glutamatergic antidepressants with greater target specificity and/or decreased adverse effects.

Acetylcholinesterase inhibitors and memantine in bipolar disorder: A systematic review and best evidence synthesis of the efficacy and safety for multiple disease dimensions

“…Moreover memantine acts as a non-competitive NMDA antagonist, with suggested antidepressant and mood stabilizing effects (Lee et al, 2013). Its mechanism of action on NMDA receptors is shared with ketamine, which in turn showed antidepressant properties, but which can also have strong dose-dependent dissociative properties and potential neurotoxic effects (Iadarola et al, 2015). Conversely, these side effects do not occur with memantine, which has a safer profile.…”

On the Eve of Upgrading Antidepressants: (R)-Ketamine and Its Metabolites

“…The antidepressant efficacy of ketamine has centered on the inhibition of NMDAR-mediated glutamate neurotransmission, holding promise for future glutamate-modulating strategies. However, other NMDAR antagonists have only relatively modest antidepressant effects compared with ketamine, in both pre-clinical and clinical studies [10,11]. Further investigations are needed to improve our understanding of ketamine's mechanism of action.…”

Ketamine as an adjunct to patient-controlled analgesia: why, for whom, and how much?

“…[1][2][3] As a result, ketamine has now been increasingly used for a range of effects, including antinociceptive effects for treating pain in its various forms (acute, chronic, neuropathic, cancer-related) as well as for addressing treatment-resistant depression. 4,5 Recent investigations have focused on the role of subanesthetic doses of ketamine in improving analgesia and the potential for reducing requirements for other analgesics, especially opioids. In this issue of the Journal, Wang et al present results of their systematic review and meta-analysis of 36 randomized-controlled trials (RCTs) in English and Chinese languages.…”

“…Ketamine may be useful as an adjuvant in this setting because it can reduce acute postoperative pain (an important risk factor for PPP) through its antagonism at the NMDA receptor. 20 Antagonism of NMDA receptors is also responsible for the antidepressant effects of ketamine, 5 opening an interesting avenue for research among patients with depression (subclinical or overt). Will ketamine treatment result in an improvement in depressive symptoms as well as in lower pain scores?…”

“…4,5 Des recherches récentes se sont concentrées sur le rôle de doses infra-anesthésiques de kétamine dans l'amélioration de l'analgésie et sur la possibilité de diminuer les besoins d'autres analgésiques, plus particulièrement des morphiniques. Dans ce numéro du Journal, Wang et coll.…”