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.

Keywords: N-methyl-D-aspartate receptor; NR2B; antagonist; bipolar depression; bipolar disorder; glutamate; ketamine; major depressive disorder; treatment-resistant depression.

Conflict of interest statement

Conflict of interest statement: Dr. Zarate is listed as a coinventor on a patent application for the use of ketamine and its metabolites in major depression. Dr. Zarate has assigned his rights in the patent to the US Government but will share a percentage of any royalties that may be received by the Government. All other authors have no potential conflicts of interest to disclose.

Figures

Figure 1.

Ketamine-induced synaptoplasticity and rapid-acting antidepressant efficacy. At subnanesthetic doses, ketamine-induced NMDA receptor antagonism on GABAergic interneurons releases outflow (glutamatergic) neuronal inhibition, for example, cortical pyramidal neurons. This results in an acute glutamate ‘surge’ that then preferentially activates AMPA receptors to increase intracellular sodium (Na+) and fast excitatory currents. This stimulates numerous downstream second messenger/signal transduction cascades leading to the following: (1) eEF2K inhibition, (2) GSK-3 inhibition, and (3) mTOR activation. Other postsynaptic cellular and molecular effects stimulated by ketamine include increased AMPA receptor cycling, increased postsynaptic density protein expression, and dendritic spine morphogenesis (from immature filopodia-shaped spines to mature mushroom-shaped spines). The complex interplay of metabotropic glutamate receptors and exchangers on the surface of neurons and astrocytes regulate synaptic and extrasynaptic glutamate levels to facilitate recycling back to the presynaptic neuron and prevent excitotoxic cell damage/death. Black circles: glutamate; grey circles: glutamine; blue circles: BDNF; maroon channel: NMDA receptor complex; blue channel: AMPA receptor complex; red channel: glial transporter-1/excitatory amino acid transporter 2 (GLT-1/EAAT2); olive channel: system xC-; peach channel: vesicular glutamate transporter; maroon seven-transmembrane receptor: metabotropic glutamate receptor type 2/3; olive seven-transmembrane receptor: metabotropic glutamate receptor type 1/5; grey dimeric receptor: TrkB receptor. Akt, Ak thymoma/protein kinase B; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; eEF2, eukaryotic elongation factor 2; ERK, extracellular signal-regulated kinase; GABA, γ-aminobutyric acid; mTOR, mammalian target of rapamycin; NMDA, N-methyl-D-aspartate; SNARE, soluble NSF attachment protein receptor (superfamily); TrkB, tropomyosin-related kinase B.