Therapeutic Modulation of Glutamate Receptors in Major Depressive Disorder

Abstract

Current pharmacotherapies for major depressive disorder (MDD) have a distinct lag of onset that can prolong distress and impairment for patients, and real-world effectiveness trials further suggest that antidepressant efficacy is limited in many patients. All currently approved antidepressant medications for MDD act primarily through monoaminergic mechanisms, e.g., receptor/reuptake agonists or antagonists with varying affinities for serotonin, norepinephrine, or dopamine. Glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamate and its cognate receptors are implicated in the pathophysiology of MDD, as well as in the development of novel therapeutics for this disorder. Since the rapid and robust antidepressant effects of the N-methyl-D-aspartate (NMDA) antagonist ketamine were first observed in 2000, other NMDA receptor antagonists have been studied in MDD. These have been associated with relatively modest antidepressant effects compared to ketamine, but some have shown more favorable characteristics with increased potential in clinical practice (for instance, oral administration, decreased dissociative and/or psychotomimetic effects, and reduced abuse/diversion liability). This article reviews the clinical evidence supporting the use of glutamate receptor modulators with direct affinity for cognate receptors: 1) non-competitive NMDA receptor antagonists (ketamine, memantine, dextromethorphan, AZD6765); 2) subunit (NR2B)-specific NMDA receptor antagonists (CP-101,606/traxoprodil, MK-0657); 3) NMDA receptor glycine-site partial agonists (D-cycloserine, GLYX-13); and 4) metabotropic glutamate receptor (mGluR) modulators (AZD2066, RO4917523/basimglurant). Several other theoretical glutamate receptor targets with preclinical antidepressant-like efficacy, but that have yet to be studied clinically, are also briefly discussed; these include α-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid (AMPA) agonists, mGluR2/3 negative allosteric modulators, and mGluR7 agonists.

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…Elevated peripheral blood TNF, IL-1β, and IL-6 predicted favorable antidepressant response to ketamine administration in a small sample of depressed patients (Hashimoto, 2015). Other studies report that increased body mass index (BMI) and plasma adipokine concentrations (both of which are associated with inflammation) correlated with ketamine response (Jaso et al, 2016;Machado-Vieira et al, 2016;Machado-Vieira et al, 2009). Intriguingly, as noted above, astrocytes express adipokine receptors such as the leptin receptors (LepR) and LepRs are increased in number in the astrocytes of obese animals and in C6 astrocytoma cells treated with LPS and TNF (Hsuchou et al, 2009;Pan et al, 2012).…”

What Is New about New Antidepressants?

“…Examples include noncompetitive NMDA receptor antagonists (memantine, dextromethorphan/quin idine, dextromethorphan/bupropion, and lanicemine), NR2B subunit-specific NMDA receptor antagonists (traxoprodil, MK-0657), NMDA receptor glycine site partial agonists (D-cycloserine, rapastinel), and metabotropic glutamate receptor (mGluR) antagonists (basimglurant, declogurant) [8, 49, 50, 60-62]. Memantine, MK-0657, and rapastinel have not convincingly outperformed placebo, while the other preparations are still under study [49].…”

Investigational drugs in recent clinical trials for treatment-resistant depression

“…New NMDAR antagonists (modulators) are therefore continuously being introduced for use in TRD [13,48,49,82–84,88–91]. These show relatively modest antidepressant effects compared to ketamine, but some are orally bioavailable and/or have shown more favorable tolerability profiles (reduced dissociative and/or psychotomimetic effects) [13].…”

“…These show relatively modest antidepressant effects compared to ketamine, but some are orally bioavailable and/or have shown more favorable tolerability profiles (reduced dissociative and/or psychotomimetic effects) [13]. …”

“…TRD is a complex, multifactorial, and heterogeneous group of disorders, integrating neurobiological and environmental factors, which reduces the sensitivity to selective serotonin reuptake inhibitors (SSRIs) and second-line antidepressants [10–12]. Among these factors, converging lines of evidence indicate an important pathophysiological role of the glutamatergic system [13,14]. Recent evidence is suggesting that TRD may involve a maladaptive response to stress in early life, leading to disturbances characterized by a complex crosstalk within the extrasynaptic glutamatergic receptor signal pathway, involving glutamate reuptake and release by glial cells [14].…”