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 realworld 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.

Fig. (1)

Direct NMDA Receptor Modulators. As displayed in the lower left-hand corner, N-methyl-D-aspartate (NMDA) receptors are tetra/heteromeric receptor complexes whose natural ligands in the brain are glutamate and glycine. Activation of these receptors leads to the release of the magnesium (Mg²⁺) pore block and the flux of cations (Ca²⁺ preferentially) from the synapse into the postsynaptic cytoplasm, which facilitates continuing neuronal depolarization. Non-selective, non-competitive antagonists of NMDA receptors include phencyclidine (PCP), ketamine, memantine, and AZD6765 (lanicemine). NR2B-subunit selective NMDA receptor antagonists include CP-101,606/
traxoprodil, MK-0657, and Ro 25-6981. Glycine, D-serine, D-cycloserine, and GLYX-13 are putative agonists at the glycine modulatory site.

Fig. (2)

Single and Multiple Subanesthetic Dose Ketamine Infusion Studies in Major Depression. A. Change in severity of depressive symptoms after a single subanesthetic dose ketamine infusion (0.5mg/kg x 40 minutes) in treatment-resistant major depressive disorder (MDD) and bipolar I/II depression (n=136) as measured by the 17-item Hamilton Depression Rating Scale (HAM-D17) score (mean ± SE) over one week post-infusion. The 136 subjects were obtained from four separate protocols: 1) unmedicated subjects with treatment-resistant MDD (TRD) (n=21) [10]; 2) subjects with treatment-resistant bipolar depression maintained on either lithium or valproate (n=34) [102, 103]; 3) unmedicated TRD subjects who received an open-label ketamine infusion followed by double-blind randomization to either placebo (n=31) or riluzole (n=24) [104]; and 4) an unpublished cohort of combined TRD and treatment-resistant bipolar depression subjects who underwent neuroimaging (n=26). B. Change in severity of depressive symptoms after repeated ketamine infusions in TRD. The figure depicts change in depression severity as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) (mean ± SD) over a 12-day period during which ketamine (0.5 mg/kg) was administered intravenously on a Monday-Wednesday-Friday schedule, corresponding to study days 0, 3, 5, 8, 10, and 12. Trajectories of depressive symptom severity are plotted for Phase I responder and nonresponder subgroups, defined using final observed MADRS score. Depression severity was initially measured at baseline before the first ketamine infusion and then at 2, 4, and 24 hours while participants were inpatients. Subsequent infusions occurred on an outpatient basis, and depression severity was measured in the morning before each infusion and then at four hours post-infusion. *MADRS score significantly decreased at given time point compared with baseline, p <0.05. #MADRS score significantly different at given time point between responder and nonresponder subgroups. ^aThree participants in the nonresponder group did not receive all six ketamine infusions. Fig. 2B and its corresponding legend are reproduced with permission from [16].