Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder

Abstract

Monoaminergic neurotransmitter (serotonin, norepinephrine and dopamine) mechanisms of disease dominated the research landscape in the pathophysiology and treatment of major depressive disorder (MDD) for more than 50 years and still dominate available treatment options. However, the sum of all brain neurons that use monoamines as their primary neurotransmitter is <20%. In addition, most patients treated with monoaminergic antidepressants are left with significant residual symptoms and psychosocial disability not to mention side effects, e.g., sexual dysfunction. In the past several decades, there has been greater focus on the major excitatory neurotransmitter in the human brain, glutamate, in the pathophysiology and treatment of MDD. Although several preclinical and human magnetic resonance spectroscopy studies had already implicated glutamatergic abnormalities in the human brain, it was rocketed by the discovery that the N-methyl-D-aspartate receptor antagonist ketamine has rapid and potent antidepressant effects in even the most treatment-resistant MDD patients, including those who failed to respond to electroconvulsive therapy and who have active suicidal ideation. In this review, we will first provide a brief introduction to glutamate and its receptors in the mammalian brain. We will then review the clinical evidence for glutamatergic dysfunction in MDD, the discovery and progress-to-date with ketamine as a rapidly acting antidepressant, and other glutamate receptor modulators (including proprietary medications) for treatment-resistant depression. We will finally conclude by offering potential future directions necessary to realize the enormous therapeutic promise of glutamatergic antidepressants.

Fig. 1

Glutamate receptor classes. Glutamate receptors are first stratified functionally—ionotropic receptors flux cations from the extracellular milieu into the cytosol when activated while metabotropic receptors exert their physiological effects via the indirect stimulation of intracellular second messenger/signal transduction cascades. Ionotropic receptors are then divided based on pharmacodynamics activation—NMDA, AMPA, and kainate. Metabotropic receptors have been classified into three groups based on structural and functional similarity—group I (mGluR1/5), group II (mGluR2/3), and group III (mGluR4/6/7/8). NMDA N-methyl-D-aspartate, AMPA α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, mGluR metabotropic glutamate receptor

Fig. 2

Synaptic and intracellular events stimulated by the rapid-acting antidepressant ketamine. Preliminary preclinical and unpublished clinical data suggest that postsynaptic NMDA receptor antagonism increases presynaptic glutamate release (i.e., glutamate “surge”). Glutamate is then hypothesized to increase AMPA/NMDA receptor flux. AMPA channel opening in the CNS increases sodium and, indirectly, calcium, stimulating the PI3K cascade to phosphorylate mTOR through Akt. Activated mTOR then phosphorylates p70S6K, increasing translation of downstream postsynaptic targets (notably, mTOR activity can be inhibited by rapamycin through the formation of an inhibitory complex with FKBP12). Activated mTOR also inhibits 4E-BP to relieve inhibition upon translation. NMDA receptor activation also inhibits eEF2K, which increases levels of dephosphorylated eEF2. Dephosphorylated eEF2 relieves inhibition upon BDNF translation in dendritic spines and promotes local secretion, which, in turn, binds to cognate TrkB receptors to activate intracellular mTOR and its downstream targets. In sum, the translational activation induced by acute NMDA receptor blockade increases the expression of several neuromodulatory proteins involved in, among other effects, postsynaptic scaffolding, neurotransmitter dynamics, and dendritic spine morphogenesis from immature thin filopodia-to-mature mushroom-shaped spines (see inset), which form the morphological substrate for antidepressant-like behavioral effects. Through release of inhibition upon local translation of BDNF, ketamine increases excitatory postsynaptic currents in prefrontal cortical and hippocampal neurons. 4E-BP 4E-binding protein, AMPA α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, AMPA-R AMPA receptor, BDNF brain-derived neurotrophic factor, CNS central nervous system, eEF2 eukaryotic elongation factor 2, eEF2K eEF2 kinase, ERK extracellular signal-regulated kinase, FKBP FK506 binding protein, MAPK mitogen-activated protein kinase, mTOR mammalian target of rapamycin, NMDA N-methyl-D-aspartate, NMDA-R NMDA receptor, p70S6K p70 S6 kinase, PI3K phosphoinositide-3 kinase, TrkB neurotrophic tyrosine kinase, type 2