Targeting the glutamatergic system to treat major depressive disorder: rationale and progress to date

Abstract

Major depressive disorder (MDD) is a severe, debilitating medical illness that affects millions of individuals worldwide. The young age of onset and chronicity of the disorder has a significant impact on the long-term disability that affected individuals face. Most existing treatments have focused on the 'monoamine hypothesis' for rational design of compounds. However, patients continue to experience low remission rates, residual subsyndromal symptoms, relapses and overall functional impairment. In this context, growing evidence suggests that the glutamatergic system is uniquely central to the neurobiology and treatment of MDD. Here, we review data supporting the involvement of the glutamatergic system in the pathophysiology of MDD, and discuss the efficacy of glutamatergic agents as novel therapeutics. Preliminary clinical evidence has been promising, particularly with regard to the N-methyl-D-aspartate (NMDA) antagonist ketamine as a 'proof-of-concept' agent. The review also highlights potential molecular and inflammatory mechanisms that may contribute to the rapid antidepressant response seen with ketamine. Because existing pharmacological treatments for MDD are often insufficient for many patients, the next generation of treatments needs to be more effective, rapid acting and better tolerated than currently available medications. There is extant evidence that the glutamatergic system holds considerable promise for developing the next generation of novel and mechanistically distinct agents for the treatment of MDD.

Fig. 1

Glutamatergic neurotransmission and potential targets for drug development. Tight physiological control is maintained over glutamatergic neurotransmission. Gln is converted to Glu by glutaminase, though it can also be derived from the TCA cycle (not shown). Glu is packaged into presynaptic vesicles by VGLUT proteins and released from the neuron in an activity-dependent manner through interactions with SNARE proteins. Glu is cleared from the extracellular space by EAATs present predominantly on glia. In glial cells, Glu is converted to Gln by GS. A variety of Glu receptors are present on presynaptic and postsynaptic neurons as well as on glial cells. These include both ionotropic receptors (AMPA, NMDA and kainate), as well as mGluRs. The effect of Glu is determined by the receptor subtype, localization and interactions with various scaffolding and signalling proteins in the postsynaptic density. Activation of Glu receptors results not only in rapid ionotropic effects, but also in long-term synaptic plasticity. Potential targets for drug development numbered in the figure: (a) modulation of presynaptic vesicular loading of Glu; (b) modulation of presynaptic vesicular Glu release; (c) voltage-dependent Na⁺ channel modulation that regulates Glu release; (d) modulation of extrasynaptic Glu release; (e) and (k) mGluR modulation (mGluR2/3 receptor antagonists have demonstrated antidepressant activity, mGluR2/3 agonists have demonstrated anxiolytic activity); (f) interactions with scaffolding and signalling proteins; (g) AMPA receptor modulation; (h) and (i) NMDA receptor modulation; (j) facilitation of Glu clearance via EAATs. AMPA = α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid; BDNF = brain-derived neurotrophic factor; Ca = calcium; EAAT = excitatory amino acid transporter; Gln = glutamine; Glu = glutamate; GS = glutamine synthetase; mGluR = metabotropic glutamate receptor; Na= sodium; NMDA = N-methyl-D-aspartate; SNARE= soluble N-ethylmaleimide sensitive factor attachment receptor complex; TCA = tricarboxylic acid; VGLUT = vesicular glutamate transporter. Reproduced from Sanacora et al.,^[75] by permission from Macmillan Publishers Ltd., © 2008.