Mr. Kelmendi is a research associate in the Department of Psychiatry at Yale University School of Medicine in New Haven, Connecticut. Dr. Saricicek is a physician at Ataturk Training and Research Hospital in Izmir, Turkey. Dr. Sanacora is an associate professor in the Department of Psychiatry at Yale University School of Medicine and director of the Yale Depression Research Program.

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Abstract

Multiple findings from preclinical and clinical studies suggest that amino acid neurotransmitter systems are associated with the pathophysiology and treatment of mood disorders. Numerous studies employing in vivo magnetic resonance spectroscopy as well as peripheral and postmortem measures have shown evidence of altered glutamatergic function in depressed patients. Consistent with this observation, glutamate-modulating agents such as riluzole, ketamine, and lamotrigine have been shown to demonstrate antidepressive and anxiolytic properties in a several animal and clinical studies. Studies demonstrating significant glial cell abnormalities in several brain regions of individuals suffering from mood disorders may provide a clue to the underlying pathophysiologic mechanism associated with the abnormal glutamatergic function in mood disorders. 

Introduction

There has been a flux of recent exploration into the role of glutamate in the pathophysiology and treatment of mood disorders. This novel approach has been taken because a large percentage of depressed patients fail to achieve full remission with currently available antidepressants such as monoamine oxidase inhibitors, tricyclics, and selective serotonin reuptake inhibitors.¹ Moreover, the therapeutic effect of these drugs is often delayed, requiring up to 5 weeks of continued administration.² Convergent lines of evidence suggest that dysregulation of the glutamatergic system contributes to the pathophysiology and treatment of major depressive disorder (MDD) and other mood disorders. This article reviews the existing studies that investigate the putative role of glutamatergic systems in the pathophysiology of mood disorders and examines the efficacy of glutamate-modulating agents. Finally, a pathophysiologic model of MDD based on available data is presented in an attempt to synthesize the evidence of glutamatergic contributions to mood disorders.

 

Glutamatergic Systems and the Pathophysiology of Mood Disorders

Glutamate is ubiquitous in the mammalian central nervous system (CNS). It is the principal excitatory amino acid neurotransmitter and is used in up to 60% of all CNS synapses. The concentration of glutamate throughout the brain can be found to range from 8–15 mmol/kg, in contrast to that of monoamines, which exist at concentrations 1,000 times lower. Although glutamate is present in extremely high concentrations in brain tissue, only a small fraction of glutamate is extracellular. Thus, a great energetic expense is paid in preserving the normal physiologic concentration of extracellular glutamate that is critical to prevent toxicity, and for the maintenance of a wide array of physiologic functions.

Figure 1 illustrates the complexity of the glutamatergic system. Glutamate transmission is closely regulated by feedback inhibition of presynaptic release as well as several glutamate transporters that are located primarily on glial cells. Glutamate signaling occurs at both pre- and post-synaptic sites, acting on specific glutamate receptors that can be characterized as either ionotropic or metabotropic. The three excitatory ionotropic receptors are α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA), N-methyl-D-aspartate (NMDA), and kainite. The one inhibitory ionotropic receptor is 4-aminopyridine. Metabotropic glutamate receptors (mGluRs) are G protein-coupled and are divided into three groups on the basis of effector coupling and ligand sensitivity: Group I (mGluR1 a-d, mGluR5 a-b), Group II (mGluR2/3), and Group III (mGluR4, mGluR6-8).



Synaptic glutamate is taken up by high-affinity glutamate transporters, known as excitatory amino acid transporters (EAATs). Both EAAT subtypes 1 and 2 are located on glial cells and remove the majority of glutamate from the synapse; whereas EAAT subtypes 3 and 4 are primarily located on the neuronal cells and, in specific brain regions, are also involved in clearing glutamate.^3,4 The glutamate taken up by EAAT1/2 into the glial cell (Figure 1) is converted to glutamine by glutamine synthetase. The glutamine is then released by glia and taken up by neuronal terminals where it is reconverted to glutamate and stored in vesicles. This process, known as the glutamate/glutamine cycle, is tightly coupled to energy consumption in the brain.⁵

 

Preclinical Evidence for the Role of Glutamate in the Physiology of Mood Disorders

Animal Studies Suggesting Glutamate’s Involvement in the Pathogenesis of MDD

The Effect of Stress on Glutamate
Stress has long been thought to be associated with the pathogenesis of mood disorders. Several lines of evidence from preclinical studies suggest that glutamate may partially mediate this association. Glutamatergic neurotransmission is enhanced by stress.^6-10 Brain insults lead to increased extracellular levels of glutamate and sustained activation of ionotropic receptors, especially the NMDA subtype that can contribute to a variety of neurotoxic effects.^11-14 Numerous animal studies have implicated stress-responsive neurotoxicity as the mechanism responsible for decreased dendritic branching, neuronal regeneration of hippocampal pyramidal cells, and atrophy of hippocampal neurons.^15,16 The observed cellular and morphologic alterations induced by stress have been implicated in the pathophysiologic process, resulting in volume reductions that have been observed in several brain regions in patients with MDD. Studies utilizing glutamate transporter transgenic mice—resulting in excessive extracellular glutamate—have demonstrated degenerative effects on hippocampal neurons, consistent with the stress-responsive neurotoxicity hypothesis. Moreover, chronic exposure to stress has effects on gene expression leading to increased expression of hippocampal messenger ribonucleic acid AMPA receptors and altered levels of glutamatergic excitation.

 

Animal Studies Suggesting the Glutamatergic System May Serve as a Target for the Development of Novel Antidepressants

In support of the claim that glutamate neurotransmission contributes to the pathophysiology associated with stress and depression, strong pharmacologic evidence exists demonstrating the effectiveness of glutamatergic agents in preventing and reversing stress-related rodent models of depression. Moreover, there is also evidence that the existing classes of antidepressants have significant modulatory effects on the glutamatergic system.

NMDA Antagonists
Several drugs with NMDA-antagonist properties have antidepressant and anxiolytic profiles in animal models. The NMDA receptor-channel complex is a large protein consisting of numerous modulatory binding sites with an integral ion channel. It is possible to modulate NMDA receptor activity in various pharmacologic ways. Although it is not replicated in all studies, several laboratories have demonstrated that functional antagonists of the NMDA receptor, including ligands at glutamate, glycine, polyamine, bivalent cation (Zn²⁺) and ionophore recognition sites, have antidepressant and anxiolytic properties in mice and rats (Table 1).^5,17-34 In addition, other preclinical studies suggest that many existing classes of antidepressants modulate NMDA receptor activity.³⁵ Thus, it is possible that even for the classical antidepressants, effects on the NMDA receptor may contribute to the mechanism of antidepressant activity.



Metabotropic Glutamate Receptor Modulators
Most recent studies indicate that group I (mGluR1 and mGluR5) receptor antagonists possess antidepressive and anxiolytic properties. For example, 2-methyl-6-(phenylethynyl)-pyridine, an mGluR5 receptor antagonist, was found to have antidepressant-like effect in olfactory bulbectomy and tail-suspension tests.^36,37 The group II (mGluR2 and mGluR3) agents also appear to have antidepressive and anxiolytic properties; however, group II agonists appear to act as anxiolytics³⁸ while the antagonists act as antidepressants.³⁹

AMPA/Kainate/Potentiators
AMPA receptor potentiators produced antidepressant-like effects in several animal models including forced-swim and tail suspension tests.^40-42 Although there are some contradictory results,²⁹ potentiation of AMPA receptors has also been found effective in animal models of anxiety, including elevated plus maze and Vogel conflict tests.^43,44

Glutamate-Release Inhibitors and Uptake Facilitators
It is difficult to interpret data from preclinical studies with compounds that act as glutamate-release inhibitors. Lamotrigine failed to show any significant effect in the forced swim model. However, it reduced the immobility time when administered with folic acid.⁴⁵ Riluzole, an agent also believed to act as a glutamate-release inhibitor and glutamate-uptake enhancer, has been shown to have an effect on neurotrophic factor synthesis. In one study, riluzole antagonized the anxiogenic effect of the β-carboline derivative FG7142, an inverse agonist at the GABA-benzodiazepine-chloride ionophore receptor complex.⁴⁶ Additionally, a recent study has shown that ceftriaxone, a β-lactam agent that increases glutamate uptake via increased expression of EAAT2, possesses antidepressant-like activity in several rodent behavioral models.⁴⁷

 

Evidence of Glutamatergic Abnormalities in Mood Disorder Patients

Similar to the reports of GABAergic abnormalities associated with depression,⁴⁸ glutamatergic abnormalities have been demonstrated in several studies. However, unlike the consistently reported finding of reduced GABA concentrations, glutamate studies appear less congruent in regard to direction of change.

Several studies utilize peripheral tissue and postmortem brains to investigate the glutamatergic system in mood disorders (Table 2).^13,49-57 Nowak and colleagues¹³ reported that the proportion of high affinity glycine-displaceable [3H]CGP-39653 binding to glutamate receptors was reduced in age- and postmortem interval-matched suicide victims, but no significant differences in the binding of a non-competitive antagonist to the NMDA receptor were found between depressed suicide victims and an age matched comparison group.⁵⁸



There appears to be a trend showing elevated plasma and cerebrospinal fluid glutamate levels in depressed patients, but this is difficult to disentangle from the treatment effects.⁵⁹ In vivo measures of excitatory amino acids in the brain can be made with the use of proton magnetic resonance spectroscopy (¹H-MRS). However, using standard clinical field strength magnets, the visibility of these metabolites is limited by several factors that make it extremely difficult to assign unequivocal resonance peaks. This has led to the use of a combined measure, termed Glx, including glutamate, glutamine, and GABA, of which the greatest proportion reflects the glutamate concentration. In a unique study, Cousins and Harper⁶⁰ used this methodology to demonstrate temporary decreases in Glx levels coinciding with a patient’s transient experience of suicidal depression following paclitaxel and filgrastim chemotherapy. A preliminary study also showed a similar decrease in baseline anterior cingulate Glx levels that later increased following treatment with ECT.⁶¹ Reduced glutamate content was also recently reported in the ventral medial and dorsal medial prefrontal cortex.⁶²

Elevated levels of Glx were found in both the frontal lobe and basal ganglia of depressed bipolar children compared to a control group.⁶³ A recently completed ¹H-MRS study of 29 depressed subjects and 28 healthy comparison subjects demonstrated significantly increased cortical glutamate levels in the occipital region of depressed subjects. Similar to findings of reduced GABA concentrations, the increased glutamate concentrations appeared especially evident in the subgroup of melancholic subjects.⁶⁴

In summary, studies strongly suggest that abnormalities exist within the glutamatergic system of MDD patients; however, the extent and direction of the changes are still to be determined.

 

Evidence of Glutamatergic Involvement in Antidepressant and Anxiolytic Mechanisms-of-Action in Clinical Studies

NMDA Antagonists

A serendipitous finding revealed that ketamine has a rapid and sustained antidepressant activity after only a single dose. In a randomized controlled trial initially designed to explore the acute effects of ketamine on cognition, the drug demonstrated marked improvement in depression-rating scores, lasting for several days, following a single infusion of ketamine 0.5 mg/kg to depressed subjects.⁶⁵ A similar prolonged antidepressant effect was also found following the use of ketamine anesthesia in depressed patients undergoing orthopedic surgery,⁶⁶ and in a recently completed larger replication study at the National Institute of Mental Health.⁶⁷ Ketamine’s antidepressant efficacy is also supported by a recent case report of a depressed patient receiving ketamine anesthesia for electroconvulsive therapy.⁶¹ Ketamine’s efficacy in anxiety disorders is not known. In an early study, ketamine was found to reduce negative affect in stressful conditions when administrated to healthy subjects during induced-anxiety therapy.⁶⁸

 

Glutamate-Release Inhibitors

Lamotrigine, an anticonvulsant agent, is recommended in the 2002 American Psychiatric Association guidelines⁶⁹ as a first-line treatment for acute bipolar depression and one of several options for maintenance therapy. It is believed to inhibit the excessive release of glutamate via inhibition of use-dependent sodium channels, P-type and N-type calcium channels, and effects on potassium channels.⁷⁰ Several recent case series and open-label studies suggest riluzole, a drug believed to both decrease glutamate release and facilitate glutamate uptake, possesses antidepressant and anxiolytic activity (Table 3).^71-79

 

A Potential Mechanism Relating Glutamate Dysfunction to Depression

In review of the available evidence, it appears there are widespread abnormalities in the amino acid neurotransmitter (AANt) systems in a subset of individuals with MDD, and that drugs targeting the glutamatergic system have antidepressant and anxiolytic effects. Based on these findings and several studies showing reduced glial cell number and density in several brain regions of depressed individuals,^80-87 it has been hypothesized that a disruption in the neuronal/glial pathways regulating GABA and glutamate cycling could account for several of the differences observed between MDD and healthy comparison subjects.⁶⁴ Recent work highlights the importance of glial cells in the functioning and regulation of both the GABAergic and glutamatergic neurotransmitter systems.⁸⁸ A reduction in glial function could provide an explanation for the AANt system abnormalities associated with mood disorders, as it would result in decreased flux through the glutamate/glutamine cycle (Figure 2). The decreased glial mediated glutamine synthesis could also lead to reduced glutamine supplies to GABAergic neurons and therefore to reduced rates of GABA synthesis.⁸⁸ In addition, the impairment in glial uptake of glutamate and conversion to glutamine would lead to an elevation of extracellular glutamate during intense neuronal activity. Studies suggests that this glutamate spillover is likely to lead to decreased rates of brain-derived neurotrophic factor production and impaired neuronal plasticity by activation of extracellular NMDA receptors.⁸⁹ This spillover could also potentially activate the presynaptic metabotropic glutamate receptors, resulting in reduced glutamate release and a reduction of metabolic activity. Such a model of impaired glial cell function is also congruous with other recent findings demonstrating the role of excitotoxicity in the pathogenesis of mood disorders and the antidepressant actions of antiglutamatergic agents.⁹⁰ A recent publication by Choudary and colleagues⁵⁷ demonstrating downregulation of SLC1A2 (EAAT2) and SLC1A3 (EAAT1) in postmortem tissue from the anterior cingulate gyrus and the dorsal lateral prefrontal cortex from depressed subjects is highly consistent with this hypothesis.

 

Conclusion

There is increasing evidence supporting the involvement of the AANt systems in the pathophysiology of mood disorders and the mechanism of antidepressant action. Preclinical studies suggest stress related effects on glutamate neurotransmission may contribute to the pathogenesis and pathophysiology associated with mood disorders. Other preclinical studies demonstrate the ability of glutamatergic agents to modify the behavioral responses in several rodent models used to screen for antidepressant and anxiolytic drug activity. In humans, the finding of lamotrigine’s mood-stabilizing properties combined with reports of abnormal glutamate content in the brain and peripheral tissues of individuals diagnosed with mood disorders has stimulated interest in the possibility of using other glutamatergic agents in the treatment of mood disorders. Initial preliminary studies with riluzole and ketamine further support this claim. However, much more research is needed before the true clinical significance of this novel class of agents can be fully determined. PP

 

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