Elsevier

Neuropharmacology

Volume 62, Issue 1, January 2012, Pages 63-77
Neuropharmacology

Review
Towards a glutamate hypothesis of depression: An emerging frontier of neuropsychopharmacology for mood disorders

https://doi.org/10.1016/j.neuropharm.2011.07.036Get rights and content

Abstract

Half a century after the first formulation of the monoamine hypothesis, compelling evidence implies that long-term changes in an array of brain areas and circuits mediating complex cognitive–emotional behaviors represent the biological underpinnings of mood/anxiety disorders. A large number of clinical studies suggest that pathophysiology is associated with dysfunction of the predominant glutamatergic system, malfunction in the mechanisms regulating clearance and metabolism of glutamate, and cytoarchitectural/morphological maladaptive changes in a number of brain areas mediating cognitive–emotional behaviors. Concurrently, a wealth of data from animal models have shown that different types of environmental stress enhance glutamate release/transmission in limbic/cortical areas and exert powerful structural effects, inducing dendritic remodeling, reduction of synapses and possibly volumetric reductions resembling those observed in depressed patients. Because a vast majority of neurons and synapses in these areas and circuits use glutamate as neurotransmitter, it would be limiting to maintain that glutamate is in some way ‘involved’ in mood/anxiety disorders; rather it should be recognized that the glutamatergic system is a primary mediator of psychiatric pathology and, potentially, also a final common pathway for the therapeutic action of antidepressant agents.

A paradigm shift from a monoamine hypothesis of depression to a neuroplasticity hypothesis focused on glutamate may represent a substantial advancement in the working hypothesis that drives research for new drugs and therapies. Importantly, despite the availability of multiple classes of drugs with monoamine-based mechanisms of action, there remains a large percentage of patients who fail to achieve a sustained remission of depressive symptoms. The unmet need for improved pharmacotherapies for treatment-resistant depression means there is a large space for the development of new compounds with novel mechanisms of action such as glutamate transmission and related pathways.

This article is part of a Special Issue entitled ‘Anxiety and Depression’.

Highlights

► Pathophysiology of depression is associated with dysfunction of glutamatergic system. ► Drugs targeting glutamate system may have rapid and sustained antidepressant effects. ► A paradigm shift from monoamine to glutamate may bring new impulse to the field.

Section snippets

Introduction. Do we need a glutamate hypothesis of depression?

The fields of neuropsychopharmacology and biological psychiatry have been dominated for over half a century by the monoamine hypothesis, which has driven the research on pathophysiology of neuropsychiatric disorders, in particular mood/anxiety disorders, as well as the development of therapeutic drugs. The basic version of the hypothesis, with regard to depression, speculated that pathology was due to (or accompanied by) reduced availability of monoamines, particularly serotonin and

Brain is in good part a glutamatergic/GABAergic machine

Although it was not readily recognized as a neurotransmitter until the early 1980s, much later than the monoaminergic transmitters, the amino acid glutamate is now accepted as the major excitatory neurotransmitter in the nervous system (Orrego and Villanueva, 1993). Glutamate mediates the vast majority of fast excitatory transmission in the brain, while γ-aminobutyric acid (GABA), another amino acid neurotransmitter, mediates the vast majority of fast inhibitory transmission. As an example, it

Emotion vs cognition. The role of glutamate transmission

The last three decades of neurobiological research have clearly associated cognitive processes in the brain with functional and structural changes in glutamate neurotransmission. A wealth of studies (particularly in the hippocampus) have shown that activity-dependent changes in the synaptic strength of central glutamate synapses correlate with the processes of learning and memory, and that interfering with these changes impairs the fixation of memories (Citri and Malenka, 2008, Diamond et al.,

Glutamate levels: plasma, cerebrospinal fluid, tissue studies

There is now rapidly growing evidence that pathophysiological changes within the amino acid neurotransmitter systems are associated with mood and cognitive dysfunction. Similar to reports of wide ranging abnormalities in GABA content in individuals with mood disorders (Brambilla et al., 2003, Tunnicliff and Malatynska, 2003, Sanacora and Saricicek, 2007), glutamatergic abnormalities have been demonstrated in the plasma, cerebrospinal fluid (CSF) and brain tissue of individuals afflicted with

Cytoarchitectural and morphological correlates to mood disorders

Consistent with the idea that changes in glial cell function may be related to the reports of abnormal levels of glutamate and glutamine in patients with mood disorders, reduced numbers and density of glial cells have been reported in a number of postmortem studies (Rajkowska, 2000, Rajkowska et al., 1999, Rajkowska et al., 2001, Bowley et al., 2002, Miguel-Hidalgo et al., 2002, Webster et al., 2001, Cotter et al., 2001, Miguel-Hidalgo et al., 2000, Ongur et al., 1998, Hamidi et al., 2004) (see

Dendritic remodeling in the brain. Evidence from preclinical stress models

The effects of stress on structural remodeling in the brain have been investigated by a number of studies (for a review see: Gorman and Docherty, 2010, Holmes and Wellman, 2009, McEwen, 2005, Musazzi et al., 2011, Pittenger and Duman, 2008, Shansky and Morrison, 2009). The largest number of studies has been carried out in hippocampus, but prefrontal cortex and amygdala were also analyzed (Table 1). Different forms of stress have been shown to induce atrophy, retraction and consistently

The effects of stress and glucocorticoids on glutamate synapses and neurotransmission

A remarkable feature of glutamate synapses is their ability to undergo structural, as well as functional change, in response to environmental stimuli (Südhof and Malenka, 2008, Wong and Ghosh, 2002). Accordingly, synaptic terminals, spines and dendritic branches are constantly remodeled as a result of experience, learning and memory, emotion processing. As outlined above, environmental stress has a heavy impact on brain tissue morphology and is considered a risk factor for mood/anxiety

Antidepressant agents and glutamate: preclinical evidence

The monoamine hypothesis was largely based on the serendipitous discovery of the first antidepressant agents. However, early findings that these drugs affect synaptic plasticity, modulate the function of NMDA-R, and that NMDA-R antagonists possess antidepressant activity, have started a variegated field of research that in time has contributed to disclose the role of glutamatergic system in mood disorder and in antidepressant action. In this section, we summarize the known effects of

Conclusions: future perspectives and novel targets

There is compelling accumulated evidence that long-term changes in an array of brain areas and circuits mediating complex cognitive–emotional behaviors represent the biological underpinnings of mood/anxiety disorders. As the vast majority of neurons and synapses in these areas and circuits use glutamate as neurotransmitter, today it would be limiting to maintain that glutamate is in some way ‘involved’ in these neuropsychiatric disorders; rather it should be recognized that the glutamatergic

References (228)

  • Z. Bhagwagar et al.

    Reduction in occipital cortex gamma-aminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects

    Biol. Psychiatry

    (2007)
  • C.D. Bonavita et al.

    Tolerance to the sedative effect of lorazepam correlates with a diminution in cortical release and affinity for glutamate

    Neuropharmacology

    (2002)
  • M.P. Bowley et al.

    Low glial numbers in the amygdala in major depressive disorder

    Biol. Psychiatry

    (2002)
  • E. Celano et al.

    Selective regulation of presynaptic calcium/calmodulin-dependent protein kinase II by psychotropic drugs

    Biol. Psychiatry

    (2003)
  • C. Cleary et al.

    Antidepressive-like effects of rapamycin in animal models: implications for mTOR inhibition as a new target for treatment of affective disorders

    Brain Res. Bull.

    (2008)
  • D.R. Cotter et al.

    Glial cell abnormalities in major psychiatric disorders: the evidence and implications

    Brain Res. Bull.

    (2001)
  • J.P. Cousins et al.

    Neurobiochemical changes from taxol/neupogen chemotherapy for metastatic breast carcinoma corresponds with suicidal depression

    Cancer Lett.

    (1996)
  • C.A. do Nascimento et al.

    Changes in [(3)H]-glutamate uptake into platelets from patients with bipolar I disorder

    Psychiatry Res.

    (2006)
  • R.J. Douglas et al.

    Mapping the matrix: the ways of neocortex

    Neuron

    (2007)
  • J. Du et al.

    Enhancing AMPA to NMDA throughput as a convergent mechanism for antidepressant action

    Drug Discov. Today Ther. Strat.

    (2006)
  • R.S. Duman

    Depression: a case of neuronal life and death?

    Biol. Psychiatry

    (2004)
  • S.H. Fatemi et al.

    Glial fibrillary acidic protein is reduced in cerebellum of subjects with major depression, but not schizophrenia

    Schizophr. Res.

    (2004)
  • P.T. Francis et al.

    Brain amino acid concentrations and Ca2+-dependent release in intractable depression assessed antemortem

    Brain Res.

    (1989)
  • M.A. Frye et al.

    Low cerebrospinal fluid glutamate and glycine in refractory affective disorder

    Biol. Psychiatry

    (2007)
  • L. Glodzik-Sobanska et al.

    Single voxel proton magnetic resonance spectroscopy in post-stroke depression

    Psychiatry Res.

    (2006)
  • T. Hajszan et al.

    Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression

    Biol. Psychiatry

    (2009)
  • M. Hamidi et al.

    Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes

    Biol. Psychiatry

    (2004)
  • K. Hashimoto et al.

    Increased levels of glutamate in brains from patients with mood disorders

    Biol. Psychiatry

    (2007)
  • A. Holmes et al.

    Stress-induced prefrontal reorganization and executive dysfunction in rodents

    Neurosci. Biobehav. Rev.

    (2009)
  • M. Joels

    Functional actions of corticosteroids in the hippocampus

    Eur. J. Pharmacol.

    (2008)
  • H. Kober et al.

    Functional grouping and cortical–subcortical interactions in emotion: a meta-analysis of neuroimaging studies

    Neuroimage

    (2008)
  • H. Koike et al.

    Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression

    Behav. Brain Res.

    (2011)
  • T. Kojima et al.

    Fluvoxamine suppresses the long-term potentiation in the hippocampal CA1 field of anesthetized rats: an effect mediated via 5-HT1A receptors

    Brain Res.

    (2003)
  • M. Leventopoulos et al.

    Long-term effects of early life deprivation on brain glia in Fischer rats

    Brain Res.

    (2007)
  • J. Levine et al.

    Increased cerebrospinal fluid glutamine levels in depressed patients

    Biol. Psychiatry

    (2000)
  • Y. Agid et al.

    How can drug discovery for psychiatric disorders be improved?

    Nat. Rev. Drug Discov.

    (2007)
  • R.F. Almeida et al.

    Effects of depressive-like behavior of rats on brain glutamate uptake

    Neurochem. Res.

    (2010)
  • C.A. Altamura et al.

    Plasma and platelet excitatory amino acids in psychiatric disorders

    Am. J. Psychiatry

    (1993)
  • L.L. Altshuler et al.

    Amygdala astrocyte reduction in subjects with major depressive disorder but not bipolar disorder

    Bipolar Disord.

    (2010)
  • A.E. Autry et al.

    NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses

    Nature

    (2011)
  • M. Banasr et al.

    Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole

    Mol. Psychiatry

    (2010)
  • V.S. Barbiero et al.

    Chronic antidepressants induce redistribution and differential activation of alphaCaM Kinase II between presynaptic compartments

    Neuropsychopharmacology

    (2007)
  • A. Bechara et al.

    Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans

    Science

    (1995)
  • A. Bechara et al.

    Characterization of the decision-making deficit of patients with ventromedial prefrontal cortex lesions

    Brain

    (2000)
  • A.J. Bechtholt-Gompf et al.

    CD-1 and Balb/cJ mice do not show enduring antidepressant-like effects of ketamine in tests of acute antidepressant efficacy

    Psychopharmacology (Berl)

    (2011)
  • B. Begni et al.

    Substrate-induced modulation of glutamate uptake in human platelets

    Br. J. Pharmacol.

    (2005)
  • R. Bernard et al.

    Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression

    Mol. Psychiatry

    (2010)
  • J.M. Bessa et al.

    The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling

    Mol. Psychiatry

    (2009)
  • N. Binesh et al.

    Neurochemistry of late-life major depression: a pilot two-dimensional MR spectroscopic study

    J. Magn. Reson. Imaging

    (2004)
  • G. Bonanno et al.

    Chronic antidepressants reduce depolarization-evoked glutamate release and protein interactions favoring formation of SNARE complex in hippocampus

    J. Neurosci.

    (2005)
  • Cited by (806)

    • Progress of depression mechanism based on Omics method

      2024, Journal of Pharmaceutical and Biomedical Analysis
    View all citing articles on Scopus
    View full text