Acta Psychiatr Scand 2010: 122: 192–210  2010 John Wiley & Sons A/S

All rights reserved ACTA PSYCHIATRICA

DOI: 10.1111/j.1600-0447.2009.01529.x SCANDINAVICA

Review
An update on the role of glutamate in the
pathophysiology of depression
Mitchell ND, Baker GB. An update on the role of glutamate in the N. D. Mitchell, G. B. Baker
pathophysiology of depression. Department of Psychiatry, University of Alberta,
Edmonton, Canada
Objective: To review the literature on the involvement of glutamate
(Glu), including its interactions with other neurochemical systems, in
the pathophysiology of depression.
Method: A MEDLINE search using the terms glutamate, depression
and major depressive disorder, was performed.
Results: Alterations in proteins involved in glutamatergic signalling
are implicated in variations in behaviour in animal models of
depression. Drugs acting at Glu receptors appear to have
antidepressant-like effects in these models, and traditional Key words: glutamate; depression; pathophysiology;
antidepressant pharmacotherapies act on the glutamatergic system. neurobiology; affective disorders; neurotransmitters
Recent evidence from genetic studies and in vivo spectroscopy also Nicholas D. Mitchell, Department of Psychiatry, Uni-
correlate glutamatergic dysfunction with depression. Trials of N- versity of Alberta Hospital, 1E1 Walter C. Mackenzie
methyl-d-aspartate receptor antagonists in humans have provided Centre, 8440 112 Street, Edmonton, AB T6G 2B7,
mixed results. Canada.
Conclusion: A growing body of evidence indicates that the E-mail: ndm@ualberta.ca
glutamatergic system is involved in the pathophysiology of depression,
and may represent a target for intervention. Accepted for publication December 8, 2009

Summations
• While poorly understood, increasing evidence suggests that the glutamatergic system contributes to
the pathophysiology of depression.
• The role of the glutamatergic system in depression likely involves changes in signalling at multiple
receptors in various brain regions, primarily in the frontal and temporal lobes.
• Emerging evidence from therapeutic trials in humans and animal models suggests a role for drugs
targeting the glutamatergic system in the treatment of depression.

Considerations
• Most early evidence of glutamatergic dysfunction in depression arose from animal models and
postmortem studies.
• Technical limitations and the inclusion of heterogenous samples in some in vivo spectroscopy studies
lower the specificity of their results.
• Glutamatergic dysfunction is not limited to depression, and may represent a more general marker of
disequilibrium.

Recently, research into the neurobiology of depres-

Introduction
Early theories of depression focused primarily on
biogenic amines (serotonin, norepinephrine and
dopamine) (1–6), and most antidepressants cur-
rently available target monoamine neurotransmit-
ter reuptake mechanisms and ⁄ or receptors.
sion has focused on a number of non-monoamine
neurotransmitters and neuromodulators (7–10),
and among the most exciting avenues of investiga-
tion in this regard are those involving the excit-
atory amino acid glutamate (Glu). This study will
provide an overview of studies in animal models

192

and humans that represent increasing evidence that
Glu dysfunction is involved in the neurobiology of
depression.
Aims of the study
The primary purpose of this review is to summarize
investigations on the role of the glutamatergic
system in major depression. The secondary aims
are to review the biochemistry of Glu and to
evaluate interactions with other neurochemical
systems, with a view to exploring proposed
mechanisms of depression.
Material and methods
A MEDLINE search was performed using the key
words glutamate, depression and major depressive
disorder for articles published up to and including
June 2009. Articles were limited to those pub-
lished in English. The references for selected
articles were searched by hand for additional
relevant studies. The search was undertaken
between December 2008 and January 2009, and
updated in June 2009.
Results
Biochemistry of glutamate
Glutamate is an amino acid neurotransmitter
which cannot pass through the blood–brain barrier
(11) and must therefore be produced centrally in
the neurones and glia (12). Glu is primarily derived
from glucose and a-ketoglutarate, with a small
amount created from glutamine (Gln) (Fig. 1).
Glial cells synthesize Gln, which is then trans-
ported to the neurones where glutaminase converts
it to Glu. It is then packaged into secretory vesicles
by the vesicle Glu transporters (VGLUT). These
vesicles merge with the cellular membrane, releas-
ing Glu into the synapse. Glutamatergic activity is
regulated through the removal of Glu from the
synapse by excitatory amino acid transporters
(EAAT). Some Glu returns to the presynaptic
neurones, but most is collected into astrocytes via
this mechanism (13).
Glutamate
Glutaminase Decarboxylase
Glutamine Glutamate
Glutamine acid (GABA)
Synthetase Transaminase
-Ketoglutarate
Fig. 1. Metabolism of glutamate.
Glu in the pathophysiology of depression
Glutamatergic neurotransmission occurs thro-
ugh receptors (Table 1) which act as ion channels
(ionotropic) and receptors which are linked to
intracellular second messenger systems (metabo-
tropic) (12, 14–16). Ionotropic Glu receptors are
classified on the basis of pharmacologic affinities to
synthetic ligands. The N-methyl-d-aspartate
(NMDA), a-amino-3-hydroxy-5-methylisoxazole-
4-propionic acid (AMPA), and kainate receptors
are each composed of four subunits. Variation in
the expression of these various subunits gives rise to
different response properties. Approximately 70%
of the synapses in the mammalian brain contain
NMDA or AMPA receptors (17). These receptors
occur in particularly high density in the cerebral
cortex, hippocampus, amygdala, striatum and
septum. On a subcellular level, these receptors
have unique responses to activation by Glu (12).
Calcium influx through NMDA ion channels
activates a number of intracellular kinases and
phosphatases, thereby altering the characteristics of
the synapse; however, neuronal death results from
excess influx of calcium through the NMDA
receptor occurring in the context of anoxia or
hypoglycaemia. Therefore, glutamatergic signalling
plays a role in both neuroplasticiy and excitotoxi-
city. AMPA receptors have a lower affinity for Glu
than NMDA receptors, and are responsible for an
initial excitatory potential when Glu is present in
the synapse. This change in membrane polarization
leads to the removal of a magnesium ion from the
channel in the NMDA receptor which must occur
before calcium transit is possible. Kainate receptors
play a role in synaptic neurotransmission, but the
exact nature of this role is not yet clear. Metabo-
tropic Glu (mGlu) receptors are structurally differ-
ent from ionotropic receptors, consisting of seven
transmembrane domains (18). The eight currently
identified mGlu receptors are classified in three
groups based on the intracellular cascades that they
are coupled with, sequence homology and pharma-
cology. The type I mGlu receptors (mGlu1 and
mGlu5) are present both presynaptically and post-
synaptically, but the type II (mGlu2 and mGlu3)
and type III (mGlu4, mGlu6, mGlu7 and mGlu8)
receptors occur on glial cells and presynaptic
neurones where they act to regulate Glu release
(19). These receptors are thought to have multiple
functions related to their membrane location on the
neurone and density in different regions of the
-Aminobutyric
brain, both of which vary by type.
Investigations in animal models
Numerous animal models have been employed to
investigate the pathophysiology of major depres-
193
Mitchell and Baker
Table 1. Types of glutamate receptors
Receptor Subunits
Ionotropic glutamate receptors
N-methyl-D-aspartate (NMDA) NR1, NR2 and NR3
a-Amino-3-hydroxy-5- GluR1, GluR2 and GluR3,
methylisoxazole-4-propionic GluR4
acid (AMPA)
Kainate GluR5, GluR6, GluR7, KA1
and KA2
Metabotropic glutamate receptors (mGlu)
Type I mGlu (mGlu1, mGlu5)
Type II mGlu (mGlu2 and mGlu3)
Type III mGlu (mGlu4, mGlu6,
mGlu7 and mGlu8)
sion (10). Perturbations in Glu levels and gluta-
matergic neurotransmission have been examined in
these systems. The forced swim test is a model of
depressive-like behaviour and a screening test for
antidepressants (20, 21). In one study of rats
exposed to an adaptation of the forced swim test,
chronic forced swimming stress, decreases in Glu
levels in the prefrontal cortex and the hippocampus
were measured with ex vivo magnetic resonance
spectroscopy (MRS) (22). However, in another
model (23), animals bred to express congenital
learned helplessness showed increases in the ratio
of Glu ⁄ c-aminobutyric acid (GABA) in the
prefrontal cortex and hippocampus. These ratios
normalized when rats were administered either of
two effective treatments for depression in humans,
desipramine or electroconvulsive shock. While the
quality of change in Glu levels appears to differ in
these two studies, dysregulation of Glu was present
in both.
Alterations in proteins associated with glutama-
tergic neurotransmission in animals influence, and
are influenced by, depressive-like behaviours
(Table 2). Knockout studies involve the isolation
and removal of a single gene product, allowing for
evaluation of the effect of that protein on an
organismÕs physiology and behaviour. The vesicu-
lar Glu transporter protein VGLUT1 is found in
the cortex and hippocampus where it plays a
primary role in loading Glu into synaptic vesicles
for release, thus affecting the efficacy of glutama-
tergic neurotransmission in these regions. A line of
mice bred for reduced VGLUT1 expression had
increased depressive-like behaviours in a forced
swim test (24) and when exposed to chronic mild
stress (25). Antidepressant effects in forced swim
and tail suspension tests are observed in knockout
mice deficient in the NR2A NMDA receptor
subunit (26), suggesting that this particular subunit
is involved in the modulation of emotional behav-
iours. Mice that do not express the gene for the
194
Signalling mechanism Location
Calcium channel Postsynaptic
Sodium channel (primary) calcium channel (subset) Postsynaptic
Sodium channel Pre- and postsynaptic
G-protein coupled to phosphatidylinositol ⁄ calcium pathway and Pre- and postsynaptic
diacylglycerol ⁄ protein kinase-C pathway
G-protein coupled to adenylyl cyclase Presynaptic
G-protein coupled to adenylyl cyclase and phosphodiesterase Presynaptic
mGlu7 receptor show a similar decrease in depres-
sion-like behaviours (27, 28). One study using rats
bred to spontaneously demonstrate a depressive
phenotype showed decreased expression of the
mGlu2 ⁄ 3 receptor in the hippocampus compared
with depression-resistant controls (29). Chronic
stress in rats, modelled through restraint, increased
the expression of the KA1 subunit of the kainate
receptor in the same brain region (30). In another
experiment on chronic stress in rats, mGlu5 recep-
tor expression was increased in the CA1 region of
the hippocampus, but decreased in the CA3 region
(31). Ryan et al. (32) evaluated the interaction of
genetic predisposition and environmental stress on
the hippocampus of rats. At baseline, lower
expression of the NR1 subunit of the NMDA
receptor was present in the genetically sensitive
rats. When exposed to early maternal separation, a
form of early life stress, expression of NR1and the
mGlu2 ⁄ 3 receptor increased in sensitive rats but not
in genetically resistant rats. The expression of Glu
receptors and their component subunits varies in
response to genetic and environmental pressures,
and these fluctuations are associated with depres-
sion in animal models.
Administration of glutamatergic drugs influ-
ences the behaviour of animals in models of
depression (Table 3). Antidepressant effects
observed when competitive and non-competitive
NMDA receptor antagonists were administered in
a rat model of inescapable stress (33) provided
early evidence for involvement of Glu in depres-
sion. The NMDA receptor antagonist ketamine
reduces immobility in the forced swim test in rats
(34). Similarly, riluzole, a molecule that inhibits the
release of Glu from presynaptic neurones, reverses
decreases in glial metabolism, decreases in glial
fibrillary associated protein mRNA expression,
and behavioural effects of chronic unpredictable
stress in rats (35). The antibiotic ceftriaxone is
known to increase Glu reuptake and prevents the
 Glu in the pathophysiology of depression

development of depression-like behaviours in mice

Increased mGlu5 receptor expression in the CA1 region of the hippocampus, but decreased

Decreased expression of VGLUT1 in the frontal cortex and hippocampus of heterozygous

exposed to a tail suspension test or a forced swim

animals, associated with enhanced depressive-like behaviour on the forced swim test
Decreased depressive-like behaviours in the forced swim test and tail suspension test

Decreased depressive-like behaviours in the forced swim test and tail suspension test

in heterozygous animals. Antidepressant effects were observed with intraperitoneal

Increased NR1 and mGlu2 ⁄ 3 expression in sensitive rats with maternal separation
test (36). Compounds with activity at mGlu recep-

Decreased VGLUT1 and EAAT1 expression and increased depression-like behaviour

Increased expression in the hippocampus of animals exposed to chronic restraint
tors are also being investigated in animal models

Decreased expression of mGlu2 ⁄ 3 receptors in genetically sensitive animals

for antidepressant effects. Antagonists at type II

Lower baseline expression of NR1 subunit in genetically sensitive animals.

mGlu receptors and agonists at type III mGlu
receptors reduce depression-like behaviour (37–
39). AMN082, a specific agonist at the mGlu7
receptor, has antidepressant-like effects in wild
type rats, but has no behavioural effect on mGlu7
Results

expression in the CA3 level of the hippocampus

receptor knockout rats (40). This suggests that

there may be a specific role of the mGlu7 receptor
in depression. In one study examining sleep archi-

*Chronic mild stress in this model included: food or water deprivation, 45 cage tilt, intermittent illumination, soiled cage, paired housing, and low intensity stroboscopic illumination.
tecture, the mGlu2 ⁄ 3 receptor agonist LY354740
significantly suppressed rapid eye movement
(REM) sleep in rats and increased its latency of
onset (41). Although the clinical relevance of this
imipramine exposure

finding is not yet known, unipolar depression in

in knockout mice

in knockout mice

humans is accompanied by an increase in total

REM sleep and a decrease in REM latency. As
well, LY379268, another mGlu2 ⁄ 3 receptor agonist,
acts synergistically with fluoxetine to increase
neurogenesis in cultures of granular cells from the
transporter-1 (EAAT1)
NR1 subunit, mGlu2 ⁄ 3

rat cerebellum (42, 43). Neurogenesis, primarily in

Protein of interest

VGLUT1, excitatory
mGlu2 ⁄ 3 receptor

the hippocampus, is increasingly recognized as

mGlu5 receptor

mGlu7 receptor

NR2A subunit

amino acid

playing a role in the pathophysiology and treat-

KA1 subunit

ment of depression (44–46). Antagonists at the

VGLUT1

mGlu1 and mGlu5 receptors decrease the amount

of time mice spend immobile during forced swim
and hippocampus

and tail suspension tasks, a marker for antidepres-

Brain region
Table 2. Studies of proteins associated with glutamatergic neurotransmission in animal models of depression

sant activity, when used alone (47, 48) or in

Frontal cortex
Hippocampus

Hippocampus

Hippocampus

Hippocampus
Hippocampus
CA1 region

combination with minocycline, an antibiotic

which reduces glutamatergic neurotransmission
N ⁄A

N ⁄A

(49, 50). The potent mGlu5 receptor antagonist

2-methyl-6-(phenylethyl)-pyridine also produces
Genetic sensitivity and
Model of depression

maternal separation
Chronic mild stress*

Chronic mild stress*

antidepressant effects in a passive avoidance task

Genetic sensitivity

Chronic restraint

in rats similar to that seen with desipramine, a

tricyclic antidepressant (51). Although animal
studies provide provocative results, the effects of
TST

TST
FST

FST

FST

these same compounds on glutamatergic neuro-

transmission and depressive symptoms in humans
NR2A subunit knockout (NR2A) ⁄ ))

remain to be determined.
Adult male sprague-dawley rats
Male flinders sensitive line and

Male flinders sensitive line and

Vesicular glutamate transporter

Vesicular glutamate transporter

Traditional antidepressant therapies, which are

heterozygous (VGLUT1+ ⁄ ))

heterozygous (VGLUT1+ ⁄ ))
(mGlu7) ⁄ ))

flinders resistant line rats

flinders resistant line rats

known to affect monoamine neurotransmitter sys-

Population

Adult male Wistar rats

tems, also influence the glutamatergic system.

and wild type mice

and wild type mice

and wild type mice

and wild type mice

FST, forced swim test; TST, tail suspension test.

Using microdialysis to directly observe changes in

mGlu7 knockout

Glu in the amygdalae of rats, Reznikov et al. (52)

demonstrated increases in Glu related to acute
stress. These elevations were not affected by the
selective serotonin reuptake inhibitor (SSRI) fluo-
xetine, but were inhibited by tianeptine, an antide-
Boyce-Rustay et al. (26)

Matrisciano et al. (29)

Wieronska et al. (31)

pressant that increases serotonin reuptake in the

Tordera et al. (24)

Hunter et al. (30)

Garcia et al. (25)
Cryan et al. (27)

cortex and hippocampus, suggesting that this

Ryan et al. (32)

medication may mediate its effects through the

glutamatergic system. Tianeptine has antidepres-
Study

sant effects in animal models and in humans, and is

195
 Table 3. Studies using glutamatergic agents in animal models of depression
196
Study Population
Trullas et al. (33) Male NIH-Swiss mice
Wieronska et al. (51) Male wistar rats
Yilmaz et al. (34) Male wistar rats
Chaki et al. (37) Male ICR mice
Palucha et al. (38) Male wistar rats
Palucha et al. (47) Male wistar rats
Belozertseva et al. (48) Male wistar rats
Male C57BL ⁄ 6J ⁄ Han mice
Klak et al. (39) Male wistar rats
Mineur et al. (36) Male C57BL ⁄ 6J mice
Palucha et al. (40) mGlu7 knockout (mGlu7) ⁄ ))
and Wild type mice
Model Experimental agent Neurochemical activity Route Results
FST 2-Amino-7-phosphonoheptanoic Competitive NMDA receptor Intraperitoneal All three compounds reduced depressive-
TST acid (AP7) antagonist like behaviour in the FST. Only ACPC was
tested in the TST, and resulted in
decreased depressive-like behaviour
Dizolcipine Non-competitive NMDA
Mitchell and Baker
receptor antagonist
1-Aminocylopropanecarboxylic NMDA receptor partial
acid (ACPC) agonist
Olfactory bulbectomy 2-Methyl-6-(phenylethynyl)-pyri mGlu5 receptor antagonist Intraperitoneal Decreased depressive-like behaviour in
and passive avoid- dine (MPEP) animals following administration of MPEP
ance
FST Ketamine Non-competitive NMDA Intraperitoneal Decreased depressive-like behaviour in
receptor antagonist ketamine treated animals
FST (1R,2R,3R,5R,6R)-2-amino-3-(3,4- mGlu2 ⁄ 3 receptor antagonist Intraperitoneal Decreased depressive-like behaviour in
TST dichlorobenzyloxy)-6-fluorobicy animals administered MGS0039.
Elevated Plus Maze clo[3.1.0]hexane-2,6-dicarboxylic
acid (MGS0039)
FST (1S,3R,4S)-1-aminocyclo-pentane- Type III mGlu receptor agonist Infusion into Administration of each compound produced
1,3,4-tricarboxylic acid (ACPT-I) hippocampus decreases in depression-like behaviour
2-Amino-4-(3-hydroxy-5meth- Type III mGlu receptor agonist
ylisoxazol-4-yl)butyric acid
(HomoAMPA)
FST 3-[(2-Methyl-1,3-thiazol-4-yl) mGlu5 receptor antagonist Intraperitoneal Decreased depressive-like behaviour was
TST ethinyl]-pyridine (MTEP) seen on the tail suspension test but not
the FST following administration of MTEP
FST (JNJ16567083 3-ethyl-2-methyl- mGlu1 receptor antagonist Intraperitoneal Both compounds reduced depressive-like
quinolin-6-yl)-(4-methoxy-cyclo- behaviour on the FST
hexyl)-methanone methanesulfo-
nate (EMQMCM)
MTEP mGlu5 receptor antagonist
TST EMQMCM mGlu1 receptor antagonist All compounds reduced depression-like
behaviour in the TST
MPEP mGlu5 receptor antagonist
MTEP mGlu5 receptor antagonist
FST ())-N-phenyl-7-(hydroxamino) Positive allosteric modulator Intra-cerbroventricular ACPT-I alone reduced depression-like
cyclopropa(b)chromen-1a-carbox- of mGlu4 receptor inejctions behaviour in the FST at effective doses.
amide (PHCCC) PHCCC coadministered with non-effective
doses of ACPT-I also reduced
depression-like behaviour
ACPT-I Type III mGlu receptor agonist
FST Ceftriaxone Increase Glu uptake Intraperitoneal Decreased depressive-like behaviour in
TST animals treated with Ceftriaxone
FST N,NÕ-dibenzyhydryl-ethane-1,2-de- mGlu7 receptor agonist Intraperitoneal Decreased depressive-like behaviour in
TST amine dihydrochloride (AMN082) AMN082 treated wild type mice. No
behavioural effect seen in knockout mice
 Table 3. Continued
Study
Banasr et al. (35)
Matrisciano et al. (43)
Molina-Hernandez et al. (49)
Molina Hernandez et al. (50)
Ahnaou et al. (41)
FST, forced swim test; TST, tail suspension test; WT, wild type.
197
Population
Male Sprague-Dawley rats
Cerebellar cell cultures of
flinders sensitive line rats
Adult male Wistar rats
Adult male Wistar rats
mGlu2 knockout (mGlu2) ⁄ ))
and wild type male Sprague-
Dawley rats
Model Experimental agent Neurochemical activity Route Results
Chronic unpredictable Riluzole Inhibitor of Glu release Intraperitoneal Decreased depressive-like behaviour in rats
stress treated with Riluzole. Decreases in glial
metabolism seen with chronic
unpredictable stress were reversed upon
treatment with riluzole
TST (1R,4R,5S,6R)-4-amino-2-oxabicy- mGlu2 ⁄ 3 receptor agonist N ⁄A Increased neurogenesis as a result of
clo[3.1.0]hexane-4,6-dicarboxylic administration of either LY379268 or
acid (LY379268) fluoxetine. A strong synergistic effect was
noted
Fluoxetine Selective serotonin reuptake
inhibitor
FST Minocycline Reduces glutamatergic Intraperitoneal All drugs reduced depressive-like behaviour
neurotransmission similar to the effect of desipramine, and
fluoxetine
Dizolcipine Non-competitive NMDA
receptor antagonist
EMQMCM mGlu5 receptor antagonist
MTEP mGlu5 receptor antagonist
Desipramine Tricyclic antidepressant
Fluoxetine SSRI antidepressant
Minocycline Reduces glutamatergic Infusion into nucleus accum- All drugs reduced depressive-like behaviour
neurotransmission bens similar to the effect of desipramine and
fluoxetine
Dizolcipine Non-competitive NMDA
receptor antagonist
EMQMCM mGlu5 receptor antagonist
MTEP mGlu5 receptor antagonist
Desipramine TCA
Fluoxetine SSRI
Sleep–wake cycle (1S,2S,5R,6S)-2-aminobicy- mGlu2 ⁄ 3 receptor agonist Subcutaneous Each compound significantly decreased
clo[3.1.0]hexane-2,6-dicarboxylic total REM sleep and REM latency in WT,
acid LY354740 but not knockout animals. When
administered together, a synergistic effect
was noted
Biphenylindanone A (BINA) Positive allosteric modulator
of mGlu2 receptor
Glu in the pathophysiology of depression
Mitchell and Baker
known to also exert effects on the signal transduc-
tion pathways activated by Glu receptors (53, 54).
In a study employing in vivo MRS in rats,
phenelzine, a monoamine oxidase inhibitor, dem-
onstrated an acute decrease in the rate of cycling of
Glu–Gln between the neurones and glia following
exposure (55). This observation was made in non-
depressed rats, and the effect on behaviour is
unknown. In a study of mice bred to express
reduced levels of VGLUT1, intraperitoneal imip-
ramine reversed depression-like behaviours in a
model of chronic mild stress (22). Postmortem
samples of rat prefrontal cortex showed decreased
K+-stimulated Glu outflow in rats exposed to
either imipramine or phenelzine (56), which the
authors suggest could be as a result of effects on
Glu receptor expression. Indeed, a subsequent
study involving administration of imipramine for
21 days resulted in decreased inhibitory autorecep-
tor activity of mGlu2 and mGlu3 receptors in the
prefrontal cortex (57). In the rat hippocampus,
chronic adminstration of fluoxetine results in
increased K+-stimulated Glu release in control
animals, and appears to counteract a decrease
occurring in rats exposed to a model of learned
helplessness (58). The potential antidepressant
compound LY367265, which acts as a serotonin
2A receptor agonist and inhibitor of the serotonin
transporter protein, also decreases Glu release in
samples of rat cerebral cortex (59). Transcranial
magnetic stimulation (TMS), a somatic therapy
with evidence of antidepressant effect in humans,
administered over the frontal cortex of rats results
in increased Glu and dopamine release in the
nucleus accumbens (60). The relationship of this
finding to the therapeutic effect of TMS has not
been determined.
Table 4. Studies of the effects of antidepressant treatments on the glutamatergic system in animals
Study Population Antidepressant
Martinez-Turillas Male Wistar rats Paroxetine
et al. (61)
Williams et al. Adult Quackenbush Imipramine
(63) mice
Citalopram
Ploski et al. (64) Male Sprague- Electroconculsive N ⁄ A Bilateral
Dawley rats shock
Tan et al. (62) Adult mice Maprotiline
Garcia et al. (25) Vesicular glutamate Imipramine
transporter
heterozygous
(VGLUT1+ ⁄ )) and
wild type mice
198
Chronic administration of antidepressants also
has the capacity to alter expression of proteins
involved in glutamatergic neurotransmission in
animal brains (Table 4). Intraperitoneal adminis-
tration of paroxetine, an SSRI, over 3 weeks
resulted in increased expression of mGlu1,
mGlu2 ⁄ 3 and AMPA receptors in the hippocampus
of rats (61). Elevations in the GluR1, GluR2 and
GluR3 subunits of the AMPA receptor in the
hippocampus occur in mice following a 30-day
administration of maprotiline, an antidepressant
that primarily inhibits reuptake of noradrenaline
(62). However, a study investigating the effect of
the antidepressants imipramine and citalopram
found no changes in Glu transporter expression
in any cortical regions of mice when these drugs
were administered for 4 weeks (63). Electroconvul-
sive shock administered to rats in one study
population resulted in increases in the EAAT1
which is responsible for reuptake of Glu from the
synapse (64). None of these studies used animals
exposed to behavioural models of depression, and
conclusions regarding the effects of these com-
pounds in depressed brains cannot be directly
extrapolated from these findings.
Investigations in humans
Evidence of dysregulation of Glu in depression in
humans has been mounting in recent years (65).
Parallel to studies in animal models, investigations
have associated depressive phenotypes in humans
with changes in levels of Glu and its metabolites
(Table 5). An early study by Kim et al. (66)
reported elevations in plasma Glu in individuals
with major depression compared with healthy
controls. However, this study did not differentiate
Class Route Protein of interest Results
SSRI Intraperitoneal AMPA, mGlu1, and mGlu2 ⁄ 3 Increased expression in the hippocampus
receptors following administration for 3 weeks
TCA Intraperitoneal Glutamate aspartate No changes in glutamate transporter levels
transporter (GLAST) and following 4-week administration of
glutamate transporter-1 (GLT-1) antidepressants
SSRI
EAAT1 Increases in EAAT1 levels following
administration daily for 10 days
TCA Intraperitoneal GluR1, GluR2, GluR3 subunits Increased expression of AMPA subunits
of the AMPA receptor following a 30-day administration of
Maprotiline
TCA VGLUT1, excitatory VGLUT1, EAAT1 Decreased VGLUT1 and EAAT1 expression
amino acid in the hippocampus and increased
transporter-1 depression-like behaviour in heterozygous
(EAAT1) animals. Antidepressant effects were
observed with intraperitoneal imipramine
exposure

Table 5. Measurements of glutamate in human depression
Study Population
Kim et al. (66) Neurotic depression
Endogenous depression Schizophrenia
Schizoaffective disorder
Francis et al. (73) Treatment-resistant major depression
undergoing psychosurgery
Altamura et al. (69) Unmedicated major depression
Maes et al. (70) Treatment-resistant major depression
Mauri et al. (67) Major depression
Levine et al. (75) Unmedicated major depression
Berk et al. (109) Unmedicated major depression
Mitani et al. (68) Major depression on
Medication
Frye et al. (74) Major depression bipolar I
Bipolar II
Hashimoto et al. Major depression-postmortem samples
(72)
between medicated and unmedicated subjects.
Similarly, elevated levels of plasma and platelet
Glu have been observed in outpatients with major
depression (67), and in one recent study these
concentrations were directly proportional to the
severity of depressive symptoms (68). Other studies
have not associated elevations in Glu with depres-
sion (69, 70). Maes et al. (70) measured serum
levels in patients with treatment-resistant depres-
sion, and reported no differences from concentra-
tions in healthy controls, but after 5 weeks of
treatment with the serotonergic antidepressants
trazodone and fluoxetine, Glu levels were signifi-
cantly decreased from baseline. A study using
electroshock therapy (ECT) showed that plasma
Glu in depressed patients was increased 6 h after
treatment, which the authors suggested may be
related to the mechanism of action of ECT (71).
Measurements of Glu in the central nervous
system come from postmortem analysis and cere-
brospinal fluid (CSF) collection. In a study of
postmortem tissue from the human frontal cortex,
Glu levels were elevated in subjects with a history
of depression compared with controls (72). How-
ever, subjects were not necessarily depressed at the
time of death. Conversely, in neurosurgical sam-
ples of the frontal cortex taken from patients
undergoing psychosurgery for active major depres-
sion, there were no differences in Glu concentra-
tions compared with tissue samples from
non-depressed controls (73). Frye et al. (74)
reported decreased levels of Glu in the CSF of
depressed individuals from a mixed population of
unipolar and bipolar mood disorders. Individuals
with unipolar depression represented the minority
of the cohort, and these results have not been
replicated in a population of purely Major Depres-
Glu in the pathophysiology of depression
Primary outcome measure Results
Plasma Glu Elevated levels of plasma Glu in depressed individuals
Glu in neurosurgical samples No difference in Glu compared with control neurosurgical samples
of frontal cortex
Plasma Glu No difference in plasma Glu
Plasma Glu No baseline difference in plasma Glu, treatment with antidepressants
for 5 weeks reduced levels of Glu
Plasma Glu Elevated plasma Glu in depressed individuals, no influence of
treatment with fluvoxamine
CSF Gln Increased CSF Gln in depressed individuals
Platelet Glu receptor response Hypersensitivity of platelet NMDA receptors in depressed individuals
Plasma Glu Elevated plasma Glu in depressed individuals, severity of depression
correlates with degree of increase
CSF Glu Decreased CSF Glu in individuals with mood disorders
Glu in frontal cortex Increased Glu in the frontal cortex of patients with major depression
compared with controls
sive Disorder. One study found increased levels of
Gln in the CSF associated with depression (75).
Magnetic resonance spectroscopy is the only
currently available imaging technique that allows
for real-time in vivo quantification of brain meta-
bolites (76). Identification of Glu using MRS in
humans is technically challenging, as the spectrum
of Glu overlaps with a number of other neuro-
chemicals, primarily Gln. Stronger magnetic fields
and advanced imaging techniques allow for the
isolation of the Glu signal; however, early MRS
studies report the combined Glu + Gln peak as
ÔglutamixÕ (Glx) (77). The first clinical report of
MRS used to examine Glx in depression was of a
cancer patient who had recurrent suicidal ideation
and depressive symptoms associated with chemo-
therapy (78). In this individual, Glx was decreased
in the cerebral white matter. Various brain regions
have been targeted in investigations using MRS in
depression (Table 6). Imaging of the anterior
cingulate cortex shows decreased levels of Glx in
depressed adults (79) and children (80, 81) which
resolves following clinical recovery (82). Interest-
ingly, Glx appears to be elevated in the cingulate
cortex of depressed bipolar patients (83), and this
may be a biological marker distinguishing the two
disorders. One conflicting study found no differ-
ences in Glx in the anterior cingulate or occipital
cortex between individuals with treatment-resistant
major depression, individuals with major depres-
sion without treatment-resistance, and healthy
controls (84). A 2006 meta-analysis of published
studies found a significant decrease in Glx in
frontal structures in depressed adults (85). Glx is
reduced bilaterally in the dorsolateral prefrontal
subcortical white matter in patients with type II
diabetes and depression (86) and in the left
199
Mitchell and Baker

Table 6. Magnetic resonance spectroscopy imaging studies of glutamate in human depression

Study Population Region of interest Results

Auer et al. (79) Major depression Anterior cingulate cortex Reduced Glx in individuals with MDD
Michael et al. (88) Treatment-resistant major depression Left Amygdala Reduced Glx in individuals with MDD which resolved
with successful treatment with ECT
Michael et al. (89) Major depression with melancholic Left dorsolateral prefrontal cortex Reduced Glx in individuals with MDD which resolved
features with successful treatment with ECT
Pfleiderer et al. (90) Major depression Anterior cingulate cortex Reduced Glx in individuals with MDD which resolved
with successful treatment with ECT
Rosenburg et al. (80) Paediatric major depression with Anterior cingulate cortex Reduced Glx in individuals with MDD and OCD compared
comorbid OCD with those with OCD only
Sanacora et al. (96) Major depression Occipital cortex Increased Glx in individuals with MDD
Rosenburg et al. (81) Paediatric major depression Anterior cingulate cortex Reduced Glx in individuals with MDD
Glodzik-Slobanska et al. Poststroke depression Frontal lobe (contralateral to side Increased Glx in individuals with poststroke depression
(97) of stroke)
Luborzewski et al. (91) Major depression Dorsolateral prefrontal cortex Decreased Glu in the dorsolateral prefrontal cortex of
Anterior cingulate cortex individuals with MDD which increased following
transcranial magnetic stimulation (TMS) no changes
in the Anterior cingulate cortex with TMS
Ajilore et al. (86) Major depression and type II diabetes Dorsolateral prefrontal subcortical Decreased Glx in individuals with MDD
white matter
Hasler et al. (93) Major depression Ventromedial and dorsomedial Decreased Glx in individuals with MDD
prefrontal cortex
Batra et al. (98) Premenstrual dysphoric disorder Medial prefrontal cortex No difference in Glu between individuals with PMDD
and controls
Block et al. (94) Major depression Hippocampus Decreased Gln in individuals with MDD
Milne et al. (95) First major depressive episode Hippocampus No difference in Glx between first episode patients
Recurrent major depression and controls or recurrent MDD and controls
Murck et al. (92) Major depression Dorsolateral prefrontal cortex Increases in Glx and Gln in male responders to therapeutic
sleep deprivation and increases in Gln in responders
with melancholic signs
Price et al. (84) Major depression Occipital cortex No difference in Glx in either region in depressed individuals
Treatment-resistant major depression Anterior cingulate cortex with or without treatment resistance and controls
Taylor et al. (82) Recovered major depression Anterior cingulate cortex No difference in Glx between individuals with a history
of MDD and controls

MDD, major depressive disorder; OCD, obsessive compulsive disorder.

dorsolateral prefrontal cortex (DLPFC) in paedi-
atric patients with major depression (87). In
patients who respond to ECT, reduced Glx levels
in the left amygdala (88), left DLPFC (89), and
anterior cingulate cortex (90) resolve following
treatment. Responders to TMS in one trial showed
lower baseline Glu concentrations in the left
DLPFC which increased in a dose-dependent
fashion after exposure (91). Therapeutic sleep
deprivation also increases Glx and Gln in the
same brain area in male responders with major
depression and in responders with melancholic
depression (92). Hasler et al. (93) have also dem-
onstrated decreases in Glx in the ventromedial and
dorsomedial ⁄ dorsal anterolateral prefrontal
regions of depressed individuals. Newly published
evidence suggests that Gln is decreased in the
hippocampus of depressed individuals (94), but
another study found no differences in Glx between
newly depressed patients, those with multiple
episodes of low mood, or matched controls (95).
One study showed increases in Glu in the occipital
lobe of depressed individuals, and the authors
suggested that this may depend on the presence of
certain clinical subtypes (96). Other studies exam-
ining specific sub-populations have demonstrated
elevated Glx in frontal lobes of patients with
poststroke depression (97), and no difference in the
medial prefrontal cortex between controls and
individuals with premenstrual dysphoric disorder,
a catamenial variant of MDD thought to be related
to fluctuations in ovarian hormones (98). Proteins
involved in glutamatergic neurotransmission and
transport have also been investigated in mood
disorders in humans (Table 7).
Genetic variability appears to be associated
with treatment response to antidepressant medi-
cations. Data from the first phase of the
Sequenced Treatment Alternatives to Relieve
Depression (STAR*D) revealed that the effective-
ness of citalopram was associated with a poly-
morphism in a gene encoding the KA1 subunit of
the kainate receptor (99). A separate analysis of
the STAR*D trial showed that treatment-emer-
gent suicidal ideation with the antidepressant
citalopram was associated with two single
nucleotide polymorphisms in genes encoding su-
bunits of the AMPA receptor and the kainate

200
 Table 7. Studies of proteins associated with glutamatergic neurotransmission in depression in humans
Study
Freed et al. (112)
Holemans et al. (103)
Nowak et al. (102)
Noga et al. (113)
Berk et al. (109)
Dwivedi et al. (114)
McCullumsmith et al. (108)
Choudary et al. (110)
Karolewicz et al. (106)
Kristiansen et al. (107)
Beneyto et al. (115)
Laje et al. (100)
Paddock et al. (99)
Toro et al. (105)
Feyissa et al. (104)
Menke et al. (101)
201
Population Sample type Brain region Protein of interest Results
Schizophrenia, schizoaffective Postmortem Caudate nucleus AMPA receptor No difference between diagnostic groups and controls. AMPA binding in the caudate
disorder, and affective disorder tissue was significantly higher in victims of suicide
with psychosis
Including suicide victims
Suicide victims with a history of Postmortem Cerebral cortex NMDA receptor No differences in receptor density in the cortex compared with controls
major depression tissue
Suicide victims Postmortem Frontal cortex NMDA receptor Decreased high affinity binding compared with samples from controls
tissue
Schizophrenia including suicide Postmortem Striatum AMPA receptor Increased AMPA receptor density in victims of suicide
victims tissue
Major depression Platelet N ⁄A NMDA receptor Increased calcium release in response to Glu that was antagonised by dizocilpine.
sample This suggests platelet NMDA receptor hypersensitivity in depression
Suicide victims with a history Postmortem Prefrontal cortex Extracellular regulated Decreases in ERK1 ⁄ 2 and MAPK activity (which are coupled to AMPA receptors)
of major depression tissue Hippocampus kinase 1 ⁄ 2 (ERK1 ⁄ 2) in the prefrontal cortex and hippocampus of depressed individuals compared with
Cerebellum Mitogen activated protein controls. No differences in the cerebellum were noted
kinase (MAPK)
Major depression, bipolar Postmortem Striatum Excitatory amino acid Decreased EAAT4 in the striatum of depressed individuals, decreased EAAT3 in
disorder, tissue transporter (EAAT) 1–4 schizophrenia, and decreased EAAT3 and EAAT4 in bipolar disorder compared
and schizophrenia with controls
Major depression and bipolar Postmortem Anterior cingulate cortex Glutamate transporter Decreased expression of the genes encoding glial glutamate transporters in the
disorder including suicides tissue Dorsolateral prefrontal cortex proteins, Multiple anterior cingulate and dorsolateral prefrontal cortex in major depression. Increased
AMPA and mGlu expression of GluR1 and KA2 in the cingulate, and increased expression of GluR3,
receptor subunits GluR5, and KA2 subunits in the dorsolateral prefrontal cortex in major depression
A different pattern of changes in gene expression was noted in bipolar disorder
Major depression or dysthymia Postmortem Locus ceruleus NR1 subunit Increased NR1 subunit of the NMDA receptor in depressed individuals
tissue
Major depression, bipolar disorder, Postmortem Striatum SAP-102 Decreased mRNA for SAP-102, a protein involved in intracellular signalling and
and schizophrenia tissue membrane localization of the NMDA in all three diagnostic groups
Temporal lobe epilepsy and major Neurosurgical Hippocampus Ionotropic Glu No changes in transcript expression were observed in the hippocampus. In the
depression, bipolar disorder, or sample Entorhinal cortex receptor subunits entorhinal cortex, bipolar disorder was associated with decreased GluR2, GluR3,
schizophrenia Perirhinal cortex and GluR6 mRNA expression. In the perirhinal cortex decreased expression of GluR5
occurred in all three diagnoses. Decreases in NR1 occurred in bipolar disorder,
decreased NR2A occurred in major depression, and decreased GluR1, GluR3, and
NR2B were present in both
Outpatients with major depression Genetic N ⁄A GluR3 subunit, Treatment-emergent suicidal ideation with citalopram was associated with
sample GluR6 subunit polymorphisms in genes encoding the GluR6 subunit of the kainate receptor
and the GluR3 subunit of the AMPA receptor
Outpatients with major depression Genetic N ⁄A KA1 subunit Treatment response with citalopram was associated with single nucleotide
sample polymorphisms (SNP) in genes encoding the KA1 subunit of the kainate receptor
Temporal lobe epilepsy and major Neurosurgical Hippocampus NR1 subunit Increased NR1 subunit of NMDA receptor in the hippocampus of depressed and
depression or dysthymia sample dysthymic individuals
Major depression including suicide Postmortem Prefrontal cortex NR2A subunit, Decreased NR2A and NR2B NMDA receptor subunits in the prefrontal cortex of
victims sample NR2B subunit individuals with depression
Inpatients with major depression Genetic N ⁄A GluR3 subunit, Treatment-emergent suicidal ideation associated with SNP in genes for the GluR6
sample GluR6 subunit subunit of the kainate receptor and the GluR3 subunit of the AMPA receptor
Glu in the pathophysiology of depression
Mitchell and Baker
receptor (100). Treatment-emergent suicidal idea-
tion has also been associated with different genetic
polymorphisms affecting the same subunits of Glu
receptors (101). NMDA receptors in the frontal
cortex of patients who had died by suicide exhibi-
ted decreased high affinity binding in a postmortem
study (102), though no difference was found in
receptor density in any brain region in an earlier
study (103). Alterations in the expression of
subunits of the NMDA receptor associated with
depression have been observed in the prefrontal
cortex (104), the temporal lobe (105) and the locus
ceruleus (106). Kristiansen et al. (107) recently
reported decreased expression of mRNA for SAP-
102, a protein associated with membrane localiza-
tion of the NMDA receptor and intracellular
signalling, in the striatum in depression. The
same region of the brain exhibits decreased tran-
scription of EAAT4, which is necessary for Glu
reuptake (108), in depressed individuals. These
changes in glutamatergic activity are not limited to
the brain. A unique study by Berk et al. (109)
demonstrated elevated platelet Glu receptor sensi-
tivity in depressed individuals. This was attenuated
by the NMDA receptor antagonist dizocilpine,
suggesting a specific hyperactivity of the NMDA
receptors. Postmortem brain samples of individuals
with Major Depressive Disorder show decreases in
the expression of genes for glial Glu transporters in
the anterior cingulate and DLPFC, and increases
in expression of certain subunits of the AMPA and
kainate receptors in these same regions (110).
Conflicting data on the role of the AMPA receptor
come from postmortem studies (111). Increased
AMPA receptor density occurs in the striatum in
victims of suicide (112, 113), but the signalling
pathways activated by AMPA are decreased in a
study of a similar population (114). Dysregulation
in the expression of Glu receptors is not limited to
unipolar depression. In one study examining
neurosurgical samples taken from patients with
Table 8. Clinical trials of glutamatergic drugs in human depression
Study Population
Berman et al. (117) Treatment-resistant major depression
Zarate et al. (120) Recurrent major depression
Zarate et al. (118) Treatment-resistant major depression
Sanacora et al. (121) Treatment-resistant major depression
Muhonen et al. (123) Alcohol dependence and major depression
Mathew et al. (122) Treatment-resistant major depression
202
temporal lobe epilepsy and mood disorders,
changes in expression of a number of Glu receptor
subunits occurred in the perirhinal cortex, but did
not differentiate between bipolar disorder and
unipolar depression (115).
Some of the most compelling evidence comes
from clinical trials with glutamatergic agents (116)
(Table 8). Ketamine, an antagonist at the NMDA
receptor, has rapid and prolonged antidepressant
effects in individuals with treatment-resistant
depression after a single intravenous administra-
tion in randomized trials (117, 118). Riluzole,
another NMDA receptor antagonist, has been used
in clinical trials for numerous psychiatric condi-
tions (119), and showed antidepressant effects as
monotherapy in one trial (120), and as an aug-
menting agent in another trial (121). However, a
trial of riluzole following treatment with intrave-
nous ketamine showed no difference in time to
relapse when compared with placebo (122). In a
study of patients with comorbid alcohol depen-
dence and depression, both the NMDA receptor
antagonist memantine and the SSRI escitalopram
had similar antidepressant effects (123).
Models of glutamate in depression
Multiple observations of glutamatergic dysfunc-
tion in animal models and humans provide evi-
dence for a role of Glu in the pathophysiology of
depression. Zarate et al. (118) suggest that obser-
vations of rapid antidepressant effects following
administration of intravenous ketamine may lead
to the development of rapid acting antidepressants.
However, with numerous MRS studies showing
decreases in Glu related to depression (22, 78–81,
85–94), the relationship of the antagonistic activity
of ketamine at the NMDA receptor to antidepres-
sant effects seems counterintuitive. A recent study
(124) demonstrated that pretreatment with 2,3-
dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-
Intervention Results
Intravenous ketamine vs. placebo Antidepressant response with ketamine greater
than with placebo
Oral riluzole vs. placebo Antidepressant effect with riluzole greater with
than placebo
Intravenous ketamine vs. placebo Antidepressant response with ketamine greater
than with placebo
Augmentation of antidepressants with Antidepressant effect enhanced with riluzole
oral riluzole vs. placebo greater than with placebo
Oral memantine vs. escitalopram Both interventions had similar antidepressant
effects
Intravenous ketamine + oral riluzole vs. No change in time to relapse between groups
intravenous ketamine + placebo

2,3-dione, an AMPA receptor antagonist, blocked
the antidepressant action of intravenous ketamine
in rats. The authors suggest that increased AMPA–
NMDA receptor throughput is a necessary for the
antidepressant effect of this medication (125). In
the same study, phosphorylation of the GluR1
subunit of the AMPA receptor was significantly
reduced following the administration of ketamine.
Normally, phosphorylation of the GluR1 subunit
plays a role in desensitization of the AMPA
receptor in the presence of Glu (126), reducing
glutamatergic neurotransmission. However, phos-
phorylation also increases membrane expression of
the AMPA receptor (127). It has been proposed
that the delayed effects of traditional antidepres-
sant medications are mediated through increased
GluR1 phosphorylation (128, 129). In a review of
clinical trials implicating Glu in mood disorders,
Sanacora et al. (65) suggest that dysregulation of
Glu seen in depression may be a result of glial
dysfunction. Decreased uptake of Glu by astro-
cytes would increase glutamatergic neurotransmis-
sion, and the antidepressant effect of NMDA
antagonists would be a result of increased activa-
tion of AMPA and kainate receptors. Pilc et al.
suggest (130) that the antidepressant effects of
agents acting at mGlu receptors occur as a result of
dampening of NMDA receptor activity and ampli-
fication of AMPA receptor activity. While the
exact mechanisms of glutamatergic involvement in
depression is not clear, the contribution of Glu to
the pathophysiology of depression likely involves
both ionotropic and metabotropic receptors.
The glutamatergic system communicates with
other potential neurochemical contributors to
depression. While currently available antidepres-
sants affect monoamine systems rapidly, behavio-
ural effects are considerably delayed. One theory
posits that the targets of these antidepressants are
considerably upstream of the neurobiological sub-
strates that eventually produce the antidepressant
effect (131). Downstream systems are eventually
altered over time by changes in neurotransmission
occurring upstream, and Glu has been identified as
a potential endpoint where these changes affect the
depressive phenotype (132). This suggests interplay
of Glu and monoamine systems. Glu in the normal
brain operates in balance with GABA, and GAB-
Aergic neurones synapse on glutamatergic neuro-
nes to modulate their activity (15). Parallel to the
evidence for glutamatergic dysfunction, there is
also growing evidence for dysregulation of GABA
in depression (65, 133–135).
The hypothalamic–pituitary–adrenal (HPA) axis
regulates various peripheral processes, including
metabolism and immunity, and influences brain
Glu in the pathophysiology of depression
function (136). The HPA axis is the primary
regulator of the physiological stress reaction.
Over-activity of the HPA axis has long been
associated with depression, and recent research
has focused on it as a potential target of interven-
tion (8, 137). Interactions between the HPA axis
and Glu are recognized in the literature, with early
investigations in animals noting that direct admin-
istration of Glu into the amygdala stimulates the
release of corticotropin-releasing factor (CRF)
(138), and that administration into the periventric-
ular nucleus (PVN) of the hypothalamus results in
the secretion of adrenocorticotropic hormone
(139). Systemic exposure to Glu agonists, specifi-
cally kainate and NMDA, activates the HPA axis
in rats at the level of the PVN (140), and kainate
receptor activity in this region mediates the release
of CRF (141). More recent investigations suggest
that Glu receptors play a role in the regulation of
the stress response (142). Intraperitoneal admin-
istration of 2-methyl-6-(phenylethynyl)pyridine,
a mGlu5 receptor antagonist, results in an increase
in plasma corticosterone in rats (143). Similarly,
increases in corticosterone levels were observed
following intracerebroventricular infusions of the
non-selective mGlu receptor agonist (1S,3S)-1-am-
inocyclopentane-1,3-dicarboxylic acid (144). How-
ever, agonism of mGlu2 ⁄ 3 receptors in the
hypothalamus inhibits the release of CRF (145).
Knockout mice failing to express the gene for the
mGlu7 receptor show dysregulation at numerous
sites within the HPA axis including at the level of
transcription of glucocorticoid receptors and at the
level of feedback mechanisms (28). These mice also
show anxiolytic and antidepressant-like effects, and
the authors suggest that changes in the HPA axis
occurring because of removal of the mGlu7 recep-
tor may account for these behavioural differences.
Alterations in HPA axis function also influence the
glutamatergic system. Rats administered a moder-
ate dose of corticosterone for 21 days show
increased expression of KA1 subunit mRNA in
the dentate gyrus (30). Proteomic analysis of
mice brains following administration of corticoste-
rone for 14 days revealed changes in Glu metab-
olism in the hippocampus, hypothalamus and
cerebral cortex (146). Changes in the expression
of various proteins involved in glutamatergic
signalling are noted in various animal models
which use stress to induce depression-like behav-
iours (30–32). The function of the interplay of Glu
and the HPA axis in depression requires further
elucidation.
Brain-derived neurotrophic factor (BDNF), the
most extensively studied neurotrophin in depres-
sion, is implicated in intracellular mechanisms
203
Mitchell and Baker
associated with neural plasticity (9, 46, 147, 148).
Decreased levels of BDNF are observed in the
hippocampi of postmortem samples of depressed
individuals (149) and in animal models of depres-
sion (150). An antidepressant effect follows direct
infusion of BDNF into the hippocampus of rat
models of depression (151), and knockout animals
that do not express BDNF fail to respond to
antidepressant treatment (152). Indeed, chronic
administration of most antidepressant therapies
results in increased expression of BDNF in humans
(153, 154) and increased neurogenesis in the
hippocampus of animals (155). It has been sug-
gested that alterations in BDNF are a necessary
condition for an antidepressant effect (46). Evi-
dence suggests that glutamatergic neurotransmis-
sion interacts with BDNF production and release.
Direct exposure to Glu results in release of BDNF
from astrocytes in the basal forebrain mediated
through mGlu1 ⁄ 5 receptors (156). Administration
of ketamine induces BDNF expression in the
substantia nigra of a rat model of presymptomatic
ParkinsonÕs disease (157). However, one recent
study using chronic mild stress in rats showed that
effective antidepressant therapy with ketamine did
not alter expression of BDNF in the hippocampus
(25). The relationship between Glu and BDNF is
bidirectional, with BDNF influencing Glu release
and signalling. BDNF activates the phospholipase
C-gamma ⁄ Ca2+ intracellular system which pro-
motes Glu release in cultured mouse neurones
(158). This signalling is inhibited by glucocortic-
oids, suggesting a role for chronic stress. Phos-
phorylation of subunits of Glu receptors, which in
turn affects their response characteristics, is
induced by BDNF (159). The antidepressant
effect of increased activity of AMPA receptors
may be mediated through increased production of
BDNF (111, 160). The complex relationship
between Glu and BDNF in the production and
treatment of depression is not fully understood;
however, it provides further evidence that the role
of Glu in depression is interrelated with the activity
of other neurochemical systems.
Discussion
Historically, interest in Glu dysfunction in psychi-
atric disorders has focused primarily on schizo-
phrenia (161, 162), but exciting findings in recent
years on NMDA receptor antagonists in depres-
sion have led to a flurry of research on the possible
role of Glu in the aetiology and pharmacotherapy
of depression (10, 15, 85). In this regard, it is of
interest that, based on the literature to date,
generally the nature of the glutamatergic dysfunc-
204
tion and the effects of drugs acting on Glu
receptors appear to be quite different in schizo-
phrenia and major depressive disorder (163–165).
The reasons for the differences are not clear at this
time, but further investigations into the glutama-
tergic systems should provide valuable information
about the aetiology and symptomatic overlap
related to these two disorders. This study has
focused on recent research from both studies in
both humans and animal models that have con-
tributed to the increasing understanding of the role
of Glu in the development of depression.
Findings from knockout studies show that
multiple gene products involved with glutamatergic
neurotransmission affect depression-like behaviour
in rats and mice. Similarly, exposure to chronic
stress in animals appears to change the expression
of some Glu receptor subunits. Taken together,
these observations suggest that glutamatergic neu-
rotransmission is involved in the genesis of these
behaviours. The antidepressant-like effects of
glutamatergic agents, and the changes in the
glutamatergic system that are seen following
administration of antidepressants thought to act
on monoamine systems, also support a role for Glu
in the treatment of depression. However, there are
limitations to these investigations. Translating the
behavioural measures in animal models of depres-
sion to emotional, cognitive and behavioural
changes in humans is difficult.
Early studies in humans examining Glu levels
were limited by available technology. As Glu does
not cross the blood–brain barrier, the use of
peripheral measures of Glu as a marker for central
concentrations is questionable. As well, changes in
levels of Gln in the CSF may represent changes in
overall Glu throughout the central nervous system,
but do not account for region-specific dysregula-
tion in metabolism or neurotransmission. MRS
allows for real-time in vivo measurement of Glu,
and regional fluctuations of Glu observed in these
studies are the most direct evidence of changes in
glutamatergic neurotransmission associated with
depression. These alterations in Glu may be state
markers of depression, as they resolve with suc-
cessful treatment. The most compelling evidence
for the role of Glu in depression in humans comes
from the rapid antidepressant effects of ketamine
(117, 118).
While glutamatergic dysfunction is increasingly
recognized in depression, a number of important
questions remain to be answered. First, depression
is a clinical syndrome consisting of a variety of
cognitive, behavioural and emotional symptoms.
The function of Glu in depression may be related
to some or all of these symptoms. It is also unclear

whether certain subtypes of depression are more
associated with alterations in Glu. There is an early
signal that bipolar and unipolar depression may
differ regarding Glu levels in the cingulate mea-
sured on MRS (83), but this needs to be confirmed
in other brain regions. Second, the timing of
changes in central Glu in relation to the develop-
ment of depressive symptoms needs to be clarified.
It may be that Glu levels change in certain brain
regions prior to the development of clinical symp-
toms, and if so, these changes could be used to
monitor individuals at high risk of developing
depression, such as those discontinuing antidepres-
sant therapy. As well, the relationship between Glu
and other neurotransmitter ⁄ neuromodulatory sys-
tems must be further clarified. Changes in mono-
amine systems may be a cause or a result of
changes in Glu neurotransmission. One way to test
this would be to observe changes in Glu in
individuals subjected to amino acid protocols,
which can precipitate depression through reduc-
tions in central monoamines. Finally, further
research may lead to the development of glutama-
tergic antidepressants for use in clinical practice.
Currently, trials in humans have only focused on
agents acting at the NMDA receptor, however
theoretically AMPA receptor agonists or agents
acting at mGlu receptors may also provide antide-
pressant benefit. Further study of the metabolism,
receptors, and intracellular pathways related to
Glu will continue to provide insight into the
pathophysiology and treatment of depression.
Acknowledgements
The authors gratefully acknowledge financial support from the
Department of Psychiatry, University of Alberta, the Canadian
Institutes of Health Research (CIHR) and the Canada
Research Chairs and Canada Foundation for Innovation
programs.
Declaration of interest
The authors declare no conflict of interest.
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