A number of pharmacological interventions are now established
and available for the treatment of mood disorders . However,
there are considerable drawbacks of currently available treatment
modalities, such as relatively slow therapeutic effects and limited
efficacy for treatment-resistant cases , which impose substantial
burdens on the affected individuals as well as on public health
and society [3, 4]. Accordingly, there exists a compelling need
for a more improved neurobiological understanding of mood
disorders, which may complement the limitations of the prevailing
monoamine hypothesis , and corresponding new treatment
strategies . In line with these circumstances, the glutamatergic
system is receiving more attention as one of the potential targets
of novel therapeutic agents for mood disorders [2, 5]. Glutamate
is the major excitatory neurotransmitter in the brain, and growing
Disturbance of the Glutamatergic System
in Mood Disorders
Chansoo Jun1,2#, Yera Choi2,3#, Soo Mee Lim2,4, Sujin Bae5,
Young Sun Hong2,6, Jieun E. Kim2,7* and In Kyoon Lyoo1,2*
1College of Pharmacy and Graduate School of Pharmaceutical Sciences, 2Ewha Brain Institute, Ewha Womans University,
Seoul 120-750, 3Interdisciplinary Program in Neuroscience, Seoul National University College of Natural Sciences, Seoul
151-747, 4Department of Radiology, Ewha Womans University College of Medicine, Seoul 158-710, Korea, 5Brain Institute
and Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA, 6Department of
Internal Medicine, Ewha Womans University College of Medicine, Seoul 158-710, 7Department of Brain and Cognitive
Sciences, Ewha Womans University Graduate School, Seoul 120-750, Korea
Exp Neurobiol. 2014 Mar;23(1):28-35.
pISSN 1226-2560 • eISSN 2093-8144
Received December 3, 2013, Revised February 24, 2014,
Accepted February 24, 2014
*To whom correspondence should be addressed.
Jieun E. Kim
TEL: 82-2-3277-6932, FAX: 82-2-3277-6932
In Kyoon Lyoo
TEL: 82-2-3277-3039, FAX: 82-2-3277-3044
#These authors equally contributed to the present review.
The role of glutamatergic system in the neurobiology of mood disorders draws increasing attention, as disturbance of this system is
consistently implicated in mood disorders including major depressive disorder and bipolar disorder. Thus, the glutamate hypothesis
of mood disorders is expected to complement and improve the prevailing monoamine hypothesis, and may indicate novel
therapeutic targets. Since the contribution of astrocytes is found to be crucial not only in the modulation of the glutamatergic system
but also in the maintenance of brain energy metabolism, alterations in the astrocytic function and neuroenergetic environment are
suggested as the potential neurobiological underpinnings of mood disorders. In the present review, the evidence of glutamatergic
abnormalities in mood disorders based on postmortem and magnetic resonance spectroscopy (MRS) studies is presented, and
disrupted energy metabolism involving astrocytic dysfunction is proposed as the underlying mechanism linking altered energy
metabolism, perturbations in the glutamatergic system, and pathogenesis of mood disorders.
Key words: mood disorders, major depressive disorder, bipolar disorder, glutamate, astrocytes, magnetic resonance spectroscopy
Copyright © Experimental Neurobiology 2014.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License
(http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Glutamatergic Disturbance in Mood Disorders
evidence indicates abnormalities in the glutamatergic system of
patients with mood disorders [2, 5]. Researchers are working to
develop medications acting on the glutamatergic system, which
may lead to a breakthrough in the pursuit of more effective
measures to treat mood disorders .
Glutamate is a ubiquitous molecule that is engaged in the
majority of the excitatory transmission in the brain, yet excessive
glutamate release may cause brain damage due to excitotoxicity
. For the adequate neurotransmission of glutamate, not only
glutamatergic neurons but also astrocytes are indispensable .
Indeed, astrocytes are essential in glutamatergic activities including
glutamate reuptake, synthesis of glutamate precursors, and
removal of excess glutamate [8, 9]. In addition, there is evidence
that astrocytes play an important role in the neuroglial system
which enables an efficient coupling of glutamatergic neuronal
activities and task-dependent changes in brain energy utilization
. Thus, perturbations in astrocytic function may contribute to
alterations in glutamate and energy metabolism observed in mood
disorders . In the present review, we will discuss the roles of the
glutamatergic system, astrocytes, and brain energy metabolism in
the pathogenesis of mood disorders.
ABNORMALITIES OF THE GLUTAMATERGIC SYSTEM IN
Glutamate is an essential and abundant amino acid with
various functions in the brain, most notably as an excitatory
neurotransmitter and precursor of the inhibitory neurotransmitter
γ-aminobutyric acid (GABA) [5, 12]. Inappropriate regulation of
glutamate is known to incur neurotoxicity and other deleterious
effects on neurotransmission, neuroenergetics, and cell viability
. Accordingly, a considerable number of studies have been
conducted to investigate the potential association between the
glutamatergic system and neurological or psychiatric disorders .
In line with these studies, the importance of the glutamatergic
system has been increasingly emphasized in the study of mood
disorders . As glutamate plays a crucial role in synaptic
transmission and plasticity, perturbation of the glutamatergic
system is considered to be at least partially involved in synaptic
abnormalities found in mood disorders . Indeed, several studies
observed abnormalities of the glutamatergic system in depression,
particularly in glutamate clearance at the synaptic space and in
modulation of astrocytic energy metabolism involving glutamate
[13, 14]. The fast-onset antidepressant effect of the drug tianeptine
is also notable in light of the glutamate hypothesis of depression,
as the medication appears to exert its influence partly through the
glutamatergic system . Ketamine, an N-methyl-D-aspartate
(NMDA) receptor antagonist, has also been reported to exert a
rapid antidepressant effect in patients with MDD [6, 16].
Several findings from postmortem studies, which may provide
important histological and molecular information for the
neurobiological understanding of psychiatric disorders , are
also in accordance with the evidence of glutamate abnormalities
in mood disorders. For instance, an elevated level of glutamate
was identified in the postmortem frontal cortex of patients with
MDD or BD , while dysregulated expression of glutamate-
related genes was observed in the hippocampus of patients with
depression . Also, the level of glutathione, which functions as
a physiologic reservoir of neuronal glutamate, was reduced in the
postmortem prefrontal cortex . There also have been reports of
altered binding properties of the NMDA receptor in the brain of
suicide victims , decreased expression of the NMDA receptor
subunits in the prefrontal cortex of patients with MDD , and
abnormalities in the levels of excitatory amino acid transporters
(EAATs) in the postmortem prefrontal cortex of patients with
bipolar disorder (BD) . However, the inherent shortcomings
of postmortem studies, including the extremely limited repository
of available brain tissues which often results in underpowered
studies with small sample sizes  and the confounding effects
of varying durations of premortem agonal period or postmortem
interval and terminal stress level, suggest that in-vivo approaches
are warranted to obtain a more complete picture of the living
In contrast to the postmortem approach, magnetic resonance
spectroscopy (MRS) provides a non-invasive method which allows
in-vivo study of the biochemical environment in the brain .
Since glutamate and glutamine share a highly similar structure
and thereby have overlapping chemical shifts, MRS studies
conducted at field strength lower than 3.0 tesla generally assess
the combined signal that mainly comes from the two metabolites,
which is referred to as “Glx” . In the following sections, we will
summarize the glutamate- or Glx-related outcomes from MRS
studies in MDD and BD.
Glx in Major Depressive Disorder
The existing MRS literature consistently indicates reductions in
the Glx level of several brain regions in MDD . For example,
in a study which assessed the levels of various brain metabolites
in the anterior cingulate cortex (ACC) and parietal white matter,
the level of Glx was significantly lower in patients with MDD
. In the same study, when only severely depressed patients
were considered, the levels of glutamate alone as well as Glx were
reduced . Another study found a decreased ACC Glx level in
MDD, which was later restored to the normal level in the MDD
Chansoo Jun, et al.
group effectively treated with electroconvulsive therapy (ECT)
but not in the untreated MDD group . It was also reported by
a different study that the Glx level was reduced in the dorsolateral
prefrontal cortex (PFC) of patients with treatment-resistant MDD,
and that the difference in the Glx level between the patient and
control groups disappeared after successful treatment of MDD
with ECT . MDD-associated reductions in the Glx level were
also observed in the dorsomedial/dorsal anterolateral PFC and
ventromedial PFC, in a study that controlled the possible influence
of medication by implementing a minimum medication-free
period of four weeks as a selection criterion . In addition, even
in a study which used a minimum medication-free period of eight
weeks, the hippocampal Glx level was significantly lower in the
MDD group .
Interestingly, there exist a number of studies which reported
normal or elevated Glx levels in remitted MDD [32, 33]. In
association with the reports of normalized Glx level after successful
ECT for MDD, these results suggest that Glx, which declines along
with the depressive state, may be restored or compensated [28, 29,
32]. Also, an MRS study conducted in the melancholic subtype of
depression reported that the level of glutamate in the occipital lobe
was actually increased . Meanwhile, there are a few studies that
did not observe Glx reductions in MDD [35, 36], although they
appear to have limited implications. A study reported an elevated
Glx level in elderly patients with MDD, but the increase was not
statistically significant and the outcome may not be generalized to
non-elderly populations . In another study that focused on the
ACC and occipital cortex, MDD-related differences in Glx were
found to be not significant, even though a decreasing trend in the
ACC Glx level was observed . As suggested by these studies,
it is possible that the direction and magnitude of changes in the
level of glutamate may differ in different brain regions, but the
converging evidence generally suggests that meaningful alterations
in glutamate level do occur in MDD .
Glx in Bipolar Disorder
Unlike the case of MDD, the level of Glx is generally reported
to be elevated in BD [25, 37]. In the acute manic state of BD,
an increased Glx level in the left dorsolateral PFC was found
. Furthermore, elevated Glx levels were also observed in the
cingulate gyrus of the patients with BD, not only in the manic
state but also in the mixed or depressed states . Based on the
concurrent increases in Glx and lactate, the researchers of the
study proposed that disturbance in the brain energy metabolism,
in particular the change in the energy redox state from oxidative
phosphorylation to glycolysis, might explain the changed Glx
level . Findings from studies that used phosphorus MRS,
which showed pH level decreases in conjunction with lactate level
increases, corroborate the shift toward glycolysis in brain energy
According to a study which distinguished the melancholic
and non-melancholic subtypes of BD depression, Glx was more
heightened in the BD group in comparison with the control group,
and the increase in Glx was more pronounced in the melancholic
BD subgroup . In addition, after treatment with lamotrigine,
an anti-glutamatergic mood stabilizer, the treatment group that
had undergone remission showed a significant reduction in Glx,
compared to the non-remission group . In a study which
included patients with rapid cycling (RC) bipolar II disorder, those
with non-RC BD, and healthy controls, the Glx level in the left
dorsolateral PFC turned out to be significantly higher in the RC
group in all mood states . Although the study was conducted
in a small population at a preliminary scale, the fact that the RC
subtype is considered as a severe BD subtype  implicates the
possibility that the elevated Glx level may be an important factor
in the manifestation of characteristic symptoms of BD.
There exists a report suggesting that a substantial number of
patients with postpartum depression should be diagnosed to
have BD . It is thus notable that the level of glutamate, which
is generally increased in BD, was reported to be increased in the
medial PFC of patients with postpartum depression . As
changes in female hormones are known to be associated with
fluctuations in the glutamate level in the medial PFC , it can
be hypothesized that the hormonal changes that occur during the
postpartum period may induce disturbance in the glutamatergic
system, which would in turn lead to the pathogenesis of
postpartum depression . It is intriguing that the increasing
tendency of glutamate level in postpartum depression is more
comparable to the glutamatergic change in BD than to the change
in MDD. Continued research would be necessary to further
elucidate the pathophysiology of postpartum depression and its
possible association with that of BD.
In sum, the general tendencies of decreased Glx level in MDD
and increased Glx level in BD are considered to be significant,
even when the effect of brain regional differences in the level of
glutamate is taken into account [25, 37].
THE ROLE OF ASTROCYTES IN MOOD DISORDERS
Astrocytes are deeply involved not only in glutamate metabolism
but also in neuronal energy supply [10, 47]. Indeed, astrocytes
uptake glutamate released to the synaptic cleft and synthesize
glutamine from glutamate, while they deliver energy sources
including glucose and lactate based on neuronal energy
Glutamatergic Disturbance in Mood Disorders
requirements [8-10]. Thus, there exists a tight coupling between
the glutamatergic system and brain energy metabolism via
It is thus of particular interest that astrocytic abnormalities are
continuously implicated in human and animal studies of mood
disorders, although changes in other kinds of glial cells have also
been noticed [48-50]. Animal models of mood disorders have
revealed several changes in astrocytes, which are manifested by
phenomena such as altered expression or immunoreactivity of
glial fibrillary acid protein (GFAP), which is a common marker
of astrogliosis  and astrocytic glutamate transporters .
Evidence from human postmortem studies also indicates glial
abnormalities including reductions in astrocytic densities or
decreased GFAP levels . For instance, a study which used
postmortem amygdala sample showed that the density of GFAP-
immunoreactive astrocytes was significantly lower in MDD
samples than in BD, schizophrenia, or control samples . A
series of in vivo human studies conducted by a research group
suggest that reduced density of reactive astrocytes is associated
with MDD in an age-dependent manner, as age was positively
correlated with GFAP immunoreactivity or level [54, 55]. These
studies imply a meaningful relationship between mood disorders
and reduced astrocytic density or GFAP levels, especially in
younger patients with MDD [54, 55].
Based on these findings, it has been proposed that the
interplay of stress-induced changes, glial dysfunction and
disturbed glutamatergic system may be deeply involved in the
pathogenesis of depression . As stress may incur an excess
of glucocorticoids or reductions in neutrophin levels which are
thought to be associated with decreased astrocytic density and
impaired astrocytic function, it may in turn lead to disruption of
glutamatergic system and subsequent neurotoxicity [48, 52, 56].
Furthermore, it has been suggested that antidepressants may at
least partially exert their effects via directly affecting astrocytes, as
these drugs have been shown to influence several factors including
the number of astrocytes, GFAP expression, and astrocytic
signaling pathways . Accordingly, further research to elucidate
the association between astrocytes and the pathogenesis of mood
disorders as well as the pharmacodynamics of antidepressants
may contribute to the development of novel therapeutic targets.
DEPRESSION IN DIABETES MELLITUS: IN ASSOCIATION WITH
Extensive clinical evidence indicates that depression is a
common comorbidity of diabetes mellitus (DM), a disorder
of dysregulated glycemic control . According to a meta-
analysis, having DM was observed to increase by twice the odds
of comorbid depression . There have been attempts from
different approaches to investigate the underpinnings of the
association between depression and DM, which is suggested to be
bidirectional and complex . For the influence of depression
on DM, depressive symptoms are reported to exacerbate DM by
hindering self-care and management in patients with DM .
For the influence of DM on depression, psychosocial factors did
not significantly predict the incidence of depression in DM ,
whereas biochemical factors, notably glutamate abnormalities, are
shown to be implicated in DM-related depression [62, 63]. In a
rat model of streptozotocin-induced diabetes, DM was shown to
deter glutamate oxidation and glutamine synthesis in the retina
. Also, in the identical model, an elevated level of glutamate
was observed in the retina of diabetic rats . A human MRS
study reported a higher prefrontal Glx level in patients with type
1 DM , whereas the levels of glutamate and glutamine in
the subcortical brain regions were found be significantly lower
in patients with type 2 DM and MDD than in those with DM
alone . As indicated by the evidence suggesting glutamatergic
abnormalities in DM-related depression, medications acting on
the glutamatergic system may prove to be effective in the treatment
of depressive symptoms in DM .
In consideration of the importance of astrocytes in the regulation
of the glutamatergic system, it may be of particular interest that
DM appears to be associated with changes in the number or
function of astrocytes. A number of studies showed DM-induced
reductions in GFAP levels in streptozotocin-induced DM, which
are suggested to be due to hyperglycemia [66, 67]. Also, in diabetic
rats, ischemia resulted in rapid astrocytic death as well as increased
synthesis of inducible nitric oxide synthase, which would lead to
an increase in the level of nitric oxide . Although it has been
proposed that reactive astrocytes may have protective effects
against central nervous system injury, this result suggests that
diabetic hyperglycemia may induce prolonged or excess response
of reactive astrocytes and astrocytic death . Another rat study
showed that the level of astrocytic GFAP was reduced while
glutamate uptake was increased in streptozotocin-induced DM,
and these DM-related effects were suppressed by insulin treatment
. As these studies consistently indicate astrocytic alterations
in DM, future investigations on whether there is an association
between DM-induced depressive symptoms and changes in the
number and function of astrocytes.
As discussed in earlier sections, the evidence of glutamate
Chansoo Jun, et al.
disturbance in mood disorders has been established by a
considerable amount of research [5, 70]. Because the glutamatergic
system plays many important roles in neurotransmission and
neuroenergetic metabolism, the glutamate hypothesis of mood
disorders may have important implications, which may be useful
to overcome the shortcomings of the monoamine hypothesis as
well as to identify novel therapeutic targets. As the importance of
the glutamatergic system is more highlighted, the role of astrocytes,
which is suggested to be impaired in mood disorders, is also being
emphasized . For a better understanding of the neurobiology
of mood disorders, further research to elucidate the complex
relationships between perturbations in the glutamatergic system,
astrocytic dysfunction, and altered brain energy metabolism
should be conducted.
The present work was supported in part by grants A112009 (JEK)
and A121080 (IKL) from the Korean Ministry of Health and
Welfare; and the Global Top 5 program, Ewha Womans University
1. Li X, Frye MA, Shelton RC (2012) Review of pharmacological
treatment in mood disorders and future directions for drug
development. Neuropsychopharmacology 37:77-101.
2. Sanacora G, Treccani G, Popoli M (2012) Towards a gluta-
mate hypothesis of depression: an emerging frontier of
neuropsychopharmacology for mood disorders. Neurophar-
3. Gibson TB, Jing Y, Smith Carls G, Kim E, Bagalman JE, Burton
WN, Tran QV, Pikalov A, Goetzel RZ (2010) Cost burden of
treatment resistance in patients with depression. Am J Manag
4. Greden JF (2001) The burden of disease for treatment-
resistant depression. J Clin Psychiatry 62 Suppl 16:26-31.
5. Sanacora G, Zarate CA, Krystal JH, Manji HK (2008)
Targeting the glutamatergic system to develop novel,
improved therapeutics for mood disorders. Nat Rev Drug
6. Lapidus KA, Soleimani L, Murrough JW (2013) Novel
glutamatergic drugs for the treatment of mood disorders.
Neuropsychiatr Dis Treat 9:1101-1112.
7. Meldrum BS (2000) Glutamate as a neurotransmitter
in the brain: review of physiology and pathology. J Nutr
8. Hertz L, Zielke HR (2004) Astrocytic control of glutamatergic
activity: astrocytes as stars of the show. Trends Neurosci
9. Anderson CM, Swanson RA (2000) Astrocyte glutamate
transport: review of properties, regulation, and physiological
functions. Glia 32:1-14.
10. Bélanger M, Allaman I, Magistretti PJ (2011) Brain
energy metabolism: focus on astrocyte-neuron metabolic
cooperation. Cell Metab 14:724-738.
11. Cotter DR, Pariante CM, Everall IP (2001) Glial cell abnor-
malities in major psychiatric disorders: the evidence and
implications. Brain Res Bull 55:585-595.
12. Bak LK, Schousboe A, Waagepetersen HS (2006) The
glutamate/GABA-glutamine cycle: aspects of transport,
neurotransmitter homeostasis and ammonia transfer. J
13. John CS, Smith KL, Van’t Veer A, Gompf HS, Carlezon WA Jr,
Cohen BM, Öngür D, Bechtholt-Gompf AJ (2012) Blockade
of astrocytic glutamate uptake in the prefrontal cortex
induces anhedonia. Neuropsychopharmacology 37:2467-
14. Walter M, Henning A, Grimm S, Schulte RF, Beck J, Dydak
U, Schnepf B, Boeker H, Boesiger P, Northoff G (2009)
The relationship between aberrant neuronal activation
in the pregenual anterior cingulate, altered glutamatergic
metabolism, and anhedonia in major depression. Arch Gen
15. McEwen BS, Chattarji S, Diamond DM, Jay TM, Reagan
LP, Svenningsson P, Fuchs E (2010) The neurobiological
properties of tianeptine (Stablon): from monoamine
hypothesis to glutamatergic modulation. Mol Psychiatry
16. Berman RM, Cappiello A, Anand A, Oren DA, Heninger
GR, Charney DS, Krystal JH (2000) Antidepressant effects of
ketamine in depressed patients. Biol Psychiatry 47:351-354.
17. McCullumsmith RE, Meador-Woodruff JH (2011) Novel
approaches to the study of postmortem brain in psychiatric
illness: old limitations and new challenges. Biol Psychiatry
18. Hashimoto K, Sawa A, Iyo M (2007) Increased levels of
glutamate in brains from patients with mood disorders. Biol
19. Duric V, Banasr M, Stockmeier CA, Simen AA, Newton
SS, Overholser JC, Jurjus GJ, Dieter L, Duman RS (2013)
Altered expression of synapse and glutamate related genes
in post-mortem hippocampus of depressed subjects. Int J
Glutamatergic Disturbance in Mood Disorders
20. Gawryluk JW, Wang JF, Andreazza AC, Shao L, Young LT
(2011) Decreased levels of glutathione, the major brain
antioxidant, in post-mortem prefrontal cortex from patients
with psychiatric disorders. Int J Neuropsychopharmacol
21. Nowak G, Ordway GA, Paul IA (1995) Alterations in the
N-methyl-D-aspartate (NMDA) receptor complex in the
frontal cortex of suicide victims. Brain Res 675:157-164.
22. Feyissa AM, Chandran A, Stockmeier CA, Karolewicz B
(2009) Reduced levels of NR2A and NR2B subunits of
NMDA receptor and PSD-95 in the prefrontal cortex
in major depression. Prog Neuropsychopharmacol Biol
23. Rao JS, Kellom M, Reese EA, Rapoport SI, Kim HW (2012)
Dysregulated glutamate and dopamine transporters in
postmortem frontal cortex from bipolar and schizophrenic
patients. J Affect Disord 136:63-71.
24. Deep-Soboslay A, Iglesias B, Hyde TM, Bigelow LB, Imamovic
V, Herman MM, Kleinman JE (2008) Evaluation of tissue
collection for postmortem studies of bipolar disorder. Bipolar
25. Yüksel C, Öngür D (2010) Magnetic resonance spectroscopy
studies of glutamate-related abnormalities in mood disorders.
Biol Psychiatry 68:785-794.
26. Govindaraju V, Young K, Maudsley AA (2000) Proton NMR
chemical shifts and coupling constants for brain metabolites.
NMR Biomed 13:129-153.
27. Auer DP, Pütz B, Kraft E, Lipinski B, Schill J, Holsboer F
(2000) Reduced glutamate in the anterior cingulate cortex in
depression: an in vivo proton magnetic resonance spectro-
scopy study. Biol Psychiatry 47:305-313.
28. Pfleiderer B, Michael N, Erfurth A, Ohrmann P, Hohmann U,
Wolgast M, Fiebich M, Arolt V, Heindel W (2003) Effective
electroconvulsive therapy reverses glutamate/glutamine
deficit in the left anterior cingulum of unipolar depressed
patients. Psychiatry Res 122:185-192.
29. Michael N, Erfurth A, Ohrmann P, Arolt V, Heindel W,
Pfleiderer B (2003) Metabolic changes within the left
dorsolateral prefrontal cortex occurring with electrocon-
vulsive therapy in patients with treatment resistant unipolar
depression. Psychol Med 33:1277-1284.
30. Hasler G, van der Veen JW, Tumonis T, Meyers N, Shen J,
Drevets WC (2007) Reduced prefrontal glutamate/glutamine
and gamma-aminobutyric acid levels in major depression
determined using proton magnetic resonance spectroscopy.
Arch Gen Psychiatry 64:193-200.
31. Block W, Träber F, von Widdern O, Metten M, Schild H,
Maier W, Zobel A, Jessen F (2009) Proton MR spectroscopy
of the hippocampus at 3 T in patients with unipolar major
depressive disorder: correlates and predictors of treatment
response. Int J Neuropsychopharmacol 12:415-422.
32. Bhagwagar Z, Wylezinska M, Jezzard P, Evans J, Ashworth
F, Sule A, Matthews PM, Cowen PJ (2007) Reduction in
occipital cortex gamma-aminobutyric acid concentrations
in medication-free recovered unipolar depressed and bipolar
subjects. Biol Psychiatry 61:806-812.
33. Hasler G, Neumeister A, van der Veen JW, Tumonis T,
Bain EE, Shen J, Drevets WC, Charney DS (2005) Normal
prefrontal gamma-aminobutyric acid levels in remitted
depressed subjects determined by proton magnetic resonance
spectroscopy. Biol Psychiatry 58:969-973.
34. Sanacora G, Gueorguieva R, Epperson CN, Wu YT, Appel M,
Rothman DL, Krystal JH, Mason GF (2004) Subtype-specific
alterations of gamma-aminobutyric acid and glutamate in
patients with major depression. Arch Gen Psychiatry 61:705-
35. Binesh N, Kumar A, Hwang S, Mintz J, Thomas MA (2004)
Neurochemistry of late-life major depression: a pilot two-
dimensional MR spectroscopic study. J Magn Reson Imaging
36. Price RB, Shungu DC, Mao X, Nestadt P, Kelly C, Collins KA,
Murrough JW, Charney DS, Mathew SJ (2009) Amino acid
neurotransmitters assessed by proton magnetic resonance
spectroscopy: relationship to treatment resistance in major
depressive disorder. Biol Psychiatry 65:792-800.
37. Gigante AD, Bond DJ, Lafer B, Lam RW, Young LT, Yatham
LN (2012) Brain glutamate levels measured by magnetic
resonance spectroscopy in patients with bipolar disorder: a
meta-analysis. Bipolar Disord 14:478-487.
38. Michael N, Erfurth A, Ohrmann P, Gössling M, Arolt V,
Heindel W, Pfleiderer B (2003) Acute mania is accompanied
by elevated glutamate/glutamine levels within the left
dorsolateral prefrontal cortex. Psychopharmacology (Berl)
39. Dager SR, Friedman SD, Parow A, Demopulos C, Stoll AL,
Lyoo IK, Dunner DL, Renshaw PF (2004) Brain metabolic
alterations in medication-free patients with bipolar disorder.
Arch Gen Psychiatry 61:450-458.
40. Kim JE, Lyoo IK, Renshaw PF (2012) Neurochemical and
metabolic imaging in bipolar disorder. In: The bipolar brain:
integrating neuroimaging and genetics (Strakowski SM, ed),
pp 79-102. Oxford University Press, New York, NY.
41. Frye MA, Watzl J, Banakar S, O’Neill J, Mintz J, Davanzo
P, Fischer J, Chirichigno JW, Ventura J, Elman S, Tsuang J,
Chansoo Jun, et al.
Walot I, Thomas MA (2007) Increased anterior cingulate/
medial prefrontal cortical glutamate and creatine in bipolar
depression. Neuropsychopharmacology 32:2490-2499.
42. Michael N, Erfurth A, Pfleiderer B (2009) Elevated
metabolites within dorsolateral prefrontal cortex in rapid
cycling bipolar disorder. Psychiatry Res 172:78-81.
43. Schneck CD, Miklowitz DJ, Miyahara S, Araga M, Wisniewski
S, Gyulai L, Allen MH, Thase ME, Sachs GS (2008) The
prospective course of rapid-cycling bipolar disorder: findings
from the STEP-BD. Am J Psychiatry 165:370-377.
44. Sharma V, Khan M (2010) Identification of bipolar disorder
in women with postpartum depression. Bipolar Disord
45. McEwen AM, Burgess DT, Hanstock CC, Seres P, Khalili
P, Newman SC, Baker GB, Mitchell ND, Khudabux-Der J,
Allen PS, LeMelledo JM (2012) Increased glutamate levels
in the medial prefrontal cortex in patients with postpartum
depression. Neuropsychopharmacology 37:2428-2435.
46. Batra NA, Seres-Mailo J, Hanstock C, Seres P, Khudabux J,
Bellavance F, Baker G, Allen P, Tibbo P, Hui E, Le Melledo
JM (2008) Proton magnetic resonance spectroscopy
measurement of brain glutamate levels in premenstrual
dysphoric disorder. Biol Psychiatry 63:1178-1184.
47. Pellerin L, Magistretti PJ (1994) Glutamate uptake into
astrocytes stimulates aerobic glycolysis: a mechanism
coupling neuronal activity to glucose utilization. Proc Natl
Acad Sci U S A 91:10625-10629.
48. Czéh B, Fuchs E, Flügge G (2013) Altered glial plasticity
in animal models for mood disorders. Curr Drug Targets
49. Sanacora G, Banasr M (2013) From pathophysiology to novel
antidepressant drugs: glial contributions to the pathology and
treatment of mood disorders. Biol Psychiatry 73:1172-1179.
50. Schroeter ML, Abdul-Khaliq H, Sacher J, Steiner J, Blasig
IE, Mueller K (2010) Mood disorders are glial disorders:
evidence from in vivo studies. Cardiovasc Psychiatry Neurol
51. de Senna PN, Ilha J, Baptista PP, do Nascimento PS, Leite
MC, Paim MF, Gonçalves CA, Achaval M, Xavier LL (2011)
Effects of physical exercise on spatial memory and astroglial
alterations in the hippocampus of diabetic rats. Metab Brain
52. Rajkowska G, Miguel-Hidalgo JJ (2007) Gliogenesis and glial
pathology in depression. CNS Neurol Disord Drug Targets
53. Altshuler LL, Abulseoud OA, Foland-Ross L, Bartzokis G,
Chang S, Mintz J, Hellemann G, Vinters HV (2010) Amygdala
astrocyte reduction in subjects with major depressive
disorder but not bipolar disorder. Bipolar Disord 12:541-549.
54. Miguel-Hidalgo JJ, Baucom C, Dilley G, Overholser JC,
Meltzer HY, Stockmeier CA, Rajkowska G (2000) Glial
fibrillary acidic protein immunoreactivity in the prefrontal
cortex distinguishes younger from older adults in major
depressive disorder. Biol Psychiatry 48:861-873.
55. Si X, Miguel-Hidalgo JJ, O’Dwyer G, Stockmeier CA,
Rajkowska G (2004) Age-dependent reductions in the level of
glial fibrillary acidic protein in the prefrontal cortex in major
depression. Neuropsychopharmacology 29:2088-2096.
56. Musholt K, Cirillo G, Cavaliere C, Rosaria Bianco M, Bock
J, Helmeke C, Braun K, Papa M (2009) Neonatal separation
stress reduces glial fibrillary acidic protein- and S100beta-
immunoreactive astrocytes in the rat medial precentral
cortex. Dev Neurobiol 69:203-211.
57. Czéh B, Di Benedetto B (2013) Antidepressants act directly
on astrocytes: evidences and functional consequences. Eur
58. Anderson RJ, Freedland KE, Clouse RE, Lustman PJ (2001)
The prevalence of comorbid depression in adults with
diabetes: a meta-analysis. Diabetes Care 24:1069-1078.
59. Pan A, Lucas M, Sun Q, van Dam RM, Franco OH, Manson
JE, Willett WC, Ascherio A, Hu FB (2010) Bidirectional
association between depression and type 2 diabetes mellitus
in women. Arch Intern Med 170:1884-1891.
60. Ciechanowski PS, Katon WJ, Russo JE, Hirsch IB (2003)
The relationship of depressive symptoms to symptom
reporting, self-care and glucose control in diabetes. Gen Hosp
61. Connell CM, Davis WK, Gallant MP, Sharpe PA (1994)
Impact of social support, social cognitive variables, and
perceived threat on depression among adults with diabetes.
Health Psychol 13:263-273.
62. Lyoo IK, Yoon SJ, Musen G, Simonson DC, Weinger K, Bolo N,
Ryan CM, Kim JE, Renshaw PF, Jacobson AM (2009) Altered
acid levels and relation to low cognitive performance and
depressive symptoms in type 1 diabetes mellitus. Arch Gen
63. Ajilore O, Haroon E, Kumaran S, Darwin C, Binesh N, Mintz
J, Miller J, Thomas MA, Kumar A (2007) Measurement of
brain metabolites in patients with type 2 diabetes and major
depression using proton magnetic resonance spectroscopy.
64. Lieth E, LaNoue KF, Antonetti DA, Ratz M (2000) Diabetes
reduces glutamate oxidation and glutamine synthesis in the
Glutamatergic Disturbance in Mood Disorders
retina. The Penn State Retina Research Group. Exp Eye Res
65. Kowluru RA, Engerman RL, Case GL, Kern TS (2001) Retinal
glutamate in diabetes and effect of antioxidants. Neurochem
66. Coleman E, Judd R, Hoe L, Dennis J, Posner P (2004) Effects
of diabetes mellitus on astrocyte GFAP and glutamate
transporters in the CNS. Glia 48:166-178.
67. Lechuga-Sancho AM, Arroba AI, Frago LM, Pañeda C,
García-Cáceres C, Delgado Rubín de Célix A, Argente J,
Chowen JA (2006) Activation of the intrinsic cell death
pathway, increased apoptosis and modulation of astrocytes in
the cerebellum of diabetic rats. Neurobiol Dis 23:290-299.
68. Muranyi M, Ding C, He Q, Lin Y, Li PA (2006) Streptozotocin-
induced diabetes causes astrocyte death after ischemia and
reperfusion injury. Diabetes 55:349-355.
69. Coleman ES, Dennis JC, Braden TD, Judd RL, Posner P (2010)
Insulin treatment prevents diabetes-induced alterations in
astrocyte glutamate uptake and GFAP content in rats at 4 and
8 weeks of diabetes duration. Brain Res 1306:131-141.
70. Sanacora G, Rothman DL, Mason G, Krystal JH (2003) Clini-
cal studies implementing glutamate neurotransmission in
mood disorders. Ann N Y Acad Sci 1003:292-308.