Paul IA, Skolnick P
depression: clinical and preclinical studies.
N Y Acad Sci. 2003 Nov;1003250-72.
The past decade has seen a steady accumulation
of evidence supporting a role for the excitatory amino acid (EAA) neurotransmitter,
glutamate, and its receptors in depression and antidepressant activity. To date,
evidence has emerged indicating that N-methyl-d-aspartate (NMDA) receptor antagonists,
group I metabotropic glutamate receptor (mGluR1 and mGluR5) antagonists, as well
as positive modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA) receptors have antidepressant-like activity in a variety of preclinical
models. Moreover, antidepressant-like activity can be produced not only by drugs
modulating the glutamatergic synapse, but also by agents that affect subcellular
signaling systems linked to EAA receptors (e.g., nitric oxide synthase). In view
of the extensive colocalization of EAA and monoamine markers in nuclei such as
the locus coeruleus and dorsal raphe, it is likely that an intimate relationship
exists between regulation of monoaminergic and EAA neurotransmission and antidepressant
effects. Further, there is also evidence implicating disturbances in glutamate
metabolism, NMDA, and mGluR1,5 receptors in depression and suicidality. Finally,
recent data indicate that a single intravenous dose of an NMDA receptor antagonist
is sufficient to produce sustained relief from depressive symptoms. Taken together
with the proposed role of neurotrophic factors in the neuroplastic responses to
stressors and antidepressant treatments, these findings represent exciting and
novel avenues to both understand depressive symptomatology and develop more effective
DP, Pütz B, Kraft E, Lipinski B, Schill J, Holsboer F
glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic
resonance spectroscopy study.
Biol Psychiatry. 2000
BACKGROUND: Functional imaging studies suggest a specific
role of the anterior brain regions in the pathogenesis of major depression. The
aim of this study was to evaluate possible neurochemical alterations in the frontomesial
cortex in patients with major depressive episode using in vivo proton magnetic
resonance spectroscopy ((1)H-MRS). METHODS: Single voxel (1)H-MRS was performed
in 19 patients with major depressive episodes and 18 age-matched healthy controls
within the anterior cingulate cortex and the parietal white matter. Absolute concentrations
were estimated for N-acetyl-aspartate, choline-containing compounds, total creatine,
myo-inositol, unresolved glutamate and glutamine (Glx) and glutamate alone (Glu).
Voxel composition was analyzed by image segmentation into cerebrospinal fluid
(CSF), grey and white matter. RESULTS: MANOVA test for Glx and Glu using age,
percent CSF and percent grey matter contribution as covariates yielded a significant
group effect within the anterior cingulate due to decrease of Glx in patients
(-10.4%, p =.013). Considering only severely depressed patients, both Glx and
Glu (-14.3%, p =.03) showed a significant decrease. There was no significant group
effect for the neuronal marker NAA, creatine, choline or myo-inositol in either
localization. CONCLUSIONS: This study suggests a possible role of altered glutamatergic
neurotransmission within the anterior cingulate in the pathogenesis of mood disorders.
The otherwise unremarkable findings of major brain metabolites confirms lack of
neurodegenerative or membrane metabolic changes in major depression. [Abstract]
Y, Tang J, Russell A, Banerjee SP, Bhandari R, Ivey J, Rose M, Moore GJ, Rosenberg
Reduced anterior cingulate cortex glutamatergic
concentrations in childhood major depression.
Acad Child Adolesc Psychiatry. 2004 Mar;43(3):341-8.
OBJECTIVE: To examine
in vivo glutamatergic neurochemical alterations in the anterior cingulate cortex
of children with major depressive disorder (MDD). METHOD: Single-voxel proton
magnetic resonance spectroscopic (H-MRS) examinations of the anterior cingulate
cortex were conducted in 13 psychotropic-naïve children and adolescents with MDD
and 13 age- and sex-matched healthy children and adolescents. Ten of the 13 MDD
patient-control pairs also had a H-MRS examination of occipital cortex. RESULTS:
Anterior cingulate glutamatergic (Glx) concentrations were significantly lower
(19% decrease) in MDD patients versus controls (9.27 +/- 0.43 versus 11.47 +/-
0.26, respectively, p = 0.000). Reduced anterior cingulate Glx in MDD patients
was associated with increased severity of functional impairment. These results
remained comparably significant after controlling for age and anterior cingulate
volume. Occipital cortex Glx did not differ between MDD patients and controls.
CONCLUSIONS: These preliminary findings provide new evidence of localized functional
neurochemical marker alterations in Glx in anterior cingulate cortex in pediatric
MDD. Altered anterior cingulate Glx neurotransmission may be involved in the pathogenesis
of MDD. [Abstract]
DR, Mirza Y, Russell A, Tang J, Smith JM, Banerjee SP, Bhandari R, Rose M, Ivey
J, Boyd C, Moore GJ.
Reduced Anterior Cingulate Glutamatergic Concentrations
in Childhood OCD and Major Depression Versus Healthy Controls.
Am Acad Child Adolesc Psychiatry. 2004 Sep;43(9):1146-1153.
examine in vivo glutamatergic neurochemical alterations in the anterior cingulate
cortex of pediatric patients with obsessive-compulsive disorder (OCD) without
major depressive disorder (MDD) versus pediatric patients with MDD without OCD
and healthy controls. METHOD:: Single-voxel proton magnetic resonance spectroscopic
examinations of the anterior cingulate cortex were conducted in 14 psychotropic-naive
children and adolescents with MDD without OCD, 10 to 19 years of age, 14 case-matched
healthy controls, and 20 nondepressed, psychotropic-naive pediatric patients with
OCD 7 to 19 years of age. RESULTS:: Anterior cingulate glutamatergic concentrations
were significantly reduced in both patients with OCD (15.1% decrease) and patients
with MDD (18.7% decrease) compared with controls. Anterior cingulate glutamatergic
concentrations did not differ significantly between patients with OCD and those
with MDD. CONCLUSIONS:: Altered anterior cingulate glutamatergic neurotransmission
may be involved in the pathogenesis of OCD and MDD. These preliminary findings
further suggest that reduced anterior cingulate glutamate does not differentiate
pediatric patients with OCD from pediatric patients with MDD. [Abstract]
B, Michael N, Erfurth A, Ohrmann P, Hohmann U, Wolgast M, Fiebich M, Arolt V,
Effective electroconvulsive therapy reverses
glutamate/glutamine deficit in the left anterior cingulum of unipolar depressed
Psychiatry Res. 2003 Apr 1;122(3):185-92.
glutamate/glutamine (Glx) metabolism seems to be affected by a major depressive
disorder. Recently, a Glx deficit was detected by proton magnetic resonance spectroscopy
(1H-MRS) in the bilateral anterior cingulum of depressives. The aim of this study
was to assess the effect of successful electroconvulsive therapy (ECT) on Glx
levels in the anterior cingulum. The left anterior cingulum of 17 severely depressed
unipolar patients was measured by 1H STEAM spectroscopy before and after ECT,
and the results were compared with those for 17 age- and gender-matched controls.
We observed significantly reduced Glx levels in the patients' left cingulum compared
to healthy controls. In ECT responders, in contrast to non-responders, Glx levels
normalized (P=0.04) and then did not differ statistically from controls. Severe
depression seems to be associated with a Glx deficit and increasing Glx may be
an important mechanism of ECT action. [Abstract]
G, Gueorguieva R, Epperson CN, Wu YT, Appel M, Rothman DL, Krystal JH, Mason GF
alterations of gamma-aminobutyric acid and glutamate in patients with major depression.
Gen Psychiatry. 2004 Jul;61(7):705-13.
BACKGROUND: Measurement of cortical
gamma-aminobutyric acid (GABA) and glutamate concentrations is possible using
proton magnetic resonance spectroscopy. An initial report, using this technique,
suggested that occipital cortex GABA concentrations are reduced in patients with
major depressive disorder (MDD) relative to healthy comparison subjects. OBJECTIVES:
To replicate the GABA findings in a larger sample of MDD patients, to examine
the clinical correlates of the GABA reductions in these subjects, and to examine
other critical metabolite levels. DESIGN: Study for association. SETTING: Academic
clinical research program. PARTICIPANTS: The GABA measurements were made on 38
healthy control subjects and 33 depressed subjects. INTERVENTIONS: Occipital cortex
metabolite levels were measured using proton magnetic resonance spectroscopy.
MAIN OUTCOME MEASURES: The levels of occipital cortex GABA, glutamate, N-acetylaspartate,
aspartate, creatine, and choline-containing compounds, along with several measures
of tissue composition, were compared between the 2 groups. RESULTS: Depressed
subjects had significantly lower occipital cortex GABA concentrations compared
with healthy controls (P =.01). In addition, mean glutamate levels were significantly
increased in depressed subjects compared with healthy controls (P<.001). Significant
reductions in the percentage of solid tissue (P =.009) and the percentage of white
matter (P =.04) in the voxel were also observed. An examination of a combined
database including subjects from the original study suggests that GABA and glutamate
concentrations differ among MDD subtypes. CONCLUSIONS: The study replicates the
findings of decreased GABA concentrations in the occipital cortex of subjects
with MDD. It also demonstrates that there is a change in the ratio of excitatory-inhibitory
neurotransmitter levels in the cortex of depressed subjects that may be related
to altered brain function. Last, the combined data set suggests that magnetic
resonance spectroscopy GABA measures may serve as a biological marker for a subtype
of MDD. [Abstract]
N, Erfurth A, Ohrmann P, Arolt V, Heindel W, Pfleiderer B
changes within the left dorsolateral prefrontal cortex occurring with electroconvulsive
therapy in patients with treatment resistant unipolar depression.
Med. 2003 Oct;33(7):1277-84.
BACKGROUND: The dorsolateral prefrontal cortex
(DLPFC) is involved in the pathophysiology of major depression. In particular,
metabolic (functional hypometabolism) and structural alterations have been described.
In this study metabolic changes within the DLPFC of severely depressed patients
before and after electroconvulsive therapy (ECT) were evaluated by proton STEAM
spectroscopy (1H-MRS). METHOD: Twelve severely depressed patients with a diagnosis
of major depressive episode, unipolar with melancholic features (DSM-IV), were
enrolled, and the left dorsolateral prefrontal cortex (DLPFC) was investigated
before and after unilateral ECT by 1H-MRS. Three of the four non-responding patients
were remeasured a third time after a combined ECT/antidepressant pharmacotherapy.
The results were compared with 12 age- and gender-matched controls. RESULTS: In
depressed patients reduced glutamate/glutamine (Glx) levels were measured pre-ECT;
Glx concentrations correlated negatively with severity of depression. After successful
treatment, Glx increased significantly and levels no longer differed from those
of age-matched controls. CONCLUSIONS: Our results indicate that major depressive
disorder is accompanied by state-dependent metabolic alterations, especially in
glutamate/glutamine metabolism, which can be reversed by successful ECT. [Abstract]
N, Erfurth A, Ohrmann P, Arolt V, Heindel W, Pfleiderer B
effects of electroconvulsive therapy: a proton magnetic resonance study of the
left amygdalar region in patients with treatment-resistant depression.
Negatively balanced neurotrophic factors may be important
in precipitating clinical depression. Recently, it has been reported that antidepressant
therapy may exert positive neurotrophic effects. The aim of this study was to
detect probable neurotrophic changes during electroconvulsive therapy (ECT). For
this purpose, N-acetylaspartate (NAA), an amino acid exclusively located in neurons,
and other brain metabolites such as glutamine/glutamate (Glx), choline (Cho),
and creatine (Cr) were measured in patients by localized proton magnetic resonance
spectroscopy. A total of 28 severely depressed patients (DSM-IV) were enrolled,
and the left amygdalar region was investigated by proton STEAM spectroscopy before
and after unilateral ECT. The results were compared with 28 age- and gender-matched
controls using nonparametric paired and unpaired tests. A significant increase
in NAA was observed only in ECT responders (n=14; p=0.019). Five out of 14 nonresponders
to ECT monotherapy were remeasured following a clinical improvement after continued
ECT combined with antidepressants and were then found also to present a significant
increase in NAA. In all successfully treated patients, parallel observations,
that is, increased levels, were made for Glx, whereas Cho and Cr were unchanged.
In conclusion, our preliminary finding of increased NAA concentrations after successful
ECT may indicate a probable neurotrophic effect of ECT. [Abstract]
The possibility of neurotoxicity in the hippocampus
in major depression: a primer on neuron death.
Psychiatry. 2000 Oct 15;48(8):755-65.
A number of studies indicate that prolonged,
major depression is associated with a selective loss of hippocampal volume that
persists long after the depression has resolved. This review is prompted by two
ideas. The first is that overt neuron loss may be a contributing factor to the
decrease in hippocampal volume. As such, the first half of this article reviews
current knowledge about how hippocampal neurons die during insults, focusing on
issues related to the trafficking of glutamate and calcium, glutamate receptor
subtypes, oxygen radical generation, programmed cell death, and neuronal defenses.
This is meant to orient the reader toward the biology that is likely to underlie
any such instances of neuron loss in major depression. The second idea is that
glucocorticoids, the adrenal steroids secreted during stress, may play a contributing
role to any such neuron loss. The subtypes of depression associated with the hippocampal
atrophy typically involve significant hypersecretion of glucocorticoids, and the
steroid has a variety of adverse effects in the hippocampus, including causing
overt neuron loss. The second half of this article reviews the steps in this cascade
of hippocampal neuron death that are regulated by glucocorticoids. [Abstract]
Does interaction between zinc and glutamate system
play a significant role in the mechanism of antidepressant action?
Pol Pharm. 2001 Jan-Feb;58(1):73-5.
In the central nervous system, zinc modulates
predominantly the excitatory amino acid (glutamatergic) neurotransmission. Recent
studies demonstrated that chronic antidepressant treatment, which is required
for clinical improvement, reduced the reactivity/function of the glutamate/NMDA
receptor complex and altered zinc concentration/interaction with this receptor
type in the rodent brain. In the cerebral cortex: chronic antidepressant treatment
"down-regulated" (reduced density/affinity) of the cortical (but not
hippocampal) NMDA receptors measured by radioligand-receptor binding methods.
Moreover, chronic imipramine treatment increased the ability of zinc ion to inhibit
the NMDA receptor complex in the cerebral cortex but not in the hippocampus. In
the hippocampus: chronic treatment with antidepressant drugs (imipramine or citalopram)
increased the hippocampus/brain region ratio of zinc concentration, which may
indicate redistribution of the rat brain zinc. On the other hand, electroconvulsive
shocks induced robust increase of zinc concentration in the hippocampus (with
a slight effect in the rest of brain). In spite of the lack of alterations in
the hippocampal NMDA receptors (measured by receptor binding methods), inhibitory
effect of the increased hippocampal zinc concentration induced by chronic antidepressant
treatment, may be responsible for reduction in the function of that receptor complex
also in the hippocampus. These data indicate a critical and complex role of the
interaction between zinc and NMDA receptor complex in the mechanism of antidepressant
treatment and strongly support the glutamate hypothesis of the mechanism of antidepressant
Skolnick P, Layer RT, Popik P, Nowak G, Paul IA,
Adaptation of N-methyl-D-aspartate (NMDA)
receptors following antidepressant treatment: implications for the pharmacotherapy
Pharmacopsychiatry. 1996 Jan;29(1):23-6.
antagonists mimic the effects of clinically effective antidepressants in both
preclinical tests predictive of antidepressant action and procedures designed
to model aspects of depressive symptomatology. These findings led to experiments
demonstrating that chronic administration of NMDA antagonists to rodents results
in a downregulation of cortical beta-adrenoceptors, a phenomenon also observed
following chronic treatment with many antidepressants. These neurochemical and
behavioral similarities between antidepressants and NMDA antagonists prompted
us to examine the impact of chronic antidepressant treatment on NMDA receptors.
Chronic (14 days) but not acute (1 day) administration of seventeen different
antidepressants to mice produced adaptive changes in radioligand binding to NMDA
receptors. Detailed studies with three antidepressants (imipramine, citalopram,
and electroconvulsive shock) show that these changes develop slowly, persist for
some time after cessation of treatment, and (for imipramine and citalopram) are
dose dependent. Moreover, following chronic treatment with imipramine, these changes
in radioligand binding to NMDA receptors appear restricted to the cerebral cortex.
Based on the consistency of these effects across antidepressant treatments, we
propose that adaptive changes in NMDA receptors may be the final common pathway
for antidepressant action. The recent demonstration (Nowak et al., 1995) that
radioligand binding to NMDA receptors is altered in frontal cortex of suicide
victims (compared to age and post-mortem interval matched controls) is consistent
with the hypothesis (Trullas and Skolnick, 1990) that this family of ligand gated
ion channels is involved in the pathophysiology of depression. [Abstract]
AT, Bains S, Jeetle J, Whelpton R
Imipramine and phenelzine
decrease glutamate overflow in the prefrontal cortex--a possible mechanism of
neuroprotection in major depression?
Antidepressant drugs have been used for decades, but the
neurobiological substrate of their efficacy is not completely understood. Although
these drugs have well-established effects on monoamines, evidence is emerging
that they may also affect other neurotransmitter systems. It has been shown that
treatment with a wide range of antidepressants changes the binding characteristics
of the N-methyl-D-aspartate type of glutamate receptor. This change is delayed
and occurs only in the cortex. The mechanism that triggers it is unknown. We hypothesized
that N-methyl-D-aspartate receptor alterations may be due to changes in the dynamics
of cortical excitatory amino acid release. Such changes are of particular interest
in areas such as the prefrontal cortex, a region involved in stress responses
and affected in major depression. We investigated the effects of two antidepressants
with different modes of action, imipramine and phenelzine, on glutamate and aspartate
outflow in rat prefrontal cortex and striatum. We showed that antidepressants
significantly decreased stimulated glutamate outflow. The effect had a rapid onset,
was sustained during chronic administration and was only seen in the prefrontal
cortex. This change may initiate receptor alterations. Furthermore, if antidepressants
can dampen states of hyperglutamatergic activity and the subsequent excitotoxicity,
their chronic use may have a considerable neuroprotective potential in major depression.
RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH
effects of ketamine in depressed patients.
2000 Feb 15;47(4):351-4.
BACKGROUND: A growing body of preclinical research
suggests that brain glutamate systems may be involved in the pathophysiology of
major depression and the mechanism of action of antidepressants. This is the first
placebo-controlled, double-blinded trial to assess the treatment effects of a
single dose of an N-methyl-D-aspartate (NMDA) receptor antagonist in patients
with depression. METHODS: Seven subjects with major depression completed 2 test
days that involved intravenous treatment with ketamine hydrochloride (.5 mg/kg)
or saline solutions under randomized, double-blind conditions. RESULTS: Subjects
with depression evidenced significant improvement in depressive symptoms within
72 hours after ketamine but not placebo infusion (i.e., mean 25-item Hamilton
Depression Rating Scale scores decreased by 14 +/- SD 10 points vs. 0 +/- 12 points,
respectively during active and sham treatment). CONCLUSIONS: These results suggest
a potential role for NMDA receptor-modulating drugs in the treatment of depression.
A, Takahira Y, Katagai H, Takazawa T
improves the postoperative state of depressed patients.
Analg. 2002 Jul;95(1):114-8, table of contents.
We investigated whether ketamine
is suitable for depressed patients who had undergone orthopedic surgery. We studied
70 patients with major depression and 25 patients as the control (Group C). The
depressed patients were divided randomly into two groups; patients in Group A
(n = 35) were induced with propofol, fentanyl, and ketamine and patients in Group
B (n = 35) were induced with propofol and fentanyl, and all patients were maintained
with 1.5%-2.0% isoflurane plus nitrous oxide. The mean Hamilton Depression Rating
(HDR) score was 12.7 +/- 5.4 for Group A and 12.3 +/- 6.0 for Group B 2 days before
surgery and 9.9 +/- 4.1 for Group A and 14.4 +/- 3.8 for Group B 1 day after surgery.
The HDR score in Group A 1 day after surgery was significantly (P < 0.05)
lower than that in Group B. The HDR score in Group C was 4.2 +/- 1.7 2 days before
surgery and 4.8 +/- 1.6 1 day after surgery. Depressed mood, suicidal tendencies,
somatic anxiety, and hypochondriasis significantly decreased in Group A as compared
with Group B. Postoperative pain scores in Group A at 8 and 16 h after the end
of anesthesia were 26.6 +/- 8.7 and 24.9 +/- 8.2, respectively, which were significantly
(P < 0.05) lower than 34.3 +/- 12.0 and 31.1 +/- 8.8 in Group B. In conclusion,
small-dose ketamine improved the postoperative depressive state and relieved postoperative
pain in depressed patients. IMPLICATIONS: NMDA receptor antagonists are reported
to be effective for improving depression. It remains unclear whether ketamine,
which is an NMDA receptor antagonist, postoperatively affects the psychological
state in depressed patients. We investigated the effect of 1.0 mg/kg of ketamine
on postoperative outcomes in depressed patients. [Abstract]
P, Steinberg J, Oliver C, Grino M.
Glutamate and N-methyl-D-aspartate
stimulate rat hypothalamic corticotropin-releasing factor secretion in vitro.
Neuroendocrinol. 1997 Feb;9(2):93-7.
It is known that in vivo excitatory amino
acids (EAA) stimulate the hypothalamo-pituitary-adrenal axis. However their site
of action is not fully understood. We investigated the possibility of a direct
action of EAA on the secretion of the major adrenocorticotropin hormone (ACTH)
secretagogue: corticotropin-releasing factor (CRF) from incubated rat hypothalamic
slices. N-methyl-D-aspartic acid (NMDA) or L-glutamate (1 x 10(-7) to 1 x 10(-3)
M) stimulated in a dose-dependent fashion CRF release. The maximal effect was
obtained at a concentration of 1 x 10(-4) M for both drugs. The IC50 was 1.3 x
10(-5) M and 3.3 x 10(-5) M for NMDA and L-glutamate, respectively. Incubation
with 2.5 x 10(-4) M D-2-amino-5-phosphonovalerate (a NMDA receptor antagonist)
or 2-amino-4-phosphonobutyrate (a metabotropic receptor antagonist) was without
significant effect on basal CRF secretion and completely blocked the increase
in CRF release induced by 5 x 10(-5) M NMDA or L-glutamate, respectively. Incubation
with 1 x 10(-4) M kainate or 0.5 x 10(-4) M AMPA did not change basal CRF secretion.
Incubation with 2 x 10(-4) M gamma-D-glutamylglycine (a specific antagonist of
kainate and AMPA receptor) had no effect under basal conditions or during exposure
to kainate or AMPA. Our data demonstrate that EAA could stimulate directly CRF
secretion, by an action through NMDA and metabotropic receptors, but not kainate
or AMPA receptors. These findings may be relevant to the regulation of the hypothalamo-pituitary
adrenal axis, both under basal conditions and during exposure to stress. [Abstract]
M, Plein H, Ferreira D
Platelet glutamate receptor
supersensitivity in major depressive disorder.
Neuropharmacol. 2001 May-Jun;24(3):129-32.
Dysregulation of glutamate has been
described in depression, and supersensitivity of platelet glutamate receptors
has been found in both psychotic major depression and schizophrenia. The aim of
this study was to examine the platelet glutamate receptor sensitivity in patients
with nonpsychotic, unipolar major depression to assess whether this is a marker
of depression or of psychosis. Glutamate receptor sensitivity was assessed using
the platelet intracellular calcium response to glutamate (0-100 micromol) measured
by spectrofluorometry. The depression group showed a significantly greater platelet
intracellular calcium response to glutamate stimulation than the control group,
both in terms of absolute values (p = 0.007) and percentage of response from baseline
(p = 0.030). These data suggest that platelet glutamate receptors may be supersensitive
in depression and that the platelet may be a possible peripheral marker of glutamate
function in depression. [Abstract]
MC, Ferrara A, Boscati L, Bravin S, Zamberlan F, Alecci M, Invernizzi G
and platelet amino acid concentrations in patients affected by major depression
and under fluvoxamine treatment.
Plasma and platelet levels of 18 amino acids were measured
in 29 outpatients (mean age +/- SD 47.41 +/- 10.85 years; 14 F, 15 M) affected
by major depression (DSM IV) and in 28 healthy volunteers (mean age 42.46 +/-
14.19 years; 12 F, 16 M). Plasma and platelet levels of amino acids tended to
be higher in depressed patients than in healthy controls. In particular, glutamate,
taurine and lysine plasma levels and aspartate, serine and lysine platelet levels
were significantly higher. Tryptophan/large neutral amino acids ratio (trp/LNAAs)
was significantly lower in depressed patients. Fluvoxamine treatment did not influence
plasma and platelet levels of amino acids or trp/LNAAs ratio. [Abstract]
M, Verkerk R, Vandoolaeghe E, Lin A, Scharpé S
levels of excitatory amino acids, serine, glycine, histidine, threonine, taurine,
alanine and arginine in treatment-resistant depression: modulation by treatment
with antidepressants and prediction of clinical responsivity.
Psychiatr Scand. 1998 Apr;97(4):302-8.
Previous research has revealed that
major depression is accompanied by disorders in excitatory amino acids, e.g. glutamate
and aspartate, and alterations in serum levels of other amino acids, e.g. serine,
glycine and taurine. The aim of the present study was to examine serum levels
of aspartate, asparagine, glutamate, glutamine, serine, glycine, threonine, histidine,
alanine, taurine and arginine in major depression patients with treatment-resistant
depression (TRD). No significant differences in the serum concentrations of any
of the above amino acids could be found between patients with and without TRD
and normal controls. Non-responders to treatment with antidepressants during a
period of 5 weeks were characterized by significantly lower serum levels of aspartate,
asparagine, serine, threonine and taurine. A 5-week period of treatment with antidepressants
significantly reduced the serum levels of aspartate, glutamate and taurine, and
significantly increased the serum concentrations of glutamine. The results suggest
that alterations in serum levels of aspartate, asparagine, serine, threonine and
taurine may predict the subsequent response to treatment with antidepressants,
and that the latter may modulate serum levels of excitatory amino acids and taurine.
C, Maes M, Dai J, Meltzer HY
of excitatory amino acids, serine, glycine, taurine and histidine in major depression.
Neuropsychopharmacol. 1995;5 Suppl71-5.
This study was carried out to investigate
plasma levels of excitatory amino acids, such as glutamate and aspartate, and
glutamine, serine, glycine, taurine and histidine in major depression. The plasma
amino acids were determined by means of HPLC in 22 normal controls and 25 unmedicated
patients with major depression. Major depression was characterized by higher plasma
taurine levels than normal controls. Significantly lower plasma glycine values
and a higher serine/glycine ratio were observed in the depressed group. No significant
differences in glutamine, histidine, serine or aspartate levels could be detected
between the study groups. By means of linear discriminant analysis, a highly significant
separation between major depressed subjects and normal volunteers was found using
glycine, glutamate and taurine as discriminatory variables. No significant relationships
between any of the amino acids and severity of depression could be found. The
results suggest that major depression is accompanied by perturbations in the serine/glycine
ratio, excitatory amino acids, such as glutamate, and inhibitory amino acids,
such as taurine. [Abstract]
J, Panchalingam K, Rapoport A, Gershon S, McClure RJ, Pettegrew JW
cerebrospinal fluid glutamine levels in depressed patients.
Psychiatry. 2000 Apr 1;47(7):586-93.
BACKGROUND: There is increasing evidence
for an association between alterations of brain glutamatergic neurotransmission
and the pathophysiology of affective disorders. METHODS: We studied the association
between cerebrospinal fluid (CSF) metabolites, including glutamine, in unipolar
and bipolar depressed patients versus control subjects using a proton magnetic
resonance spectroscopy technique. Cerebrospinal fluid samples were obtained from
18 hospitalized patients with acute unmedicated severe depression without medical
problems and compared with those of 22 control subjects. RESULTS: Compared with
the control group, the depressed patient group had significantly higher CSF glutamine
concentrations, which correlated positively with CSF magnesium levels. CONCLUSIONS:
These findings suggest an abnormality of the brain glial-neuronal glutamine/glutamate
cycle associated with N-methyl-D-aspartate receptor systems in patients with depression.
RE, Meador-Woodruff JH
Striatal excitatory amino acid
transporter transcript expression in schizophrenia, bipolar disorder, and major
Because abnormalities of glutamatergic neurotransmission
in psychiatric illness are likely not limited to glutamate receptor expression,
we investigated expression of excitatory amino acid transporters (EAATs) in the
striatum. The EAATs, normally expressed in both glia (EAAT1 and EAAT2) and neurons
(EAAT3 and EAAT4), have previously been implicated in Huntington's disease, amyotrophic
lateral sclerosis, and schizophrenia. In this study, we investigated striatal
expression of transcripts encoding EAATs in tissue from mood disordered and schizophrenic
subjects. With probes designed for the human EAAT1, EAAT2, EAAT3, and EAAT4 transcripts,
we performed in situ hybridization and detected decreased expression of EAAT3
and EAAT4 transcripts in the striatum in bipolar disorder. We also detected decreased
EAAT3 transcript expression in schizophrenia and decreased EAAT4 transcript expression
in major depressive disorder. These results suggest that changes in striatal transporter
mRNA expression are restricted to neuronal EAATs and extend the body of evidence
implicating abnormal glutamatergic neurotransmission in schizophrenia and mood
PT, Poynton A, Lowe SL, Najlerahim A, Bridges PK, Bartlett JR, Procter AW, Bruton
CJ, Bowen DM
Brain amino acid concentrations and Ca2+-dependent
release in intractable depression assessed antemortem.
Res. 1989 Aug 14;494(2):315-24.
The concentrations of 3 putative neurotransmitters
(glutamate, aspartate and gamma-aminobutyrate), 4 related amino acids and 5 non-transmitter-related
amino acids have been measured in neurosurgical samples (frontal cortex) from
patients with intractable depression and controls. In addition, the glutamate
receptor agonist 2-amino-4-sulpho-butanoic acid (homocysteic acid) has been identified
in human brain and measured in these samples. There were no changes in the concentrations
of amino acids in depressed patients compared to control with the exception of
aspartic and homocysteic acids which were elevated in a sub-group of patients
with depression compared to control. The Ca2+-dependent release (K+-stimulated)
of putative neurotransmitters has been demonstrated for the first time from brain
tissue of depressed patients. Glutamate release was unaltered from the control
value. Aspartate values showed unexplained variability but it's release and that
of gamma-aminobutyrate were elevated in some depressed subjects. These results
do not support the hypothesis of reduced amino acid function in depressive illness.
JH, Hogg AJ, Smith RE
Striatal ionotropic glutamate
receptor expression in schizophrenia, bipolar disorder, and major depressive disorder.
Res Bull. 2001 Jul 15;55(5):631-40.
Abnormalities of the ionotropic glutamate
receptors (N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic
acid [AMPA], and kainate) have been reported in the brain in schizophrenia, although
in complex, region-specific patterns. While limbic cortex and medial temporal
lobe structures have been most often studied in psychiatric illnesses, glutamate
receptors are expressed in other brain regions associated with limbic circuitry,
especially the striatum. In this study, we have determined striatal ionotropic
glutamate receptor expression in brains from persons with schizophrenia, bipolar
disorder, major depression, and a comparison group, using samples from the Stanley
Foundation Neuropathology Consortium. We have determined the expression of these
receptors at multiple levels of gene expression by using both in situ hybridization
and receptor autoradiography. The expression of nearly all of these molecules
was not different in these psychiatric conditions. The only significant changes
noted were NR2D and gluR1 transcripts, and [(3)H]AMPA binding. This is the first
comprehensive study of striatal ionotropic glutamate receptor expression in schizophrenia
and affective disorders, and suggests that there are minimal changes in these
receptors in this region of the brain in these illnesses. [Abstract]