glutamate and unipolar depression

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(Updated 9/13/04)

Paul IA, Skolnick P
Glutamate and depression: clinical and preclinical studies.
Ann 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 antidepressants. [Abstract]

Auer DP, Pütz B, Kraft E, Lipinski B, Schill J, Holsboer F
Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study.
Biol Psychiatry. 2000 Feb 15;47(4):305-13.
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]

Mirza Y, Tang J, Russell A, Banerjee SP, Bhandari R, Ivey J, Rose M, Moore GJ, Rosenberg DR
Reduced anterior cingulate cortex glutamatergic concentrations in childhood major depression.
J Am 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-naďve 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]

Rosenberg 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.
J Am Acad Child Adolesc Psychiatry. 2004 Sep;43(9):1146-1153.
OBJECTIVE:: To 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]

Pfleiderer B, Michael N, Erfurth A, Ohrmann P, Hohmann U, Wolgast M, Fiebich M, Arolt V, Heindel W
Effective electroconvulsive therapy reverses glutamate/glutamine deficit in the left anterior cingulum of unipolar depressed patients.
Psychiatry Res. 2003 Apr 1;122(3):185-92.
Cortical 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]

Sanacora G, Gueorguieva R, Epperson CN, Wu YT, Appel M, Rothman DL, Krystal JH, Mason GF
Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression.
Arch 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]

Michael N, Erfurth A, Ohrmann P, Arolt V, Heindel W, Pfleiderer B
Metabolic changes within the left dorsolateral prefrontal cortex occurring with electroconvulsive therapy in patients with treatment resistant unipolar depression.
Psychol 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]

Michael N, Erfurth A, Ohrmann P, Arolt V, Heindel W, Pfleiderer B
Neurotrophic effects of electroconvulsive therapy: a proton magnetic resonance study of the left amygdalar region in patients with treatment-resistant depression.
Neuropsychopharmacology. 2003 Apr;28(4):720-5.
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]

Sapolsky RM
The possibility of neurotoxicity in the hippocampus in major depression: a primer on neuron death.
Biol 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]

Nowak G
Does interaction between zinc and glutamate system play a significant role in the mechanism of antidepressant action?
Acta 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 action. [Abstract]

Skolnick P, Layer RT, Popik P, Nowak G, Paul IA, Trullas R
Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression.
Pharmacopsychiatry. 1996 Jan;29(1):23-6.
NMDA 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]

Michael-Titus 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?
Neuroscience. 2000;100(4):681-4.
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. [Abstract]

Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH
Antidepressant effects of ketamine in depressed patients.
Biol Psychiatry. 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. [Abstract]

Kudoh A, Takahira Y, Katagai H, Takazawa T
Small-dose ketamine improves the postoperative state of depressed patients.
Anesth 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]

Joanny P, Steinberg J, Oliver C, Grino M.
Glutamate and N-methyl-D-aspartate stimulate rat hypothalamic corticotropin-releasing factor secretion in vitro.
J 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]

Berk M, Plein H, Ferreira D
Platelet glutamate receptor supersensitivity in major depressive disorder.
Clin 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]

Mauri MC, Ferrara A, Boscati L, Bravin S, Zamberlan F, Alecci M, Invernizzi G
Plasma and platelet amino acid concentrations in patients affected by major depression and under fluvoxamine treatment.
Neuropsychobiology. 1998;37(3):124-9.
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]

Maes M, Verkerk R, Vandoolaeghe E, Lin A, Scharpé S
Serum 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.
Acta 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. [Abstract]

Altamura C, Maes M, Dai J, Meltzer HY
Plasma concentrations of excitatory amino acids, serine, glycine, taurine and histidine in major depression.
Eur 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]

Levine J, Panchalingam K, Rapoport A, Gershon S, McClure RJ, Pettegrew JW
Increased cerebrospinal fluid glutamine levels in depressed patients.
Biol 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. [Abstract]

McCullumsmith RE, Meador-Woodruff JH
Striatal excitatory amino acid transporter transcript expression in schizophrenia, bipolar disorder, and major depressive disorder.
Neuropsychopharmacology. 2002 Mar;26(3):368-75.
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 disorders. [Abstract]

Francis 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.
Brain 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. [Abstract]

Meador-Woodruff JH, Hogg AJ, Smith RE
Striatal ionotropic glutamate receptor expression in schizophrenia, bipolar disorder, and major depressive disorder.
Brain 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]

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Recent Glutamate and Depression Research

1) Muhonen LH, Lönnqvist J, Juva K, Alho H
Double-blind, randomized comparison of memantine and escitalopram for the treatment of major depressive disorder comorbid with alcohol dependence.
J Clin Psychiatry. 2008 Mar;69(3):392-9.
OBJECTIVE: The aim of the study was to evaluate possible new treatments for major depressive disorder in patients with comorbid alcohol dependence in a municipal alcohol treatment unit. The efficacy of memantine, a noncompetitive glutamate N-methyl-D-aspartate (NMDA)-receptor blocker used for the treatment of moderate to severe Alzheimer's disease, was compared with that of escitalopram, a selective serotonin reuptake inhibitor antidepressant. METHOD: Eighty alcohol-dependent outpatients with major depressive disorder (DSM-IV criteria) seeking treatment from municipal alcohol treatment clinics in Helsinki, Finland, were randomly assigned 1:1 to receive memantine 20 mg/day or escitalopram 20 mg/day. During the study period, patients continued their routine treatment at the clinics. Abstinence was not required. Concomitant interventions or imposed treatment goals were not offered by the study physician. The patients returned to the treatment clinics at weeks 1, 2, 4, 12, and 26 for data collection and for medication checking and dispensing. Outcome measures were the Montgomery-Asberg Depression Rating Scale (MADRS) and Beck Depression Inventory-II for depression, Hamilton Rating Scale for Anxiety (HAM-A) and Beck Anxiety Inventory for anxiety, Consortium to Establish a Registry for Alzheimer's Disease test battery for cognitive functions, and Social and Occupational Functioning Assessment Scale for social and occupational functions and quality-of-life measures. Twenty-nine patients in each group completed the study. All primary and secondary outcome statistical analyses were performed by an independent source for intent-to-treat populations, which included all patients randomly assigned to treatment. The study was conducted from December 2004 to May 2006. RESULTS: Both treatments significantly reduced the baseline level of depression and anxiety according to MADRS and HAM-A, which were the primary measures (p < .0001). There was no significant difference between the memantine and escitalopram groups. Assessed cognitive functioning scores were primarily within the normative range and were unchanged in both groups. Quality-of-life outcomes equally improved in both treatment groups. CONCLUSIONS: These data provide new evidence for the safety and potential efficacy of memantine and escitalopram for major depressive disorder in patients with comorbid alcohol dependence. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00368862. [PubMed Citation] [Order full text from Infotrieve]

2) Maeng S, Zarate CA
The role of glutamate in mood disorders: results from the ketamine in major depression study and the presumed cellular mechanism underlying its antidepressant effects.
Curr Psychiatry Rep. 2007 Dec;9(6):467-74.
In this article, we first review a study showing that the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine leads to rapid, robust, and relatively sustained antidepressant effects in patients with treatment-resistant major depression. We then discuss our hypothesis that the therapeutic effects of monoaminergic antidepressants and ketamine may be mediated by increased AMPA-to-NMDA glutamate receptor throughput in critical neuronal circuits. We hypothesize that ketamine directly mediates this throughput, whereas monoaminergic antidepressants work indirectly and gradually; this may explain, in part, the lag of onset of several weeks to months that is observed with traditional antidepressants. [PubMed Citation] [Order full text from Infotrieve]

3) Chaki S, Okubo T, Sekiguchi Y
Non-monoamine-based approach for the treatment of depression and anxiety disorders.
Recent Patents CNS Drug Discov. 2006 Jan;1(1):1-27.
Although currently prescribed antidepressants with actions mediated through alteration of monoaminergic transmission have been proven to be useful for the treatment of depressive and anxiety disorders, they are far from ideal due to their slow onset of action and low rate of responses. Although the brain monoamine systems have long been the focus of drug therapy for depression and anxiety disorders, current drug discovery has aimed at new molecular targets outside the monoamine systems to overcome these problems. Recent increase in understanding of the molecular mechanisms of depression and anxiety has provided alternative molecular targets for these disorders. In particular, receptors within the glutamate, gamma-aminobutyric acid and neuropeptide systems provide a diversity of drug targets, and molecular biological and behavioral studies of these receptors have revealed the important roles they play in depression and anxiety. Here, we review recent patents and advances in research on these emerging molecular targets for the treatment of depression and anxiety, and discuss their advantages over currently used antidepressants and anxiolytics. [PDF] [PubMed Citation] [Order full text from Infotrieve]

4) Guilarte TR, Hammoud DA, McGlothan JL, Caffo BS, Foss CA, Kozikowski AP, Pomper MG
Dysregulation of glutamate carboxypeptidase II in psychiatric disease.
Schizophr Res. 2008 Feb;99(1-3):324-32.
Experimental evidence is beginning to converge on an important role for dysregulation of glutamate carboxypeptidase II (GCPII) in schizophrenia. The goal of this study was to determine GCPII levels in postmortem brain specimens of patients with schizophrenia, bipolar disorder or unipolar depression and age-matched control subjects. We used N-[N-(S)-1,3-dicarboxypropyl]carbamoyl]-S-3-[(125)I]iodo-l-tyrosine ([(125)I]DCIT), a high-affinity radioligand for GCPII, to probe for GCPII expression in prefrontal cortex (PFC) and mesial temporal lobe, two brain regions implicated in the pathophysiology of schizophrenia. We found that GCPII levels measured by [(125)I]DCIT quantitative autoradiography were significantly lower in the PFC and entorhinal cortex in patients with schizophrenia compared to age-matched controls. Patients with bipolar disorder also expressed significantly lower GCPII levels in PFC than controls. The decrease in [(125)I]DCIT binding in schizophrenia and bipolar disorder remained significant after adjusting for drug abuse. A significant difference in GCPII levels was also observed between schizophrenia relative to bipolar disorder and depressed subjects in the hippocampus-stratum lucidum and between schizophrenia and bipolar in the CA2 region of the hippocampus, with bipolar and depressed subjects expressing higher levels of GCPII than subjects with schizophrenia. These differences in hippocampal GCPII levels may implicate differences in the etiologies of these mental disorders. In summary, this study demonstrates a regional dysregulation of GCPII expression in the brain of patients with schizophrenia and other psychiatric disorders and supports a hypoglutamatergic state of the former illness. GCPII may represent a viable therapeutic target for intervention in psychiatric disease. [PubMed Citation] [Order full text from Infotrieve]

5) Leonard BE
Psychopathology of depression.
Drugs Today (Barc). 2007 Oct;43(10):705-16.
This review assesses some of the important advances that have been made in our understanding of the psychopathology of depression. While the monoamine theory, that postulates dysfunctional noradrenergic and serotonergic systems as the underlying cause of depression, has been valuable in the development of conventional antidepressants that are thought to act by reversing these dysfunctional states, recent clinical and experimental studies have questioned this reductionist view of depression. This has led to an assessment of the role of dysfunctional endocrine and immune systems in the aetiology of depression. In addition to explaining the link between defective neurotransmitter function and the symptoms of depression, changes in the endocrine and immune axes also help to explain the link between major depression and physical ill health. In addition, experimental and clinical studies have extended the possible involvement of neurotransmitters to include the glutamate and GABA systems. Such approaches may stimulate the development of new types of antidepressants that hopefully will combine increased efficacy with shorter speed of onset and improved side effect profiles. [PubMed Citation] [Order full text from Infotrieve]

6) Grueter BA, McElligott ZA, Winder DG
Group I mGluRs and long-term depression: potential roles in addiction?
Mol Neurobiol. 2007 Dec;36(3):232-44.
Addiction is an enormous societal problem. A number of recent studies have focused on adaptations at glutamatergic synapses that may play a role in the behavioral responses to drugs of abuse. These studies have largely focused on NMDA receptor-dependent forms of synaptic plasticity such as NMDA receptor-dependent long-term potentiation (LTP) and long-term depression (LTD). A growing body of evidence, however, suggests that metabotropic glutamate receptors (mGluRs) also play important roles in the behavioral responses to drugs of abuse and participate in producing synaptic plasticity at glutamate synapses. In this review, we focus first on the evidence supporting a role for mGluRs in addiction and then on the properties of mGluR-dependent forms of synaptic plasticity, focusing in particular on Gq-linked receptor-induced LTD. [PubMed Citation] [Order full text from Infotrieve]

7) O'Connor JA, Hemby SE
Elevated GRIA1 mRNA expression in Layer II/III and V pyramidal cells of the DLPFC in schizophrenia.
Schizophr Res. 2007 Dec;97(1-3):277-88.
The functional integrity of the dorsolateral prefrontal cortex (DLPFC) is altered in schizophrenia leading to profound deficits in working memory and cognition. Growing evidence indicates that dysregulation of glutamate signaling may be a significant contributor to the pathophysiology mediating these effects; however, the contribution of NMDA and AMPA receptors in the mediation of this deficit remains unclear. The equivocality of data regarding ionotropic glutamate receptor alterations of subunit expression in the DLPFC of schizophrenics is likely reflective of subtle alterations in the cellular and molecular composition of specific neuronal populations within the region. Given previous evidence of Layer II/III and V pyramidal cell alterations in schizophrenia and the significant influence of subunit composition on NMDA and AMPA receptor function, laser capture microdissection combined with quantitative PCR was used to examine the expression of AMPA (GRIA1-4) and NMDA (GRIN1, 2A and 2B) subunit mRNA levels in Layer II/III and Layer V pyramidal cells in the DLPFC. Comparisons were made between individuals diagnosed with schizophrenia, bipolar disorder, major depressive disorder and controls (n=15/group). All subunits were expressed at detectable levels in both cell populations for all diseases as well as for the control group. Interestingly, GRIA1 mRNA was significantly increased in both cell types in the schizophrenia group compare to controls, while similar trends were observed in major depressive disorder (Layers II/III and V) and bipolar disorder (Layer V). These data suggest that increased GRIA1 subunit expression may contribute to schizophrenia pathology. [PubMed Citation] [Order full text from Infotrieve]

8) Molina-Hernández M, Tellez-Alcántara NP, Pérez-García J, Olivera-Lopez JI, Jaramillo-Jaimes MT
Antidepressant-like actions of minocycline combined with several glutamate antagonists.
Prog Neuropsychopharmacol Biol Psychiatry. 2008 Feb 15;32(2):380-6.
This study tested the potential antidepressant activity of minocycline alone or combined with two traditional antidepressant drugs or several glutamate receptor antagonists, using the time sampling method in the forced swimming test. Results showed that: desipramine (10.0 mg/kg, P<0.05; 15.0 mg/kg, P<0.05), minocycline (60.0 mg/kg, P<0.05; 80.0 mg/kg, P<0.05) and EMQMCM (1.5 mg/kg, P<0.05; 2.0 mg/kg, P<0.05), reduced immobility by increasing climbing. Fluoxetine (20.0 mg/kg, P<0.05; 25.0 mg/kg, P<0.05) reduced immobility by increasing swimming. MTEP (5.0 mg/kg, P<0.05; 10.0 mg/kg, P<0.05) and dizolcipine (1.0 mg/kg, P<0.05; 1.5 mg/kg, P<0.05) reduced immobility by increasing swimming and climbing. Combination experiments showed that a subthreshold dose of minocycline (50.0 mg/kg) synergized the antidepressant-like actions of subthreshold doses of: desipramine (5.0 mg/kg; P<0.05), EMQMCM (0.6 mg/kg; P<0.05), MTEP (2.5 mg/kg; P<0.05) and dizolcipine (0.5 mg/kg; P<0.05). In conclusion, minocycline produced antidepressant-like actions in the FST and subthreshold dose of minocycline combined with subthreshold dose of desipramine and several glutamate receptor antagonists and produced antidepressant-like actions. [PubMed Citation] [Order full text from Infotrieve]

9) Toro CT, Hallak JE, Dunham JS, Leite JP, Sakamoto AC, Guarnieri R, Fong V, Deakin JF
The NR1 N-methyl-D-aspartate subunit and brain-derived neurotrophic factor in temporal lobe epilepsy hippocampus: a comparison of patients with and without coexisting psychiatric symptoms.
Epilepsia. 2007 Dec;48(12):2352-6.
PURPOSE: The glutamate N-methyl-D-aspartate (NMDA) receptor and the neurotrophin brain-derived neurotrophic factor have been implicated in the pathophysiology of schizophrenia and depression. Since these psychiatric disorders are common in temporal lobe epilepsy (TLE), a comparison of TLE patients with and without coexisting psychiatric symptoms may be useful to unravel pathophysiologic mechanisms for psychosis or depression. METHODS: We used immunoautoradiography to assess the NR1 NMDA receptor subunit and brain-derived neurotrophic factor in resected TLE hippocampus. RESULTS: No changes relative to comparison controls were found for TLE patients with schizophrenia-like psychosis or depression. Increased NR1 was found in the dentate molecular layer in the dysphoria group and unmedicated depressed patients. CONCLUSIONS: An increase in NR1 protein in the dentate molecular layer suggests an upregulation of NMDA receptors in granule cells in TLE patients with dysphoria and depression. This finding is compatible with the theory that increased NMDA receptor function is involved in the pathogenesis of depression and that antidepressants may act by opposing this mechanism. [PubMed Citation] [Order full text from Infotrieve]

10) Laje G, Paddock S, Manji H, Rush AJ, Wilson AF, Charney D, McMahon FJ
Genetic markers of suicidal ideation emerging during citalopram treatment of major depression.
Am J Psychiatry. 2007 Oct;164(10):1530-8.
OBJECTIVE: Suicidal ideation is an uncommon symptom than can emerge during antidepressant treatment. The biological basis of treatment-emergent suicidal ideation is unknown. Genetic markers may shed light on the causes of treatment-emergent suicidal ideation and help identify individuals at high risk who may benefit from closer monitoring, alternative treatments, or specialty care. METHOD: A clinically representative cohort of outpatients with major depressive disorder who enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial were treated with citalopram under a standard protocol for up to 14 weeks. DNA samples from 1,915 participants were genotyped for 768 single-nucleotide polymorphisms in 68 candidate genes. Allele and genotype frequencies were compared between the 120 participants who developed treatment-emergent suicidal ideation and those who did not. RESULTS: Two markers were significantly associated with treatment-emergent suicidal ideation in this sample (marker rs4825476, p=0.0000784, odds ratio=1.94; permutation p=0.01; marker rs2518224, p=0.0000243, odds ratio=8.23; permutation p=0.003). These markers reside within the genes GRIA3 and GRIK2, respectively, both of which encode ionotropic glutamate receptors. CONCLUSIONS: Markers within GRIK2 and GRIA3 were associated with treatment-emergent suicidal ideation during citalopram therapy. If replicated, these findings may shed light on the biological basis of this potentially dangerous adverse event and help identify patients at increased risk. [PDF] [PubMed Citation] [Order full text from Infotrieve]

11) Tsai GE
Searching for rational anti N-methyl-D-aspartate treatment for depression.
Arch Gen Psychiatry. 2007 Sep;64(9):1099-100; author reply 1100-1.
[PubMed Citation] [Order full text from Infotrieve]

12) Tsai SJ
Sipatrigine could have therapeutic potential for major depression and bipolar depression through antagonism of the two-pore-domain K+ channel TREK-1.
Med Hypotheses. 2008;70(3):548-50.
Major depressive disorder (MDD) is a chronic, recurring and potentially life-threatening mental illness. Current treatments are inadequate - many depression medications, although safe and effective, generally have a slow onset of clinical benefit and around half of the MDD patients do not show full remission with optimized treatment. Therefore, there is still a need for the development of faster-acting and more effective medication for MDD. Recent studies have demonstrated that the TREK-1 protein, one of the 17 members of the two-pore domain K+ (K2P) potassium channel family, is inhibited by the antidepressant fluoxetine. Deletion of TREK-1 in mice caused a substantially reduced elevation of corticosterone levels under stress, and produced behaviour similar to that of naive animals treated with fluoxetine in various behavioural tests. These findings suggested that the blocker of the TREK-1 channel might potentially be a new type of antidepressant. Sipatrigine (BW619C89), a neuroprotective agent, has been found to be a potent antagonist of TREK-1. Its related compound, lamotrigine, has been approved for the treatment of bipolar depression and is used to supplement antidepressant medication in patients with treatment-resistant depression. Furthermore, in addition to its antagonistic effect on TREK-1, sipatrigine is also a glutamate release inhibitor. Excessive glutamatergic neurotransmission is associated with depressive-like behaviours and inhibiting glutamate neurotransmission may be implicated in antidepressant therapeutic mechanisms. From the above findings of the effects of sipatrigine on TREK-1 and glutamate neurotransmission, it is hypothesised that sipatrigine could have potential therapeutic effects for MDD or bipolar depression. Further evaluation of its antidepressant therapeutic and toxic effects in animal models is needed before clinical application. [PubMed Citation] [Order full text from Infotrieve]

13) Paddock S, Laje G, Charney D, Rush AJ, Wilson AF, Sorant AJ, Lipsky R, Wisniewski SR, Manji H, McMahon FJ
Association of GRIK4 with outcome of antidepressant treatment in the STAR*D cohort.
Am J Psychiatry. 2007 Aug;164(8):1181-8.
OBJECTIVE: An initial pharmacogenetic study of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical trial reported an association between genetic variation in the HTR2A gene and outcome of citalopram treatment. By design, the study analyzed only those markers that showed reproducible association in the first wave of genotypes (comprising 1,297 patients) in the complete cohort of patients. The purpose of the present study was to utilize a second wave of genotype results, for a more powerful analysis, in the complete cohort of patients with available deoxyribonucleic acid (DNA) samples. METHOD: The authors tested the association between treatment response and 768 markers that were genotyped in the full set of 1,816 eligible patients from the STAR*D cohort. In order to control for multiple testing, the subjects were divided into two study groups: discovery and replication. RESULTS: In addition to the previously identified marker in the HTR2A gene, a new marker (rs1954787) in the GRIK4 gene, which codes for the kainic acid-type glutamate receptor KA1, was observed. The effect size of the GRIK4 marker alone was modest, but homozygote carriers of the treatment-response-associated marker alleles of both the GRIK4 and HTR2A genes were 23% less likely to experience nonresponse to treatment relative to participants who did not carry any of these marker alleles. CONCLUSIONS: The findings demonstrate that genetic variation in a kainic acid-type glutamate receptor is reproducibly associated with response to the antidepressant citalopram. This finding suggests that the glutamate system plays an important role in modulating response to selective serotonin reuptake inhibitors (SSRIs). [PubMed Citation] [Order full text from Infotrieve]

14) Matrisciano F, Panaccione I, Zusso M, Giusti P, Tatarelli R, Iacovelli L, Mathé AA, Gruber SH, Nicoletti F, Girardi P
Group-II metabotropic glutamate receptor ligands as adjunctive drugs in the treatment of depression: a new strategy to shorten the latency of antidepressant medication?
Mol Psychiatry. 2007 Aug;12(8):704-6.
[PubMed Citation] [Order full text from Infotrieve]

15) Maeng S, Zarate CA, Du J, Schloesser RJ, McCammon J, Chen G, Manji HK
Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors.
Biol Psychiatry. 2008 Feb 15;63(4):349-52.
BACKGROUND: Ketamine exerts a robust, rapid, and relatively sustained antidepressant effect in patients with major depression. Understanding the mechanisms underlying the intriguing effects of N-methyl d-aspartate (NMDA) antagonists could lead to novel treatments with a rapid onset of action. METHODS: The learned helplessness, forced swim, and passive avoidance tests were used to investigate ketamine's behavioral effects in mice. Additional biochemical and behavioral experiments were undertaken to determine whether the antidepressant-like properties of ketamine and other NMDA antagonists involve alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor throughput. RESULTS: Subanesthetic doses of ketamine treatment caused acute and sustained antidepressant-like effects. At these doses, ketamine did not impair fear memory retention. MK-801 (dizocilpine) and Ro25-6981, an NR2B selective antagonist, also exerted antidepressant-like effects; these effects, however, were not sustained as long as those of ketamine. Pre-treatment with NBQX, an AMPA receptor antagonist, attenuated both ketamine-induced antidepressant-like behavior and regulation of hippocampal phosphorylated GluR1 AMPA receptors. CONCLUSIONS: NMDA antagonists might exert rapid antidepressant-like effects by enhancing AMPA relative to NMDA throughput in critical neuronal circuits. [PubMed Citation] [Order full text from Infotrieve]

16) Hashimoto K, Sawa A, Iyo M
Increased levels of glutamate in brains from patients with mood disorders.
Biol Psychiatry. 2007 Dec 1;62(11):1310-6.
BACKGROUND: Glutamate has been thought to have a role in mental disorders. Because the postmortem interval (PMI) has such a pronounced effect on glutamate and other amino acids, it is important that a study be conducted to examine the effects of PMI on these amino acids in postmortem brains and that the analysis of intergroup differences be adjusted accordingly. We determined the levels of amino acids in postmortem brains from patients with major mental disorders by normalizing the effects of the postmortem interval with equations derived from control studies using rodent and primate postmortem brains. METHODS: First, we examined the influence of postmortem intervals on the levels of the amino acids by using rodent brains and derived equations for normalizing the raw data of the amino acids from human brains according to their postmortem intervals. Second, we measured the levels of the amino acids in postmortem human brains, normalized their raw data with the equations, and analyzed the normalized data. RESULTS: Increased levels of glutamate were observed in the frontal cortex from patients with bipolar disorder and major depression. In addition, positive correlations were observed between several pairs of amino acids, including D-serine and glutamate. CONCLUSIONS: This study suggests that glutamate plays a role in the pathophysiology of bipolar disorder and major depression. [PubMed Citation] [Order full text from Infotrieve]

17) Reznikov LR, Grillo CA, Piroli GG, Pasumarthi RK, Reagan LP, Fadel J
Acute stress-mediated increases in extracellular glutamate levels in the rat amygdala: differential effects of antidepressant treatment.
Eur J Neurosci. 2007 May;25(10):3109-14.
Depressive illness is associated with changes in amygdalar volume, and stressful life events are known to precipitate depressive episodes in this patient population. Stress affects amygdalar synaptic plasticity and several neurotransmitter systems have been implicated in stress-mediated changes in the brain, including the glutamatergic system. However, the role of the glutamatergic system in stress-mediated plasticity in the amygdala remains to be determined. Accordingly the current study examined the stress modulation of extracellular glutamate levels in the basolateral nucleus (BLA) and the central nucleus (CeA) of the amygdala by in vivo microdialysis. Acute stress increased extracellular glutamate levels in the BLA and CeA, although the dynamics of these stress-mediated changes were dramatically different in these amygdalar nuclei. Tetrodotoxin administration reduced basal, and completely eliminated stress-mediated increases in glutamate efflux in the amygdala, demonstrating that stress effects are dependent on local axonal depolarization. Moreover, stress-mediated increases in glutamate efflux in the BLA were inhibited by the antidepressant tianeptine but not by the selective serotonin-reuptake inhibitor fluoxetine. Collectively, these data demonstrate that stress-induced modulation of glutamate neurochemistry reflects a fundamental pathological change that may contribute to the aetiology and progression of depressive illness, and suggest that some antidepressants such as tianeptine may elicit their clinical effects by modulation of glutamatergic neurotransmission. [PubMed Citation] [Order full text from Infotrieve]

18) Bennett MR
Synaptic P2X7 receptor regenerative-loop hypothesis for depression.
Aust N Z J Psychiatry. 2007 Jul;41(7):563-71.
Forty-five years ago the surprising discovery was made, in a Melbourne University laboratory, that peripheral synapses exist that release neither noradrenaline nor acetylcholine. The same laboratory went on to show that one of these then novel transmitters is adenosine 5'-triphosphate (ATP), for which a class of receptors has been dubbed P2X7. Recent linkage studies have shown that the P2X7 gene is associated with major depression and bipolar disorder. This speculative paper considers possible mechanisms that could link polymorphisms in the P2X7 gene with the functioning of neural networks, especially in the hippocampus. A selective review of the neurobiological literature on the location and function of the P2X7 receptor at synapses and on astrocytes as well as microglial cells was performed in the context of determining viable hypotheses as to the function of these receptors during synaptic transmission in the neural networks of the hippocampus. It is suggested that P2X7 receptors participate in a regenerative loop at central glutamatergic synapses. In this loop glutamate-evoked release of ATP from both astrocytes and microglia cells, as well as ATP derived from an autocatalytic release from astrocytes, provides purines that can act on presynaptic P2X7 purinergic receptors. This increases glutamate release to further the amount of ATP at the synapse, leading to a new functional state of the neural network in which the synapse participates. This synaptic ATP can also act on microglia P2X7 receptors to release the cytokine tumour necrosis factor-alpha (TNF-alpha), as can glutamate, with this TNF-alpha acting on the post-synaptic neuronal membrane to increase glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors there. As synaptic ATP and glutamate are maintained by the regenerative loop they provide a sustained release of TNF-alpha, and therefore of AMPA receptor enhancement, increasing synaptic efficacy, and so contributing to the new functional state of the neural network. Infections can change this state by activating toll-like (TOL) receptors on the microglia concomitantly with their P2X7 receptor activation by the regenerative loop, thereby releasing the cytokine interleukin-1beta, which decreases the AMPA receptors in the neural membrane, so decreasing synaptic efficacy and changing the functional state of the neural network in which the synapse resides. Polymorphisms in the P2X7 gene that modify operation of the regenerative loop or the release of cytokines, as can infections, change the functional state of neural networks, which may then lead to vulnerability to mood disorders. [PubMed Citation] [Order full text from Infotrieve]

19) Rajkowska G, Miguel-Hidalgo JJ
Gliogenesis and glial pathol