Dorsolateral Prefrontal Cortex Glutamate Research Articles

Glutamate in the Dorsolateral Prefrontal Cortex in Patients With Schizophrenia: A Meta-analysis of 1H-Magnetic Resonance Spectroscopy Studies

BackgroundTo date, there is no systematic overview of glutamate in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia. Here, we meta-analyzed case-control studies of high-field proton magnetic resonance spectroscopy (1H-MRS) investigating glutamate in DLPFC. Additionally, we estimated variance ratios to investigate homo/heterogeneity. MethodsPreregistration of the study was performed on September 20, 2019. The predefined literature search on PubMed comprised articles with search terms (magnetic resonance spectroscopy OR MRS) AND (glutamate OR glut∗ OR GLX) AND (schizophrenia OR psychosis OR schizophren∗). Meta-analyses with a fixed- and random-effects model with inverse variance method, DerSimonian-Laird estimator for τ2, and Cohen's d were calculated. For differences in variability, we calculated a random-effects model for measures of variance ratios. The primary study outcome was the difference in glutamate in the DLPFC in cases versus controls. Secondary outcomes were differences in variability. ResultsThe quantitative analysis comprised 429 cases and 365 controls. Overall, we found no group difference (d = 0.03 [95% confidence interval (CI), −0.20 to 0.26], z = 0.28, p = .78). Sensitivity analysis revealed an effect for medication status (Q = 8.35, p = .039), i.e., increased glutamate in antipsychotic-naïve patients (d = 0.46 [95% CI, 0.08 to 0.84], z = 2.37, p = .018). Concerning variance ratios, we found an effect of medication status (Q = 16.95, p < .001) due to lower coefficient of variation ratio (CVR) in medication-naïve patients (logCVR = −0.49 [95% CI, −0.78 to −0.20], z = −3.33, p < .001). In studies with medicated patients, we found higher CVR (logCVR = 0.22 [95% CI, 0.06 to 0.39], z = 2.67; p = .008). ConclusionsWe carefully interpret the higher levels and lower variability in cortical glutamate in antipsychotic-naïve patients as a possible key factor resulting from a putative allostatic mechanism. We conclude that care has to be taken when evaluating metabolite levels in clinical samples in which medication might confound findings.

T17. GLUTAMATE IN DORSOLATERAL PREFRONTAL CORTEX IN PATIENTS WITH SCHIZOPHRENIA: A META-ANALYSIS OF 1-HMRS STUDIES

BackgroundGlutamate especially in frontal cortical areas was proposed to be altered in patients with schizophrenia. In the dorsolateral prefrontal cortex (DLPFC), glutamate levels might serve as functional markers of schizophrenia since this region is involved in working memory function which is impaired in schizophrenia patients. To date, there is no systematic overview on glutamate in dorsolateral prefrontal cortex at high-field intensities. We here meta-analyze magnetic resonance spectroscopy (1-HMRS) studies comprising measurement in dorsolateral prefrontal cortex (DLPFC).MethodsPreregistration of the study was performed on September 20th 2019 (osf.io/5uyr6). Predefined literature search on pubmed comprised articles with search terms: (Magnetic Resonance Spectroscopy OR MRS) AND (Glutamate OR Glut* OR GLX) AND (schizophrenia OR psychosis OR schizophren*). We screened for case-control studies comprising glutamate levels as measured by 1-HMRS in DLPFC. Meta-analysis with a fixed and random effects model with inverse variance method, DerSimonian-Laird estimator for tau2 and Cohen’s d were estimated.Results329 studies were initially screened. 13 Studies were included into quantitative analysis comprising n=436 patients and n=365 controls. The random effects model revealed no difference between patients and controls (d=0.033 [-0.19; 0.26], z=0.29, p=0.77). The test for heterogeneity shows a moderate amount of heterogeneity (tau2=0.096, I2=57.4%). Subsequent sensitivity analysis reveals significant between group effect for medication status (Q=7.94, p=0.0473) i.e. an increased glutamate level in antipsychotic naïve patients (d=0.46 [0.08; 0.84], z=2.37, p=0.018).DiscussionWe conclude that care has to be taken when evaluating metabolite levels in such a heterogeneous group and interpret that increase cortical glutamate in antipsychotic naïve patients with schizophrenia might be due to possible allostatic mechanisms.

Glutamate in Dorsolateral Prefrontal Cortex in Patients With Schizophrenia: A Meta-Analysis of 1-HMRS Studies

Abstract Background To date, there is no systematic overview of glutamate in dorsolateral prefrontal cortex (DLPFC) of schizophrenia patients. We here meta-analyzed case-control studies of high-field magnetic resonance spectroscopy (1H-MRS) investigating glutamate in DLPFC. Additionally, we estimated variance ratios, to investigate homo-/heterogeneity. Methods Preregistration of the study was performed on September 20th 2019 (osf.io/5uyr6). Predefined literature search on PubMed comprised articles with search terms: (Magnetic Resonance Spectroscopy OR MRS) AND (Glutamate OR Glut* OR GLX) AND (schizophrenia OR psychosis OR schizophren*). Meta-analyses with a fixed and random-effects model with inverse variance method, DerSimonian-Laird estimator for τ2, and Cohen's d were calculated. For differences in variability, we calculated a random-effects model for measures of variance ratios. The primary study outcome was the difference in glutamate in DLPFC in cases vs. controls. Secondary outcomes were differences in variability. Results The quantitative analysis comprised n=429 patients and n=365 controls. Overall, we found no group difference (d=0.03[-0.20; 0.26],z=0.28,p=0.78). Sensitivity analysis revealed an effect for medication status (Q=8.35,p=0.039) i.e. increased glutamate in antipsychotic naive patients (d=0.46[0.08; 0.84],z=2.37,p=0.018). Concerning variance ratios, we found an effect of medication status (Q=16.95, p Conclusion We carefully interpret the higher levels and lower variability in cortical glutamate in antipsychotic naive patients as a possible key factor due to a putative allostatic mechanism. We conclude that care has to be taken when evaluating metabolite levels in clinical samples where medication might confound findings.

Modulation of brain metabolites by prefrontal transcranial direct current stimulation (tDCS) in healthy subjects - the double-blinded hypothesis

Introduction The physiological effects of transcranial direct current stimulation (tDCS) in non-motor cortex areas are not well understood. The dorsolateral prefrontal cortex (DLPFC) is a key tDCS target in several psychiatric disorders, and mechanisms of tDCS action are of particular interest. We therefore investigated the effects of tDCS over the DLPFC evaluating GABA, glutamate/glutamine (Glx) and glutamate (Glu) concentrations in healthy subjects. Methods Nineteen healthy subjects (11 women, mean age 23) were randomly assigned to active (20 min, 2 mA, 5 × 7 cm electrodes) and sham tDCS using a double-blind, cross-over design. The anode was positioned over F3 (left DLPFC), the cathode over F4 (right DLPFC). A MRS MEGA-PRESS sequence (TE = 68 ms, TR = 2000 ms) was acquired before, during, and after stimulation. Gannet 3.0 and LcModel were used to quantify GABA, Glx and Glu concentrations. Repeated-measures mixed effects models were conducted comparing pre, during and post measurements of active and sham tDCS. Mistakenly, the right and not the left DLPFC was targeted using MRS, therefore evaluating changes induced by cathodal tDCS in the right DLPFC. Results We found a significant reduction of right DLPFC glutamate concentrations during active stimulation (df = 133; P = .023; effect size d = 0.398) as well as a significant reduction of Glx concentration during active stimulation (df = 133; P = .007; effect size d = 0.477). No changes of GABA concentration in cortical regions in proximity to the cathode was observed during or after anodal tDCS stimulation. Conclusions Despite the methodological mistake on prefrontal data collection, the results are biologically plausible and contribute to unveil cathodal tDCS mechanisms of action over the right DLPFC. Confirming results of other trials by Stagg et al. (2009) [1] and Kim et al. (2014) [2] , cathodal stimulation exerts inhibitory effects on the brain. However, several methodological factors (e.g electrical field strengths and distribution, tDCS parameters and individual differences) may limit conclusive interpretation.

S221. Glutamate in Dorsolateral Prefrontal Cortex is Related to Working Memory Dependent Effective Connectivity in Patients Suffering From Schizophrenia: A Combined fMRI- and MRS-Study

Cognitive deficits are a core feature of schizophrenia. However, the underlying neurobiology is not fully understood. One candidate biochemical marker for the integrity of connectivity is glutamatergic neurotransmission. Here we tested for group differences in effective connectivity and for a possible association of connectivity with glutamate in dorsolateral prefrontal cortex (DLPFC) during working memory.

P.2.049 - Fronto-parietal connectivity and its relation to frontal glutamate in patients suffering from schizophrenia

Cognitive deficits like working memory impairment in schizophrenia are of great importance for clinical outcome, but the underlying neurobiology is not fully understood. During working memory (WM) altered connectivity patterns in the fronto-parietal network are present in patients suffering from schizophrenia [1–3]. One candidate biochemical marker for the integrity of connectivity is glutamate [4]. Here we tested for group differences in fronto-parietal connectivity and it’s relation to possible glutamatergic influences. During a functional magnetic resonance imaging (fMRI) scan, a sample of 42 medicated patients (SZ) and 41 age and gender matched healthy controls (HC) were asked to perform a numeric n-back working memory task, which consisted of two conditions “2-back” and “0-back”. FMRI was conducted on a 3T Siemens Trio scanner with a 12 channel head coil using gradient-echo echo-planar imaging. Data were further preprocessed using the statistical parametric mapping (SPM 8; Welcome Department of Imaging Neuroscience, London, UK; htt://www.fil.ion.ucl.ac.uk/spm) in MATLAB 2009b. We performed dynamic causal modeling [5] (DCM) on a model space comprising regions of interest for a visual input, parietal (PC) and dorsolateral prefrontal cortex (DLPFC). We calculated Bayesian model averages to obtain weighted connectivity parameters. One-sample t-tests were calculated on parameters for PC->DLPFC and DLPFC->PC connectivity within each group in order to evaluate modulatory effects of working memory on the executive network. Glutamate levels were measured in left DLPFC using magnetic resonance spectroscopy. We used LCmodel (Linear Combination of Model spectra, a commercial spectral fitting package) to estimate local glutamate concentration. Absolute glutamate concentrations were adjusted for grey and white matter volume. We performed group comparisons (two-sample t-test) on connectivity parameters as well as on glutamate levels. Due to non-normality two-sided Spearman correlation analysis were calculated between connectivity parameters and glutamate levels. Working memory dependent connectivity effects (between PC and DLPFC) could be observed in the left hemisphere on backward connections (PC->DLPFC, HC: t=2.77, p=0.008; SZ: t=2.62, p=0.012), whereas no significant working memory effects were present on DLPFC->PC connectivity. We found no group difference in fronto-parietal connectivity parameters and no difference in glutamate levels. Nonetheless numerically controls show higher glutamate levels as compared to patients. To explore possible effects of local Glutamate levels on working memory dependent connectivity, we correlated parameters for PC->DLPFC connectivity (where we found significant working memory dependent effects) with glutamate levels. We found a significant negative association between parieto-frontal connectivity and glutamate in DLPFC in patients (rho=-0.47, p=0.0035). Controls did not show any significant association (rho=-0.12, p=0.53). Comparing correlation coefficients, we found a trend-wise significant difference between groups (z=1.55, p=0.06). Although our data neither showed a difference in connectivity nor in glutamate levels, our findings suggest that glutamate is differentially related to working memory dependent connectivity from parietal to frontal areas in patients as compared to controls.

Glutamate in dorsolateral prefrontal cortex and auditory verbal hallucinations in patients with schizophrenia: A 1H MRS study

PurposeGlutamatergic models of psychosis propose that dysfunction of N-methyl-d-aspartate (NMDA) receptors, and associated excess of glutamate, may underlie psychotic experiences in people with schizophrenia. However, little is known about the specific relation between glutamate and auditory verbal hallucinations (AVH) in patients with psychosis. In this study, levels of glutamate+glutamine (Glx) in the left lateral prefrontal lobe were determined using proton magnetic resonance spectroscopy (1H MRS) to calculate their association with AVH. MethodsSixty-seven patients with schizophrenia and thirty healthy control participants (HC) underwent magnetic resonance spectroscopy (MRS) to estimate levels of Glx in the white matter of the left prefrontal lobe. The spectrum was estimated from an 8mm3 voxel placed in the left lateral prefrontal region, belonging to both the cingulum and forceps minor. Patients with lifetime AVH (AVH group; n=45) and patients without lifetime AVH were compared (NoAVH group; n=22) to control participants. ResultsLevels of Glx were significantly different between the groups (F(2,94)=5.27, p=0.007). Planned comparisons showed that higher Glx levels were found in control participants than in the total patient group (p=0.010). However, patients with lifetime AVH had higher levels of Glx compared to patients without lifetime AVH (p=0.019). Creatin levels were similar in all three groups. We found no association between Glx and the severity of symptoms (item P3 of the PANSS or PANSS positive subscale). ConclusionThe higher Glx levels in patients with lifetime AVH as compared to patients without lifetime AVH suggest a mediating role for Glx in AVH. Our results are consistent with a previous study that found similar decreased levels of Glx in patients with schizophrenia, and increased levels in an AVH group as compared to a NoAVH group. The role of the glutamatergic system deserves further investigation, for example in different brain regions and in relation to clinical variables.

Dorsolateral Prefrontal Cortex GABA Concentration in Humans Predicts Working Memory Load Processing Capacity.

This study demonstrated for the first time that the amount of gamma-aminobutryic acid (GABA), the major inhibitory neurotransmitter of the brain, in an individual's prefrontal cortex predicts working memory (WM) task performance. Given that WM is required for many of the most characteristic cognitive and behavioral capabilities in humans, this finding could have a significant impact on our understanding of the neural basis of complex human behavior. Furthermore, this finding suggests that efforts to preserve or increase brain GABA levels could be fruitful in remediating WM-related deficits associated with neuropsychiatric conditions.

The effect of repetitive transcranial magnetic stimulation on dorsolateral prefrontal glutamate in youth with treatment-resistant depression

Background Major Depressive Disorder (MDD) is a debilitating psychiatric disorder characterized by feelings of low selfworth, loss of interest and suicidal thoughts. An estimated 350 million people are affected worldwide, 15% being adolescents. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive intervention that modulates cortical excitability by inducing electric currents in neurons by administering pulsating magnetic fields to the scalp. Studies have shown the left dorsolateral prefrontal cortex (DLPFC) to be implicated in positive effects on emotion, and glutamate/Glx levels to be decreased in MDD patients. In adults, rTMS has been shown to significantly improve mood, decrease Hamilton Depression Scores and increase glutamate, glutamine and choline levels in the DLPFC. We hypothesize an increase in DLPFC glutamate levels following treatment.

P.3.b.007 Altered dorsolateral prefrontal cortex glutamate and striatal dopamine relationship in subjects at ultra high risk of psychosis

P.3.b.007 Altered dorsolateral prefrontal cortex glutamate and striatal dopamine relationship in subjects at ultra high risk of psychosis

Glutamate alterations associated with transcranial magnetic stimulation in youth depression: a case series.

We hypothesized an increase in dorsolateral prefrontal cortex (DLPFC) glutamate levels would occur after 3 weeks of repetitive transcranial magnetic stimulation (rTMS) treatment and a decrease in major depressive disorder (MDD) symptoms. We report 6 patients (4 females) 15 to 21 years of age with treatment-resistant MDD. Participants had a mean (SD) age of 18.7 (1.95) years and a mean (SD) IQ of 102.3 (3.39). Short echo proton magnetic resonance spectroscopy (¹H-MRS) was used to quantify glutamate levels in the left DLPFC (4.5 cc) before and after rTMS treatment. Repetitive transcranial magnetic stimulation was localized to the left DLPFC and applied for 15 consecutive weekdays (120% resting motor threshold; 40 pulses over 4 seconds [10 Hz]; intertrain interval, 26 seconds; 75 trains; 3000 pulses). Treatment response was defined as a greater than 50% reduction in Hamilton Depression Rating Scale scores. Short echo proton magnetic resonance spectroscopy data were analyzed with LCModel to determine glutamate concentration. After rTMS, treatment responders (n = 4) showed an increase (relative to baseline) in left DLPFC glutamate levels (11%), which corresponded to an improvement in depressive symptom severity (68% Hamilton Depression Rating Scale score reduction). Treatment nonresponders (n = 2) had elevated baseline glutamate levels compared to responders in that same region, which decreased with rTMS (-10%). Procedures were generally well tolerated with no adverse events. Repetitive transcranial magnetic stimulation is feasible and possibly efficacious in adolescents with MDD. In responders, rTMS may act by induced elevations in elevating DFPLC glutamate levels in the left DLPFC, thereby leading to symptom improvement.

EPA-1180 – Glutamate alterations associated with transcranial magnetic stimulation in youth depression: a case series

Objective We hypothesized an increase in dorsolateral prefrontal cortex (DLPFC) glutamate levels would occur after three weeks of repetitive transcranial magnetic stimulation (rTMS) treatment and a decrease in major depressive disorder (MDD) symptoms. Method We report six cases (four females) 15–21 years of age with treatment-resistant MDD. Participants had a mean age of 18.7 years (SD ±1.95) and a mean IQ of 102.3(±3.39). Short echo proton magnetic resonance spectroscopy (1H-MRS) was used to quantify glutamate levels in the left DLPFC (4.5 cc) before and after rTMS treatment. rTMS was localized to the left DLPFC and applied for 15 consecutive weekdays (120% RMT, 40 pulses over 4 seconds (10 Hz), inter-train interval 26 seconds, 75 trains, 3000 pulses). Treatment response was defined as a greater than 50% reduction in Hamilton Depression Rating Scale scores (Ham-D). 1H-MRS data was analyzed with LCModel to determine glutamate concentration. Results Following rTMS, treatment responders (N=4) showed an increase (relative to baseline) in left DLPFC glutamate levels (11%), which corresponded to an improvement in depressive symptom severity (68% Ham-D score reduction). Treatment non-responders (N=2) had elevated baseline glutamate levels compared to responders in that same region, which decreased with rTMS (−10%). Procedures were generally well tolerated with no adverse events. Conclusions rTMS is feasible and possibly efficacious in adolescents with MDD. In responders, rTMS may act by Induced elevations in elevating DFPLC glutamate levels in the left DLPFC, thereby leading to symptom improvement. Transcranial Magnetic Stimulation for Adolescent Depression (TMSAD).

EPA-0076 – The effect of repetitive transcranial magnetic stimulation on dorsolateral prefrontal glutamate in youth with treatment-resistant depression

Major Depressive Disorder (MDD) is a debilitating psychiatric disorder characterized by feelings of low self-worth and high self-criticism. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive intervention that modulates cortical excitability by administering pulsating magnetic fields to the scalp. Studies have shown the left dorsolateral prefrontal cortex (DLPFC) glutamate to be decreased in MDD patients. In adults, rTMS has been shown to improve mood, decrease Hamilton Depression Rating Scale scores and increase glutamate in the DLPFC. The aim of this investigation is to determine whether this effect could be seen in adolescents. We hypothesize an increase in DLPFC glutamate levels following treatment. Eleven treatment-resistant MDD patients (4 females and 7 males, ages 15–21) were clinically assessed and underwent baseline and posttreatment MRI scans. Treatments were performed every weekday for three weeks. Magnetic resonance spectroscopy was used to measure glutamate levels and was analysed using the LC Model method. Seven patients were treatment responders who had a 62% decrease in Ham-D scores from 25.43 (±7.85) to 9.57 (±1.51) and a 30% decrease in Children's Depression Rating Scale scores from 74.43 (±11.04) to 52.14 (±8.99). Responders showed lower baseline glutamate levels at 8.73 (±1.21) mmol/kg-wet-weight, which increased by 12% to 9.77 (±1.18). Non-responders had higher baseline glutamate levels at 11.87 (±0.47) and levels decreased by 9% to 10.75 (±0.13). Evidence of increases in excitatory neurotransmitter levels in the DLPFC and alleviation of symptoms indicate that rTMS exerts anti-depressant effects and can be pursued as a safe and effective therapy for adolescent MDD.

EPA-0491 – Glutamate alterations associated with transcranial magnetic stimulation in youth depression: a case series ‘ptsd and the phantom of the opera’

Objective We hypothesized an increase in dorsolateral prefrontal cortex (DLPFC) glutamate levels would occur after three weeks of repetitve transcranial magnetic stimulation (rTMS) treatment and a decrease in major depressive disorder (MDD) symptoms. Method We report six cases (four females) 15–21 years of age with treatment-resistant MDD. Participants had a mean age of 18.7 years and a mean IQ of 102.3. Short echo proton magnetic resonance spectroscopy (H-MRS) was used to quantify glutamate levels in the left DLPFC (4.5cc) before and after rTMS treatment. rTMS was localized to the left DLPFC and applied for 15 consecutive weekdays. Treatment response was defined as a greater than 50% reduction in Hamilton Depression Rating Scale scores (Ham-D).1H-MRS data was analyzed with LCModel to determine glutamate concentration. Results Following rTMS, treatment responders (N=4) showed an increase (relative to baseline) in left DLPFC glutamate levels (11%), which corresponded to an improvement in depressive symptom severity (68% Ham-D score reduction). Treatment non-responders (N=2) had elevated baseline glutamate levels compared to responders in that same region, which decreased with rTMS (−10%). Procedures were generally well tolerated with no adverse events. Conclusions rTMS is feasible and possibly efficacious in adolescents with MDD. In responders, rTMS may act by Induced elevations in elevating DFPLC glutamate levels in the left DLPFC, thereby leading to symptom improvement. Transcranial Magnetic Stimulation for Adolescent Depression (TMSAD)

Region-specific glutamate changes in patients with unipolar depression

The present study aimed to investigate glutamate concentrations in patients with unipolar depression in the midcingulate cortex (MCC) as compared to the left dorsolateral prefrontal cortex (DLPFC). We hypothesized a dissociation of glutamate levels with unchanged levels in DLPFC and abnormally changed levels in MCC as well as differential effects of antidepressant pharmacotherapy. Glutamate was determined using magnetic resonance spectroscopy at 3 T in DLPFC and MCC in fourteen depressed patients and matched healthy volunteers. A follow-up measurement was performed after 4 weeks of antidepressant treatment. The main finding is a region-specific pattern of glutamate concentrations with increased MCC glutamate concentrations and no significant differences in DLPFC glutamate concentrations in unipolar depressive patients compared to healthy controls. Response and non-response to antidepressant pharmacotherapy were predicted by high glutamate at baseline in DLPFC and MCC, respectively. In addition, treatment responders showed a further increase in DLPFC glutamate levels after successful antidepressant treatment. Findings indicate altered region-specific glutamate concentrations in DLPFC and MCC that are predictive of response and non-response, respectively, to antidepressant pharmacotherapy. These findings might serve as a starting point for future studies in which the value of this metabolite pattern for treatment response prediction should be investigated.

Metabolic alterations in the dorsolateral prefrontal cortex after treatment with high-frequency repetitive transcranial magnetic stimulation in patients with unipolar major depression

Neuroimaging studies suggest a specific role of anterior cingulate cortex (ACC) and left dorsolateral prefrontal cortex (DLPFC) in major depression. Stimulation of the latter by means of repetitive transcranial magnetic stimulation (rTMS) as an antidepressant intervention has increasingly been investigated in the past. The objective of the present study was to examine in vivo neurochemical alterations in both brain regions in 17 patients with unipolar major depression before and after 10 days of high-frequency (20 Hz) rTMS of the left DLPFC using 3-tesla proton magnetic resonance spectroscopy. Six out of seventeen patients were treatment responders, defined as a 50% reduction of the Hamilton depression rating scale. No neurochemical alterations in the ACC were detected after rTMS. As compared to the non-responders, responders had lower baseline concentrations of DLPFC glutamate which increased after successful rTMS. Correspondingly, besides a correlation between clinical improvement and an increase in glutamate concentration, an interaction between glutamate concentration changes and stimulation intensity was observed. Our results indicate that metabolic, state-dependent changes within the left DLPFC in major depressive disorder involve the glutamate system and can be reversed in a dose-dependent manner by rTMS.

Implications for altered glutamate and GABA metabolism in the dorsolateral prefrontal cortex of aged schizophrenic patients.

Pharmacological, clinical, and postmortem studies suggest altered gamma-aminobutyric acid (GABA)-ergic and glutamatergic function in patients with schizophrenia. The dorsolateral prefrontal cortex is one key locus of abnormality. The precise neurochemical mechanisms underlying neurotransmitter alterations, such as hypoglutamatergia or GABA dysfunction, are not well understood. This study investigated key biochemical elements of GABA and glutamate metabolism in brain specimens from schizophrenic patients. The activities of nine principal GABA and glutamate-associated metabolic enzymes were measured concurrently in the dorsolateral prefrontal cortex of antemortem-assessed and neuropathologically characterized schizophrenic and comparison subjects. Postmortem dorsolateral prefrontal cortex specimens from schizophrenia, Alzheimer's disease, and normal nonpsychiatric comparison subjects were assayed to determine activities of the principal glutamate and GABA-metabolizing enzymes glutamine synthetase, glutamate dehydrogenase, alpha-ketoglutarate dehydrogenase, phosphate-activated glutaminase, alanine aminotransferase, aspartate aminotransferase, glutamic acid decarboxylase, GABA-transaminase, and succinic semialdehyde dehydrogenase. Glutamic acid decarboxylase activities were twofold greater and phosphate-activated glutaminase activities were fourfold greater in the schizophrenic group than in the comparison group. Differences in postmortem interval, tissue pH, inhibition of phosphate-activated glutaminase, and medication effects could not account for the differences. Differences in phosphate-activated glutaminase and glutamic acid decarboxylase activities in equivalent specimens from Alzheimer's patients were not observed. The activities of the remaining enzymes were unchanged. Greater phosphate-activated glutaminase and glutamic acid decarboxylase activities, specific to schizophrenia patients, provide additional biochemical evidence that dorsolateral prefrontal cortex glutamate and GABA metabolism is altered in schizophrenic subjects. These greater activities are consistent with models of a dysregulated glutamatergic/GABA-ergic state in schizophrenia.