Emotional scene processing in biotypes of psychosis.

Social-emotional deficits in psychosis may be indexed by deviations in emotional scene processing, but event-related potential (ERP) studies indicate such deviations may not map cleanly to diagnostic categories. Neurobiologically defined psychosis subgroups offer an alternative that may better capture neurophysiological correlates of social-emotional deficits. The current study investigates emotional scene-elicited ERPs in Biotypes of psychosis in a large (N = 622), well-characterized sample. Electroencephalography was recorded in healthy persons (N = 129), Biotype-1 (N = 195), Biotype-2 (N = 131), and Biotype-3 (N = 167) psychosis cases. ERPs were measured from posterior and centroparietal scalp locations. Neural responses to emotional scenes were compared between healthy and psychosis groups. Multivariate group discrimination analyses resulted in two composite variates that differentiated groups. The first variate displayed large differences between low-cognition (Biotype-1, Biotype-2) and intact-cognition groups (Biotype-3, healthy persons). The second indicated a small-to-moderate distinction of Biotypes-2 and -3 from Biotype-1 and healthy persons. Two multivariate correlations were identified indicating associations between 1) self-reported emotional experience and generalized cognition and 2) socio-occupational functioning and late-stage emotional processing. Psychosis Biotypes displayed emotional processing deficits not apparent in DSM psychosis subgroups. Future translational research may benefit from exploring emotional scene processing in such neurobiologically-defined psychosis groups.

Deviation from expected cognitive ability across psychotic disorders.

Patients with schizophrenia show a deficit in cognitive ability compared to estimated premorbid and familial intellectual abilities. However, the degree to which this pattern holds across psychotic disorders and is familial is unclear. The present study examined deviation from expected cognitive level in schizophrenia, schizoaffective disorder, and psychotic bipolar disorder probands and their first-degree relatives. Using a norm-based regression approach, parental education and WRAT-IV Reading scores (both significant predictors of cognitive level in the healthy control group) were used to predict global neuropsychological function as measured by the composite score from the Brief Assessment of Cognition in Schizophrenia (BACS) test in probands and relatives. When compared to healthy control group, psychotic probands showed a significant gap between observed and predicted BACS composite scores and a greater likelihood of robust cognitive decline. This effect was not seen in unaffected relatives. While BACS and WRAT-IV Reading scores were themselves highly familial, the decline in cognitive function from expectation had lower estimates of familiality. Thus, illness-related factors such as epigenetic, treatment, or pathophysiological factors may be important causes of illness related decline in cognitive abilities across psychotic disorders. This is consistent with the markedly greater level of cognitive impairment seen in affected individuals compared to their unaffected family members.

VGF function in depression and antidepressant efficacy.

Brain-derived neurotrophic factor (BDNF) is a critical effector of depression-like behaviors and antidepressant responses. Here, we show that VGF (non-acronymic), which is robustly regulated by BDNF/TrkB signaling, is downregulated in hippocampus (male/female) and upregulated in nucleus accumbens (NAc) (male) in depressed human subjects and in mice subjected to chronic social defeat stress (CSDS). Adeno-associated virus (AAV)-Cre-mediated Vgf ablation in floxed VGF mice, in dorsal hippocampus (dHc) or NAc, led to pro-depressant or antidepressant behaviors, respectively, while dHc- or NAc-AAV-VGF overexpression induced opposite outcomes. Mice with reduced VGF levels in the germ line (Vgf+/-) or in dHc (AAV-Cre-injected floxed mice) showed increased susceptibility to CSDS and impaired responses to ketamine treatment in the forced swim test. Floxed mice with conditional pan-neuronal (Synapsin-Cre) but not those with forebrain (αCaMKII-Cre) Vgf ablation displayed increased susceptibility to subthreshold social defeat stress, suggesting that neuronal VGF, expressed in part in inhibitory interneurons, regulates depression-like behavior. Acute antibody-mediated sequestration of VGF-derived C-terminal peptides AQEE-30 and TLQP-62 in dHc induced pro-depressant effects. Conversely, dHc TLQP-62 infusion had rapid antidepressant efficacy, which was reduced in BDNF floxed mice injected in dHc with AAV-Cre, and in NBQX- and rapamycin-pretreated wild-type mice, these compounds blocking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mammalian target of rapamycin (mTOR) signaling, respectively. VGF is therefore a critical modulator of depression-like behaviors in dHc and NAc. In hippocampus, the antidepressant response to ketamine is associated with rapid VGF translation, is impaired by reduced VGF expression, and as previously reported, requires coincident, rapid BDNF translation and release.

Genome-wide association studies of smooth pursuit and antisaccade eye movements in psychotic disorders: findings from the B-SNIP study.

Eye movement deviations, particularly deficits of initial sensorimotor processing and sustained pursuit maintenance, and antisaccade inhibition errors, are established intermediate phenotypes for psychotic disorders. We here studied eye movement measures of 849 participants from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study (schizophrenia N=230, schizoaffective disorder N=155, psychotic bipolar disorder N=206 and healthy controls N=258) as quantitative phenotypes in relation to genetic data, while controlling for genetically derived ancestry measures, age and sex. A mixed-modeling genome-wide association studies approach was used including ~4.4 million genotypes (PsychChip and 1000 Genomes imputation). Across participants, sensorimotor processing at pursuit initiation was significantly associated with a single nucleotide polymorphism in IPO8 (12p11.21, P=8 × 10-11), whereas suggestive associations with sustained pursuit maintenance were identified with SNPs in SH3GL2 (9p22.2, P=3 × 10-8). In participants of predominantly African ancestry, sensorimotor processing was also significantly associated with SNPs in PCDH12 (5q31.3, P=1.6 × 10-10), and suggestive associations were observed with NRSN1 (6p22.3, P=5.4 × 10-8) and LMO7 (13q22.2, P=7.3x10-8), whereas antisaccade error rate was significantly associated with a non-coding region at chromosome 7 (P=6.5 × 10-9). Exploratory pathway analyses revealed associations with nervous system development and function for 40 top genes with sensorimotor processing and pursuit maintenance (P=4.9 × 10-2-9.8 × 10-4). Our findings suggest novel patterns of genetic variation relevant for brain systems subserving eye movement control known to be impaired in psychotic disorders. They include genes involved in nuclear trafficking and gene silencing (IPO8), fast axonal guidance and synaptic specificity (PCDH12), transduction of nerve signals (NRSN1), retinal degeneration (LMO7), synaptic glutamate release (SH3GL2), and broader nervous system development and function.

Unitary construct of generalized cognitive ability underlying BACS performance across psychotic disorders and in their first-degree relatives.

Despite robust evidence of neurocognitive dysfunction in psychotic patients, the degree of similarity in cognitive architecture across psychotic disorders and among their respective first-degree relatives is not well delineated. The present study examined the latent factor structure of the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery. Analyses were conducted on 783 psychosis spectrum probands (schizophrenia, schizoaffective, psychotic bipolar), 887 of their first-degree relatives, and 396 non-psychiatric controls from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium. Exploratory factor analysis of BACS subtest scores indicated a single-factor solution that was similar across all groups and provided the best overall data fit in confirmatory analyses. Correlations between the standard BACS composite score and the sum of subscale scores weighted by their loadings on this unitary factor were very high in all groups (r≥.99). Thus, the BACS assesses a similar unitary cognitive construct in probands with different psychotic disorders, in their first-degree relatives, and in healthy controls, and this factor is well measured by the test's standard composite score.

Schizophrenia: Evidence implicating hippocampal GluN2B protein and REST epigenetics in psychosis pathophysiology.

The hippocampus is strongly implicated in the psychotic symptoms of schizophrenia. Functionally, basal hippocampal activity (perfusion) is elevated in schizophrenic psychosis, as measured with positron emission tomography (PET) and with magnetic resonance (MR) perfusion techniques, while hippocampal activation to memory tasks is reduced. Subfield-specific hippocampal molecular pathology exists in human psychosis tissue which could underlie this neuronal hyperactivity, including increased GluN2B-containing NMDA receptors in hippocampal CA3, along with increased postsynaptic density protein-95 (PSD-95) along with augmented dendritic spines on the pyramidal neuron apical dendrites. We interpret these observations to implicate a reduction in the influence of a ubiquitous gene repressor, repressor element-1 silencing transcription factor (REST) in psychosis; REST is involved in the age-related maturation of the NMDA receptor from GluN2B- to GluN2A-containing NMDA receptors through epigenetic remodeling. These CA3 changes in psychosis leave the hippocampus liable to pathological increases in neuronal activity, feedforward excitation and false memory formation, sometimes with psychotic content.

Multivariate genetic determinants of EEG oscillations in schizophrenia and psychotic bipolar disorder from the BSNIP study.

Schizophrenia (SZ) and psychotic bipolar disorder (PBP) are disabling psychiatric illnesses with complex and unclear etiologies. Electroencephalogram (EEG) oscillatory abnormalities in SZ and PBP probands are heritable and expressed in their relatives, but the neurobiology and genetic factors mediating these abnormalities in the psychosis dimension of either disorder are less explored. We examined the polygenic architecture of eyes-open resting state EEG frequency activity (intrinsic frequency) from 64 channels in 105 SZ, 145 PBP probands and 56 healthy controls (HCs) from the multisite BSNIP (Bipolar-Schizophrenia Network on Intermediate Phenotypes) study. One million single-nucleotide polymorphisms (SNPs) were derived from DNA. We assessed eight data-driven EEG frequency activity derived from group-independent component analysis (ICA) in conjunction with a reduced subset of 10,422 SNPs through novel multivariate association using parallel ICA (para-ICA). Genes contributing to the association were examined collectively using pathway analysis tools. Para-ICA extracted five frequency and nine SNP components, of which theta and delta activities were significantly correlated with two different gene components, comprising genes participating extensively in brain development, neurogenesis and synaptogenesis. Delta and theta abnormality was present in both SZ and PBP, while theta differed between the two disorders. Theta abnormalities were also mediated by gene clusters involved in glutamic acid pathways, cadherin and synaptic contact-based cell adhesion processes. Our data suggest plausible multifactorial genetic networks, including novel and several previously identified (DISC1) candidate risk genes, mediating low frequency delta and theta abnormalities in psychoses. The gene clusters were enriched for biological properties affecting neural circuitry and involved in brain function and/or development.

Effects of lithium on cortical thickness and hippocampal subfield volumes in psychotic bipolar disorder.

Relative to healthy controls, lithium free bipolar patients exhibit significant gray matter abnormalities. Lithium, the long-time reference standard medication treatment for bipolar disorder, has been proposed to be neuro-protective against these abnormalities. However, its effects on cortical thickness and hippocampal subfield (HSF) volumes remain unstudied and unclear, respectively, in bipolar disorder. This study included 342 healthy controls (HC), 51 lithium free PBD patients (NoLi), and 51 PBD patients taking lithium (Li). Regional gray matter thickness and HSF volume values were extracted from 3T MRI images. After matching NoLi and Li samples, regions where HC differed from either Li or NoLi were identified. In regions of significant or trending HC-NoLi difference, Li-NoLi comparisons were made. No significant HC-Li thickness or HSF volume differences were found. Significantly thinner occipital cortices were observed in NoLi compared to HC. In these regions, Li consistently exhibited non-significant trends for greater cortical thickness relative to NoLi. Significantly less volume was observed in NoLi compared to both HC and Li in right HSFs. Our results suggest that PBD in patients not treated with Li is associated with thinner occipital cortices and reduced HSF volumes compared with HC. Patients treated with Li exhibited significantly larger HSF volumes than NoLi, and those treated with Li were no different from HC in cortical thickness or hippocampal volumes. This evidence directly supports the hypothesis that Li may counteract the locally thinner and smaller gray matter structure found in PBD.

Resting-state brain function in schizophrenia and psychotic bipolar probands and their first-degree relatives.

BACKGROUND: Schizophrenia (SCZ) and psychotic bipolar disorder (PBD) share considerable overlap in clinical features, genetic risk factors and co-occurrence among relatives. The common and unique functional cerebral deficits in these disorders, and in unaffected relatives, remain to be identified. METHOD: A total of 59 healthy controls, 37 SCZ and 57 PBD probands and their unaffected first-degree relatives (38 and 28, respectively) were studied using resting-state functional magnetic resonance imaging (rfMRI). Regional cerebral function was evaluated by measuring the amplitude of low-frequency fluctuations (ALFF). Areas with ALFF alterations were used as seeds in whole-brain functional connectivity analysis. We then tested whether abnormalities identified in probands were present in unaffected relatives. RESULTS: SCZ and PBD probands both demonstrated regional hypoactivity in the orbital frontal cortex and cingulate gyrus, as well as abnormal connectivity within striatal-thalamo-cortical networks. SCZ probands showed greater and more widely distributed ALFF alterations including the thalamus and bilateral parahippocampal gyri. Increased parahippocampal ALFF was related to positive symptoms and cognitive deficit. PBD patients showed uniquely increased functional connectivity between the thalamus and bilateral insula. Only PBD relatives showed abnormal connectivity within striatal-thalamo-cortical networks seen in both proband groups. CONCLUSIONS: The present findings reveal a common pattern of deficits in frontostriatal circuitry across SCZ and PBD, and unique regional and functional connectivity abnormalities that distinguish them. The abnormal network connectivity in PBD relatives that was present in both proband groups may reflect genetic susceptibility associated with risk for psychosis, but within-family associations of this measure were not high.

Magnetic resonance spectroscopy and tissue protein concentrations together suggest lower glutamate signaling in dentate gyrus in schizophrenia.

Hippocampal dysfunction in schizophrenia is widely acknowledged, yet the mechanism of such dysfunction remains debated. In this study we investigate the excitatory and inhibitory hippocampal neurotransmission using two complementary methodologies, proton magnetic resonance spectroscopy (MRS) and tissue biochemistry, sampling individuals with schizophrenia in vivo and postmortem hippocampal tissue in vitro. The results show significantly lower glutamate concentrations in hippocampus in schizophrenia, an in vivo finding mirrored by lower GluN1 protein levels selectively in the dentate gyrus (DG) in vitro. In a mouse model with a DG knockout of the GRIN1 gene, we further confirmed that a selective decrease in DG GluN1 is sufficient to decrease the glutamate concentrations in the whole hippocampus. Gamma-aminobutyric acid (GABA) concentrations and GAD67 protein were not significantly different in hippocampus in schizophrenia. Similarly, GABA concentrations in the hippocampi of mice with a DG knockout of the GRIN1 gene were not significantly different from wild type. These findings provide strong evidence implicating the excitatory system within hippocampus in the pathophysiology of schizophrenia, particularly indicating the DG as a site of pathology.

Kv3.1-containing K(+) channels are reduced in untreated schizophrenia and normalized with antipsychotic drugs.

Neuronal firing is a fundamental element of cerebral function; and, voltage-gated potassium (K(+)) channels regulate that firing through the repolarization of action potentials. Kv3-type channels (Kv3.1-Kv3.4) represent a family of voltage-gated K(+) channels that have fast-spiking properties. Kv3.1 channel subunits are predominantly localized to cortical parvalbumin (PV)-positive, inhibitory interneurons. The firing properties of these interneurons participate in establishing the normal gamma oscillations and synchrony of cortical neuronal populations, thought to be the signature of higher information processing in human brain. Schizophrenia (SZ) is associated with abnormalities in cortical gamma synchrony and in information processing, particularly with dysfunction in working memory and executive function. Here, we report the distribution of Kv3.1b and Kv3.2 protein in normal human brain, showing that Kv3.1b is limited to neocortical areas, whereas Kv3.2 is abundantly represented in neo- and subcortical regions. In SZ cases, levels of Kv3.1b protein are decreased in the neocortex, but only in cases without antipsychotic drug (APD) treatment; Kv3.1 levels are normal in antipsychotic-treated cases. Kv3.2 is not different in distribution or in level between normal and SZ cases, nor influenced by APD, in any region tested. The apparent increase in Kv3.1b protein levels by APDs in SZ neocortex was confirmed in laboratory rodents treated with chronic APDs. These findings show a decrease in Kv3.1b channel protein in SZ neocortex, a deficit that is restored by APDs. This alteration could be fundamentally involved in the cortical manifestations of SZ and in the therapeutic response to APDs.

Treating impaired cognition in schizophrenia.

Cognitive impairment is a core feature of schizophrenia that substantially accounts for poor functional outcomes associated with this disease in areas such as work, independent living and social relationships. Until recently, drug development in schizophrenia has focused on developing compounds that mainly target the positive psychotic symptoms of the illness. Although current antipsychotic drugs treat psychosis in schizophrenia rather well, their impact on cognitive dysfunction is minimal. In recent years there has been growing interest in developing novel treatments for cognitive deficits in schizophrenia. In this review we discuss pharmacologic strategies considered most likely to improve cognition. These putative molecular targets include receptors for acetylcholine, dopamine, glutamate, g-aminobutyric acid (GABA), serotonin and histamine. In addition, we propose that not only pharmacological, but also psychological treatments should be considered to enhance cognition in schizophrenia.

Stimulating and inhibitory effects of the dopamine "stabilizer" (-)-OSU6162 on dopamine D2 receptor function in vitro.

The effect of (-)-OSU6162 on the incorporation of GTPgammaS(35) in the membranes of hD(2l)-transfected CHO cells was investigated. In the absence of dopamine the compound exerted a slight but significant stimulating action, suggesting a weak partial agonism. In the presence of dopamine, low concentrations (10 to 100 nM) enhanced the stimulating action of dopamine. This enhancing effect was reversed by higher concentrations of (-)-OSU6162 in a complex biphasic manner. The dopamine-enhancing action is proposed to be mediated by binding to an allosteric site with high affinity and the inhibitory component by a low-affinity binding to the orthosteric site of the dopamine receptor.

Phenotype of schizophrenia: a review and formulation.

The discovery of the pathophysiology(ies) for schizophrenia is necessary to direct rational treatment directions for this brain disorder. Firm knowledge about this illness is limited to areas of phenomenology, clinical electrophysiology, and genetic risk; some aspects of dopamine pharmacology, cognitive symptoms, and risk genes are known. Basic questions remain about diagnostic heterogeneity, tissue neurochemistry, and in vivo brain function. It is an illness ripe for molecular characterization using a rational approach with a confirmatory strategy; drug discovery based on knowledge is the only way to advance fully effective treatments. This paper reviews the status of general knowledge in this area and proposes an approach to discovery, including identifying brain regions of dysfunction and subsequent localized, hypothesis-driven molecular screening.

Partial dopamine agonists in the treatment of psychosis.

The discovery and characterization of dopamine in the mammalian brain earned Dr. Arvid Carlsson the Nobel Prize in 2000. Along with his many insights about dopamine pharmacology, came his proposal of the existence and critical role of dopamine autoreceptors in the overall regulation of dopamine-mediated neurotransmission. In this paper, the rationale, the putative mechanisms, and pertinent clinical data are reviewed to support the idea of the clinical relevance of dopamine agonists, especially partial agonists, in the treatment of psychosis. Evidence was gathered for the usefulness of this strategy in schizophrenia in early trials with apomorphine and N-propylnoraporphine (NPA). But clinical relevance was not a reality before the application of (-)-3PPP. These clinical results are presented. Moreover, now a partial dopamine agonist, aripiprazole, has been developed and will likely be marketed by BMS and Otsuka for the treatment of psychosis and will be the first drug in this class to be commercially available. Partial dopamine agonists represent the next new class of antipsychotic drugs, effective in treating schizophrenia.

Partial dopamine agonists and dopaminergic stabilizers, in the treatment of psychosis.

The early demonstration of chlorpromazine efficacy in schizophrenia and its subsequent identification as a dopamine receptor antagonist, established the only known mechanism for antipsychotic development to date. By extension, it is easy to hypothesize that any mechanism shown to reduce dopamine-mediated transmission in brain will have antipsychotic properties. The evaluation of partial dopamine agonists for antipsychotic efficacy and their application in the treatment of psychosis has derived from this background. Partial dopamine agonists at the D2 dopamine receptor, have high affinity for that receptor, but reduced intrinsic activity. These agonists have higher affinity for the presynaptic autoreceptor than for the postsynaptic receptor. Hence, these compounds reduce dopamine synthesis and release through an agonist action at the dopamine autoreceptor. Moreover, the agonists have lower intrinsic activity at the postsynaptic receptor than its natural ligand dopamine. Therefore, they diminish the dopaminergic signal at postsynaptic sites as well through delivering a reduced message; this component of drug action becomes more prominent the lower the intrinsic activity of the drug. Several partial dopamine agonists have been evaluated in schizophrenia. One of them, aripiprazole, is nearing approval for marketing. With partial dopamine agonist treatment, advantages should accrue to schizophrenia treatment in the areas of affect control and cognitive performance.

Probing the human hippocampus using rCBF: contrasts in schizophrenia.

Regional cerebral blood flow (rCBF) data from two PET-15O water schizophrenia studies were analyzed using individually placed, magnetic resonance (MR)-guided hippocampal volumes of interest (VOI). In one study, normal (N = 10) and schizophrenic (N = 18) volunteers performed an overlearned auditory discrimination task in rest, control, and decision conditions. In the other study, schizophrenic and normal volunteers received the noncompetitive NMDA receptor antagonist ketamine and placebo and had sequential rCBF evaluations. Moreover, the schizophrenic volunteers were off drug in one study and on antipsychotic drug in the second study, allowing an additional comparison of medication status. VOIs were placed on anterior, middle, and posterior hippocampal areas in each PET image from both studies, redirected from an MR scan, and individually adjusted. While no hippocampal activation was apparent in either the normal or schizophrenic group in the task vs. condition comparison, rCBF was higher in the schizophrenic than in the normal hippocampus in both task and control conditions, independently. In addition, at rest rCBF was significantly higher in the unmedicated group of schizophrenics than in the group of medicated patient volunteers and higher than in the normal comparison group. This suggests that schizophrenia is associated with elevated rCBF in the hippocampus, which "normalizes" with antipsychotic drug treatment. Ketamine, the noncompetitive NMDA receptor antagonist, was more potent in reducing rCBF in the schizophrenic group compared to the normal volunteer group. These data are consistent with a previous report from our laboratory of reduced NMDA receptor NR1 subunit expression and possible abnormal NMDA receptor composition in schizophrenia. These data show an abnormality of hippocampal function in schizophrenia and suggest that this abnormality may be associated with the pathophysiology of the illness.

Abnormal patterns of regional cerebral blood flow in schizophrenia with primary negative symptoms during an effortful auditory recognition task.

OBJECTIVE: Using functional brain imaging, the authors sought to replicate their earlier finding of low metabolism in the middle frontal and inferior parietal cortices of schizophrenic patients with primary negative symptoms. METHOD: According to the presence or absence of enduring negative symptoms, patients with schizophrenia were classified as having deficit or nondeficit schizophrenia, respectively. Twelve normal volunteers and 18 drug-free schizophrenic volunteers (deficit, N=8; nondeficit, N=10) were trained in a tone discrimination task. They were trained to perform with 70%-80% accuracy and were then scanned with positron emission tomography with [(15)O]H(2)O during three conditions: rest, sensory-motor control task, and decision task. RESULTS: Levels of performance of the auditory recognition task were similar in the three groups. An initial hypothesis-driven analysis revealed that across tasks the deficit group failed to show significant activation in the middle frontal cortex. This was in contrast to both the normal volunteers and nondeficit patients. When the patient groups were contrasted, the deficit patients showed significantly less activation in the middle frontal cortex bilaterally during the control task and in the right middle frontal cortex and inferior parietal cortex during the decision task. An exploratory analysis contrasting deficit and nondeficit patients across conditions did not reveal further differences between groups. CONCLUSIONS: This study replicated the finding of low activation in the middle frontal cortex and inferior parietal cortex in deficit schizophrenia. This deficit was observed without performance confound and may provide a marker of primary negative symptoms and a target for new therapies.

Increased cortical kynurenate content in schizophrenia.

BACKGROUND: Metabolites of the kynurenine pathway of tryptophan degradation may play a role in the pathogenesis of several human brain diseases. One of the key metabolites in this pathway, kynurenine, is either transaminated to form the glutamate receptor antagonist, kynurenate, or hydroxylated to 3-hydroxykynurenine, which in turn is further degraded to the excitotoxic N-methyl-D-aspartate receptor agonist quinolinate. Because a hypoglutamatergic tone may be involved in the pathophysiology of schizophrenia, it is conceivable that alterations in kynurenine pathway metabolism may play a role in the disease. METHODS: The tissue levels of kynurenine, kynurenate, and 3-hydroxykynurenine were measured in brain tissue specimens obtained from the Maryland Brain Collection. All three metabolites were determined in the same samples from three cortical brain regions (Brodmann areas 9, 10, and 19), obtained from 30 schizophrenic and 31 matched control subjects. RESULTS: Kynurenate levels were significantly increased in schizophrenic cases in Brodmann area 9 (2.9 +/- 2.2 vs. 1.9 +/- 1.3 pmol/mg protein, p <.05), but not in Brodmann areas 10 and 19. Kynurenine levels were elevated in schizophrenic cases in Brodmann areas 9 (35.2 +/- 28.0 vs. 22.4 +/- 14.3 pmol/mg protein; p <.05) and 19 (40.3 +/- 23.4 vs. 30.9 +/- 10.8; p <.05). No significant differences in 3-hydroxykynurenine content were observed between the two groups. In both groups, significant (p <.05) correlations were found in all three brain areas between kynurenine and kynurenate, but not between kynurenine and 3-hydroxykynurenine (p >.05). In rats, chronic (6-months) treatment with haloperidol did not cause an increase in kynurenate levels in the frontal cortex, indicating that the elevation observed in schizophrenia is not due to antipsychotic medication. CONCLUSIONS: The data demonstrate an impairment of brain kynurenine pathway metabolism in schizophrenia, resulting in elevated kynurenate levels and suggesting a possible concomitant reduction in glutamate receptor function.