Search

This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan's unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = -0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = -0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = -0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = -0.02, p < 0.001) and frontal white matter Glx (z = -0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies., (© 2023. The Author(s).)

Decreased levels of Brain-Derived Neurotrophic Factor (BDNF) are a common finding in schizophrenia. Another well-documented protein linked to schizophrenia is intracellular Ca 2+ -independent Phospholipase (PLA2). However, the potential association between PLA2 and BDNF with regard to schizophrenia has yet to be examined. In the present study, male and female BDNF knockout mice, a possible genetic model of schizophrenia, were exposed to prenatal stress and tested in the nest test, open field test and T-maze. Following behavioral tests, whole brain and plasma samples were harvested to measure the activity of PLA2. BDNF knockout mice showed cognitive deficits in the T-maze. Furthermore, there was a quadratic association of PLA2 with performance in the open field test. Moreover, BDNF deficiency and female sex were associated with elevated plasma PLA2 levels. The cognitive impairment of BDNF heterozygous mice as well as their increased PLA2 activity in plasma is consistent with findings in schizophrenia patients. The particular elevation of PLA2 activity in females may partly explain sex differences of clinical symptoms in schizophrenia (e.g. age of onset, severity of symptoms). Additionally, PLA2 was significantly correlated with body and adrenal weight after weaning, whereby the latter emphasizes the possible connection of PLA2 with steroidogenesis., (Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Neurocognitive impairments are core early features of psychosis and are observed in those at ultra-high risk (UHR) for psychosis. The aim of the present study was to explore whether neurocognition is associated with polyunsaturated fatty acids (PUFAs), as has been observed in other clinical populations., Method: Erythrocyte levels of total omega-3-and omega-6 PUFAs the omega-3/omega-6 ratio, were measured in 265 UHR individuals. Six domains of neurocognition as well a Composite Score, were assessed using the Brief Assessment of Cognition in Schizophrenia. Pearson's correlations were used to assess the relationship between PUFAs and neurocognition. All analyses were controlled for tobacco smoking., Results: Verbal Fluency correlated positively with eicosapentaenoic acid (P = .024) and alpha-linolenic acid (P = .01), and negatively with docosahexanoic acid (P = .007) and Working Memory positively correlated with omega-3/omega-6 ratio (P = .007)., Conclusions: The current results provide support for a relationship between Verbal Fluency and omega-3 PUFAs in UHR. Further investigation is required to elucidate whether these biomarkers are useful as risk markers or in understanding the biological underpinning of neurocognitive impairment in this population., (© 2020 John Wiley & Sons Australia, Ltd.)

Importance: Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear., Objective: To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites., Data Sources: The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data., Study Selection: In total, 45 1H-MRS studies contributed data., Data Extraction and Synthesis: Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor., Main Outcomes and Measures: Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL)., Results: In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P < .001; cerebrospinal fluid-corrected Glu, F1,1216.7 = 5.610, P = .02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose., Conclusions and Relevance: Findings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia.

Aim: Recent research has indicated that preventative intervention is likely to benefit patients 'at-risk' for psychosis, both in terms of symptom reduction and delay or prevention of onset of threshold psychotic disorder. The strong preliminary results for the effectiveness of omega-3 polyunsaturated fatty acids (PUFAs), coupled with the falling transition rate in ultra high-risk (UHR) samples, mean that further study of such benign, potentially neuroprotective interventions is clinically and ethically required. Employing a multicentre approach, enabling a large sample size, this study will provide important information with regard to the use of omega-3 PUFAs in the UHR group., Methods: This trial is a 6-month, double-blind, randomized placebo-controlled trial of 1.4 g day -1 omega-3 PUFAs in UHR patients aged between 13 and 40 years. The primary hypothesis is that UHR patients receiving omega-3 PUFAs plus cognitive-behavioural case management (CBCM) will be less likely to transition to psychosis over a 6-month period compared to treatment with placebo plus CBCM. Secondary outcomes will examine symptomatic and functional changes, as well as examine if candidate risk factors predict response to omega-3 PUFA treatment in the UHR group., Conclusion: This is the protocol of the NeuraproE study. Utilizing a large sample, results from this study will be important in informing indicated prevention strategies for schizophrenia and other psychotic disorders, which may be the strongest avenue for reducing the burden, stigmatization, disability and economic consequences of these disorders., (© 2015 Wiley Publishing Asia Pty Ltd.)

A high proportion of individuals deemed at elevated risk for psychosis will actually never progress to develop the illness. Pharmaceutical intervention may not be necessary in these cases, and may in fact be damaging depending on the invasiveness of the treatment strategy. This highlights the need for biomarkers that are better able to reliably differentiate between at-risk individuals who will subsequently transition to psychosis and those who will not. Low glutathione (GSH) levels have been observed in schizophrenia and in patients with first-episode psychosis. The aim of this study was to determine the predictive value of erythrocyte GSH levels on the transition to psychosis in individuals at risk of developing the illness. Erythrocyte GSH levels were measured in 36 at-risk individuals, 15 of whom had transitioned to psychosis at the 7-year follow-up. Univariate Cox regression analysis showed that transition to psychosis at the 7-year time point was significantly associated with low GSH levels at baseline. The area under the receiving operating characteristic curve was 0.819, indicating that GSH can be considered a good predictor of outcome. Although these results need to be replicated, adding the criterion 'low erythrocyte GSH' to the set of criteria used to identify individuals at risk of psychosis may be indicated.

Patients with bipolar disorder show cognitive deficits including executive function, which appear to be related to social functioning and outcome. However, subgroups within the spectrum as well as psychopathological features, current mood state/euthymia and disease stage might be confounding factors. We analysed data tests from the Wechsler Intelligence Scale (WIE), verbal fluency (COWA) and trail making tests (TMT-A and TMT-B) obtained in a selected subgroup of currently bipolar I disorder patients, who were currently euthymic and had a history of psychotic symptoms, and compared them to patients with schizophrenia (in remission) and healthy controls, all matched for age, gender, and handedness. Schizophrenia patients showed more severe cognitive impairment, including digit symbol and arithmetic tests, as well as TMT-B (compared to healthy controls), but bipolar patients had stronger impairment on the letter number sequencing test, an indicator of working memory and processing speed. There were no group effects on most verbal fluency tasks (except impairment of schizophrenia patients on one subscale of category fluency). Within the limitations of the study design, our results suggest that even in subgroups of presumably more severely impaired bipolar patients, some cognitive dimensions might achieve remission, possibly related to considerable state effects at testing., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Bipolar disorder and schizophrenia share phenotypic and genotypic features, but might differ in aspects of abnormal neurodevelopmental trajectories. We studied gyrification, a marker of early developmental pathology, in high-resolution MRI scans of 34 patients with schizophrenia, 17 euthymic bipolar I disorder patients with previous psychotic symptoms, and 34 matched healthy controls in order to test the hypothesis of overlapping and diverging prefrontal gyrification abnormalities. We applied a novel, validated method for measuring local gyrification in each vertex point of the reconstructed cortical surface. Psychotic bipolar I patients had higher gyrification in dorsal anterior and infragenual cingulate cortex compared to either schizophrenia or healthy controls, while schizophrenia patients had higher gyrification than controls in anterior medial (BA 10) and orbitofrontal areas, altogether indicating disease-specific alterations in the prefrontal cortex. Our findings indicate gyrification changes in a specific subgroup of bipolar I disorder to affect an area relevant to emotion regulation, and distinct from changes seen in schizophrenia., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Glutamatergic dysfunction and altered membrane lipid and energy metabolism have been repeatedly demonstrated in the frontal/prefrontal and anterior cingulate cortex (ACC) in schizophrenia. Though having been already studied in animals, the presumed link between glutamatergic function and structural plasticity has not been investigated directly in the human brain yet. We measured glutamate (Glu), focal energy metabolism, and membrane phospholipid turnover to investigate main pathologies in those key brain regions of schizophrenia., Methods: (1)H- and (31)P-Chemical Shift Imaging (CSI) was combined in a single session to assess Glu and markers of energy (PCr, ATP) and membrane lipid (PME, PDE) metabolism in 31 neuroleptic-naïve first acute onset psychosis patients and 31 matched healthy controls. Multivariate analyses of covariance were used to assess disease effects on Glu and to investigate the impact of Glu alterations on phospholipid and energy metabolites., Results: Glu levels of patients were increased in the frontal and prefrontal cortex bilaterally and in the ACC. Higher Glu was associated with increased left frontal/prefrontal PME and right frontal/prefrontal PDE in patients, which was not observed in healthy controls. In contrast, higher Glu levels were associated with lower PCr or ATP values in the frontal/prefrontal cortex bilaterally and in the right ACC of controls. This was not observed in the right ACC and left frontal/prefrontal cortex of patients., Conclusion: Frontal glutamatergic hyperactivity is disconnected from physiologically regulated energy metabolism and is associated with increased membrane breakdown in right and increased membrane restoration in left frontal and prefrontal cortical regions. As indicated by previous findings, this pathology is likely dynamic during the course of first acute illness and possibly associated with negative symptoms and cognitive impairment. Our findings underline the importance of further research on neuroprotective treatment options during the early acute or even better for the ultra-high risk state of psychotic illness., (Copyright © 2015. Published by Elsevier B.V.)

Hippocampal pathology has been shown to be central to the pathophysiology of schizophrenia and a putative risk marker for developing psychosis. We applied both (1)H MRS (proton magnetic resonance spectroscopy) at 3Tesla and voxel-based morphometry (VBM) of high-resolution brain structural images in order to study the association of the metabolites glutamate (Glu) and N-acetyl-aspartate (NAA) in the hippocampus with whole-brain morphometry in 31 persons at ultra-high-risk for psychosis (UHR), 18 first-episode schizophrenia patients (Sz), and 42 healthy controls (all subjects being neuroleptic-naïve). Significantly diverging associations emerged for UHR subjects hippocampal glutamate showed positive correlation with the left superior frontal cortex, not seen in Sz or controls, while in first-episode schizophrenia patients a negative correlation was significant between glutamate and a left prefrontal area. For NAA, we observed different associations for left prefrontal and caudate clusters bilaterally for both high-risk and first-episode schizophrenia subjects, diverging from the pattern seen in healthy subjects. Our results suggest that associations of hippocampal metabolites in key areas of schizophrenia might vary due to liability to or onset of the disorder., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

Schizotypal traits are phenotypic risk factors for schizophrenia, associated with biological changes across a putative schizophrenia spectrum. In this study, we tested the hypothesis that brain structural changes in key brain areas relevant to this spectrum (esp. medial and lateral prefrontal cortex) would vary across different degrees of schizotypal trait expression and/or phenotypic markers of psychosis proneness in healthy non-clinical volunteers. We analysed high-resolution 3Tesla magnetic resonance images (MRI) of 59 healthy volunteers using voxel-based morphometry (VBM), correlating grey matter values to the positive and negative symptom factors of the schizotypal personality questionnaire (SPQ, German version) and a measure of psychosis proneness (community assessment of psychic experiences, CAPE). We found positive correlations between positive SPQ dimension and bilateral inferior and right superior frontal cortices, and positive CAPE dimension and left inferior frontal cortex, as well as CAPE negative dimension and right supplementary motor area (SMA) and left inferior parietal cortex. However, only the positive correlation of the right precuneus with negative schizotypy scores was significant after FWE correction for multiple comparisons. Our findings confirm an effect of schizotypal traits and psychosis proneness on brain structure in healthy subjects, providing further support to a biological continuum model., (Copyright © 2015 Elsevier B.V. All rights reserved.)

While schizophrenia and bipolar disorder have been assumed to share phenotypic and genotypic features, there is also evidence for overlapping brain structural correlates, although it is unclear whether these relate to shared psychotic features. In this study, we used voxel-based morphometry (VBM8) in 34 schizophrenia patients, 17 euthymic bipolar I disorder patients (with a history of psychotic symptoms), and 34 healthy controls. Our results indicate that compared to healthy controls schizophrenia patients show grey matter deficits (p<0.05, FDR corrected) in medial and right dorsolateral prefrontal, as well as bilaterally in ventrolateral prefrontal and insular cortical areas, thalamus (bilaterally), left superior temporal cortex, and minor medial parietal and parietooccipital areas. Comparing schizophrenia vs. bipolar I patients (p<0.05, FDR corrected) yielded a similar pattern, however, there was an additional significant reduction in schizophrenia patients in the (posterior) hippocampus bilaterally, left dorsolateral prefrontal cortex, and left cerebellum. Compared to healthy controls, the deficits in bipolar I patients only reached significance at p<0.001 (uncorr.) for a minor parietal cluster, but not for prefrontal areas. Our results suggest that the more extensive prefrontal, thalamic, and hippocampal deficits that might set apart schizophrenia and bipolar disorder might not be related to mere appearance of psychotic symptoms at some stage of the disorders., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Early intervention research in schizophrenia has suggested that brain structural alterations might be present in subjects at high risk of developing psychosis. The heterogeneity of regional effects of these changes, which is established in schizophrenia, however, has not been explored in prodromal or high-risk populations. We used high-resolution MRI and voxel-based morphometry (VBM8) to analyze grey matter differences in 43 ultra high-risk subjects for psychosis (meeting ARMS criteria, identified through CAARMS interviews), 24 antipsychotic-naïve first-episode schizophrenia patients and 49 healthy controls (groups matched for age and gender). Compared to healthy controls, resp., first-episode schizophrenia patients had reduced regional grey matter in left prefrontal, insula, right parietal and left temporal cortices, while the high-risk group showed reductions in right middle temporal and left anterior frontal cortices. When dividing the ultra-high-risk group in those with a genetic risk vs. those with attenuated psychotic symptoms, the former showed left anterior frontal, right caudate, as well as a smaller right hippocampus, and amygdala reduction, while the latter subgroup showed right middle temporal cortical reductions (each compared to healthy controls). Our findings in a clinical psychosis high-risk cohort demonstrate variability of brain structural changes according to subgroup and background of elevated risk, suggesting frontal and possibly also hippocampal/amygdala changes in individuals with genetic susceptibility. Heterogeneity of structural brain changes (as seen in schizophrenia) appears evident even at high-risk stage, prior to potential onset of psychosis., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Genetic variation in the gene encoding ZNF804A, a risk gene for schizophrenia, has been shown to affect brain functional endophenotypes of the disorder, while studies of white matter structure have been inconclusive., Method: We analysed effects of ZNF804A single nucleotide polymorphism rs1344706 on grey and white matter using voxel-based morphometry (VBM) in high-resolution T1-weighted magnetic resonance imaging scans of 62 schizophrenia patients and 54 matched healthy controls., Results: We found a significant (p < 0.05, family-wise error corrected for multiple comparisons) interaction effect of diagnostic group x genotype for local grey matter in the left orbitofrontal and right and left lateral temporal cortices, where patients and controls showed diverging effects of genotype. Analysing the groups separately (at p < 0.001, uncorrected), variation in rs1344706 showed effects on brain structure within the schizophrenia patients in several areas including the left and right inferior temporal, right supramarginal/superior temporal, right and left inferior frontal, left frontopolar, right and left dorsolateral/ventrolateral prefrontal cortices, and the right thalamus, as well as effects within the healthy controls in left lateral temporal, right anterior insula and left orbitofrontal cortical areas. We did not find effects of genotype of regional white matter in either of the two cohorts., Conclusions: Our findings demonstrate effects of ZNF804A genetic variation on brain structure, with diverging regional effects in schizophrenia patients and healthy controls in frontal and temporal brain areas. These effects, however, might be dependent on the impact of other (genetic or non-genetic) disease factors.

Structural deficits in the superior temporal cortex and transverse temporal gyri appear to be related to auditory hallucinations in schizophrenia, which are a key symptom of this disorder. However, the cellular and neurochemical underpinnings are poorly understood and hardly studied in vivo. We used (31)P-MRS (magnetic resonance spectroscopy) with chemical shift imaging to assess the association between left superior temporal cortex metabolism and severity of auditory hallucinations in 29 schizophrenia patients off antipsychotics. Hallucinations scores derived from the Scale for the Assessment of Positive Symptoms showed significant positive correlations with both measures of phospholipids (phosphomonoesters and phosphodiesters), and energy (inorganic phosphate and phosphocreatine, but not adenosine tri-phosphate) metabolism in left superior temporal gyrus/Heschl gyrus voxels. There was no correlation of metabolites in these regions with formal thought disorder, a symptom also linked to superior temporal pathology, thus suggesting symptom specificity. Our findings provide a link between established structural deficits and neurochemical pathology related to membrane pathology and markers of general metabolic turnover.

Schizophrenia has been linked to disturbed connectivity between large-scale brain networks. Altered thalamocortical connectivity might be a major mechanism mediating regionally distributed dysfunction, yet it is only incompletely understood. We analysed functional magnetic resonance imaging data obtained during resting state from 22 DSM-IV schizophrenia patients and 22 matched healthy controls to directly assess the differences in thalamocortical functional connectivity. We identified significantly higher overall thalamocortical functional connectivity in patients, which was mostly accounted for by difference in thalamic connections to right ventrolateral prefrontal and bilateral secondary motor and sensory (superior temporal and lateral occipital) cortical areas. Voxelwise analysis showed group differences at the thalamic level to be mostly in medial and anterior thalamic nuclei and arising thalamocortical changes to be mostly due to higher positive correlations in prefrontal and superior temporal correlations, as well as absent negative correlations to sensory areas in patients. Our findings demonstrate that different types of thalamocortical dysfunction contribute to network alterations, including lack of inhibitory interaction attributed to the lack of significant negative thalamic/sensory cortical connections. These results emphasize the functional importance of the thalamus in the pathophysiology of schizophrenia.

Probabilistic independent component analysis was applied to identify the default mode network (DMN) in resting state data obtained with functional magnetic resonance imaging from 25 DSM-IV schizophrenia and 25 matched healthy subjects. Power spectrum analysis showed a significant diagnosis × frequency interaction and higher power in one frequency band, indicating an alteration of DMN frequency spectrum in schizophrenia., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

There is considerable evidence for specific pathology of lipid metabolism in schizophrenia, affecting polyunsaturated fatty acids and in particular sphingolipids. These deficits are assumed to interfere with neuronal membrane functioning and the development and maintenance of myelin sheaths. Recent studies suggest that some of these lipid pathologies might also be detected in peripheral skin tests. In this study, we examined different skin lipids and their relation to schizophrenia. We assessed epidermal lipid profiles in 22 first-episode antipsychotic-naïve schizophrenia patients and 22 healthy controls matched for age and gender using a hexan/ethanol extraction technique and combined high-performance thin-layer chromatography/gas-chromatography. We found highly significant increase of ceramide AH and NH/AS classes in patients and decrease of EOS and NP ceramide classes. This is the first demonstration of specific peripheral sphingolipid alterations in schizophrenia. The results support recent models of systemic lipid pathology and in particular of specific sphingolipids, which are crucial in neuronal membrane integrity. Given recent findings showing amelioration of psychopathology using fatty acid supplementation, our findings also bear relevance for sphingolipids as potential biomarkers of the disease.

Antipsychotic drug action might include mechanisms related to normalising phospholipid and high-energy metabolism. We applied brain metabolic imaging with (31)P magnetic resonance spectroscopy ((31)P MRS) and two-dimensional chemical shift imaging to assess changes of metabolism of phospholipids and high-energy phosphates in schizophrenia patients at baseline (four antipsychotic-naïve and three off antipsychotics) and at follow-up, after 6 weeks of treatment with olanzapine. Results indicate a significant increase of adenosine-triphosphate (ATP) in the right inferior temporal cortex and a trend towards ATP decrease in the left cerebellum. This suggests a shift in high-energy phosphates (rather than phospholipids), possibly related to normalisation of functioning in these areas., (Copyright © 2012 John Wiley & Sons, Ltd.)

Common genetic variation in the promoter region of the glutamate receptor delta 1 (GRID1) gene has recently been shown to confer increased risk for schizophrenia in several independent large samples. We analysed high-resolution magnetic resonance imaging (MRI) data from 62 patients with schizophrenia and 54 healthy controls using voxel-based morphometry (VBM) to assess the effect of single nucleotide polymorphism rs3814614 (located in the GRID1 promoter region), of which the T allele was identified as a risk factor in a previous association study. There were no effects of genotype or group × genotype interactions on total brain grey matter or white matter, but on regional grey matter. In healthy subjects, we identified a significant effect of rs3814614 genotype in the anterior thalamus (bilaterally), superior prefrontal cortex, and orbitofrontal cortex - in all cases with the homozygous risk genotype TT resulting in higher grey matter density. We did not find this association within the schizophrenia sample, where rs3814614 variation was only associated with grey matter reduction in TT homozygous subjects in medial parietal cortex and increased grey matter in right medial cerebellum. For white matter, we did not find significant genotype effects in healthy controls, and only minor effects within schizophrenia patients in the posterior temporal lobe white matter. Our data indicate that GRID1 rs3814614 genotype is related to grey matter variation in prefrontal and anterior thalamic brain areas in healthy subjects, but not in patients indicating a potential role of this schizophrenia candidate gene in thalamo-cortical functioning., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Alterations in brain function in schizophrenia and other neuropsychiatric disorders are evident not only during specific cognitive challenges, but also from functional MRI data obtained during a resting state. Here we apply probabilistic independent component analysis (pICA) to resting state fMRI series in 25 schizophrenia patients and 25 matched healthy controls. We use an automated algorithm to extract the ICA component representing the default mode network (DMN) as defined by a DMN-specific set of 14 brain regions, resulting in z-scores for each voxel of the (whole-brain) statistical map. While goodness of fit was found to be similar between the groups, the region of interest (ROI) as well as voxel-wise analysis of the DMN showed significant differences between groups. Healthy controls revealed stronger effects of pICA-derived connectivity measures in right and left dorsolateral prefrontal cortices, bilateral medial frontal cortex, left precuneus and left posterior lateral parietal cortex, while stronger effects in schizophrenia patients were found in the right amygdala, left orbitofrontal cortex, right anterior cingulate and bilateral inferior temporal cortices. In patients, we also found an inverse correlation of negative symptoms with right anterior prefrontal cortex activity at rest and negative symptoms. These findings suggest that aberrant default mode network connectivity contributes to regional functional pathology in schizophrenia and bears significance for core symptoms., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Introduction: ³¹Phosphorous magnetic resonance spectroscopy (2D chemical shift imaging, CSI) allows multiregional study of membrane phospholipids and high-energy phosphates in vivo. Increased membrane lipid turnover and impaired energy supply have repeatedly been shown in first-episode schizophrenia patients, and might be a target of drug actions other than dopamine receptors. Here, we explored differential metabolic effects of a typical vs. an atypical antipsychotic on brain phospholipids., Methods: We applied 2D-CSI MR spectroscopy in 17 recurrent-episode schizophrenia patients off antipsychotics at baseline and at follow-up after 6 weeks, during which 7 patients were treated with haloperidol (10-16 mg/d) and 10 with risperidone (4-6 mg/d). Psychopathology changes were assessed using PANSS, BPRS and CGI scores., Results: Follow-up analysis using repeated measure ANOVA revealed different effects of both antipsychotic agents: while risperidone generally increased metabolite levels, haloperidol showed a tendency to decrease them. This diverging effect was significant for ATP levels in the left lateral frontal cortex. Furthermore, risperidone increased ATP in the left dorsolateral prefrontal cortex, left anterior temporal cortex and left insular cortex, basal ganglia, and anterior cerebellum, along with left frontal and prefrontal increase of PCr, PDE and PME in these brain regions., Conclusion: Risperidone seems to stimulate neuronal and synaptic phospholipid remodeling in left frontal and prefrontal regions, and to a lesser extent also in temporal and insular cortices. We discuss these effects with respect to clinical effects on negative and cognitive symptoms, as well as interaction of phospholipid metabolism with glutamatergic neurotransmission., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Although mostly conceptualized as a neurodevelopmental disorder, there is an increasing interest in progressive changes of cognitive deficits and brain structure and function in schizophrenia across the life span., Methods: In this study, we investigated age-related changes in regional gray matter using voxel-based morphometry in a sample of 99 patients (age range 18-65 years) with Diagnostic and Statistical Manual of Mental Disorders-IV schizophrenia and 113 healthy controls (age range 19-59 years) using a cross-sectional design., Results: We found steeper age-related decline in gray matter in patients in a cluster comprising the left superior temporal cortex and adjacent inferior parietal lobule. We then divided the schizophrenia sample in 3 subgroups based on a 3-factor model of psychopathology ratings. Age-related changes were markedly different in each of the 3 subgroups (compared with healthy controls). While patients with predominantly paranoid symptoms showed stronger age-related progression in the left superior temporal cortex and right inferior frontal gyrus, those of the disorganized subgroup had stronger gray matter loss in the left lateral cerebellum, while the predominantly negative subgroup showed minor effects in the left superior temporal gyrus., Conclusions: Our findings show that differences in brain structural changes associated with aging diverge between schizophrenia patients and healthy subjects and that different subgroups within a patient sample might be at higher risk of age-related regional gray matter loss.

Objectives: Intracellular phospholipases A₂ (inPLA₂) are activated during monoaminergic neurotranismision and act as key enzymes in cell membrane repair and remodelling, neuroplasticity, neurodevelopment, apoptosis, synaptic pruning, neurodegenerative processes and neuroinflammation. Several independent studies found increased inPLA₂ activity in drug-naïve first episode and chronic schizophrenia. This study investigates if inPLA₂ activity is associated with symptoms severity and treatment response in first episode schizophrenia (FES)., Methods: InPLA₂ activity was measured in serum of 35 young FES patients (mean age: 19.36 ± 3.32, mean duration of illness: 7.53 ± 6.28 months, 16 neuroleptic-naïve) before and after 12 weeks of treatment with second-generation antipsychotic medications (olanzapine, quetiapine or risperidone), as well as in 22 healthy controls matched for age. Psychopathology and social functioning were assessed at the same time points., Results: Baseline inPLA₂ activity was significantly increased in drug-naïve and treated FES patients compared to healthy controls. Baseline inPLA₂ activity was also associated with severity of negative symptoms and lower functioning at baseline. Furthermore, baseline inPLA₂ activity was associated with improvement in negative symptoms and functioning within the first 12 weeks of treatment., Conclusions: Intracellular PLA₂ activity is increased in first episode schizophrenia and associated with symptom severity and outcome after 12 weeks of treatment. Future studies should investigate the implications of inPLA₂ activity as a potential predictor of treatment response for different antipsychotic agents.

Regional structural brain changes are among the most robust biological findings in schizophrenia, yet the underlying pathophysiological changes remain poorly understood. Recent evidence suggests that abnormal neuronal/dendritic plasticity is related to alterations in membrane lipids. We examined whether serum activity of membrane lipid remodelling/repairing cytosolic phospholipase A(2) (PLA(2)) were related to regional brain structure in magnetic resonance images (MRI). The study involved 24 schizophrenia patients, who were either drug-naïve or off antipsychotic medication, and 25 healthy controls. Using voxel-based morphometry (VBM) analysis of T1-high-resolution MRI-images, we correlated both gray matter and white matter changes with serum PLA(2)-activity. PLA(2) activity was increased in patients, consistent with previous findings. VBM group comparison of patients vs. controls showed abnormalities of frontal and medial temporal cortices/hippocampus, and left middle/superior temporal gyrus in first-episode patients. Group comparison of VBM/PLA(2)-correlations revealed a distinct pattern of disease-related interactions between gray/white matter changes in patients and PLA(2)-activity: in first-episode patients (n=13), PLA(2)-activity was associated with structural alterations in the left prefrontal cortex and the bilateral thalamus. Recurrent-episode patients (n=11) showed a wide-spread pattern of associations between PLA(2)-activity and structural changes in the left (less right) prefrontal and inferior parietal cortex, the left (less right) thalamus and caudate nucleus, the left medial temporal and orbitofrontal cortex and anterior cingulum, and the cerebellum. Our findings demonstrate a potential association between membrane lipid biochemistry and focal brain structural abnormalities in schizophrenia. Differential patterns in first-episode vs. chronic patients might be related to PLA(2)-increase at disease-onset reflecting localized regenerative activity, whereas correlations in recurrent-episode patients might point to less specific neurodegenerative aspects of disease progression., (Copyright 2010 Elsevier Inc. All rights reserved.)

We applied voxel-based morphometry to high-resolution magnetic resonance images of 99 participants with schizophrenia. Voxel-wise correlations with a score of auditory hallucination severity identified areas in the left and right superior temporal cortex (including Heschl's gyrus), left supramarginal/angular gyrus, left postcentral gyrus and left posterior cingulate cortex. This study extends previous region-of-interest studies demonstrating main effects of auditory hallucinations related to modality-specific superior temporal areas including primary and secondary auditory cortices.

Increasing evidence suggests modulating effects of cannabinoids on time of onset, severity, and outcome of schizophrenia. Efforts to discover the underlying pathomechanism have led to the assumption of gene x environment interactions, including premorbid genetical vulnerability and worsening effects of continuing cannabis use. The objective of this cross-sectional study is to investigate the relationship between delta-9-tetrahydrocannabinol intake and niacin sensitivity in schizophrenia patients and healthy controls. Intensity of niacin skin flushing, indicating disturbed prostaglandin-mediated processes, was used as peripheral marker of lipid-arachidonic acid pathways and investigated in cannabis-consuming and nonconsuming schizophrenia patients and in healthy controls. Methylnicotinate was applied in three concentrations onto the forearm skin. Flush response was assessed in 3-min intervals over 15 min using optical reflection spectroscopy. In controls, skin flushing was significantly decreased in cannabis-consuming as compared to nonconsuming individuals. When comparing the nonconsuming subgroups, patients showed significantly decreased flush response. The populations as a whole (patients and controls) showed an inverse association between skin flushing and sum scores of Symptom Check List 90-R. Results demonstrate an impact of long-term cannabis use on lipid-arachidonic acid pathways. Considering pre-existing vulnerability of lipid metabolism in schizophrenia, observed effects of cannabis use support the notion of a gene x environment interaction.

Background: Disruption of arachidonic acid pathways and prostaglandin signalling has been implicated in the pathophysiology of schizophrenia., Aims: We intended to study prostaglandin signalling in groups of young schizophrenia patients, first-degree relatives, and healthy controls in order to assess effects of heritability on this biological marker-one important endophenotype criterion., Method: Namely, we assessed intensity of methylnicotinate skin flushing using optical reflection spectroscopy. Tests were applied to 19 adolescent first-episode schizophrenia patients, 21 first-degree relatives, and groups of age and gender matched healthy controls., Results: Compared to healthy controls, attenuation of skin flushing at low niacin concentrations was found only in schizophrenia patients, but not in first-degree relatives., Conclusion: While our results indicate niacin hyposensitivity as reliable biological marker in schizophrenia, they do not provide clear evidence for its heritability. Particularly, the results in adolescent schizophrenia patients are suggestive for the perception of attenuated niacin flushing as secondary to the pathophysiology at the onset of schizophrenic illness, namely increased oxidative stress, alterations of unspecific immune-response or inflammation-like processes.

(31)Phosphorus magnetic resonance spectroscopy ((31)P-MRS) allows in vivo investigation of cerebral phospholipid and energy metabolism. Using 2D chemical shift imaging, this method can be applied to study multiple brain areas and to assess concentrations of both phospholipids and high-energy phosphates. The purpose of our study was to assess multiregional metabolic profiles in schizophrenia using a 2D-resolved MRS technique, and to assess the intercorrelation of findings. We applied (31)P-MRS chemical shift imaging in 31 schizophrenia patients (12 antipsychotic-naïve first-episode and 19 antipsychotic-free multi-episode patients) and 31 healthy age- and sex-matched controls. Spatially resolved maps were compared for the main metabolites of the (31)P spectrum. Metabolites of phospholipid (PME and PDE) and energy (PCr and Pi) metabolism were significantly reduced in bilateral prefrontal and medial temporal (including hippocampal) brain regions, caudate nucleus, thalamus and anterior cerebellum as compared to controls. Moreover, factor analysis of these changes showed a characteristic spatial pattern of changes, which demonstrates significant associations between alterations of phospholipid and energy metabolism, and between metabolic alterations and severity of symptoms (BPRS total score, but not SANS or SAPS scores). This suggests a pattern of intercorrelated changes of these metabolic markers. Results support the notion of disturbed phospholipid turnover in schizophrenia, probably unrelated to prior pharmacological treatment, and associated with increased energy demand.

Bioactive lipids, in particular arachidonic acid (AA), are vital for monoaminergic neurotransmission, brain development and synaptic plasticity. Phospholipases A2 (PLA2) are key-enzymes in AA metabolism and are activated during monoaminergic neurotransmission. Reduced membrane AA levels, and an altered activity of PLA2 have been found in peripheral membranes of drug-naïve patients with schizophrenia with some conflicting results in more chronic patient populations. Furthermore, in vivo brain phosphorus-31 magnetic resonance spectroscopy suggests reduced lipid membrane precursors (phosphomonoesters) and increased membrane breakdown products (phosphodiesters) in drug-naïve or early treated first-episode schizophrenia patients compared to age-matched controls or chronic populations and these changes were correlated with peripheral red blood cell membrane AA levels. We postulate that processes modulating membrane lipid metabolism are associated with psychotic illnesses and might partially explain the mechanism of action of antipsychotic agents, as well as experimental agents such as purified ethyl-eicosapentaenoic acid (E-EPA). Recent supplementation trials suggest that E-EPA is a modestly effective augmentation treatment resulting in reduced doses of antipsychotic medication in acutely ill patients with schizophrenia (but not in residual-type schizophrenia). This review investigates the role of bioactive lipids in schizophrenia and its treatment, as well as its potential use in prevention.

Niacin (vitamin B3) flushing--a marker of altered prostaglandin signaling--is indirectly linked to the phospholipid-prostaglandin metabolism. Diminished skin flushing was repeatedly found in schizophrenia, but has not been systematically investigated at different stages of disorder as yet. We compared niacin sensitivity of 32 first-episode and 32 multi-episode patients (mainly on stable medication) with age and gender matched healthy controls. Methylnicotinate was applied in three concentrations onto the inner forearm skin. Flush response was assessed in 3 min intervals over 15 min using optical reflection spectroscopy. Whereas first-episode patients showed significantly diminished flush response as compared to controls, comparable differences were not found between multi-episode patients and controls. Comparison of niacin sensitivity at different stages of schizophrenia support the notion of altered prostaglandin signaling primarily at the onset of disorder. Longitudinal studies have to rule out possible long-term effects of neuroleptic medication.

Background: Increased activity of calcium independent phospholipase A2 (iPLA2) has repeatedly been found in the serum of unmedicated first-episode schizophrenia patients and assumed to reflect a pertubation of phospholipid metabolism. Previous studies in chronic schizophrenia were less conclusive. To explore whether iPLA2 changes are stage dependent, we investigated serum iPLA2 activity in various stages of schizophrenia., Methods: iPLA2 activity was assessed in the serum of 30 first-episode and 23 multiepisode schizophrenia patients and 53 healthy control subjects matched for age and gender. A fluorimetric assay was applied using the PLA2 specific substrate NBDC6-HPC, thin-layer chromatography of reaction products, and digital image scanning for signal detection., Results: Group comparison between first-episode and multiepisode patients and corresponding control groups revealed significantly increased iPLA2 activity only in first-episode patients. Enzyme activity in first-episode patients was also markedly increased, compared with chronic patients. iPLA2 changes observed were irrespective of neuroleptic medication, age, or gender., Conclusions: Our results suggest increased lipid turnover in the acute early phase of schizophrenia that is less obvious in chronic stages. Future longitudinal studies involving iPLA2 activity and phosphorous magnetic resonance spectroscopy need to address the relation between perturbed brain lipid metabolism and iPLA2 increment in the course of schizophrenia.

Investigation of abnormal skin response to niacin (vitamin B3) stimulation has gained increasing interest in schizophrenia research during last years. However, current efforts to implement niacin tests in routine diagnostics are jeopardised by wide inter-individual variations of skin response. We investigated age and gender as potential factors of influence on niacin sensitivity in 117 healthy subjects (63 male, 54 female). Niacin was applied in three dilution steps (0.1, 0.01, 0.001 M) onto the inner forearm skin. Skin reaction was assessed in three minute intervals over 15 min using optical reflection spectroscopy. Males displayed a significantly weaker flush response than females. The rate of non-responders at the lowest concentration was about twice as high in men than women. Significant negative correlations between age and niacin sensitivity were revealed for both sexes. Age and gender considerably influence niacin sensitivity, possibly due to the effects of sex hormones on vasomotor function and prostaglandin metabolism. Consideration of gender and age is strongly recommended for further clinical niacin studies.

The rationale of this study was to understand the complexity of kinetics of fluorogenic phospholipid substrates as well as contradictory findings of clinical papers measuring phospholipase A2 (PLA2) activity using different methodologies. The aim was to recommend to clinicians and researchers what substrate in conjunction with what assay should be used. Two methods, (i) continuous fluorometric assay and (ii) high performance thin layer chromatography (HPTLC) on microplates combined with quantitative image scanning, were studied with three different substrates (bis-BODIPY FL C11-PC, NBDC6-HPC, PED6). The study demonstrates that NBD-PC is not a suitable substrate to measure PLA2 activity using a spectrofluorometer. On the other hand, NBD-PC gives the highest and most reproducible integrated light intensities (ILls) in HPTLC studies. Slow time-dependent increases in fluorescence intensities recorded with biological samples in fluorometers, but not caused by substrate splitting, had to be classified as "perturbation kinetics". PLA2 activities in blood samples of 26 unmedicated schizophrenia patients and 26 age-matched healthy controls were measured by the spectrofluorometric method and then compared with the activity data obtained with the HPTLC method. A significant group difference was found only with the HPTLC. In order to get more reliable results, we recommend that clinicians and researchers use NBD-phosphatidylcholines as PLA2 substrates in biological samples and start with an analytical separation of reaction products followed by image analysis of the fluorescent spots.

The intracellular pH value has a profound influence on cerebral metabolism. Thus, inadequate pH control may intensify local metabolic deficits. To investigate the influence of neuroleptics on cerebral intracellular pH, we retrospectively evaluated the findings from three independent phosphorous-31 magnetic resonance spectroscopy ((31)P-MRS) studies on schizophrenic patients. A total sample of 72 patients and 32 healthy controls was investigated. A modified pH value was found only in those schizophrenic patients treated with the atypical neuroleptic clozapine.

Functional neuroimaging findings of "hypofrontality" in schizophrenic patients - as tested with the Wisconsin Card Sorting Test (WCST) - are still controversial, mainly due to methodological aspects and the heterogeneity of the patient samples. To measure WCST specific and reproducible reduced cerebral activations in schizophrenic patients, we revised the study design and patient recruitment, respectively. For this purpose, we used an adequate active control task instead of an undefined rest condition to determine exclusively WCST specific cerebral activations. In addition, we focused on the investigation of modified activations between a selected group of neuroleptic-naive schizophrenic patients and carefully matched healthy controls by means of functional magnetic resonance imaging. The results indicate that neuroleptic-naive schizophrenic patients show reduced activations in the right frontal and left temporal lobe, as well as in the left cerebellum. By utilizing an active control task all unwanted activations are suppressed. Furthermore the influence of different task performances is reduced. The findings are in line with previous PET and SPECT studies and confirm the "hypofrontality" hypothesis. The findings suggest that "hypofrontality" is not caused by neuroleptic medication.

During the last few years analyses of the lipidmetabolism have been performed on schizophrenic patients. Anabolic and katabolic metabolite-concentrations from blood and cell samples have been measured. By means of new investigation techniques, such as 31P-magnetic-resonance-spectroscopy, it is nowadays even possible to determine membrane metabolites non-invasively in vivo. Arachidonic acid deficits in peripheral cell membranes, turnover of phosphodiesters in the brain, increased phospholipase A2 (PLA2)-activity in serum and blood cells, disturbed niacin-response and abnormalities of the PLA2-gene are summarised as phospholipid-membrane-hypothesis of schizophrenia. Although there is some evidence for correlations between those findings and psychotic symptoms, the connection to the pathogenesis of schizophrenia still has speculative character. Furthermore it has to be confirmed that peripheral biochemical findings acquired in schizophrenics are transferable to the metabolism of the central nervous system. Actual results of enzyme and metabolite measurements reported in literature and current findings of our own 31P-MR-spectroscopic studies are surveyed and summarised. To point out possible connections between the phospholipid-metabolism of the central nervous system and of peripheral blood-cells, systemic approaches are considered.

Background: (31)Phosphorous magnetic resonance spectroscopy has been widely used to evaluate schizophrenic patients in comparison to control subjects, because it allows the investigation of both phospholipid and energy metabolism in vivo; however, the results achieved so far are inconsistent. Chemical shift imaging (CSI) has the advantage that instead of only one or a few preselected voxels the tissue of a whole brain slice can be examined. The aim of the present investigation was to determine whether the results of previous studies of our group, showing that phosphodiesters (PDE) are decreased in the frontal lobe of schizophrenic patients as compared to control subjects, might be confirmed in an independent unmedicated patient sample using the CSI technique., Methods: A carefully selected new cohort including 11 neuroleptic-free schizophrenic patients and 11 age- and gender-matched healthy control subjects was recruited. CSI was applied and an innovative analysis method for CSI data based on a general linear model was used., Results: PDE, phosphocreatine, and adenosine triphosphate (ATP) were found to be significantly decreased in the frontal lobe of patients with schizophrenia., Conclusions: Because PDE was decreased in schizophrenic patients, the membrane phospholipid hypothesis of schizophrenia could not be corroborated. Further results indicate decreased ATP production in the frontal lobe of patients with schizophrenia.

31Phosphorus nuclear magnetic resonance spectroscopy (31P-MRS) has gained much interest in schizophrenia research in the last years, since it allows noninvasive measurement of high energy phosphates and phospholipids of the human brain in vivo. Thus, several studies have reported cerebral metabolic differences between patients and healthy controls as well as on lateralization effects and influences of epidemiological and psychopathological factors. This review gives a survey of the potential of 31P-MRS in schizophrenia research and summarizes and comments on the results of preceding studies. The discussion covers the reduction of phospholipids in patients in the context of the membrane phospholipid hypotheses, the question of an energetic hypometabolism in schizophrenics, and the influence of neuroleptic medication.

Abstract Background Oxidative stress and impaired antioxidant defense are reported in schizophrenia and are thought to be associated with disturbed neurodevelopment, brain structural alterations, glutamatergic imbalance, negative symptomatology, and cognitive impairment. To test some of these assumptions we investigated the glutathione (GSH) antioxidant defense system (AODS) and brain structural abnormalities in drug-naïve individuals with first acute episode of psychosis (FEP). Method The study involved 27 drug-naïve FEP patients and 31 healthy controls (HC). GSH AODS markers and TBARS (thiobarbituric acid reactive substances) were measured in blood plasma and erythrocytes. High-resolution T 1 -weighted 3T MRI were acquired from all subjects. To investigate brain structural abnormalities and effects of illness on interactions between GSH metabolites or enzyme activities and local grey matter density, voxel-based morphometry (VBM) with the computational anatomy toolbox (CAT12) was used. Symptomatology was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Symptom Checklist 1990 revised (SCL-90-R). Results (i) In FEP patients, glutathione reductase activity (GSR) was lower than in the HC group. GSR activity in plasma was inversely correlated with SCL-90-R scores of depression and PANSS scores of the negative symptom subscale. (ii) A reduction of GM was observed in left inferior frontal, bilateral temporal, as well as parietal cortices of FEP patients. (iii) Interaction analyses revealed an influence of illness on GSR/GM associations in the left orbitofrontal cortex (BA 47). Conclusion Our findings support the notion of altered GSH antioxidative defense in untreated acute psychosis as a potential pathomechanism for localized brain structural abnormalities. This pathology relates to a key brain region of social cognition, affective motivation control and decision making, and is clinically accompanied by depressive and negative symptoms. Highlights • Alterations of the glutathione AODS are associated with brain structural abnormalities in drug-naïve FEP patients. • The effect of illness on associations between GSR activity and grey matter density relates to the left orbitofrontal cortex. • Glutathione reductase activity in FEP patients was associated with negative symptoms. [ABSTRACT FROM AUTHOR]

Introduction: Working memory deficits are considered a core feature of disturbed cognition in schizophrenia. Recent neuropsychological studies in twins suggest that there are shared genetic factors between schizophrenia and executive processes. Aim: We used a co-twin control design to test the hypothesis that prefrontal activation during a working memory task is seen both in affected as well as unaffected twins discordant for schizophrenia, thus reflecting genetic load on this putative endophenotype. Methods: As part of EUTwinsS, a multi-centre collaborative study on twins with schizophrenia, we obtained functional MRI scans during a Sternberg working memory task (with one maintenance and one manipulation variations) of twins discordant for schizophrenia (5 monozygotic pairs, 7 dizygotic pairs) and compared them to 10/4 healthy MZ/DZ twins, matched for age and gender. Results: Comparing the overall task-related effects (p<0.001, uncorrected), we found stronger activation in control twins compared to either Sz-affected or unaffected twins in the right middle frontal gyrus and medial fronto-orbital cortex, and compared to Sz-affected twins also in the left cerebellum and right inferior occipital cortex. Comparing the manipulation vs. maintenance trials, healthy controls showed stronger activation than Sz-affected twins in the left hippocampus, but smaller in right caudate and anterior cingulate, while unaffected co-twins showed diminished right middle and left superior and middle frontal gyri compared to either group. Conclusions: While diminished prefrontal activation in unaffected co-twins might indicate compensatory processes during executive control, the overall activation deficits are consistent with a genetic effect on prefrontal cortical efficiency. [ABSTRACT FROM AUTHOR]

Introduction: Magnetic resonance spectroscopy (MRS) using 2D-chemical shift imaging (CSI) allows the quantification of brain metabolites in vivo across several brain regions. Previous studies using 31Phosphorus MRS have shown alterations of phospholipid compounds and high-energy phosphates like ATP in prefrontal and temporal regions in schizophrenia. Aim: We used a monozygotic (MZ) co-twin study design to examine whether metabolic alterations are due to genetic effects or the expression of disease phenotype. Methods: 31P-MRS with 2D-CSI was applied at 1.5 T in 8 MZ twin pairs (3 male, 5 female; mean age 33.8, SD 13.1) discordant for a DSM-IV and ICD-10 diagnosis of either schizophrenia (4 pairs), acute schizophreniform psychosis (1 pair), or schizoaffective disorder (3 pairs)) and 8 age- and gender-matched healthy control MZ twins (mean age: 32.9, SD 14.3). Metabolic profiles were compared using oneway ANOVAs. Results: Voxel-wise comparisons between affected twins and healthy control twins revealed increased PDE concentrations in right cerebellum and increased ATP concentrations in right frontal cortex, insular cortex and bilateral cerebellum. Alterations in energy metabolism were shown in healthy co-twins compared to healthy control twins with an increase in PDE concentrations in right posterior lateral cerebellum, an increase in ATP concentration in left lateral prefrontal cortex as well as left anterior/ lateral temporal cortex and an increase in PCr in left lateral prefrontal cortex. Conclusions: Our findings suggest that metabolic alterations in schizophrenia result from a combination of both genetic effects and disease manifestation, which can be further explored in larger twin samples. [ABSTRACT FROM AUTHOR]