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Both brain structural abnormalities and neurocognitive impairments are core features of schizophrenia. We have previously reported enlargements in subcortical brain structure volumes and impairment of neurocognitive functioning as measured by the MATRICS Cognitive Consensus Battery (MCCB) in early onset schizophrenia spectrum disorders (EOS). To our knowledge, no previous study has investigated whether neurocognitive performance and volumetric abnormalities in subcortical brain structures are related in EOS.Twenty-four patients with EOS and 33 healthy controls (HC) were included in the study. Relationships between the caudate nucleus, the lateral and fourth ventricles volumes and neurocognitive performance were investigated with multivariate linear regression analyses. Intracranial volume, age, antipsychotic medication and IQ were included as independent predictor-variables.The caudate volume was negatively correlated with verbal learning performance uniquely in the EOS group (r=-.454, p=.034). There were comparable positive correlations between the lateral ventricular volume and the processing speed, attention and reasoning and problem solving domains for both the EOS patients and the healthy controls. Antipsychotic medication was related to ventricular enlargements, but did not affect the brain structure-function relationship.Enlargement of the caudate volume was related to poorer verbal learning performance in patients with EOS. Despite a 32% enlargement of the lateral ventricles in the EOS group, associations to processing speed, attention and reasoning and problem solving were similar for both the EOS and the HC groups.

© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.Analyses of gray matter concentration (GMC) deficits in patients with schizophrenia (Sz) have identified robust changes throughout the cortex. We assessed the relationships between diagnosis, overall symptom severity, and patterns of gray matter in the largest aggregated structural imaging dataset to date. We performed both sourcebased morphometry (SBM) and voxel-based morphometry (VBM) analyses on GMC images from 784 Sz and 936 controls (Ct) across 23 scanning sites in Europe and the United States. After correcting for age, gender, site, and diagnosis by site interactions, SBM analyses showed 9 patterns of diagnostic differences. They comprised separate cortical, subcortical, and cerebellar regions. Seven patterns showed greater GMC in Ct than Sz, while 2 (brainstem and cerebellum) showed greater GMC for Sz. The greatest GMC deficit was in a single pattern comprising regions in the superior temporal gyrus, inferior frontal gyrus, and medial frontal cortex, which replicated over analyses of data subsets. VBM analyses identified overall cortical GMC loss and one small cluster of increased GMC in Sz, which overlapped with the SBM brainstem component. We found no significant association between the component loadings and symptom severity in either analysis. This mega-analysis confirms that the commonly found GMC loss in Sz in the anterior temporal lobe, insula, and medial frontal lobe form a single, consistent spatial pattern even in such a diverse dataset. The separation of GMC loss into robust, repeatable spatial patterns across multiple datasets paves the way for the application of these methods to identify subtle genetic and clinical cohort effects.

Glutamate-related genes have been associated with schizophrenia, but the results have been ambiguous and difficult to replicate. Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major degradation products of the monoamines dopamine, serotonin and noradrenaline, respectively, and their concentrations in the cerebrospinal fluid (CSF), mainly HVA, have been associated with schizophrenia. In the present study, we hypothesized that CSF HVA, 5-HIAA and MHPG concentrations represent intermediate phenotypes in the association between glutamate-related genes and psychosis. To test this hypothesis, we searched for association between 238 single nucleotide polymorphisms (SNPs) in ten genes shown to be directly or indirectly implicated in glutamate transmission and CSF HVA, 5-HIAA and MHPG concentrations in 74 patients with psychotic disease. Thirty-eight nominally significant associations were found. Further analyses in 111 healthy controls showed that 87% of the nominal associations were restricted to the patients with psychosis. Some of the psychosis-only-associated SNPs found in the d-amino acid oxidase activator (DAOA) and the kynurenine 3-monooxygenase (KMO) genes have previously been reported to be associated with schizophrenia. The present results suggest that CSF monoamine metabolite concentrations may represent intermediate phenotypes in the association between glutamate-related genes and psychosis.

Objective We investigated whether elevated plasma levels of immune markers were associated with verbal memory and hippocampal subfield volumes in patients with severe mental illnesses and in healthy controls. Method In total, 230 patients with a broad DSM-IV schizophrenia spectrum illness or bipolar disorder and 236 healthy controls were recruited. Memory was assessed using the Wechsler Memory Scale-Third Edition (WMS-III) Logical Memory immediate and delayed recall, and the California Verbal Learning Test summed recall over learning list (CVLT learning) and delayed free recall. We measured plasma levels of soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin-1 receptor antagonist, interleukin-6, von Willebrand factor, osteoprotegerin, high-sensitivity C-reactive protein and sCD40 ligand. Hippocampal subfield estimates were obtained using FreeSurfer. Results We found a moderate negative association between sTNF-R1 and performance on verbal memory learning and recall tests as measured by the WMS-III Logical Memory after controlling for age, sex and diagnosis. We observed no interaction effect of diagnosis and sTNF-R1 on memory scores. We also found a nominally significant positive association between CVLT learning and hippocampal volumes. Conclusion The findings suggest a role for immune involvement in memory independent of severe mental disorders and may support the 'bigger is better' hypothesis of hippocampal subfield volumes.

IntroductionThe ENIGMA-EOP collaboration aims to identify structural phenotypic markers that robustly discriminate adolescents with early-onset psychosis (EOP) from healthy controls through mega- or meta-analysis of magnetic resonance imaging (MR) data. Through larger samples we will obtain sufficient power to detect the brain structural correlates, overcome some of the clinical heterogeneity and characterize the developmental trajectories.MethodsMultiple linear regression was used to investigate structural brain differences in two Scandinavian adolescent EOP cohorts (altogether 50 patients; ages 12.1-18.3 years (mean 16.4 years), 60% female; 68 controls; ages 12.0-18.8 years (mean 16.2 years), 62% female) acquired on two different 3 T GE MRI scanners. The statistical analysis included site as a covariate in addition to age, sex and intracranial volume (ICV). The results are presented by p-values, Cohens's-d effect size and with an indication of directionality. MRI scans were processed following the ENIGMA (http://enigma.ini.usc.edu/) structural image processing protocols using FreeSurfer (Fischl 2012) version 5.3.0 to measure subcortical brain volumes.ResultsPreliminary results show significant or trend-significant group effects on right amygdala (P = 0.001, d = 0.33, patients < controls), total grey matter volume (P = 0.037, d = 0.21, patients < controls), ICV (P = 0.028, d = 0.22, patients < controls) and third ventricle (P = 0.067, d = 0.19, patients > controls). Sub-analyses in the two individual groups show overlapping findings in right amygdala. Previously reported enlarged lateral and 4th ventricles, and caudate, from a similar Scandinavian adolescent EOP cohort (Juuhl-Langseth, 2012) were not replicated.ConclusionThere is a need for larger subject samples in EOP to better capture disease mechanisms. Research groups interested in participating can join ENIGMA-EOP through: http://enigma.ini.usc.edu/ongoing/enigma-eop-working-group/.Disclosure of interestThe authors have not supplied their declaration of competing interest.

IntroductionSmaller auditory cortex volume in schizophrenia patients with auditory hallucinations (AH) may be a result of reduced cortical surface area and/or cortical thickness. A neuro–imaging study from our group demonstrated that adult schizophrenia spectrum patients with AH had significantly thinner cortex in the left side Heschl's gyrus (HG), compared to patients without AH, and healthy controls (HC).ObjectivesThis study aims to investigate if adolescents with early-onset psychosis (EOP) and AH demonstrate thinner cortices in HG, as found in Mørch-Johnsen et al. in 2016, compared to EOP patients without AH, and HC.MethodsEOP patients (schizophrenia spectrum, psychotic disorder not otherwise specified) (n = 29) underwent MRI. Mean volume, cortical thickness and surface area in auditory cortex regions (HG, superior temporal gyrus [STG]) were compared between patients with AH (n = 20) and without AH (n = 9), measured with item P3 from the Positive And Negative Syndrome Scale (PANSS), and 48 HC.ResultsPreliminary results show no significant differences between patients with and without AH and HC in mean volume, cortical thickness, or surface area in HG or STG. There were no significant side differences across hemispheres for these structures.ConclusionsAH in EOP were not related to smaller volume, thinner cortex or reduced surface area in auditory cortex regions. To overcome the limitation of having a relatively small sample size, the sample will be expanded with other EOP cohorts. Investigations into HG structure variation in relation to AH in EOP will also be conducted.Disclosure of interestThe authors have not supplied their declaration of competing interest.

IntroductionCortical brain abnormalities are frequently observed in adults with psychotic disorders, but few studies have investigated adolescents with early-onset psychosis (EOP). A previous magnetic resonance imaging (MRI) study from the NORMENT group in Norway, found widespread cortical thinning and smaller subcortical volumes in adult patients with psychotic disorders, particularly schizophrenia, compared to healthy controls.MethodsParticipants from the ongoing NORMENT adolescent EOP-study, 30 patients (age: 13.3–18.3 years, mean age: 16.5, 66% female) and 45 healthy adolescents (age: 13.6–18.8 years, mean age: 16.2, 58% female), underwent 3 T MRI on the same scanner. Surface-based morphometric analyses were performed using FreeSurfer version 5.3.0. Group differences in vertex-wise cortical volume, thickness and surface area were investigated by fitting general linear models at each vertex on the surface. Age, sex and group were entered as covariates, and a non-parametric cluster-wise correction method for multiple comparisons was applied and cluster-forming and cluster-wise threshold set at 0.05.ResultsPreliminary results show thinner cortex in the left medial frontal lobe and smaller surface area in the left temporoparietal junction in EOP patients compared to healthy controls after correction for multiple comparisons.ConclusionSurface-based analysis is sensitive to alterations in cortical morphology in an adolescent EOP sample. The regions exhibiting reduced cortical thickness and area in EOP overlap with findings in an adult psychosis sample. Large-scale studies are warranted to better identify the pattern of abnormalities and clarify effects of age, diagnosis and medication.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Background: Genetics is known to influence both schizophrenia risk and brain structure. Thereby a question emerges as to whether the genetic underpinnings of these two traits overlap.

BackgroundCommon variants in the Vaccinia-related kinase 2 (VRK2) gene have been associated with schizophrenia, but the relevance of its encoded protein VRK2 in the disorder remains unclear.AimsTo identify potential differences in VRK2 gene expression levels between schizophrenia, bipolar disorder, psychosis not otherwise specified (PNOS) and healthy controls.MethodVRK2 mRNA level was measured in whole blood in 652 individuals (schizophrenia, n = 201; bipolar disorder, n = 167; PNOS, n = 61; healthy controls, n = 223), and compared across diagnostic categories and subcategories. Additionally, we analysed for association between 1566 VRK2 single nucleotide polymorphisms and mRNA levels.ResultsWe found lower VRK2 mRNA levels in schizophrenia compared with healthy controls (P–12), bipolar disorder (P–12) and PNOS (P = 0.0011), and lower levels in PNOS than in healthy controls (P = 0.0042) and bipolar disorder (P = 0.00026). Expression quantitative trait loci in close proximity to the transcription start site of the short isoforms of the VRK2 gene were identified.ConclusionsAltered VRK2 gene expression seems specific for schizophrenia and PNOS, which is in accordance with findings from genome-wide association studies. These results suggest that reduced VRK2 mRNA levels are involved in the underlying mechanisms in schizophrenia spectrum disorders.

Background Both brain structural abnormalities and neurocognitive impairments are core features of schizophrenia. We have previously reported enlargements in subcortical brain structure volumes and impairment of neurocognitive functioning as measured by the MATRICS Cognitive Consensus Battery (MCCB) in early onset schizophrenia spectrum disorders (EOS). To our knowledge, no previous study has investigated whether neurocognitive performance and volumetric abnormalities in subcortical brain structures are related in EOS. Methods Twenty-four patients with EOS and 33 healthy controls (HC) were included in the study. Relationships between the caudate nucleus, the lateral and fourth ventricles volumes and neurocognitive performance were investigated with multivariate linear regression analyses. Intracranial volume, age, antipsychotic medication and IQ were included as independent predictor-variables. Results The caudate volume was negatively correlated with verbal learning performance uniquely in the EOS group (r=-.454, p=.034). There were comparable positive correlations between the lateral ventricular volume and the processing speed, attention and reasoning and problem solving domains for both the EOS patients and the healthy controls. Antipsychotic medication was related to ventricular enlargements, but did not affect the brain structure-function relationship. Conclusion Enlargement of the caudate volume was related to poorer verbal learning performance in patients with EOS. Despite a 32% enlargement of the lateral ventricles in the EOS group, associations to processing speed, attention and reasoning and problem solving were similar for both the EOS and the HC groups.

Objective Insight into psychosis has been linked to suicidality, although inconsistently. The co-variation between insight and suicidality over time is under-investigated. The aim of the present study was to investigate predictors of suicidality in patients with first episode of psychosis (FEP) over one year, focusing on the relationship between insight and suicidality. Methods Patients with FEP (n = 146) were interviewed as soon as possible after treatment starts and at one year follow-up. Results At baseline 37% of patients were suicidal, significantly reduced to 20% at follow-up. The effect of insight on suicidality was in different directions at different time-points, with insight at baseline increasing and insight at follow-up decreasing the risk of suicidality at follow-up. Patients with stable levels of insight across baseline and follow-up did not differ in risk for suicidality at follow-up. However, patients who lost insight from baseline to follow-up were more often suicidal at follow-up, whilst patients who gained insight were more seldom suicidal at follow-up. Other predictors of suicidality at follow-up were more depressive episodes before study entry, longer duration of untreated psychosis, more suicide attempts six months prior to follow-up, and depression at follow-up. Conclusion The results indicate that the effect of insight on suicidality in FEP-patients depends on time of assessment and of changes in insight. Gaining insight during treatment was associated with reduced risk for suicidality, whilst losing insight had the opposite effect, underlining the need to monitor insight over time and tailor interventions according to illness phase.

Background The mechanisms underlying cognitive impairment in schizophrenia and bipolar disorders are largely unknown. Immune abnormalities have been found in both disorders, and inflammatory mediators may play roles in cognitive function. We investigated if inflammatory markers are associated with general cognitive abilities. Methods Participants with schizophrenia spectrum (N = 121) and bipolar spectrum (N = 111) disorders and healthy controls (N = 241) were included. General intellectual abilities were assessed using the Wechsler Abbreviated Scale of Intelligence (WASI). Serum concentrations of the following immune markers were measured: Soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin 1 receptor antagonist (IL-1Ra), osteoprotegerin, von Willebrand factor, C-reactive protein, interleukin-6 and CD40 ligand. Results After adjusting for age, sex and diagnostic group, significant negative associations with general cognitive function were found for sTNF-R1 (p = 2 × 10 − 5 ), IL-1Ra (p = 0.002) and sCD40 ligand (p = 0.003). Among patients, the associations remained significant (p = 0.006, p = 0.005 and p = 0.02) after adjusting for possible confounders including education, smoking, psychotic and affective symptoms, body mass index, cortisol, medication and time of blood sampling. Subgroup analysis, showed that general cognitive abilities were significantly associated with IL-1Ra and sTNF-R1 in schizophrenia patients, with sCD40L and IL-1Ra in bipolar disorder patients and with sTNF-R1 in healthy controls. Conclusion The study shows significant negative associations between inflammatory markers and general cognitive abilities after adjusting for possible confounders. The findings strongly support a role for inflammation in the neurophysiology of cognitive impairment.

Objective Here we investigated a two hit gene environment model in relation to functional genomic factors (BDNF mRNA), and volume of hippocampal subfields in schizophrenia spectrum and bipolar disorders, focusing on both an environmental (childhood trauma) and genetic risk factor (BDNF val66met). Method A total of 323 patients with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder were consecutively recruited. A history of childhood trauma was obtained using the Childhood Trauma Questionnaire. BDNF DNA and RNA were analyzed using standardized procedures. A subsample of n = 108 underwent MRI scanning, and the FreeSurfer was used to obtain measures of hippocampal subfield. All MRI data were corrected for age and gender, with post-hoc analysis correcting for ICV. Results A history of childhood trauma or being a met carrier of the BDNF val66met was associated with significantly reduced BDNF mRNA level. Additive effects were observed between a history of childhood trauma and BDNF val66met, in the direction of met carriers with high levels of childhood trauma having the lowest BDNF mRNA levels. Lastly, met carriers reporting high levels of childhood trauma (specifically sexual or physical abuse) had significantly reduced hippocampal subfield volumes CA2/3 and CA4 dentate gyrus. Conclusion The current findings demonstrate that the reduced BDNF mRNA levels found in psychosis may be associated with both a history of childhood trauma and BDNF val66met variants. Further, our study supports a two hit model including a history of childhood trauma as well as genetic vulnerability (met carriers of the BDNF val66met) behind reduced volume of hippocampal subfields in psychosis. This was specifically found for areas important for neurogenesis, the CA2/3and the CA4 DG.

Data suggest that individuals with schizophrenia (SZ) and superior intelligence can present without specific neurocognitive deficits. However, neurocognitive decrements, defined as worse cognition than expected, have been reported in practically all SZ cases. This study investigated if neurocognitive decrements are present in intellectually superior SZ by comparing the neuropsychological profile of SZ cases with IQ-matched healthy controls (HC) across intellectual levels. Participants with SZ and HCs were stratified into three IQ-groups; intellectually low (IQ 80–95; SZ n = 65 and HC n = 13), intellectually normal (IQ = 100–115; SZ n = 111 and HC n = 115), and intellectually superior (IQ ≥ 120; SZ n = 20 and HC n = 50). A repeated measures multivariate analysis of co-variance compared performance on eight selected neuropsychological tests across IQ-strata and diagnostic group. Differences in clinical characteristics and social functioning in SZ across IQ-strata were investigated with multivariate and univariate analyses of variance. Intellectually superior SZ participants scored within normal limits, but had neurocognitive decrements compared to superior HCs. Decrements were of the same magnitude as in the low and normal IQ-strata. Levels of functional impairments and clinical characteristics in participants with SZ did not differ significantly across IQ-strata. Results indicate that neurocognitive decrements are present in intellectually superior SZ to the same extent as in intellectually low and intellectually normal SZ, supporting the notion that SZ is a neurocognitive disorder. Similar levels of social functional deficits and clinical symptoms suggest similar disease processes in SZ across intellectual level.

Imaging genetics aims to discover how variants in the human genome influence brain measures derived from images. Genome-wide association scans (GWAS) can screen the genome for common differences in our DNA that relate to brain measures. In small samples, GWAS has low power as individual gene effects are weak and one must also correct for multiple comparisons across the genome and the image. Here we extend recent work on genetic clustering of images, to analyze surface-based models of anatomy using GWAS. We performed spherical harmonic analysis of hippocampal surfaces, automatically extracted from brain MRI scans of 1254 subjects. We clustered hippocampal surface regions with common genetic influences by examining genetic correlations (r(g)) between the normalized deformation values at all pairs of surface points. Using genetic correlations to cluster surface measures, we were able to boost effect sizes for genetic associations, compared to clustering with traditional phenotypic correlations using Pearson's r.

Reliable measurement of different tissue volumes in the living brain is of great importance for human brain research. In this article, we report on the inter- and intraoperator reliability and scan-rescan reproducibility of segmented intracranial tissue volumes from MR images using the image analysis software suite BRAINS. The absolute data of tissue volume measurements are also presented. The reliability and consistency of the measurements of the segmented volumes were excellent. The segmentation is robust and rapid and the volume measurements are plausible and suitable for quantitative studies in clinical brain research.

Background Schizophrenia is a serious mental disease of unknown aetiology. Genetic liability is the most important risk factor. Several studies have demonstrated that pre and perinatal complications/traumas are associated with an increased risk of developing schizophrenia in adult age. The purpose of this article is to provide an overview of research on obstetric complications as risk factors for schizophrenia. Material and methods The article is based on literature identified through non-systematic searches in the databases PubMed and Embase. Results The putative association between obstetric complications and schizophrenia has been investigated for almost 80 years. Numerous controlled studies have found that maternal infection (influenza, rubella, toxoplasmosis), prenatal malnutrition and birth-associated complications (such as low birth weight and asphyxia) are associated with an increased risk of developing schizophrenia. Experiments in animal models suggest that foetal hypoxia and maternal inflammatory responses may affect neuronal development. However, underlying pathophysiological mechanisms and modes of interaction with schizophrenia susceptibility genes are unknown. Interpretation An association between obstetric complications and an increased risk of schizophrenia is strongly supported by scientific evidence.

The MCTP2 gene is involved in intercellular signal transduction and synapse function. We genotyped 37 tagging SNPs across the MCTP2 gene to study a possible association with schizophrenia in three independent Scandinavian samples. We report, for the first time, a possible involvement of MCTP2 as a potential novel susceptibility gene for schizophrenia.

BackgroundSchizophrenia and bipolar disorder are severe mental disorders with overlapping genetic and clinical characteristics, including cognitive impairments. An important question is whether these disorders also have overlapping neuronal deficits.AimsTo determine whether large-scale brain networks associated with working memory, as measured with functional magnetic resonance imaging (fMRI), are the same in both schizophrenia and bipolar disorder, and how they differ from those in healthy individuals.MethodPatients with schizophrenia (n = 100) and bipolar disorder (n = 100) and a healthy control group (n = 100) performed a 2-back working memory task while fMRI data were acquired. The imaging data were analysed using independent component analysis to extract large-scale networks of task-related activations.ResultsSimilar working memory networks were activated in all groups. However, in three out of nine networks related to the experimental task there was a graded response difference in fMRI signal amplitudes, where patients with schizophrenia showed greater activation than those with bipolar disorder, who in turn showed more activation than healthy controls. Secondary analysis of the patient groups showed that these activation patterns were associated with history of psychosis and current elevated mood in bipolar disorder.ConclusionsThe same brain networks were related to working memory in schizophrenia, bipolar disorder and controls. However, some key networks showed a graded hyperactivation in the two patient groups, in line with a continuum of neuronal abnormalities across psychotic disorders.

Background Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) are the major monoamine metabolites in the central nervous system (CNS). Their cerebrospinal fluid (CSF) concentrations, reflecting the monoamine turnover rates in CNS, are partially under genetic influence and have been associated with schizophrenia. We have hypothesized that CSF monoamine metabolite concentrations represent intermediate steps between single nucleotide polymorphisms (SNPs) in genes implicated in monoaminergic pathways and psychosis. Methods We have searched for association between 119 SNPs in genes implicated in monoaminergic pathways [tryptophan hydroxylase 1 (TPH1), TPH2, tyrosine hydroxylase (TH), DOPA decarboxylase (DDC), dopamine beta-hydroxylase (DBH), catechol-O-methyltransferase (COMT), monoamine oxidase A (MAOA) and MAOB] and monoamine metabolite concentrations in CSF in 74 patients with psychotic disorder. Results There were 42 nominally significant associations between SNPs and CSF monoamine metabolite concentrations, which exceeded the expected number (20) of nominal associations given the total number of tests performed. The strongest association (p = 0.0004) was found between MAOB rs5905512, a SNP previously reported to be associated with schizophrenia in men, and MHPG concentrations in men with psychotic disorder. Further analyses in 111 healthy individuals revealed that 41 of the 42 nominal associations were restricted to patients with psychosis and were absent in healthy controls. Conclusions The present study suggests that altered monoamine turnover rates in CNS reflect intermediate steps in the associations between SNPs and psychosis.

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia. ispartof: Nature vol:511 issue:7510 pages:421-7 ispartof: location:England status: published

The cerebral cortex is highly convoluted, and principal folding patterns are determined early in life. Degree of cortical folding in adult life may index aberrations in brain development. Results from previous studies of cortical folding in schizophrenia are inconsistent. Here we investigated cortical folding patterns in the hitherto largest sample of patients with schizophrenia drawn from two independent cohorts. Magnetic resonance imaging scans were acquired from 207 patients and 206 healthy subjects recruited to two separate research projects in Sweden and Norway. Local gyrification index (lGI) was estimated continuously across the cortex using automated methods. Group differences in lGI were analyzed using general linear models. Patients had lower lGI in three large clusters of the cortex with peak differences found in the left precentral gyrus, right middle temporal gyrus, and right precuneus. Similar, although not completely overlapping results were found when the two cohorts were analyzed separately. There were no significant interaction effects between age and diagnosis and gender and diagnosis. The finding of reduced degree of folding in large regions of the cerebral cortex across two independent samples indicates that reduced gyrification is an inherent feature of the brain pathology in schizophrenia.

Background Hippocampal dysfunction and volume reductions have been reported in patients with schizophrenia and bipolar disorder. The hippocampus consists of anatomically distinct subfields. We investigated to determine whether in vivo volumes of hippocampal subfields differ between clinical groups and healthy control subjects. Methods Clinical examination and magnetic resonance imaging were performed in 702 subjects (patients with schizophrenia spectrum [ n = 210; mean age, 32.0 ± 9.3 (SD) years; 59% male], patients with bipolar spectrum [ n = 192; mean age, 35.5 ± 11.5 years; 40% male] and healthy control subjects [ n = 300; mean age, 35.3 ± 9.9 years; 53% male]). Hippocampal subfield volumes were estimated with FreeSurfer. General linear models were used to explore diagnostic differences in hippocampal subfield volumes, covarying for age, intracranial volume, and medication. Post hoc analyses of associations to psychosis symptoms (Positive and Negative Syndrome Scale) and cognitive function (verbal memory [California Verbal Learning Test, second edition] and IQ [Wechsler Abbreviated Scale of Intelligence]) were performed. Results Patient groups had smaller cornu ammonis (CA) subfields CA2/3 (left, p = 7.2 × 10 −6 ; right, p = 2.3 × 10 −6 ), CA4/dentate gyrus (left, p = 1.4 × 10 −5 ; right, p = 2.3 × 10 −6 ), subiculum (left, p = 3.7 × 10 −6 ; right, p = 2.8 × 10 −8 ), and right CA1 ( p = .006) volumes than healthy control subjects, but smaller presubiculum volumes were found only in patients with schizophrenia (left, p = 6.7 × 10 −5 ; right, p = 1.6 × 10 −7 ). Patients with schizophrenia had smaller subiculum (left, p = .035; right, p = .031) and right presubiculum ( p = .002) volumes than patients with bipolar disorder. Smaller subiculum volumes were related to poorer verbal memory in patients with bipolar disorder and healthy control subjects and to negative symptoms in patients with schizophrenia. Conclusions Hippocampal subfield volume reductions are found in patients with schizophrenia and bipolar disorder. The magnitude of reduction is greater in patients with schizophrenia, particularly in the hippocampal outflow regions presubiculum and subiculum.

This study aimed to investigate associations between a history of childhood trauma and levels of affective lability in bipolar patients compared to controls. Forty-two patients and 14 controls were assessed using the Affective Lability Scale (ALS) and the Childhood Trauma Questionnaire (CTQ). Affective Lability Score was significantly associated with scores on the Childhood Trauma Questionnaire. A multivariate regression model indicated a relationship between childhood trauma scores and differences in affective lability between patients and controls.

AM Vicente - Cross-Disorder Group of the Psychiatric Genomics Consortium Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

BackgroundPre- and perinatal adversities may increase the risk for schizophrenia and bipolar disorder. Hypoxia-related obstetric complications (OCs) are associated with brain anatomical abnormalities in schizophrenia, but their association with brain anatomy variation in bipolar disorder is unknown.MethodMagnetic resonance imaging brain scans, clinical examinations and data from the Medical Birth Registry of Norway were obtained for 219 adults, including 79 patients with a DSM-IV diagnosis of bipolar disorder (age 29.4 years,s.d. = 11.8 years, 39% male) and 140 healthy controls (age 30.8 years,s.d. = 12.0 years, 53% male). Severe hypoxia-related OCs throughout pregnancy/birth and perinatal asphyxia were each studied in relation toa prioriselected brain volumes (hippocampus, lateral ventricles and amygdala, obtained with FreeSurfer), using linear regression models covarying for age, sex, medication use and intracranial volume. Multiple comparison adjustment was applied.ResultsPerinatal asphyxia was associated with smaller left amygdala volume (t = −2.59,p = 0.012) in bipolar disorder patients, but not in healthy controls. Patients with psychotic bipolar disorder showed distinct associations between perinatal asphyxia and smaller left amygdala volume (t = −2.69,p = 0.010), whereas patients with non-psychotic bipolar disorder showed smaller right hippocampal volumes related to both perinatal asphyxia (t = −2.60,p = 0.015) and severe OCs (t = −3.25,p = 0.003). No associations between asphyxia or severe OCs and the lateral ventricles were found.ConclusionsPre- and perinatal hypoxia-related OCs are related to brain morphometry in bipolar disorder in adulthood, with specific patterns in patients with psychoticversusnon-psychotic illness.

The association between clinical insight and social cognition assessed with an emotion perception task was investigated in schizophrenia (n = 29) and bipolar I disorder (n = 19). Persons with schizophrenia had reduced auditory emotion perception compared with individuals with bipolar I disorder, but levels of visual emotion perception and clinical insight were comparable. In the schizophrenia group, clinical insight was moderately associated with auditory and visual emotion perception (r = 0.36-0.44) and negative symptoms (r = -0.33). Better insight was associated with better social cognition and fewer negative symptoms. In the bipolar I disorder group, clinical insight showed small associations with social cognition (largest r = -0.28) and moderate to large associations with positive, negative, manic, and depressive symptoms. Poorer insight was associated with higher symptom load. Social cognition seems to be of importance for clinical insight in schizophrenia, whereas symptoms are important in bipolar I disorder.

Schizophrenia is a serious mental disorder that affects several brain functions. MRI technology has enabled in vivo studies of brain anatomy in patients with schizophrenia aimed at understanding more about the disorder.This article is based on a search in PubMed on «schizophrenia MRI» and on the authors' own research and experience. We included structural MRI studies, carried out on humans, written in English. Here we present a selection of studies that we believe are representative of the field.In patients with schizophrenia, MR imaging shows a smaller total brain volume and enlarged ventricles. Specific subcortical regions are affected, with reduced hippocampal and thalamic volumes, and an increase in the volume of the globus pallidus. In the cortex can be seen changes in folding patterns and a reduction in cortical volume and thickness, most pronounced in the frontal and temporal lobes. These findings are at group level--there is a high degree of overlap between sick and healthy individuals, and the effect sizes are medium to small. Several of the changes are present at onset of the disorder; this supports the theory that schizophrenia may be related to abnormal neurodevelopment. Longitudinal anatomical changes are reported, but it is uncertain what these changes represent.The research literature shows that schizophrenia has neuroanatomical correlates that can be seen at group level by studying MR images. Structural MRI cannot currently be used to identify schizophrenia at the level of the individual.

Longitudinal studies on first-episode psychosis (FEP) patients have shown a decrease of substance use disorders (SUDs) over the first years of illness, but there has been less focus on the gender aspect. The present study examines stability of alcohol and illicit substance use, with specific focus on gender, in a one year follow-up investigation of 154 FEP patients (91 men, 63 women) in Oslo, Norway, using criteria for DSM-IV substance use disorder diagnosis, the Alcohol Use Disorders Identification Test (AUDIT) and the Drug Use Disorders Identification Test (DUDIT). The results show that cannabis was the most frequently used illicit substance at both times. Significantly more men (34%) than women (13%) had a current illicit SUD at baseline. At follow-up, the rate of illicit SUDs was significantly reduced in men (18%) but not in women (11%). There were no significant gender differences in the rate of current alcohol use disorders (AUD) (men 14%; women 8%) at baseline, and no significant reduction in AUD in any of the genders at follow-up. At follow-up, total AUDIT and DUDIT scores were reduced in men only. In conclusion, the high and persistent rate of SUDs, particularly of cannabis, among men and women during the first year of treatment for psychosis should be addressed in the clinical management of the patients. Female FEP patients who are also substance users may be particularly vulnerable in this regard and warrant closer attention.

Background Normal birth weight variation affects schizophrenia risk and cognitive performance in schizophrenia patients and healthy controls. Brain cortical anatomy is altered in psychotic disorders and in low birth weight subjects, but if birth weight variation relates to cortical morphology across the psychosis spectrum is not known. Methods Magnetic Resonance Imaging brain scans and clinical-, neurocognitive-, and medical birth registry data were collected from 359 adults including patients with a DSM-IV diagnosis of schizophrenia (n = 90, mean age 29.4±10.2 [95% CI], 62% male), bipolar disorder (n = 79, age 29.4±11.8, 39% male) or other psychosis (n = 40, age 26.3±10.0, 56% male), and healthy controls (n = 140, age 30.8±12.0,53% male). We explored the relationship between whole-range birth weight variation and cortical surface area and thickness and their possible associations to cognitive performance. Results Across all groups, lower birth weight was associated with smaller total surface area (t = 3.87, P = .0001), within specific regions of the temporal, parietal, and frontal cortex bilaterally. There were no associations between birth weight and cortical thickness, and no diagnosis by birth weight interaction effects on cortical thickness or surface area. Smaller cortical area (t = 2.50, P = .013) and lower birth weight (t = 2.53, P = .012) were significantly related to poorer working memory performance in all diagnostic groups except schizophrenia. Conclusion Birth weight relates to adult cortical surface area, but not cortical thickness, in patients across the psychosis spectrum and in healthy controls. Cortical area appears to be a diagnosis-independent general marker of early neurodevelopment, with a dose-response association to normal birth weight variation.

While recent genome-wide association studies have identified several new bipolar disorder (BD) risk variants, structural imaging studies have reported enlarged ventricles and volumetric reductions among the most consistent findings. We investigated whether these genetic risk variants could explain some of the structural brain abnormalities in BD.In a sample of 517 individuals (N=121 BD cases, 116 SZ cases, 61 other psychosis cases and 219 healthy controls), we tested the potential association between nine SNPs in the genes CACNA1C, ANK3, ODZ4 and SYNE1 and eight brain structural measures found to be altered in BD, and if these were specifically affecting the BD sample. We also assessed the polygenic effect of all these 9 SNPs on the brain phenotypes.Our most significant result was an association between the risk allele A in CACNA1C SNP rs4775913 and decreased cerebellar volume (pnom.=0.0075) in the total sample, which did not remain significant after multiple testing correction (pthreshold0.0064). There was no evidence for diagnostic specificity for this association in the BD group. Further, no polygenic effect of these 9 SNPs was observed.Low statistical power might increase our type II error rate.The present findings indicate that these risk SNPs do not explain a large proportion of the structural brain alterations in BD. Thus, these genes which are all related to neuronal functions must be involved in other pathophysiological aspects of BD development.

Several lines of evidence suggest that genome-wide association studies (GWASs) have the potential to explain more of the "missing heritability" of common complex phenotypes. However, reliable methods for identifying a larger proportion of SNPs are currently lacking. Here, we present a genetic-pleiotropy-informed method for improving gene discovery with the use of GWAS summary-statistics data. We applied this methodology to identify additional loci associated with schizophrenia (SCZ), a highly heritable disorder with significant missing heritability. Epidemiological and clinical studies suggest comorbidity between SCZ and cardiovascular-disease (CVD) risk factors, including systolic blood pressure, triglycerides, low- and high-density lipoprotein, body mass index, waist-to-hip ratio, and type 2 diabetes. Using stratified quantile-quantile plots, we show enrichment of SNPs associated with SCZ as a function of the association with several CVD risk factors and a corresponding reduction in false discovery rate (FDR). We validate this "pleiotropic enrichment" by demonstrating increased replication rate across independent SCZ substudies. Applying the stratified FDR method, we identified 25 loci associated with SCZ at a conditional FDR level of 0.01. Of these, ten loci are associated with both SCZ and CVD risk factors, mainly triglycerides and low- and high-density lipoproteins but also waist-to-hip ratio, systolic blood pressure, and body mass index. Together, these findings suggest the feasibility of using genetic-pleiotropy-informed methods for improving gene discovery in SCZ and identifying potential mechanistic relationships with various CVD risk factors. © 2013 The American Society of Human Genetics.

Several lines of evidence suggest that common polygenic variation influences brain function in humans. Combining high-density genetic markers with brain imaging techniques is constricted by the practicalities of collecting sufficiently large brain imaging samples. Pathway analysis promises to leverage knowledge on function of genes to detect recurring signals of moderate effect. We adapt this approach, exploiting the deep information collected on brain function by fMRI methods, to identify molecular pathways containing genetic variants which influence brain activation during a commonly applied experiment based on a face matching task (n=246) which was developed to study neural processing of faces displaying negative emotions. Genetic markers moderately associated (p

As the amygdala is part of the phylogenetic old brain, and its anatomical and functional properties are conserved across species, it is reasonable to assume genetic influence on its activity. A large corpus of candidate gene studies indicate that individual differences in amygdala activity may be caused by genetic variants within monoaminergic signaling pathways such as dopamine, serotonin, and norepinephrine. However, to our knowledge, the use of genome-wide data to discover genetic variants underlying individual differences in adult amygdala activity is novel. In the present study, the combination of genome-wide data and functional imaging phenotypes from an emotional faces task yielded a significant association between rs10014254 and the amygdala using a region of interest approach. This single nucleotide polymorphism is located in a regulatory region upstream of the Paired-like homeobox 2b (PHOX2B) gene; therefore it could affect the expression of this gene. PHOX2B regulates the expression of enzymes necessary for the synthesis of several monoamines and is essential for the development of the autonomic nervous system. However, an attempt to replicate the finding in an independent sample from North America did not succeed. The synthesis of functional magnetic resonance imaging (fMRI) and genome-wide data takes a hypothesis-free approach as to which genetic variants are of interest. Therefore, we believe that an undirected finding within such a plausible region is of interest, and that our results add further support to the hypothesis that monoaminergic signaling pathways play a central role in regulating amygdala activity.

ZNF804A SNP rs1344706 confers genome-wide risk for schizophrenia and bipolar disorder. Both disorders affect cortical thickness. To determine if single nucleotide polymorphisms (SNPs) across ZNF804A are associated with cortical thinning, we investigated 63 SNPs (including rs1344706) in 365 psychosis patients and healthy controls. Results show no significant associations.

This study describes the prevalence, clinical characteristics, and gender profile of self-harm in a cross-sectional sample of 388 patients with schizophrenia spectrum disorders. All patients were interviewed and assessed with respect to lifetime self-harm and relevant clinical variables. An overall of 49% of the patients reported self-harm which was associated with female gender, having had a depressive episode, younger age at psychosis onset, alcohol abuse or dependence, current suicidality, awareness of illness, and low adherence to prescribed medication. Higher awareness of having a mental disorder was associated with self-harm in men only, while emotional dysregulation was associated with self-harm in women only. We conclude that while self-harm in patients with schizophrenia spectrum disorders is highly prevalent in both genders, risk factors in men and women differ in several important ways.

Background Previous studies suggest elevated inflammation in schizophrenia and bipolar disorder, with increased activity of the Interleukin 1 (IL-1), interleukin 6 (IL-6), tumor necrosis factor (TNF)-alpha, von Willebrand factor (vWf) and osteoprotegerin (OPG). It is unclear how immune activation is involved in the psychopathology. We investigated if elevated inflammation was associated with disease severity (trait) or current symptom level (state), comparing psychotic with general characteristics. Methods Plasma levels of sTNF receptor 1 (sTNF-R1), IL-1 receptor antagonist (IL-1Ra), IL-6, vWf and OPG were measured with ELISA techniques in 322 patients with schizophrenia spectrum and bipolar disorder. Current symptom level (state) was measured with Global Assessment of Functioning (GAF) and Positive and Negative Syndrome Scale (PANSS). Disease severity (trait) was measured with premorbid adjustment scale (PAS), age at onset, number of psychotic episodes and number and length of hospitalizations. Results After controlling for confounders, IL-1Ra and TNF-R1 were independently associated with GAF, and significantly correlated with PANSS negative and positive, respectively. In addition, Il-1Ra was associated with PAS, and sTNF-R1 with number of hospitalizations and psychotic episodes. VWf was significantly correlated with psychotic episodes, OPG with hospitalizations and IL-6 with history of psychosis. Linear regression analysis showed that GAF remained associated with sTNF-R1 and IL-1Ra with PANSS, after controlling for the other clinical measures. Conclusions This supports that inflammatory markers, particularly IL-1Ra and sTNF-R1 are associated with both general disease severity and psychotic features. This supports a role of immune activation in the core pathological mechanisms of severe mental disorders.

Background The goal of this study was to investigate differences in executive functioning between patients with early-onset and adult-onset schizophrenia spectrum psychoses at the time of first treatment. Methods Neuropsychological tests covering executive functioning domains were performed for 20 adolescents with early-onset schizophrenia (EOS) close to first treatment and 90 first episode patients with adult onset schizophrenia (AOS) in addition to 66 adolescent- and 127 adult age and gender matched healthy controls. Results Both EOS and AOS patients had significantly poorer executive performance than their age- and gender matched healthy counterparts. Both healthy adolescent controls and EOS patients had poorer executive performance than their adult counterparts. However, there were no differences in executive functioning between EOS and AOS patients after controlling for the levels of their age matched healthy control groups. Substituting EOS/AOS status with other age-at-onset thresholds had no effect. Conclusions We find the same relative levels of executive dysfunction in EOS- and AOS groups at the time of first treatment. This does not necessarily contradict previous findings of more severe dysfunction in EOS patients over time, but indicates an interaction between the disorder and the maturational processes that only can be investigated through longitudinal studies.

Signs of social dysfunction are present early in the course of psychotic disorders. There is a lack of knowledge about how premorbid function, illness history, psychotic symptoms and neurocognitive characteristics are related to social function in patients with first episode psychosis (FEP). The relationship between these factors could provide important information about the psychopathology underlying social dysfunction and have implications for future prevention and treatment efforts. Our objective is to identify early predictors of social functioning in patients with FEP. We examined 166 patients and 166 age- and gender-matched healthy controls (HC). We used a validated and comprehensive measure of social functioning (the Social Functioning Scale), a comprehensive neurocognitive test battery, in addition to measures of psychotic symptoms, duration of untreated psychosis (DUP) and premorbid adjustment (the Premorbid Adjustment Scale). Lower childhood level of social adjustment and lower psychomotor speed had the strongest influence across measures of social functioning while symptoms and DUP had a weaker influence. The main result of the current study is that premorbid social adjustment and psychomotor speed had the strongest association with measures of social functioning in patients with FEP.

The presence of subclinical levels of psychosis in the general population may imply that schizophrenia is the extreme expression of more or less continuously distributed traits in the population. In a previous study, we identified five quantitative measures of schizophrenia (positive, negative, disorganisation, mania, and depression scores). The aim of this study is to examine the association between a direct measure of genetic risk of schizophrenia and the five quantitative measures of psychosis. Estimates of the log of the odds ratios of case/control allelic association tests were obtained from the Psychiatric GWAS Consortium (PGC) (minus our sample) which included genome-wide genotype data of 8,690 schizophrenia cases and 11,831 controls. These data were used to calculate genetic risk scores in 314 schizophrenia cases and 148 controls from the Netherlands for whom genotype data and quantitative symptom scores were available. The genetic risk score of schizophrenia was significantly associated with case-control status (p

Recent molecular studies have implicated common alleles of small to moderate effect and rare alleles with larger effect sizes in the genetic architecture of schizophrenia (SCZ). It is expected that the reliable detection of risk variants with very small effect sizes can only be achieved through the recruitment of very large samples of patients and controls (that is tens of thousands), or large, potentially more homogeneous samples that have been recruited from confined geographical areas using identical diagnostic criteria. Applying the latter strategy, we performed a genome-wide association study (GWAS) of 1169 clinically well characterized and ethnically homogeneous SCZ patients from a confined area of Western Europe (464 from Germany, 705 from The Netherlands) and 3714 ethnically matched controls (1272 and 2442, respectively). In a subsequent follow-up study of our top GWAS results, we included an additional 2569 SCZ patients and 4088 controls (from Germany, The Netherlands and Denmark). Genetic variation in a region on chromosome 11 that contains the candidate genes AMBRA1, DGKZ, CHRM4 and MDK was significantly associated with SCZ in the combined sample (n = 11 540; P = 3.89 x 10(-9), odds ratio (OR) = 1.25). This finding was replicated in 23 206 independent samples of European ancestry (P = 0.0029, OR= 1.11). In a subsequent imaging genetics study, healthy carriers of the risk allele exhibited altered activation in the cingulate cortex during a cognitive control task. The area of interest is a critical interface between emotion regulation and cognition that is structurally and functionally abnormal in SCZ and bipolar disorder. Molecular Psychiatry (2012) 17, 906-917; doi: 10.1038/mp.2011.80; published online 12 July 2011

Background Evidence of associations between neurocognitive function and cannabis use in schizophrenia is inconclusive. However, direct measures of cannabis intake and premorbid function are rarely explored in this context. We investigated the relation between cannabis use, determined by its presence in urine, and neurocognitive functioning in schizophrenia controlling for the potential bias of premorbid functioning. Methods Naturalistic study of 364 patients with schizophrenia spectrum disorder from catchment areas in Oslo, Norway. Hierarchical multiple regression analyses were used to assess the relationship between cannabis in urine and measures of neurocognitive functioning, with adjustment for confounders, including premorbid functioning. Results Cannabis was detected in the urine of 21 patients, who had significant dysfunction in several neurocognitive domains independent of a current diagnosis of cannabis abuse. However, level of premorbid functioning explained the associations for all measures. Conclusion Differences in premorbid functioning may explain apparent differences in neurocognitive function between schizophrenia spectrum patients using cannabis or not. The findings suggest that illness-related traits present early in life can affect both later cannabis use and neurocognition, probably by complex mechanisms.

Relationships between cortical brain structure and neurocognitive functioning have been reported in schizophrenia, but findings are inconclusive, and only a few studies in bipolar disorder have addressed this issue. This is the first study to directly compare relationships between cortical thickness and surface area with neurocognitive functioning in patients with schizophrenia (n = 117) and bipolar disorder (n = 121) and healthy controls (n = 192). MRI scans were obtained, and regional cortical thickness and surface area measurements were analyzed for relationships with test scores from 6 neurocognitive domains. In the combined sample, cortical thickness in the right rostral anterior cingulate was inversely related to working memory, and cortical surface area in four frontal and temporal regions were positively related to neurocognitive functioning. A positive relationship between left transverse temporal thickness and processing speed was specific to schizophrenia. A negative relationship between right temporal pole thickness and working memory was specific to bipolar disorder. In conclusion, significant cortical structure/function relationships were found in a large sample of healthy controls and patients with schizophrenia or bipolar disorder. The differences that were found between schizophrenia and bipolar may indicate differential relationship patterns in the two disorders, which may be of relevance for understanding the underlying pathophysiology. (JINS, 2011, 17, 1080–1093)

Objective: The functional polymorphism in the promoter region of the SLC6A4/5-HTT serotonin transporter gene (5-HTTLPR) has been linked to altered stress response. Carriers of the short (s-) allele have increased negative psychological reactions and stress hormone release compared with carriers of the long (l-) allele, interacting with severe life events including childhood trauma. High stress levels are associated with cognitive impairments in a variety of clinical and experimental studies. Patients with psychotic disorders are characterized both by more childhood traumatic events and abnormal stress responses and by significant but highly variable cognitive dysfunction. We hypothesize that 5-HTTLPR variations and long-term effects of childhood trauma interact and contribute to some of the variation in cognitive dysfunction seen in patients with psychotic disorders. Methods: Patients with psychotic disorders (schizophrenia and affective spectrums) were recruited from a catchment area–based treatment organization. History of childhood abuse was obtained by the Childhood Trauma Questionnaire. Cognitive function was assessed through a comprehensive, standardized neuropsychological test battery. 5-HTTLPR genotypes were analyzed using standard polymerase chain reaction. Results: We observed a significant interaction between 5-HTTLPR variants and childhood trauma across cognitive domains; here, homozygotic s-carriers exposed to high levels of childhood trauma (physical neglect and abuse) had significantly poorer cognitive functioning than all other groups. Conclusions: Our results need replication but underline the importance of investigating childhood trauma and its interaction with genetic markers when studying cognitive dysfunction in patients with psychotic disorders.