Despite the widespread use of antipsychotics, little is known of the molecular bases behind the action of antipsychotic drugs. A genome-wide study is needed to characterize the genes that affect the clinical response and their adverse effects.

Hosting nearly eighty percent of all human neurons, the cerebellum is functionally connected to large regions of the brain. Accumulating data suggest that some cerebellar resting-state alterations may constitute a key candidate mechanism for depressive psychopathology. While there is some evidence linking cerebellar function and depression, two topics remain largely unexplored. First, the genetic or environmental roots of this putative association have not been elicited. Secondly, while different mathematical representations of resting-state fMRI patterns can embed diverse information of relevance for health and disease, many of them have not been studied in detail regarding the cerebellum and depression. Here, high-resolution fMRI scans were examined to estimate functional connectivity patterns across twenty-six cerebellar regions in a sample of 48 identical twins (24 pairs) informative for depression liability. A network-based statistic approach was employed to analyze cerebellar functional networks built using three methods: the conventional approach of filtered BOLD fMRI time-series, and two analytic components of this oscillatory activity (amplitude envelope and instantaneous phase). The findings indicate that some environmental factors may lead to depression vulnerability through alterations of the neural oscillatory activity of the cerebellum during resting-state. These effects may be observed particularly when exploring the amplitude envelope of fMRI oscillations.

Different effectiveness profiles among second-generation antipsychotics may be a key point to optimize treatment in patients suffering a first episode of psychosis to affect long-term outcome. The aim of this study was to compare the clinical effectiveness of aripiprazole, ziprasidone, and quetiapine in the treatment of first episode of psychosis at 3-year follow-up.

Antipsychotic drugs are one of the largest types of prescribed drugs and have large inter-individual differences in efficacy, but there is no methodology to predict their clinical effect. Here we show a four-gene blood expression profile to predict the response to antipsychotics in schizophrenia patients before treatment. We sequenced total mRNA from blood samples of antipsychotic naïve patients who, after 3 months of treatment, were in the top 40% with the best response (15 patients) and in the bottom 40% with the worst response (15 patients) according to the Brief Psychiatric Rating Scale (BPRS). We characterized the transcriptome before treatment of these 30 patients and found 130 genes with significant differential expression (Padj value < 0.01) associated with clinical response. Then, we used Random Forests, an ensemble learning method for classification and regression, to obtain a list of predictor genes. The expression of four genes can predict the response to antipsychotic medication with a cross-validation accuracy estimation of 0.83 and an area under the curve of 0.97 using a logistic regression. We anticipate that this approach is a gateway to select the specific antipsychotic that will produce the best response to treatment for each specific patient.

Health-care Workers (HCW) are facing a critical situation caused by Coronavirus Disease 2019 (COVID-19) which could impact on their mental health status. In addition, HCW women have been identified as a group at high-risk of developing psychological distress, although no previous longitudinal studies have explored this issue in a sample of HCW.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Antipsychotics are crucial for the treatment of schizophrenia and contribute to weight gain in psychosis, particularly during early phases. Antipsychotic Induced Weight Gain (AIWG) might contribute to reduce the quality of life, drug compliance and to increase mortality. To characterize sex differences of gene expression related to AIWG, we sequenced total mRNA from blood samples of schizophrenia patients, before and after 3 months of antipsychotic-treatment. We analyzed schizophrenia patients according to their sex (38 males and 39 females) and their BMI increase after medication, characterizing the differential gene expression before and after medication. Individuals in each group were categorized in patients who gain weight and those whose do not gain weight. The "weight gain" groups included patients with an increase of body mass index (BMI) > 1.0 points (27 males and 23 females with a median BMI increase of 2.68 and 2.32 respectively). The "no weight gain" groups included patients with a change of BMI between < 1.0 and > -1.0 points (11 males and 16 females with a median BMI increase of 0.21 and 0.16 respectively). The males had 331 genes with significant differential expression in the weight gain group and 24 genes in the no weight gain group. The females had 119 genes with significant differential expression in the weight gain group and 75 genes in the no weight gain group. Both weight gain groups were significantly enriched with "obesity" genes (Fisher; p = 1.1E-09 and p = 0.0001 respectively), according to the Gene Reference into Function (GeneRIF) database.In conclusion, we characterized genes with differential expression associated to AIWG that are specific to males, to females and common to both sexes. These genes are good candidates to depict the biological processes involved in AIWG and provide additional evidence of the genetic links between weight gain and the immune system.

Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life.

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

The catechol-O-methyltransferase (COMT) enzyme plays a crucial role in dopamine degradation, and the COMT Val158Met polymorphism (rs4680) is associated with significant differences in enzymatic activity and consequently dopamine concentrations in the prefrontal cortex. Multiple studies have analyzed the COMT Val158Met variant in relation to antipsychotic response. Here, we conducted a meta-analysis examining the relationship between COMT Val158Met and antipsychotic response.

This large multi-center study investigates the relationships between genetic risk for schizophrenia and bipolar disorder, and multi-modal endophenotypes for psychosis. The sample included 4,242 individuals; 1,087 patients with psychosis, 822 unaffected first-degree relatives of patients, and 2,333 controls. Endophenotypes included the P300 event-related potential (N = 515), lateral ventricular volume (N = 798), and the cognitive measures block design (N = 3,089), digit span (N = 1,437), and the Ray Auditory Verbal Learning Task (N = 2,406). Data were collected across 11 sites in Europe and Australia; all genotyping and genetic analyses were done at the same laboratory in the United Kingdom. We calculated polygenic risk scores for schizophrenia and bipolar disorder separately, and used linear regression to test whether polygenic scores influenced the endophenotypes. Results showed that higher polygenic scores for schizophrenia were associated with poorer performance on the block design task and explained 0.2% (p = 0.009) of the variance. Associations in the same direction were found for bipolar disorder scores, but this was not statistically significant at the 1% level (p = 0.02). The schizophrenia score explained 0.4% of variance in lateral ventricular volumes, the largest across all phenotypes examined, although this was not significant (p = 0.063). None of the remaining associations reached significance after correction for multiple testing (with alpha at 1%). These results indicate that common genetic variants associated with schizophrenia predict performance in spatial visualization, providing additional evidence that this measure is an endophenotype for the disorder with shared genetic risk variants. The use of endophenotypes such as this will help to characterize the effects of common genetic variation in psychosis.

Lack of insight is a core feature of non-affective psychosis and has been associated with poorer outcomes. Brain abnormalities underlying lack of insight have been suggested, mostly in the frontal lobe, although previous research showed mixed results. We used a voxel-based morphometry (VBM) analysis in 108 first-episode non-affective psychosis patients to investigate the pattern of brain structural abnormalities related to lack of insight. In addition, 77 healthy volunteers were compared with the patients classified as having poor and good insight. The shortened version of the Scale to Assess Unawareness of Mental Disorder was used to evaluate insight. Patients with poor insight (n = 68) compared with patients with good insight (n = 40) showed a single significant cluster (kc = 5834; PcFWE = 0.001) of reduced grey matter volume (GMV) in the right occipital lobe extending to its lateral and medial surfaces, the cuneus, and the middle temporal gyrus. In addition, GMV at this cluster showed a negative correlation with the score of the SUMD (r = -0.305; p = 0.001). When comparing patients with poor insight with healthy subjects overall reductions of GMV were found, mainly in frontal and occipital lobes. Hence, poor insight in non-affective psychosis seems to be associated with specific brain abnormalities in the right occipital and temporal cortical regions. Dysfunction in any combination of these areas may contribute to lack of insight in non-affective psychosis. Specifically, the 'right' hemisphere dysfunction underlying impaired insight in our sample is consistent with previously reported similarities between lack of insight in psychosis and anosognosia in neurological disorders.

The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group.

Toll-like receptors (TLRs) are a pivotal component of the innate immune system that seem to have a role in the pathogenesis of psychosis. The purpose of this work was to compare the expression and functionality of 9 TLRs in three peripheral blood mononuclear cells (PBMCs) (monocytes, B cells, and T cells) between 33 drug-naïve first-episode psychosis (FEP) individuals and 26 healthy volunteers, at baseline and after 3-month of antipsychotic treatment. The expression of TLRs 1-9 were assessed by flow cytometry. For the assessment of the TLR functionality, cells collected in sodium heparin tubes were polyclonally stimulated for 18 h, with different agonists for human TLR1-9. The results of our study highlight the role that TLR5 and TLR8 might play in the pathophysiology of psychosis. We found a lower expression of these receptors in FEP individuals, regarding healthy volunteers at baseline and after 3-month of treatment on the three PBMCs subsets. Most TLRs showed a lower functionality (especially reduced intracellular levels of TNF-α) in patients than in healthy volunteers. These results, together with previous evidence, suggest that individuals with psychosis might show a pattern of TLR expression that differs from that of healthy volunteers, which could vary according to the intensity of immune/inflammatory response.

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging.

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders.

Cortical thickness has been widely studied in individuals with schizophrenia and, in particular, first-episode psychosis. Abnormalities have been described, although there is, to date, a lack of consensus regarding changes across time and correlations with clinical and functional outcomes of the illness. One hundred and twenty-three first-episode psychosis patients and 74 healthy volunteers were subjected to magnetic resonance imaging scans and clinical and functional assessments by different scales at four consecutive visits during a 10 year follow-up period. Linear mixed effects models were applied to our data to compute cortical thickness changes over time in (1) schizophrenia patients versus healthy controls and (2) in patients with good versus poor functional outcome. The associations between cortical thickness percentage changes and clinical and functional status at 10 years were also assessed. The patients presented a thinner cortex than the controls at baseline (b's = -0.06; q ≤ 0.00023) with non-significant coefficients for the interaction term (follow-up time x group) (b's = -0.001; q ≥ 0.681). Poor functioning patients presented statistically significant coefficients for the interaction term (follow-up time x functionality) (left: b = -0.005, q = 0.019; right: b = -0.005, q = 0.022). In contrast, no correlations were found between cortical thickness measurements and clinical variables at 10 years. Overall, there were widespread thickness anomalies in first-episode psychosis patients across cortical regions that remained stable across time. Progressive thickness changes were related to patient functional outcomes, with progressive and steeper cortical thinning in patients with worse functional outcomes and a stabilization in those with better outcomes.

Previous research suggests an association of loneliness and social isolation (LNL-ISO) with schizophrenia. Here, we demonstrate a LNL-ISO polygenic score contribution to schizophrenia risk in an independent case-control sample (N = 3,488). We then subset schizophrenia predisposing variation based on its effect on LNL-ISO. We find that genetic variation with concordant effects in both phenotypes shows significant SNP-based heritability enrichment, higher polygenic contribution in females, and positive covariance with mental disorders such as depression, anxiety, attention-deficit hyperactivity disorder, alcohol dependence, and autism. Conversely, genetic variation with discordant effects only contributes to schizophrenia risk in males and is negatively correlated with those disorders. Mendelian randomization analyses demonstrate a plausible bi-directional causal relationship between LNL-ISO and schizophrenia, with a greater effect of LNL-ISO liability on schizophrenia than vice versa. These results illustrate the genetic footprint of LNL-ISO on schizophrenia.

Our aim was to, firstly, identify characteristics at first-episode of psychosis that are associated with later antipsychotic treatment resistance (TR) and, secondly, to develop a parsimonious prediction model for TR.

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.