Associations between structural brain changes and blood neurofilament light chain protein in treatment-resistant schizophrenia.

Background and Hypothesis: Around 30% of people with schizophrenia are refractory to antipsychotic treatment (treatment-resistant schizophrenia; TRS). While abnormal structural neuroimaging findings, in particular volume and thickness reductions, are often observed in schizophrenia, it is anticipated that biomarkers of neuronal injury like neurofilament light chain protein (NfL) can improve our understanding of the pathological basis underlying schizophrenia. The current study aimed to determine whether people with TRS demonstrate different associations between plasma NfL levels and regional cortical thickness reductions compared with controls. Study Design: Measurements of plasma NfL and cortical thickness were obtained from 39 individuals with TRS, and 43 healthy controls. T1-weighted magnetic resonance imaging sequences were obtained and processed via FreeSurfer. General linear mixed models adjusting for age and weight were estimated to determine whether the interaction between diagnostic group and plasma NfL level predicted lower cortical thickness across frontotemporal structures and the insula. Study Results: Significant (false discovery rate corrected) cortical thinning of the left (p = 0.001, η2p = 0.104) and right (p < 0.001, η2p = 0.167) insula was associated with higher levels of plasma NfL in TRS, but not in healthy controls. Conclusions: The association between regional thickness reduction of the insula bilaterally and plasma NfL may reflect a neurodegenerative process during the course of TRS. The findings of the present study suggest that some level of cortical degeneration localised to the bilateral insula may exist in people with TRS, which is not observed in the normal population.

Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia: randomized trials and multiomics analysis.

BACKGROUND: Choosing the appropriate antipsychotic drug (APD) treatment for patients with schizophrenia (SCZ) can be challenging, as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers. Previous studies have indicated the association between treatment response and genetic and epigenetic factors, but no effective biomarkers have been identified. Hence, further research is imperative to enhance precision medicine in SCZ treatment. METHODS: Participants with SCZ were recruited from two randomized trials. The discovery cohort was recruited from the CAPOC trial (n = 2307) involved 6 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, Quetiapine, Aripiprazole, Ziprasidone, and Haloperidol/Perphenazine (subsequently equally assigned to one or the other) groups. The external validation cohort was recruited from the CAPEC trial (n = 1379), which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, and Aripiprazole groups. Additionally, healthy controls (n = 275) from the local community were utilized as a genetic/epigenetic reference. The genetic and epigenetic (DNA methylation) risks of SCZ were assessed using the polygenic risk score (PRS) and polymethylation score, respectively. The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis, methylation quantitative trait loci, colocalization, and promoter-anchored chromatin interaction. Machine learning was used to develop a prediction model for treatment response, which was evaluated for accuracy and clinical benefit using the area under curve (AUC) for classification, R2 for regression, and decision curve analysis. RESULTS: Six risk genes for SCZ (LINC01795, DDHD2, SBNO1, KCNG2, SEMA7A, and RUFY1) involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response. The developed and externally validated prediction model, which incorporated clinical information, PRS, genetic risk score (GRS), and proxy methylation level (proxyDNAm), demonstrated positive benefits for a wide range of patients receiving different APDs, regardless of sex [discovery cohort: AUC = 0.874 (95% CI 0.867-0.881), R2 = 0.478; external validation cohort: AUC = 0.851 (95% CI 0.841-0.861), R2 = 0.507]. CONCLUSIONS: This study presents a promising precision medicine approach to evaluate treatment response, which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ. Trial registration Chinese Clinical Trial Registry ( https://www.chictr.org.cn/ ), 18. Aug 2009 retrospectively registered: CAPOC-ChiCTR-RNC-09000521 ( https://www.chictr.org.cn/showproj.aspx?proj=9014 ), CAPEC-ChiCTR-RNC-09000522 ( https://www.chictr.org.cn/showproj.aspx?proj=9013 ).

Perturbed iron biology in the prefrontal cortex of people with schizophrenia.

Despite loss of grey matter volume and emergence of distinct cognitive deficits in young adults diagnosed with schizophrenia, current treatments for schizophrenia do not target disruptions in late maturational reshaping of the prefrontal cortex. Iron, the most abundant transition metal in the brain, is essential to brain development and function, but in excess, it can impair major neurotransmission systems and lead to lipid peroxidation, neuroinflammation and accelerated aging. However, analysis of cortical iron biology in schizophrenia has not been reported in modern literature. Using a combination of inductively coupled plasma-mass spectrometry and western blots, we quantified iron and its major-storage protein, ferritin, in post-mortem prefrontal cortex specimens obtained from three independent, well-characterised brain tissue resources. Compared to matched controls (n = 85), among schizophrenia cases (n = 86) we found elevated tissue iron, unlikely to be confounded by demographic and lifestyle variables, by duration, dose and type of antipsychotic medications used or by copper and zinc levels. We further observed a loss of physiologic age-dependent iron accumulation among people with schizophrenia, in that the iron level among cases was already high in young adulthood. Ferritin, which stores iron in a redox-inactive form, was paradoxically decreased in individuals with the disorder. Such iron-ferritin uncoupling could alter free, chemically reactive, tissue iron in key reasoning and planning areas of the young-adult schizophrenia cortex. Using a prediction model based on iron and ferritin, our data provide a pathophysiologic link between perturbed cortical iron biology and schizophrenia and indicate that achievement of optimal cortical iron homeostasis could offer a new therapeutic target.

Delineating gene-environment effects using virtual twins of patients treated with clozapine.

Studies that focus on individual covariates, while ignoring their interactions, may not be adequate for model-informed precision dosing (MIPD) in any given patient. Genetic variations that influence protein synthesis should be studied in conjunction with environmental covariates, such as cigarette smoking. The aim of this study was to build virtual twins (VTs) of real patients receiving clozapine with interacting covariates related to genetics and environment and to delineate the impact of interacting covariates on predicted clozapine plasma concentrations. Clozapine-treated patients with schizophrenia (N = 42) with observed clozapine plasma concentrations, demographic, environmental, and genotype data were used to construct VTs in Simcyp. The effect of increased covariate virtualization was assessed by performing simulations under three conditions: "low" (demographic), "medium" (demographic and environmental interaction), and "high" (demographic and environmental/genotype interaction) covariate virtualization. Increasing covariate virtualization with interaction improved the coefficient of variation (R2 ) from 0.07 in the low model to 0.391 and 0.368 in the medium and high models, respectively. Whereas R2 was similar between the medium and high models, the high covariate virtualization model had improved accuracy, with systematic bias of predicted clozapine plasma concentration improving from -138.48 ng/ml to -74.65 ng/ml. A high level of covariate virtualization (demographic, environmental, and genotype) may be required for MIPD using VTs.

IRP commission: sexual minorities and mental health: global perspectives.

Sexual orientation is a key determinant of the identity of human beings. It has also been seen as a social determinant of health. People whose sexual orientation is non-heterosexual or sexual minorities or sexually diverse are included in the broad umbrella term LGBT (Lesbian, Gay, Bisexual, and Transgender) which is a commonly used acronym in activism, social policy, and subsequently cultural literature. For this reason, this Commission focuses primarily on sexual orientation i.e. lesbian, gay and bisexual (LGB) groups. We have used terms non-heterosexual, sexual minorities or sexual variation interchangeably. We have not considered asexual individuals as research in the field is too limited. We are cognisant of the fact that topics relating to mental health and sexual orientation discussed in this Commission will intersect with other issues of personal, cultural and social identity, and will thus be relevant to individuals including many transgender individuals. The inclusion of mental health issues relevant to gender-diverse individuals as well as gender identity is important and deserves its own separate detailed discussion. The exact number of sexually diverse individuals in a population is often difficult to estimate but is likely to be somewhere around 5% of the population. Rates of various psychiatry disorders and suicidal ideation and acts of suicide in LGB populations are higher than general population and these have been attributed to minority stress hypothesis. Elimination of inequality in law can lead to reduction in psychiatric morbidity in these groups. However, these are all diverse groups but even within each group there is diversity and each individual has a distinct and unique experiences, upbringing, responses to their own sexual orientation, and generating varying responses from families, peers and friends as well as communities (including healthcare professionals). The mental healthcare needs of sexual minority individuals vary and these variations must be taken into account in design, development and delivery of healthcare and policies. Improving access to services will help engagement and outcomes and also reduce stigma. The commission recommends that there is no role for so-called conversion therapies and other recommendations are made for clinicians, researchers and policymakers.

Cortico-cognition coupling in treatment resistant schizophrenia.

BACKGROUND: Brain structural alterations and cognitive dysfunction are independent predictors for poor clinical outcome in schizophrenia, and the associations between these domains remains unclear. We employed a novel, multiblock partial least squares correlation (MB-PLS-C) technique and investigated multivariate cortico-cognitive patterns in patients with treatment-resistant schizophrenia (TRS) and matched healthy controls (HC). METHOD: Forty-one TRS patients (age 38.5 ± 9.1, 30 males (M)), and 45 HC (age 40.2 ± 10.6, 29 M) underwent 3T structural MRI. Volumes of 68 brain regions and seven variables from CANTAB covering memory and executive domains were included. Univariate group differences were assessed, followed by the MB-PLS-C analyses to identify group-specific multivariate patterns of cortico-cognitive coupling. Supplementary three-group analyses, which included 23 non-affected first-degree relatives (NAR), were also conducted. RESULTS: Univariate tests demonstrated that TRS patients showed impairments in all seven cognitive tasks and volume reductions in 12 cortical regions following Bonferroni correction. The MB-PLS-C analyses revealed two significant latent variables (LVs) explaining > 90% of the sum-of-squares variance. LV1 explained 78.86% of the sum-of-squares variance, describing a shared, widespread structure-cognitive pattern relevant to both TRS patients and HCs. In contrast, LV2 (13.47% of sum-of-squares variance explained) appeared specific to TRS and comprised a differential cortico-cognitive pattern including frontal and temporal lobes as well as paired associates learning (PAL) and intra-extra dimensional set shifting (IED). Three-group analyses also identified two significant LVs, with NARs more closely resembling healthy controls than TRS patients. CONCLUSIONS: MB-PLS-C analyses identified multivariate brain structural-cognitive patterns in the latent space that may provide a TRS signature.

Plasma neurofilament light chain protein is not increased in treatment-resistant schizophrenia and first-degree relatives.

OBJECTIVE: Schizophrenia, a complex psychiatric disorder, is often associated with cognitive, neurological and neuroimaging abnormalities. The processes underlying these abnormalities, and whether a subset of people with schizophrenia have a neuroprogressive or neurodegenerative component to schizophrenia, remain largely unknown. Examining fluid biomarkers of diverse types of neuronal damage could increase our understanding of these processes, as well as potentially provide clinically useful biomarkers, for example with assisting with differentiation from progressive neurodegenerative disorders such as Alzheimer and frontotemporal dementias. METHODS: This study measured plasma neurofilament light chain protein (NfL) using ultrasensitive Simoa technology, to investigate the degree of neuronal injury in a well-characterised cohort of people with treatment-resistant schizophrenia on clozapine (n = 82), compared to first-degree relatives (an at-risk group, n = 37), people with schizophrenia not treated with clozapine (n = 13), and age- and sex-matched controls (n = 59). RESULTS: We found no differences in NfL levels between treatment-resistant schizophrenia (mean NfL, M = 6.3 pg/mL, 95% confidence interval: [5.5, 7.2]), first-degree relatives (siblings, M = 6.7 pg/mL, 95% confidence interval: [5.2, 8.2]; parents, M after adjusting for age = 6.7 pg/mL, 95% confidence interval: [4.7, 8.8]), controls (M = 5.8 pg/mL, 95% confidence interval: [5.3, 6.3]) and not treated with clozapine (M = 4.9 pg/mL, 95% confidence interval: [4.0, 5.8]). Exploratory, hypothesis-generating analyses found weak correlations in treatment-resistant schizophrenia, between NfL and clozapine levels (Spearman's r = 0.258, 95% confidence interval: [0.034, 0.457]), dyslipidaemia (r = 0.280, 95% confidence interval: [0.064, 0.470]) and a negative correlation with weight (r = -0.305, 95% confidence interval: [-0.504, -0.076]). CONCLUSION: Treatment-resistant schizophrenia does not appear to be associated with neuronal, particularly axonal degeneration. Further studies are warranted to investigate the utility of NfL to differentiate treatment-resistant schizophrenia from neurodegenerative disorders such as behavioural variant frontotemporal dementia, and to explore NfL in other stages of schizophrenia such as the prodome and first episode.

Disruptions in white matter microstructure associated with impaired visual associative memory in schizophrenia-spectrum illness.

Episodic memory ability relies on hippocampal-prefrontal connectivity. However, few studies have examined relationships between memory performance and white matter (WM) microstructure in hippocampal-prefrontal pathways in schizophrenia-spectrum disorder (SSDs). Here, we investigated these relationships in individuals with first-episode psychosis (FEP) and chronic schizophrenia-spectrum disorders (SSDs) using tractography analysis designed to interrogate the microstructure of WM tracts in the hippocampal-prefrontal pathway. Measures of WM microstructure (fractional anisotropy [FA], radial diffusivity [RD], and axial diffusivity [AD]) were obtained for 47 individuals with chronic SSDs, 28 FEP individuals, 52 older healthy controls, and 27 younger healthy controls. Tractography analysis was performed between the hippocampus and three targets involved in hippocampal-prefrontal connectivity (thalamus, amygdala, nucleus accumbens). Measures of WM microstructure were then examined in relation to episodic memory performance separately across each group. Both those with FEP and chronic SSDs demonstrated impaired episodic memory performance. However, abnormal WM microstructure was only observed in individuals with chronic SSDs. Abnormal WM microstructure in the hippocampal-thalamic pathway in the right hemisphere was associated with poorer memory performance in individuals with chronic SSDs. These findings suggest that disruptions in WM microstructure in the hippocampal-prefrontal pathway may contribute to memory impairments in individuals with chronic SSDs but not FEP.

Clinical characteristics and impacts of HIV infection in people with bipolar disorders.

BACKGROUND: People with bipolar disorders (BD) may be at increased risk of Human Immunodeficiency Virus (HIV) infection but our understanding of the impacts of HIV infection on psychiatric outcomes is poor. This study aimed to examine the prevalence, temporal relationship, and clinical impact of HIV infection in people with BD. METHODS: In this retrospective case-control study, anonymised electronic case records of patients with BD who had been under the care of South London and Maudsley mental health services were used for data extraction. 54 HIV+ people with BD were identified and compared to a matched control group of 54 HIV- people with BD. RESULTS: The prevalence of HIV co-morbidity in the BD population was around 1%. 76% of HIV+ BD men identified as men who have sex with men (MSM). 65% of the HIV+ BD group were diagnosed with BD before becoming HIV+. The HIV+ BD group experienced significantly higher rates of stimulant, GBL/GHB and psychedelic use compared to the HIV- BD group. 85% of the HIV+ BD group were recorded as taking antiretroviral medications. LIMITATIONS: Retrospective and cross-sectional study design, and a relatively small sample size CONCLUSIONS: The prevalence of HIV comorbidity in BD was comparable to the local general population. HIV infection in BD is associated with MSM status and stimulant, GHB/GBL and psychedelics use suggesting that HIV prevention strategies should particularly target these groups. Lower use of antiretroviral medications by people with BD underlines the importance of engaging HIV+ BD people in HIV services.

Mental health services for infectious disease outbreaks including COVID-19: a rapid systematic review.

The upsurge in the number of people affected by the COVID-19 is likely to lead to increased rates of emotional trauma and mental illnesses. This article systematically reviewed the available data on the benefits of interventions to reduce adverse mental health sequelae of infectious disease outbreaks, and to offer guidance for mental health service responses to infectious disease pandemic. PubMed, Web of Science, Embase, PsycINFO, WHO Global Research Database on infectious disease, and the preprint server medRxiv were searched. Of 4278 reports identified, 32 were included in this review. Most articles of psychological interventions were implemented to address the impact of COVID-19 pandemic, followed by Ebola, SARS, and MERS for multiple vulnerable populations. Increasing mental health literacy of the public is vital to prevent the mental health crisis under the COVID-19 pandemic. Group-based cognitive behavioral therapy, psychological first aid, community-based psychosocial arts program, and other culturally adapted interventions were reported as being effective against the mental health impacts of COVID-19, Ebola, and SARS. Culturally-adapted, cost-effective, and accessible strategies integrated into the public health emergency response and established medical systems at the local and national levels are likely to be an effective option to enhance mental health response capacity for the current and for future infectious disease outbreaks. Tele-mental healthcare services were key central components of stepped care for both infectious disease outbreak management and routine support; however, the usefulness and limitations of remote health delivery should also be recognized.

Use of antidepressants with pharmacogenetic prescribing guidelines in a 10-year depression cohort of adult primary care patients.

OBJECTIVE: To describe the usage patterns of antidepressants with published CYP2D6- and CYP2C19-based prescribing guidelines among depressed primary care patients and estimate the proportion of patients taking antidepressants not recommended for them based on their CYP2C19 and CYP2D6 genotype-predicted metabolizer status. METHODS: Medication use and pharmacogenetic testing results were collected on 128 primary care patients enrolled in a 10-year depression cohort study. At each 12-month interval, we calculated the proportion of patients that: (1) reported use of one or more of the 13 antidepressant medications (i.e. amitriptyline, citalopram, escitalopram, clomipramine, desipramine, doxepin, fluvoxamine, imipramine, nortriptyline, paroxetine, sertraline, trimipramine, venlafaxine) with published CYP2D6- and CYP2C19-based prescribing guidelines, (2) were taking an antidepressant that was not recommended for them based on their CYP2C19 and CYP2D6 genotype-predicted metabolizer phenotype, and (3) switched medications from the previous 12-month interval. RESULTS: The annual proportion of individuals taking an antidepressant with a CYP2D6- and CYP2C19-based prescribing guidelines ranged from 45 to 84%. The proportion of participants that used an antidepressant that was not recommended for them, based on available CYP2D6 and CYP2C19 metabolizer phenotype, ranged from 18 to 29% and these individuals tended to switch medications more frequently (10%) compared to their counterparts taking medication aligned with their metabolizer phenotype (6%). CONCLUSION: One-quarter of primary care patients used an antidepressant that was not recommended for them based on CYP2D6- and CYP2C19-based prescribing guidelines and switching medications tended to be more common in this group. Studies to determine the impact of CYP2D6 and CYP2C19 genotyping on reducing gene-antidepressant mismatches are warranted.

Multidisciplinary research priorities for the COVID-19 pandemic: a call for action for mental health science.

The coronavirus disease 2019 (COVID-19) pandemic is having a profound effect on all aspects of society, including mental health and physical health. We explore the psychological, social, and neuroscientific effects of COVID-19 and set out the immediate priorities and longer-term strategies for mental health science research. These priorities were informed by surveys of the public and an expert panel convened by the UK Academy of Medical Sciences and the mental health research charity, MQ: Transforming Mental Health, in the first weeks of the pandemic in the UK in March, 2020. We urge UK research funding agencies to work with researchers, people with lived experience, and others to establish a high level coordination group to ensure that these research priorities are addressed, and to allow new ones to be identified over time. The need to maintain high-quality research standards is imperative. International collaboration and a global perspective will be beneficial. An immediate priority is collecting high-quality data on the mental health effects of the COVID-19 pandemic across the whole population and vulnerable groups, and on brain function, cognition, and mental health of patients with COVID-19. There is an urgent need for research to address how mental health consequences for vulnerable groups can be mitigated under pandemic conditions, and on the impact of repeated media consumption and health messaging around COVID-19. Discovery, evaluation, and refinement of mechanistically driven interventions to address the psychological, social, and neuroscientific aspects of the pandemic are required. Rising to this challenge will require integration across disciplines and sectors, and should be done together with people with lived experience. New funding will be required to meet these priorities, and it can be efficiently leveraged by the UK's world-leading infrastructure. This Position Paper provides a strategy that may be both adapted for, and integrated with, research efforts in other countries.

The ubiquitin proteasome system and schizophrenia.

The ubiquitin-proteasome system is a master regulator of neural development and the maintenance of brain structure and function. It influences neurogenesis, synaptogenesis, and neurotransmission by determining the localisation, interaction, and turnover of scaffolding, presynaptic, and postsynaptic proteins. Moreover, ubiquitin-proteasome system signalling transduces epigenetic changes in neurons independently of protein degradation and, as such, dysfunction of components and substrates of this system has been linked to a broad range of brain conditions. Although links between ubiquitin-proteasome system dysfunction and neurodegenerative disorders have been known for some time, only recently have similar links emerged for neurodevelopmental disorders, such as schizophrenia. Here, we review the components of the ubiquitin-proteasome system that are reported to be dysregulated in schizophrenia, and discuss specific molecular changes to these components that might, in part, explain the complex causes of this mental disorder.

Impact of CYP1A2, CYP2C19, and CYP2D6 genotype- and phenoconversion-predicted enzyme activity on clozapine exposure and symptom severity.

Clozapine is an atypical antipsychotic metabolized by CYP1A2, CYP2D6, and CYP2C19 enzymes. Among 66 adult schizophrenia patients treated with clozapine-based combination therapies, we explored the impact of genotype-predicted CYP1A2, CYP2D6, and CYP2C19 activity on dose-adjusted clozapine concentrations and symptom severity, with and without correction for inhibitors and inducers of these enzymes. Uncorrected activity scores were not associated with dose-adjusted clozapine concentrations or symptom severity. CYP1A2 and CYP2D6 activity scores corrected for known inducers (i.e., smoking) and inhibitors (e.g., concomitant medications) were associated with dose-adjusted clozapine levels and in the case of CYP1A2, symptom severity. However, smoking status and certain inhibitors of clozapine metabolism (i.e., esomeprazole) explained significantly more variance in dose-adjusted clozapine levels relative to corrected activity scores. These findings highlight the clinical importance of nongenetic factors (smoking, concomitant medications) and suggest that the added utility of CYP1A2, CYP2D6, and CYP2C19 activity scores to guide clozapine dosing is currently limited.

The schizophrenia genetics knowledgebase: a comprehensive update of findings from candidate gene studies.

Over 3000 candidate gene association studies have been performed to elucidate the genetic underpinnings of schizophrenia. However, a comprehensive evaluation of these studies' findings has not been undertaken since the decommissioning of the schizophrenia gene (SzGene) database in 2011. As such, we systematically identified and carried out random-effects meta-analyses for all polymorphisms with four or more independent studies in schizophrenia along with a series of expanded meta-analyses incorporating published and unpublished genome-wide association (GWA) study data. Based on 550 meta-analyses, 11 SNPs in eight linkage disequilibrium (LD) independent loci showed Bonferroni-significant associations with schizophrenia. Expanded meta-analyses identified an additional 10 SNPs, for a total of 21 Bonferroni-significant SNPs in 14 LD-independent loci. Three of these loci (MTHFR, DAOA, ARVCF) had never been implicated by a schizophrenia GWA study. In sum, the present study has provided a comprehensive summary of the current schizophrenia genetics knowledgebase and has made available all the collected data as a resource for the research community.

Adverse effect of catechol-O-methyltransferase (COMT) Val158Met met/met genotype in methamphetamine-related executive dysfunction.

INTRODUCTION: The Val allele of the Val158Met single-nucleotide polymorphism of the catechol-o-methyltransferase gene (COMT) confers greater catabolism of dopamine (DA) in the prefrontal cortex (PFC) than the Met allele. Met/Met homozygotes typically outperform Val-carriers on tests of executive function (EF), perhaps resulting from increased DA bioavailability. Methamphetamine (METH) causes large releases of DA, which is associated with neurotoxicity and executive dysfunction in chronic METH users. We hypothesized that, contrary to its effect in non-METH-using populations, slower DA clearance conferred by Met/Met will relate to worse EF in METH users. METHODS: 149 non-Hispanic White men, stratified by METH dependence (METH+/-) and COMT (Val/Val, Val/Met, Met/Met), completed three tests of EF: Wisconsin Card Sorting Test (WCST), Stroop Color-Word Test (Stroop), and Trail Making Test Part B (Trails B). Demographically-adjusted test scores were averaged to create an EF composite T-score. We examined the interaction of METH and COMT on the EF composite and individual test T-scores, controlling for premorbid functioning and alcohol use. RESULTS: METH group differences in EF were evident only among Met/Met carriers (beta = -9.36, p < .001) but not among Val carriers: Val/Met (beta = -1.38, p = .44) and Val/Val (beta = -4.34, p = .10). These effects were most salient on the WCST. CONCLUSIONS: In the pre-frontal hyperdopaminergic state triggered by methamphetamine, greater DA inactivation conferred by the Val allele may protect against METH-related executive dysfunction, suggesting genetically-driven differences in vulnerability to METH.

Evidence for Network-Based Cortical Thickness Reductions in Schizophrenia.

OBJECTIVE: Cortical thickness reductions in schizophrenia are irregularly distributed across multiple loci. The authors hypothesized that cortical connectivity networks would explain the distribution of cortical thickness reductions across the cortex, and, specifically, that cortico-cortical connectivity between loci with these reductions would be exceptionally strong and form an interconnected network. This hypothesis was tested in three cross-sectional schizophrenia cohorts: first-episode psychosis, chronic schizophrenia, and treatment-resistant schizophrenia. METHODS: Structural brain images were acquired for 70 patients with first-episode psychosis, 153 patients with chronic schizophrenia, and 47 patients with treatment-resistant schizophrenia and in matching healthy control groups (N=57, N=168, and N=54, respectively). Cortical thickness was compared between the patient and respective control groups at 148 regions spanning the cortex. Structural connectivity strength between pairs of cortical regions was quantified with structural covariance analysis. Connectivity strength between regions with cortical thickness reductions was compared with connectivity strength between 5,000 sets of randomly chosen regions to establish whether regions with reductions were interconnected more strongly than would be expected by chance. RESULTS: Significant (false discovery rate corrected) and widespread cortical thickness reductions were found in the chronic schizophrenia (79 regions) and treatment-resistant schizophrenia (106 regions) groups, with more circumscribed reductions in the first-episode psychosis group (34 regions). Cortical thickness reductions with the largest effect sizes were found in frontal, temporal, cingulate, and insular regions. In all cohorts, both the patient and healthy control groups showed significantly increased structural covariance between regions with cortical thickness reductions compared with randomly selected regions. CONCLUSIONS: Brain network architecture can explain the irregular topographic distribution of cortical thickness reductions in schizophrenia. This finding, replicated in three distinct schizophrenia cohorts, suggests that the effect is robust and independent of illness stage.

Interrogating the Evolutionary Paradox of Schizophrenia: A Novel Framework and Evidence Supporting Recent Negative Selection of Schizophrenia Risk Alleles.

Schizophrenia is a psychiatric disorder with a worldwide prevalence of ∼1%. The high heritability and reduced fertility among schizophrenia patients have raised an evolutionary paradox: why has negative selection not eliminated schizophrenia associated alleles during evolution? To address this question, we examined evolutionary markers, known as modern-human-specific (MD) sites and archaic-human-specific sites, using existing genome-wide association study (GWAS) data from 34,241 individuals with schizophrenia and 45,604 healthy controls included in the Psychiatric Genomics Consortium (PGC). By testing the distribution of schizophrenia single nucleotide polymorphisms (SNPs) with risk and protective effects in the human-specific sites, we observed a negative selection of risk alleles for schizophrenia in modern humans relative to archaic humans (e.g., Neanderthal and Denisovans). Such findings indicate that risk alleles of schizophrenia have been gradually removed from the modern human genome due to negative selection pressure. This novel evidence contributes to our understanding of the genetic origins of schizophrenia.