Charting brain growth and aging at high spatial precision.

Defining reference models for population variation, and the ability to study individual deviations is essential for understanding inter-individual variability and its relation to the onset and progression of medical conditions. In this work, we assembled a reference cohort of neuroimaging data from 82 sites (N=58,836; ages 2-100) and used normative modeling to characterize lifespan trajectories of cortical thickness and subcortical volume. Models are validated against a manually quality checked subset (N=24,354) and we provide an interface for transferring to new data sources. We showcase the clinical value by applying the models to a transdiagnostic psychiatric sample (N=1985), showing they can be used to quantify variability underlying multiple disorders whilst also refining case-control inferences. These models will be augmented with additional samples and imaging modalities as they become available. This provides a common reference platform to bind results from different studies and ultimately paves the way for personalized clinical decision-making.

Towards Precision Medicine in Psychosis: Benefits and Challenges of Multimodal Multicenter Studies-PSYSCAN: Translating Neuroimaging Findings From Research into Clinical Practice.

In the last 2 decades, several neuroimaging studies investigated brain abnormalities associated with the early stages of psychosis in the hope that these could aid the prediction of onset and clinical outcome. Despite advancements in the field, neuroimaging has yet to deliver. This is in part explained by the use of univariate analytical techniques, small samples and lack of statistical power, lack of external validation of potential biomarkers, and lack of integration of nonimaging measures (eg, genetic, clinical, cognitive data). PSYSCAN is an international, longitudinal, multicenter study on the early stages of psychosis which uses machine learning techniques to analyze imaging, clinical, cognitive, and biological data with the aim of facilitating the prediction of psychosis onset and outcome. In this article, we provide an overview of the PSYSCAN protocol and we discuss benefits and methodological challenges of large multicenter studies that employ neuroimaging measures.

The case for improved care and provision of treatment for people with first-episode mania.

The care of people with first-episode mania has been overlooked in comparison with the care of patients with other non-affective psychoses, despite evidence suggesting targeted treatments might be of benefit for this patient group. In this Personal View, we outline the general epidemiology of first-episode mania in the context of bipolar disorder, the natural history of mania (with an emphasis on its recurrent nature), current evidence for pharmacological, psychological, and service-level interventions, current guidelines for the treatment of first-episode mania, and provide a patient's point of view of the care pathway (appendix). We note the paucity of high-quality evidence for interventions in first-episode mania and the lack of agreement among treatment guidelines in relation to treatment, especially maintenance treatment. We suggest that, based on high morbidity and clinical need, research evidence to inform guideline development is necessary, and in the interim, clearer guidance on treatment and diagnosis should be given; specifically, we have suggested that patients should be cared for within a first-episode psychosis service, when such a service exists.

Child Maltreatment and Clinical Outcome in Individuals at Ultra-High Risk for Psychosis in the EU-GEI High Risk Study.

Background: Child maltreatment has been associated with a wide range of mental disorders in adulthood. Whether child maltreatment is specifically associated with psychosis risk in individuals at ultra-high risk (UHR) for psychosis, or leads to a general vulnerability for overall psychopathology in the UHR stage remains unclear. The present study examines the association between child maltreatment and transition to psychosis and other mental disorders. Methods: The sample consisted of 259 UHR individuals from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study. Participants were followed-up for 2 years to assess clinical outcome. Clinical outcome was assessed at 6 months, 12 months, and 24 months after baseline. Child maltreatment before the age of 17 years was assessed at baseline. Results: Our findings show that a history of emotional abuse was associated with an increased risk for transition to psychosis (OR = 3.78, 95% CI = 1.17 to 12.39, P = .027). Apart from psychosis, a history of physical abuse was associated with depressive disorder (OR = 4.92, 95% CI = 2.12 to 11.39, P = .001), post-traumatic stress disorder (OR = 2.06, 95% CI = 1.10 to 3.86, P = .023), panic disorder (OR = 2.00, 95% CI = 1.00 to 3.99, P = .048) and social phobia (OR = 2.47, 95% CI = 1.18 to 5.16, P = .016) at follow-up. Conclusion: Our findings suggest that in the UHR stage child maltreatment is a pluripotent risk factor for developing psychosis, depressive disorder, post-traumatic stress disorder (PTSD), panic disorder, and social phobia in adulthood.

Association between stressful life events and psychotic experiences in adolescence: evidence for gene-environment correlations.

BACKGROUND: Stressful life events (SLEs) are associated with psychotic experiences. SLEs might act as an environmental risk factor, but may also share a genetic propensity with psychotic experiences. AIMS: To estimate the extent to which genetic and environmental factors influence the relationship between SLEs and psychotic experiences. METHOD: Self- and parent reports from a community-based twin sample (4830 16-year-old pairs) were analysed using structural equation model fitting. RESULTS: SLEs correlated with positive psychotic experiences (r = 0.12-0.14, all P<0.001). Modest heritability was shown for psychotic experiences (25-57%) and dependent SLEs (32%). Genetic influences explained the majority of the modest covariation between dependent SLEs and paranoia and cognitive disorganisation (bivariate heritabilities 74-86%). The relationship between SLEs and hallucinations and grandiosity was explained by both genetic and common environmental effects. CONCLUSIONS: Further to dependent SLEs being an environmental risk factor, individuals may have an underlying genetic propensity increasing their risk of dependent SLEs and positive psychotic experiences.

The Optimization of Treatment and Management of Schizophrenia in Europe (OPTiMiSE) Trial: Rationale for Its Methodology and a Review of the Effectiveness of Switching Antipsychotics.

(Reprinted with permission from Schizophrenia Bulletin 2015; 41(3):549-558).

The optimization of treatment and management of schizophrenia in Europe (OPTiMiSE) trial: rationale for its methodology and a review of the effectiveness of switching antipsychotics.

BACKGROUND: Most of the 13 542 trials contained in the Cochrane Schizophrenia Group's register just tested the general efficacy of pharmacological or psychosocial interventions. Studies on the subsequent treatment steps, which are essential to guide clinicians, are largely missing. This knowledge gap leaves important questions unanswered. For example, when a first antipsychotic failed, is switching to another drug effective? And when should we use clozapine? The aim of this article is to review the efficacy of switching antipsychotics in case of nonresponse. We also present the European Commission sponsored "Optimization of Treatment and Management of Schizophrenia in Europe" (OPTiMiSE) trial which aims to provide a treatment algorithm for patients with a first episode of schizophrenia. METHODS: We searched Pubmed (October 29, 2014) for randomized controlled trials (RCTs) that examined switching the drug in nonresponders to another antipsychotic. We described important methodological choices of the OPTiMiSE trial. RESULTS: We found 10 RCTs on switching antipsychotic drugs. No trial was conclusive and none was concerned with first-episode schizophrenia. In OPTiMiSE, 500 first episode patients are treated with amisulpride for 4 weeks, followed by a 6-week double-blind RCT comparing continuation of amisulpride with switching to olanzapine and ultimately a 12-week clozapine treatment in nonremitters. A subsequent 1-year RCT validates psychosocial interventions to enhance adherence. DISCUSSION: Current literature fails to provide basic guidance for the pharmacological treatment of schizophrenia. The OPTiMiSE trial is expected to provide a basis for clinical guidelines to treat patients with a first episode of schizophrenia.

Modeling determinants of medication attitudes and poor adherence in early nonaffective psychosis: implications for intervention.

We aimed to design a multimodal intervention to improve adherence following first episode psychosis, consistent with current evidence. Existing literature identified medication attitudes, insight, and characteristics of support as important determinants of adherence to medication: we examined medication attitudes, self-esteem, and insight in an early psychosis cohort better to understand their relationships. Existing longitudinal data from 309 patients with early Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, nonaffective psychosis (83% first episode) were analyzed to test the hypothesis that medication attitudes, while meaningfully different from "insight," correlated with insight and self-esteem, and change in each influenced the others. Rosenberg Self-Esteem Scale, Birchwood Insight Scale, and Positive and Negative Syndrome Scale insight were assessed at presentation, after 6 weeks and 3 and 18 months. Drug Attitudes Inventory (DAI) and treatment satisfaction were rated from 6 weeks onward. Structural equation models of their relationships were compared. Insight measures' and DAI's predictive validity were compared against relapse, readmission, and remission. Analysis found five latent constructs best fitted the data: medication attitudes, self-esteem, accepting need for treatment, self-rated insight, and objective insight. All were related and each affected the others as it changed, except self-esteem and medication attitudes. Low self-reported insight at presentation predicted readmission. Good 6-week insight (unlike drug attitudes) predicted remission. Literature review and data modeling indicated that a multimodal intervention using motivational interviewing, online psychoeducation, and SMS text medication reminders to enhance adherence without damaging self-concept was feasible and appropriate.

The promise of biological markers for treatment response in first-episode psychosis: a systematic review.

Successful treatment of first-episode psychosis is one of the major factors that impacts long-term prognosis. Currently, there are no satisfactory biological markers (biomarkers) to predict which patients with a first-episode psychosis will respond to which treatment. In addition, a non-negligible rate of patients does not respond to any treatment or may develop side effects that affect adherence to the treatments as well as negatively impact physical health. Thus, there clearly is a pressing need for defining biomarkers that may be helpful to predict response to treatment and sensitivity to side effects in first-episode psychosis. The present systematic review provides (1) trials that assessed biological markers associated with antipsychotic response or side effects in first-episode psychosis and (2) potential biomarkers associated with biological disturbances that may guide the choice of conventional treatments or the prescription of innovative treatments. Trials including first-episode psychoses are few in number. Most of the available data focused on pharmacogenetics markers with so far only preliminary results. To date, these studies yielded-beside markers for metabolism of antipsychotics-no or only a few biomarkers for response or side effects, none of which have been implemented in daily clinical practice. Other biomarkers exploring immunoinflammatory, oxidative, and hormonal disturbances emerged as biomarkers of first-episode psychoses in the last decades, and some of them have been associated with treatment response. In addition to pharmacogenetics, further efforts should focus on the association of emergent biomarkers with conventional treatments or with innovative therapies efficacy, where some preliminary data suggest promising results.

A shared genetic propensity underlies experiences of bullying victimization in late childhood and self-rated paranoid thinking in adolescence.

BACKGROUND: Bullying is a risk factor for developing psychotic experiences (PEs). Whether bullying is associated with particular PEs, and the extent to which genes and environments influence the association, are unknown. This study investigated which specific PEs in adolescence are associated with earlier bullying victimization and the genetic and environmental contributions underlying their association. METHOD: Participants were 4826 twin pairs from a longitudinal community-based twin study in England and Wales who reported on their bullying victimization at the age of 12 years. Measures of specific PEs (self-rated Paranoia, Hallucinations, Cognitive disorganization, Grandiosity, Anhedonia, and parent-rated Negative Symptoms) were recorded at age of 16 years. RESULTS: Childhood bullying victimization was most strongly associated with Paranoia in adolescence (r = .26; P < .01), with weaker associations with Hallucinations, Cognitive Disorganization, parent-rated Negative Symptoms (r = .12-.20; P < .01), Grandiosity (r = .04; P < .05), and Anhedonia (r = .00, n.s.). Bivariate twin model-fitting demonstrated that bullying victimization and Paranoia were both heritable (35% and 52%, respectively) with unique environmental influences (39% and 48%, respectively), and bullying victimization showed common environmental influences (26%). The association between bullying victimization and Paranoia operated almost entirely via genetic influences (bivariate heritability = 93%), with considerable genetic overlap (genetic correlation = .55). CONCLUSION: In contrast to the assumed role of bullying victimization as an environmental trigger, these data suggest that bullying victimization in late childhood is particularly linked to self-rated Paranoia in adolescence via a shared genetic propensity. Clinically, individuals with a history of bullying victimization are predicted to be particularly susceptible to paranoid symptoms.

Adhesio interthalamica alterations in schizophrenia spectrum disorders: A systematic review and meta-analysis.

Magnetic resonance imaging (MRI) studies have reported a variety of brain abnormalities in association with schizophrenia. These include a higher prevalence of an absent adhesio interthalamica (AI; also known massa intermedia), a gray matter junction that is present between the two thalami in approximately 80% of healthy subjects. In this meta-analytic review, we describe and discuss the main AI MRI findings in schizophrenia spectrum disorders (SSDs) to date. The MEDLINE and ISI Web of Knowledge databases were searched up to December 2010, for studies that used MRI to assess AI in patients with SSD and controls. From fourteen potential reports, eleven were eligible to be part of the current review. These studies included 822 patients with SSD and 718 healthy volunteers. There was a large degree of variability in the MRI methods they employed. Patients with SSD had a higher prevalence of absent AI than healthy volunteers (odds ratio = 1.98; 95% confidence interval 1.33-2.94; p = 0.0008). This association was evident in both male and female SSD subjects, and there was no evidence that the prevalence was related to age or duration of illness. The significance of the absence of an AI for SSD may be clarified by studies in large, longitudinal community-based samples using standardized methods.

Are cavum septum pellucidum abnormalities more common in schizophrenia spectrum disorders? A systematic review and meta-analysis.

Magnetic resonance imaging (MRI) studies have reported a variety of brain abnormalities in association with schizophrenia. These include a higher incidence of cavum septum pellucidum (CSP), which is consistent with a neurodevelopmental model for this disorder. In this meta-analytic review, we describe and discuss the main CSP MRI findings in schizophrenia spectrum disorders (SSDs) to date. We adopted as keywords cavum and schizophrenia or psychosis, and the inclusion criteria were articles in English, with samples of SSD patients compared to healthy subjects, which used MRI to assess CSP, without time limit. From 18 potential reports, fifteen were eligible to be part of the current review. These studies included 1054 patients with SSD and 866 healthy volunteers. Six out of 15 studies pointed to a higher prevalence of CSP of any size in SSD patients, while five out of 15 showed that subjects with SSD had a greater occurrence of a large CSP than healthy individuals. However, the meta-analysis demonstrated that only the incidence of a large CSP was significantly higher in SSD relative to healthy comparisons (odds ratio=1.59; 95%CI 1.07-2.38; p=0.02). Overall our results suggest that only a large CSP is associated with SSD while a small CSP may be considered a normal neuroanatomical variation. Our review revealed a large degree of variability in the methods employed across the MRI studies published to date, as well as evidence of publication bias. Studies in large, community-based samples with greater standardization of methods should clarify the true significance of CSP in SSD.

The interplay of cannabinoid and NMDA glutamate receptor systems in humans: preliminary evidence of interactive effects of cannabidiol and ketamine in healthy human subjects.

BACKGROUND: Interactions between glutamatergic and endocannabinoid systems may contribute to schizophrenia, dissociative states, and other psychiatric conditions. Cannabidiol (CBD), a cannabinoid-1/2 (CB1/2) receptor weak partial agonist or antagonist, may play a role in the treatment of schizophrenia. OBJECTIVE: This study tested the hypothesis that CBD would attenuate the behavioral effects of the NMDA receptor antagonist, ketamine, in healthy human subjects. METHODS: Ten male healthy volunteers were evaluated twice in a randomized order. In both sessions they received ketamine (bolus of 0.26 mg/kg/1 min followed by IV infusion of 0.25mg/kg over 30 min) preceded by either CBD (600 mg) or placebo. Psychopathology was assessed using the Brief Psychiatric Rating Scale (BPRS) and the CADSS (Clinician Administered Dissociative States Scale) at regular intervals from 30 min before to 90 min after ketamine administration. RESULTS: CBD significantly augmented the activating effects of ketamine, as measured by the activation subscales of the BPRS. However, CBD also showed a non-significant trend to reduce ketamine-induced depersonalization, as measured by the CADSS. CONCLUSION: These data describe a complex pattern of psychopharmacologic interactions between CBD and ketamine at the doses of each agent studied in this experiment.

Neurological abnormalities and cognitive ability in first-episode psychosis.

BACKGROUND: It remains unclear if the excess of neurological soft signs, or of certain types of neurological soft signs, is common to all psychoses, and whether this excess is simply an epiphenomenon of the lower general cognitive ability present in psychosis. AIMS: To investigate whether an excess of neurological soft signs is independent of diagnosis (schizophrenia v. affective psychosis) and cognitive ability (IQ). METHOD: Evaluation of types of neurological soft signs in a prospective cohort of all individuals presenting with psychoses over 2 years (n=310), and in a control group from the general population (n=239). RESULTS: Primary (P<0.001), motor coordination (P<0.001), and motor sequencing (P<0.001) sign scores were significantly higher in people with any psychosis than in the control group. However, only primary and motor coordination scores remained higher when individuals with psychosis and controls were matched for premorbid and current IQ. CONCLUSIONS: Higher rates of primary and motor coordination signs are not associated with lower cognitive ability, and are specific to the presence of psychosis.

The effects of neuregulin1 on brain function in controls and patients with schizophrenia and bipolar disorder.

Recent studies have identified neuregulin1 as a probable susceptibility gene for schizophrenia and bipolar disorder. However, little is known about how this gene may affect brain function to increase vulnerability to these disorders. The present investigation examined the impact of neuregulin1 genotype on brain function in patients with schizophrenia, patients with bipolar I disorder and healthy volunteers. We used functional magnetic resonance imaging to measure brain responses during a verbal fluency task in a total of 115 subjects comprising 41 patients with schizophrenia, 29 patients with bipolar disorder and 45 healthy volunteers. We then used statistical parametric mapping to estimate the main effects of diagnostic group, the main effect of genotype and their interaction. We tested the hypothesis that the high-risk variant of neuregulin1 would be associated with altered prefrontal function. In all three diagnostic groups, the high-risk variant of neuregulin1 was associated with greater deactivation in the left precuneus. In addition, there was an interaction between diagnosis and genotype in two regions of the prefrontal cortex. The right inferior frontal gyrus expressed increased activation in individuals with the high-risk variant, but only in patients with schizophrenia. Conversely, the right posterior orbital gyrus expressed increased activation in individuals with the high-risk variant, but only in patients with bipolar disorder. Our results suggest that genetic variation in neuregulin1 has a measurable impact on brain function and provide preliminary evidence for a disease-specific pattern of gene action in different regions of the prefrontal cortex.

Total agenesis of the corpus callosum in a patient with childhood-onset schizophrenia

The hypothesis that schizophrenia involves aberrant inter-hemispheric communication has a long pedigree, however its precise role remains unclear. We therefore report the case of a total agenesis of the corpus callosum in a 21-year-old man with childhood-onset schizophrenia. The presence of schizophrenia with very early onset on absence of corpus callosum offers an opportunity to examine neurodevelopmental model and theories regarding to interhemispheric communication in the pathogenesis of psychosis.

A hipótese que a esquizofrenia envolve comunicação inter-hemisférica aberrante possui longa tradição, entretanto seu papel permanece incerto. Nós relatamos um caso de agenesia total do corpo caloso em um homem de 21 anos portador de esquizofrenia de início na infância. A associação de esquizofrenia de início precoce na ausência de corpo caloso oferece uma oportunidade para exame do modelo neurodesenvolvimental e de teorias que envolvem a comunicação interemisférica na patogênese da psicose.

The Lambeth Early Onset Crisis Assessment Team Study: general practitioner education and access to an early detection team in first-episode psychosis.

BACKGROUND: There are few evaluations of strategies to improve rates of early detection and treatment of patients with first-episode psychosis. AIMS: To evaluate the effectiveness of a general practitioner (GP) education programme and an early detection assessment team (the Lambeth Early Onset Crisis Assessment Team; LEO CAT) in reducing delays in accessing treatment for first-episode psychosis patients. METHOD: 46 clusters of GP practices randomised to GP education in early detection with direct access to LEO CAT v. care as usual. Primary outcome measures were GP referral rates, duration of untreated psychosis (DUP) and delays in receiving treatment. RESULTS: 150 patients with first-episode psychosis were recruited; 113 were registered with the study GPs, who referred 54 (47.7%) directly to mental health services. Significantly more intervention group GPs (86.1% v. 65.7%) referred their patients directly to mental health services and fewer patients experienced long delays in receiving treatment. However, their overall DUP was unaffected. CONCLUSIONS: Educating GPs improves detection and referral rates of first-episode psychosis patients. An early detection team reduces the long delays in initial assessment and treatment. However, these only impact on the later phases of the DUP. Broader measures, such as public health education, are needed to reduce the earlier delays in DUP.

Total agenesis of the corpus callosum in a patient with childhood-onset schizophrenia.

The hypothesis that schizophrenia involves aberrant inter-hemispheric communication has a long pedigree, however its precise role remains unclear. We therefore report the case of a total agenesis of the corpus callosum in a 21-year-old man with childhood-onset schizophrenia. The presence of schizophrenia with very early onset on absence of corpus callosum offers an opportunity to examine neurodevelopmental model and theories regarding to interhemispheric communication in the pathogenesis of psychosis.