Associations of psychotic symptom dimensions with clinical and developmental variables in twin and general clinical samples.

BACKGROUND: Positive, negative and disorganised psychotic symptom dimensions are associated with clinical and developmental variables, but differing definitions complicate interpretation. Additionally, some variables have had little investigation. AIMS: To investigate associations of psychotic symptom dimensions with clinical and developmental variables, and familial aggregation of symptom dimensions, in multiple samples employing the same definitions. METHOD: We investigated associations between lifetime symptom dimensions and clinical and developmental variables in two twin and two general psychosis samples. Dimension symptom scores and most other variables were from the Operational Criteria Checklist. We used logistic regression in generalised linear mixed models for combined sample analysis (n = 875 probands). We also investigated correlations of dimensions within monozygotic (MZ) twin pairs concordant for psychosis (n = 96 pairs). RESULTS: Higher symptom scores on all three dimensions were associated with poor premorbid social adjustment, never marrying/cohabiting and earlier age at onset, and with a chronic course, most strongly for the negative dimension. The positive dimension was also associated with Black and minority ethnicity and lifetime cannabis use; the negative dimension with male gender; and the disorganised dimension with gradual onset, lower premorbid IQ and substantial within twin-pair correlation. In secondary analysis, disorganised symptoms in MZ twin probands were associated with lower premorbid IQ in their co-twins. CONCLUSIONS: These results confirm associations that dimensions share in common and strengthen the evidence for distinct associations of co-occurring positive symptoms with ethnic minority status, negative symptoms with male gender and disorganised symptoms with substantial familial influences, which may overlap with influences on premorbid IQ.

Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder.

First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10-5 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.

The digital divide: factors impacting on uptake of remote therapy in a South London psychological therapy service for people with psychosis.

BACKGROUND: Remote therapy promises a cost-effective way of increasing delivery of psychological-therapy in underserved populations. However, research shows a "digital divide", with some groups experiencing digital exclusion. AIMS: To assess whether technology, accessibility, and demographic factors influence remote therapy uptake among individuals with psychosis, and whether demographic factors are associated with digital exclusion. METHODS: Remote therapy uptake and demographics were assessed in people (n = 51) within a psychology-led service for psychosis, using a survey of access to digital hardware, data and private space. RESULTS: The majority of individuals had access to digital devices, but 29% did not meet minimum requirements for remote therapy. Nineteen (37%) individuals declined remote therapy. Those who accepted were significantly younger and more likely to have access to technology than those who declined. The mean age of those with access to smartphones and large screen devices was younger than those without access. CONCLUSIONS: A subgroup of people with psychosis face barriers to remote therapy and a significant minority are digitally excluded. Older age is a key factor influencing remote therapy uptake, potentially related to less access to digital devices. Services must minimize exclusion through provision of training, hardware and data, whilst promoting individual choice.

Age-Related Differences and Heritability of the Perisylvian Language Networks.

Acquisition of language skills depends on the progressive maturation of specialized brain networks that are usually lateralized in adult population. However, how genetic and environmental factors relate to the age-related differences in lateralization of these language pathways is still not known. We recruited 101 healthy right-handed subjects aged 9-40 years to investigate age-related differences in the anatomy of perisylvian language pathways and 86 adult twins (52 monozygotic and 34 dizygotic) to understand how heritability factors influence language anatomy. Diffusion tractography was used to dissect and extract indirect volume measures from the three segments of the arcuate fasciculus connecting Wernicke's to Broca's region (i.e., long segment), Broca's to Geschwind's region (i.e., anterior segment), and Wernicke's to Geschwind's region (i.e., posterior segment). We found that the long and anterior arcuate segments are lateralized before adolescence and their lateralization remains stable throughout adolescence and early adulthood. Conversely, the posterior segment shows right lateralization in childhood but becomes progressively bilateral during adolescence, driven by a reduction in volume in the right hemisphere. Analysis of the twin sample showed that genetic and shared environmental factors influence the anatomy of those segments that lateralize earlier, whereas specific environmental effects drive the variability in the volume of the posterior segment that continues to change in adolescence and adulthood. Our results suggest that the age-related differences in the lateralization of the language perisylvian pathways are related to the relative contribution of genetic and environmental effects specific to each segment. SIGNIFICANCE STATEMENT: Our study shows that, by early childhood, frontotemporal (long segment) and frontoparietal (anterior segment) connections of the arcuate fasciculus are left and right lateralized, respectively, and remain lateralized throughout adolescence and early adulthood. In contrast, temporoparietal (posterior segment) connections are right lateralized in childhood, but become progressively bilateral during adolescence. Preliminary twin analysis suggested that lateralization of the arcuate fasciculus is a heterogeneous process that depends on the interplay between genetic and environment factors specific to each segment. Tracts that exhibit higher age effects later in life (i.e., posterior segment) appear to be influenced more by specific environmental factors.

New insights into the endophenotypic status of cognition in bipolar disorder: genetic modelling study of twins and siblings.

BACKGROUND: Twin studies have lacked statistical power to apply advanced genetic modelling techniques to the search for cognitive endophenotypes for bipolar disorder. AIMS: To quantify the shared genetic variability between bipolar disorder and cognitive measures. METHOD: Structural equation modelling was performed on cognitive data collected from 331 twins/siblings of varying genetic relatedness, disease status and concordance for bipolar disorder. RESULTS: Using a parsimonious AE model, verbal episodic and spatial working memory showed statistically significant genetic correlations with bipolar disorder (rg = |0.23|-|0.27|), which lost statistical significance after covarying for affective symptoms. Using an ACE model, IQ and visual-spatial learning showed statistically significant genetic correlations with bipolar disorder (rg = |0.51|-|1.00|), which remained significant after covarying for affective symptoms. CONCLUSIONS: Verbal episodic and spatial working memory capture a modest fraction of the bipolar diathesis. IQ and visual-spatial learning may tap into genetic substrates of non-affective symptomatology in bipolar disorder.

Social networks and support in first-episode psychosis: exploring the role of loneliness and anxiety.

PURPOSE: To investigate social support and network features in people with first-episode psychosis, and to examine anxiety as a possible mediator between loneliness and a rating of paranoia. METHOD: Thirty-eight people with first-episode psychosis were recruited for a cross-sectional study. Self-report questionnaires and structured interviews assessed symptoms, functioning, and qualitative social network and support features. A mood-induction task involved watching anxiety-inducing pictures on a computer screen. Visual analogue scales assessed changes in paranoia, anxiety and loneliness and a mediation analysis was conducted. RESULTS: One-third of the sample (34%) had no confidant [95% CI (18.4, 50.0%)]. The average number of weekly contacts was 3.9, with 2.6 lonely days. Poor perceived social support, loneliness and the absence of a confidant were strongly associated with psychosis and depressive symptoms (0.35 < rs < 0.60). The association between loneliness and paranoia was mediated through anxiety (ab = 0.43, z = 3.5; p < 0.001). CONCLUSIONS: Even at first episode, a large proportion of people with psychosis have poor perceived support, no confidant and report several lonely days a week. Patients without a confidant appear to be more susceptible to feeling lonely and anxious. Anxiety may be one pathway through which loneliness affects psychosis. Interventions which focus on this are indicated.

Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder.

Studies of the major psychoses, schizophrenia (SZ) and bipolar disorder (BD), have traditionally focused on genetic and environmental risk factors, although more recent work has highlighted an additional role for epigenetic processes in mediating susceptibility. Since monozygotic (MZ) twins share a common DNA sequence, their study represents an ideal design for investigating the contribution of epigenetic factors to disease etiology. We performed a genome-wide analysis of DNA methylation on peripheral blood DNA samples obtained from a unique sample of MZ twin pairs discordant for major psychosis. Numerous loci demonstrated disease-associated DNA methylation differences between twins discordant for SZ and BD individually, and together as a combined major psychosis group. Pathway analysis of our top loci highlighted a significant enrichment of epigenetic changes in biological networks and pathways directly relevant to psychiatric disorder and neurodevelopment. The top psychosis-associated, differentially methylated region, significantly hypomethylated in affected twins, was located in the promoter of ST6GALNAC1 overlapping a previously reported rare genomic duplication observed in SZ. The mean DNA methylation difference at this locus was 6%, but there was considerable heterogeneity between families, with some twin pairs showing a 20% difference in methylation. We subsequently assessed this region in an independent sample of postmortem brain tissue from affected individuals and controls, finding marked hypomethylation (>25%) in a subset of psychosis patients. Overall, our data provide further evidence to support a role for DNA methylation differences in mediating phenotypic differences between MZ twins and in the etiology of both SZ and BD.

Interaction between effects of genes coding for dopamine and glutamate transmission on striatal and parahippocampal function.

The genes for the dopamine transporter (DAT) and the D-Amino acid oxidase activator (DAOA or G72) have been independently implicated in the risk for schizophrenia and in bipolar disorder and/or their related intermediate phenotypes. DAT and G72 respectively modulate central dopamine and glutamate transmission, the two systems most robustly implicated in these disorders. Contemporary studies have demonstrated that elevated dopamine function is associated with glutamatergic dysfunction in psychotic disorders. Using functional magnetic resonance imaging we examined whether there was an interaction between the effects of genes that influence dopamine and glutamate transmission (DAT and G72) on regional brain activation during verbal fluency, which is known to be abnormal in psychosis, in 80 healthy volunteers. Significant interactions between the effects of G72 and DAT polymorphisms on activation were evident in the striatum, parahippocampal gyrus, and supramarginal/angular gyri bilaterally, the right insula, in the right pre-/postcentral and the left posterior cingulate/retrosplenial gyri (P < 0.05, FDR-corrected across the whole brain). This provides evidence that interactions between the dopamine and the glutamate system, thought to be altered in psychosis, have an impact in executive processing which can be modulated by common genetic variation.

A call for digital inclusion initiatives in mental health services: An integrative review.

WHAT IS KNOWN ON THE SUBJECT?: Digital tools such as video calls or mobile phone applications (apps) are increasingly used in the provision of mental healthcare. There is evidence that people with mental health problems are more likely to face digital exclusion: that is, they do not have access to devices and/or skills to use technology. This leaves some people unable to use digital mental health services (e.g., apps or online appointments) or to benefit more generally from access to the digital world (e.g., online shopping or connecting with others virtually). People can be digitally included through initiatives that provide devices, Internet and digital mentoring to increase knowledge and confidence when using technology. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE?: Some initiatives in academic studies and grey literature have been shown to increase access to and knowledge of technology, but this has been outside of mental health care settings. There are currently limited digital inclusion initiatives that take into consideration the specific needs of people with mental health problems, and how they can be equipped and familiarised with digital technologies to help their recovery journey and everyday life activities. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Further work is needed to improve the provision of digital tools in mental health care, with more practical digital inclusion initiatives to ensure equal access for all. If digital exclusion is not addressed, the gap between people with and those without digital skills or access to technology will continue to grow, enlarging mental health inequalities. ABSTRACT: INTRODUCTION: The rise in the provision of digital healthcare during the pandemic has called attention to digital exclusion: inequality in access and/or capacity to use digital technologies. Digital exclusion is more profound in people with mental health problems, leaving an implementation gap of digital practice in mental health services. AIM: Identify the available evidence of (a) addressing digital exclusion in mental health care and (b) the practical solutions to enhance uptake of digital mental health. METHOD: Digital inclusion initiatives were searched from both academic and grey literature available and published between the years 2007 and 2021. RESULTS: A limited number of academic studies and initiatives were found that supported people with mental health difficulties who had limited skills and/or access to overcome digital exclusion. DISCUSSION: Further work is needed to combat digital exclusion and establish ways to reduce the implementation gap in mental health services. IMPLICATIONS FOR PRACTICE: Access to devices, Internet connectivity and digital mentoring for mental health service users is essential. More studies and programmes are needed to disseminate impact and results for digital inclusion initiatives for people with mental health problems and to inform best practice for digital inclusion within mental health services.

Effect of D-amino acid oxidase activator (DAOA; G72) on brain function during verbal fluency.

BACKGROUND: The D-Amino acid oxidase activator (G72 or DAOA) is believed to play a key role in the regulation of central glutamatergic transmission which is seen to be altered in psychosis. It is thought to regulate D-amino acid oxidase (DAO), which metabolizes D-serine, a co-agonist of NMDA-type glutamate receptors and to be involved in dendritic arborization. Linkage, genetic association and expression studies have implicated the G72 gene in both schizophrenia and bipolar disorder. AIMS: To examine the influence of G72 variation on brain function in the healthy population. METHOD: Fifty healthy volunteers were assessed using functional magnetic resonance imaging while performing a verbal fluency task. Regional brain activation and task-dependent functional connectivity during word generation was compared between different rs746187 genotypes. RESULTS: G72 rs746187 genotype had a significant effect on activation in the left postcentral and supramarginal gyri (FWE P < 0.05), and on the task-dependent functional coupling of this region with the retrosplenial cingulate gyrus (FWE P < 0.05). CONCLUSIONS: Our results may reflect an effect of G72 on glutamatergic transmission, mediated by an influence on D-amino acid oxidase activity, on brain areas particularly relevant to the hypoglutamatergic model of psychosis.

The genetic and environmental influences of event-related gamma oscillations on bipolar disorder.

OBJECTIVES: Gamma oscillations have been proposed to play an important role in neural information coding. There have been a limited number of electrophysiology studies in evoked gamma band responses (GBRs) in bipolar disorder (BPD). It is also unclear whether GBR deficits, if present, are potential endophenotypes for BPD as little is known about the heritability of GBRs. The present study aimed to examine whether GBRs derived from two auditory tasks, the oddball task and the dual-click paradigm, are potential BPD endophenotypes. METHODS: A total of 308 subjects were included in this study: 198 healthy controls, 59 BPD patients (22 monozygotic BPD twins and 37 BPD patients from 31 families), and 51 unaffected relatives. The evoked gamma responses were calculated using a Morlet wavelet transformation. Structural equation modelling was applied to obtain the genetic (heritability) and environment estimates in each GBR variable and their (genetic) overlap with BPD. RESULTS: The heritability estimates of GBR to standard stimuli were 0.51 and 0.35 to target stimuli in the oddball task. However, neither response type was impaired in BPD patients or their unaffected relatives. The heritability estimates of GBR to S1 stimuli were 0.54 and 0.50 to S2 stimuli in the dual-click paradigm. BPD patients had reduced gamma power and suppression to S1 stimuli but their unaffected relatives did not. CONCLUSIONS: Evoked GBRs are heritable traits. However, GBR deficits are not observed in clinically unaffected relatives nor associated with BPD. Gamma responses do not appear to satisfy criteria for being BPD endophenotypes.

Influence of neuregulin1 genotype on neural substrate of perceptual matching in children.

Adult psychopathology is often rooted early in life and first emerges during childhood and adolescence. However, as most imaging genetic research to date has involved adult participants, little is known about how risk genes affect brain function to influence biological vulnerability in childhood. We examined the impact of neuregulin1 (NRG1), a probable susceptibility gene for schizophrenia and bipolar disorder, on brain function in a sample of 102 healthy 10-12 year old boys including 18 pairs of monozygotic twins, 24 pairs of dizygotic twins and 18 singletons. Each participant performed a perceptual matching task, while brain responses were measured using functional magnetic resonance imaging. Response accuracy and reaction times did not differ as a function of NRG1 genotype; however, individuals with two high-risk alleles showed relatively increased brain activation in a distributed network comprising the precuneus bilaterally, and the left cuneus, middle occipital gyrus, angular gyrus and caudate nucleus. These results indicate that genetic variation in NRG1 significantly affects cortical function during perceptual and monitoring processes in healthy children as young as 10-12 years of age.

Schizophrenia polygenic risk score influence on white matter microstructure.

Schizophrenia (SZ) and bipolar disorder (BD) are highly heritable, share symptomatology, and have a polygenic architecture. The impact of recent polygenic risk scores (PRS) for psychosis, which combine multiple genome-wide associated risk variations, should be assessed on heritable brain phenotypes also previously associated with the illnesses, for a better understanding of the pathways to disease. We have recently reported on the current SZ PRS's ability to predict 1st episode of psychosis case-control status and general cognition. Herein, we test its penetrance on white matter microstructure, which is known to be impaired in SZ, in BD and their relatives, using 141 participants (including SZ, BP, relatives of SZ or BP patients, and healthy volunteers), and two white matter integrity indexes: fractional anisotropy (FA) and mean diffusivity (MD). No significant correlation between the SZ PRS and FA or MD was found, thus it remains unclear whether white matter changes are primarily associated with SZ genetic risk profiles.

Increased inferior frontal activation during word generation: a marker of genetic risk for schizophrenia but not bipolar disorder?

During verbal-fluency tasks, impairments in performance and functional abnormalities in the inferior frontal cortex have been observed in both schizophrenia patients and their unaffected relatives. We sought to examine whether such functional abnormalities are a specific marker of genetic vulnerability to schizophrenia. We studied a sample of 132 subjects, comprising 39 patients with schizophrenia, 10 unaffected monozygotic (MZ) cotwins of schizophrenia probands, 28 patients with bipolar disorder, 7 unaffected MZ cotwins of bipolar disorder probands and 48 healthy controls. Blood oxygen level-dependent response was measured using functional magnetic resonance imaging during the performance of an overt verbal-fluency task with two levels of task difficulty, in a cytoarchitectonic region of interest encompassing Brodmann areas 44 and 45 bilaterally. Patients with schizophrenia and the unaffected MZ cotwins of schizophrenia probands showed increased activation in the inferior frontal cortex relative to healthy controls and bipolar patients. Increased engagement of the inferior frontal cortex during verbal-fluency may thus be a marker of genetic vulnerability to schizophrenia.

Stroop-test interference in bipolar disorder.

We analysed Stroop (neuropsychological screening test) measures of response inhibition in 18 twin pairs discordant for bipolar I disorder compared with 17 healthy control pairs, as well as 40 singletons with bipolar disorder with psychotic features and a family history of psychosis, 46 of their first-degree relatives without bipolar disorder or psychosis and 48 controls. In both studies, individuals with bipolar disorder showed Stroop deficits and their first-degree relatives showed intact performance. In the twin patients, an interference score was associated with depressive symptoms. Having a first-degree relative with bipolar disorder, even a familial, psychotic form, did not confer risk for enhanced susceptibility to interference in our studies.

The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder.

BACKGROUND: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects. METHODS: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects. RESULTS: FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects. CONCLUSIONS: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.

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.

Balancing ACT: evaluating the effectiveness of psychoeducation and Acceptance and Commitment Therapy (ACT) groups for people with bipolar disorder: study protocol for pilot randomised controlled trial.

BACKGROUND: Bipolar disorder is a chronic and disabling psychiatric condition, characterised by recurrent episodes of mania, hypomania and depression. It places a heavy burden on sufferers and families, with high societal and healthcare costs. Many service users with a diagnosis of bipolar disorder also experience prominent psychotic symptoms, with differential diagnoses of schizoaffective disorder, and relapses characterised by repeated manic psychotic episodes and grandiosity. Such presentations require specific adaptations to standard bipolar disorder interventions in order to address their psychosis, alongside mood regulation, with a particular emphasis on impulsivity, irritability, disinhibition and elation. The Balancing ACT study aims to evaluate an innovative group intervention combining Acceptance and Commitment Therapy and psychoeducation approaches (ACT/PE) with individuals experiencing bipolar disorder and/or symptoms within community psychosis services. METHODS: The Balancing ACT study is a randomised controlled trial comparing Balancing ACT groups (ACT/PE) plus routine care to routine care alone. Balancing ACT (ACT/PE) comprises ten group sessions, each lasting 2 hours, delivered weekly. The primary outcome is psychological wellbeing; secondary outcomes are mental health relapses (measured by service use averages for the 12 months pre baseline and 3 months post baseline). We will also measure mood, distress, recovery and psychological change processes. Participants will be randomised in a 1:1 ratio, after baseline assessment. Outcomes will be assessed by trained assessors blind to treatment condition at 0, 10 and 14 weeks. Recruitment began in April 2017 and is on-going until the end of October 2017. DISCUSSION: The Balancing ACT study will contribute to the currently limited evidence base for psychological interventions for people experiencing bipolar disorder and/or symptoms in the context of community psychosis services. TRIAL REGISTRATION: ISRCTN73327972 . Registered on 27 March 2017. Balancing ACT: evaluating the effectiveness of psychoeducation and Acceptance and Commitment Therapy (ACT) groups for people with bipolar disorder.

Effects of risk for bipolar disorder on brain function: A twin and family study.

Bipolar disorder (BPD) is associated with altered regional brain function during the performance of cognitive tasks. The relative contribution of genetic and environmental risk factors for BPD to these changes has not yet been quantified. We sought to address this issue in a functional neuroimaging study of people who varied in their risk for BPD. Functional magnetic resonance imaging was used to study 124 subjects (29 twin and 9 sibling pairs with at least one member with BPD, and 24 healthy twin pairs) performing a working memory task. We assessed the influence of risk for BPD on regional brain function during the task in a two stage process. Firstly, we identified areas where there were group differences in activation. Secondly, we estimated the heritability and phenotypic correlation of activation and BPD using genetic modeling. BPD was associated with increased activation in the anterior cingulate, orbitofrontal, medial prefrontal, and left precentral cortices, and in the precuneus. Within these regions, activation in the orbitofrontal cortex rendered the most significant heritability estimate (h2=0.40), and was significantly correlated with BPD phenotype (rph=0.29). A moderate proportion of the genetic influences (rg=0.69) acting on both BPD and on the degree of orbitofrontal activation were shared. These findings suggest that genetic factors that confer vulnerability to BPD alter brain function in BPD.

Genome-wide discovered psychosis-risk gene ZNF804A impacts on white matter microstructure in health, schizophrenia and bipolar disorder.

Background. Schizophrenia (SZ) and bipolar disorder (BD) have both been associated with reduced microstructural white matter integrity using, as a proxy, fractional anisotropy (FA) detected using diffusion tensor imaging (DTI). Genetic susceptibility for both illnesses has also been positively correlated in recent genome-wide association studies with allele A (adenine) of single nucleotide polymorphism (SNP) rs1344706 of the ZNF804A gene. However, little is known about how the genomic linkage disequilibrium region tagged by this SNP impacts on the brain to increase risk for psychosis. This study aimed to assess the impact of this risk variant on FA in patients with SZ, in those with BD and in healthy controls. Methods. 230 individuals were genotyped for the rs1344706 SNP and underwent DTI. We used tract-based spatial statistics (TBSS) followed by an analysis of variance, with threshold-free cluster enhancement (TFCE), to assess underlying effects of genotype, diagnosis and their interaction, on FA. Results. As predicted, statistically significant reductions in FA across a widely distributed brain network (p < 0.05, TFCE-corrected) were positively associated both with a diagnosis of SZ or BD and with the double (homozygous) presence of the ZNF804A rs1344706 risk variant (A). The main effect of genotype was medium (d = 0.48 in a 44,054-voxel cluster) and the effect in the SZ group alone was large (d = 1.01 in a 51,260-voxel cluster), with no significant effects in BD or controls, in isolation. No areas under a significant diagnosis by genotype interaction were found. Discussion. We provide the first evidence in a predominantly Caucasian clinical sample, of an association between ZNF804A rs1344706 A-homozygosity and reduced FA, both irrespective of diagnosis and particularly in SZ (in overlapping brain areas). This suggests that the previously observed involvement of this genomic region in psychosis susceptibility, and in impaired functional connectivity, may be conferred through it inducing abnormalities in white matter microstructure.