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

The effect of psychosis associated CACNA1C, and its epistasis with ZNF804A, on brain function

CACNA1C‐rs1006737 and ZNF804A‐rs1344706 polymorphisms are amongst the most robustly associated with schizophrenia (SCZ) and bipolar disorder (BD), and recently with brain phenotypes. As these patients show abnormal verbal fluency (VF) and related brain activation, we asked whether the latter was affected by these polymorphisms (alone and in interaction) – to better understand how they might induce risk. We recently reported effects on functional VF‐related (for ZNF804A‐rs1344706) and structural (for both) connectivity. We genotyped and fMRI‐scanned 54 SCZ, 40 BD and 80 controls during VF. With SPM, we assessed the main effect of CACNA1C‐rs1006737, and its interaction with ZNF804A‐rs1344706, and their interaction with diagnosis, on regional brain activation and functional connectivity (psychophysiological interactions ‐ PPI). Using public data, we reported effects of CACNA1C‐rs1006737 and diagnosis on brain expression. The CACNA1C‐rs1006737 risk allele was associated with increased activation, particularly in the bilateral prefronto‐temporal cortex and thalamus; decreased PPI, especially in the left temporal cortex; and gene expression in white matter and the cerebellum. We also found unprecedented evidence for epistasis (interaction between genetic polymorphisms) in the caudate nucleus, thalamus, and cingulate and temporal cortical activation; and CACNA1C up‐regulation in SCZ and BD parietal cortices. Some effects were dependent on BD/SCZ diagnosis. All imaging results were whole‐brain, voxel‐wise, and familywise‐error corrected. Our results support evidence implicating CACNA1C and ZNF804A in BD and SCZ, adding novel imaging evidence in clinical populations, and of epistasis – which needs further replication. Further scrutiny of the inherent neurobiological mechanisms may disclose their potential as putative drug targets

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

Structured lifestyle education for people with schizophrenia, schizoaffective disorder and first-episode psychosis (STEPWISE): randomised controlled trial

Background Obesity is a major challenge for people with schizophrenia. Aims We assessed whether STEPWISE, a theory-based, group structured lifestyle education programme could support weight reduction in people with schizophrenia. Method In this randomised controlled trial (study registration: ISRCTN19447796), we recruited adults with schizophrenia, schizoaffective disorder or first-episode psychosis from ten mental health organisations in England. Participants were randomly allocated to the STEPWISE intervention or treatment as usual. The 12-month intervention comprised four 2.5 h weekly group sessions, followed by 2-weekly maintenance contact and group sessions at 4, 7 and 10 months. The primary outcome was weight change after 12 months. Key secondary outcomes included diet, physical activity, biomedical measures and patient-related outcome measures. Cost-effectiveness was assessed and a mixed-methods process evaluation was included. Results Between 10 March 2015 and 31 March 2016, we recruited 414 people (intervention 208, usual care 206) with 341 (84.4%) participants completing the trial. At 12 months, weight reduction did not differ between groups (mean difference 0.0 kg, 95% CI-1.6 to 1.7, P = 0.963); physical activity, dietary intake and biochemical measures were unchanged. STEPWISE was well-received by participants and facilitators. The healthcare perspective incremental cost-effectiveness ratio was £246 921 per quality-adjusted life-year gained. Conclusions Participants were successfully recruited and retained, indicating a strong interest in weight interventions; however, the STEPWISE intervention was neither clinically nor cost-effective. Further research is needed to determine how to manage overweight and obesity in people with schizophrenia

STEPWISE - STructured lifestyle Education for People WIth SchizophrEnia : a study protocol for a randomised controlled trial

BACKGROUND: People with schizophrenia are two to three times more likely to be overweight than the general population. The UK National Institute of Health and Care Excellence (NICE) recommends an annual physical health review with signposting to, or provision of, a lifestyle programme to address weight concerns and obesity. The purpose of this randomised controlled trial is to assess whether a group-based structured education programme can help people with schizophrenia to lose weight. METHODS: Design: a randomised controlled trial of a group-based structured education programme. SETTING: 10 UK community mental health trusts. PARTICIPANTS: 396 adults with schizophrenia, schizoaffective, or first-episode psychosis who are prescribed antipsychotic medication will be recruited. Participants will be overweight, obese or be concerned about their weight. INTERVENTION: participants will be randomised to either the intervention or treatment as usual (TAU). The intervention arm will receive TAU plus four 2.5-h weekly sessions of theory-based lifestyle structured group education, with maintenance contact every 2 weeks and 'booster' sessions every 3 months. All participants will receive standardised written information about healthy eating, physical activity, alcohol and smoking. OUTCOMES: the primary outcome is weight (kg) change at 1 year post randomisation. Secondary outcomes, which will be assessed at 3 and 12 months, include: the proportion of participants who maintained or reduced their weight; waist circumference; body mass index; objectively measured physical activity (wrist accelerometer); self-reported diet; blood pressure; fasting plasma glucose, lipid profile and HbA1c (baseline and 1 year only); health-related quality of life (EQ-5D-5L and RAND SF-36); (adapted) brief illness perception questionnaire; the Brief Psychiatric Rating Scale; the Client Service Receipt Inventory; medication use; smoking status; adverse events; depression symptoms (Patient Health Questionnaire-9); use of weight-loss programmes; and session feedback (intervention only). Outcome assessors will be blind to trial group allocation. Qualitative interviews with a subsample of facilitators and invention-arm participants will provide data on intervention feasibility and acceptability. Assessment of intervention fidelity will also be performed. DISCUSSION: The STEPWISE trial will provide evidence for the clinical and cost-effectiveness of a tailored intervention, which, if successful, could be implemented rapidly in the NHS. TRIAL REGISTRATION: ISRCTN19447796 , registered on 20 March 2014

Why care about integrated care? Part I. Demographics, finances and workforce: immovable objects facing mental health services

Demands on health and social care are growing in quantity and complexity, with resources and staffing not projected to match this. The landmark NHS Long Term Plan calls for services in England to be delivered differently through integrated care systems (ICSs) that will better join commissioners and providers, and health and social care. The scale of these changes is immense, and the detail can feel confusing. However, they are important and will affect all clinicians in the public service. This three-part series provides a primer on integrated care, explaining why it is happening, how services are changing and why clinicians should get involved. In this first article we focus on the changing demographics, and the workforce and financial resources required to address these

Meta-analysis of magnetic resonance imaging brain morphometry studies in bipolar disorder

Several studies assessing volumetric measurements of regional brain structure in bipolar disorder have been published in recent years, but their results have been inconsistent. Our aim was to complete a meta-analysis of regional morphometry in bipolar disorder as assessed using magnetic resonance imaging (MRI). We conducted a systematic literature search of MRI studies of bipolar disorder and identified studies which reported volume measurements in a selected number of regions. Twenty-six studies comprising volumetric measurements on up to 404 independent patients with bipolar disorder were included. A meta-analysis was carried out comparing the volumes of regions in bipolar disorder to comparison subjects using a random effects model. Patients with bipolar disorder had enlargement of the right lateral ventricle, but no other regional volumetric deviations which reached significance. Strong heterogeneity existed for several regions, including the third ventricle, left subgenual prefrontal cortex, bilateral amygdala and thalamus. Regional volume of most structures we studied is preserved in bipolar disorder as a whole, which was significantly associated only with right-sided ventricular enlargement. However the extensive heterogeneity detected indicates the need for further studies to establish if consistent regional brain volume deviation exists in bipolar disorder or in specific clinical subsets of the illness.link_to_subscribed_fulltex