Network Constraints on Longitudinal Grey Matter Changes in First Episode Psychosis

Background: Different regions of the brain's grey matter are connected by a complex structural network of white matter fibres which are responsible for the propagation of action potentials and the transport of trophic and other molecules. In neurodegenerative disease, these connections constrain the way in which grey matter volume loss progresses. Here, we investigated whether connectome architecture also shapes the spatial pattern of longitudinal grey matter volume changes attributable to illness and antipsychotic medication in first episode psychosis (FEP). Methods: We conducted a triple-blind randomised placebo-control MRI study where 62 young adults with first episode psychosis received either an atypical antipsychotic or placebo over 6-months. A healthy control group was also recruited. Anatomical MRI scans were acquired at baseline, 3-months and 12-months. Deformation-based morphometry was used to estimate illness-related and antipsychotic-related grey matter volume changes over time. Representative functional and structural brain connectivity patterns were derived from an independent healthy control group using resting-state functional MRI and diffusion-weighted imaging. We used neighbourhood deformation models to predict the extent of brain change in a given area by the changes observed in areas to which it is either structurally connected or functionally coupled. Results: At baseline, we found that empirical illness-related regional volume differences were strongly correlated with predicted differences using a model constrained by structural connectivity weights (ρ = .541; p < .001). At 3-months and 12-months, we also found a strong correlation between longitudinal regional illness-related (ρ > .516; p < .001) and antipsychotic-related volume change (ρ > .591; p < .001) with volumetric changes in structurally connected areas. These correlations were significantly greater than those observed across various null models accounting for lower-order spatial and network properties of the data. Associations between empirical and predicted volume change estimates were much lower for models that only considered binary structural connectivity (all ρ < .376), or which were constrained by inter-regional functional coupling (all ρ < .436). Finally, we found that potential epicentres of volume change emerged posteriorly early in the illness and shifted to the prefrontal cortex by later illness stages. Conclusion: Psychosis- and antipsychotic-related grey matter volume changes are strongly shaped by anatomical brain connectivity. This result is consistent with findings in other neurological disorders and implies that such connections may constrain pathological processes causing brain dysfunction in FEP.

Variability of glucose, insulin, and lipid disturbances in first-episode psychosis: a meta-analysis

Background First-episode psychosis (FEP) is associated with metabolic alterations. However, it is not known if there is heterogeneity in these alterations beyond what might be expected due to normal individual differences, indicative of subgroups of patients at greater vulnerability to metabolic dysregulation. Methods We employed meta-analysis of variance, indexed using the coefficient of variation ratio (CVR), to compare variability of the following metabolic parameters in antipsychotic naïve FEP and controls: fasting glucose, glucose post-oral glucose tolerance test (OGTT), fasting insulin, insulin resistance, haemoglobin A1c (HbA1c), total-cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglycerides. Standardised mean difference in metabolic parameters between groups was also calculated; meta-regression analyses examined physiological/demographic/psychopathological moderators of metabolic change. Results Twenty-eight studies were analysed (1716 patients, 1893 controls). Variability of fasting glucose [CVR = 1.32; 95% confidence interval (CI) 1.12–1.55; p = 0.001], glucose post-OGTT (CVR = 1.43; 95% CI 1.10–1.87; p = 0.008), fasting insulin (CVR = 1.31; 95% CI 1.09–1.58; p = 0.01), insulin resistance (CVR = 1.34; 95% CI 1.12–1.60; p = 0.001), HbA1c (CVR = 1.18; 95% CI 1.06–1.27; p < 0.0001), total-cholesterol (CVR = 1.15; 95% CI 1.01–1.31; p = 0.03), LDL-cholesterol (CVR = 1.28; 95% CI 1.09–1.50; p = 0.002), and HDL-cholesterol (CVR = 1.15; 95% CI 1.00–1.31; p < 0.05), but not triglycerides, was greater in patients than controls. Mean glucose, glucose post-OGTT, fasting insulin, insulin resistance, and triglycerides were greater in patients; mean total-cholesterol and HDL-cholesterol were reduced in patients. Increased symptom severity and female sex were associated with worse metabolic outcomes. Conclusions Patients with FEP present with greater variability in metabolic parameters relative to controls, consistent with a subgroup of patients with more severe metabolic changes compared to others. Understanding determinants of metabolic variability could help identify patients at-risk of developing metabolic syndrome. Female sex and severe psychopathology are associated with poorer metabolic outcomes, with implications for metabolic monitoring in clinical practice.

Liraglutide and the management of overweight and obesity in people with severe mental illness: qualitative sub-study

Background People with severe mental illness are two to three times more likely to be overweight or have obesity than the general population and this is associated with significant morbidity and premature mortality. Liraglutide 3 mg is a once daily injectable GLP-1 receptor agonist that is licensed for the treatment of obesity in the general population and has the potential to be used in people with severe mental illness. Aims To record the expectations and experiences of people with schizophrenia, schizoaffective disorders or first episode psychosis taking daily liraglutide 3 mg injections in a clinical trial for the treatment of obesity. To seek the views of healthcare professionals about the feasibility of delivering the intervention in routine care. Methods Qualitative interviews were undertaken with a purposive sub-sample of people with schizophrenia, schizoaffective disorders or first episode psychosis with overweight or obesity who were treated with a daily injection of liraglutide 3 mg in a double-blinded, randomised controlled pilot study evaluating the use of liraglutide for the treatment of obesity. Interviews were also conducted with healthcare professionals. Results Seventeen patient participants were interviewed. Sixteen took part in the baseline interview, eight completed both baseline and follow-up interviews, and one took part in follow-up interview only. Mean interview duration was thirteen minutes (range 5-37 min). Despite reservations by some participants about the injections before the study, most of those who completed the trial reported no challenges in the timing of or administering the injections. Key themes included despondency regarding prior medication associated weight gain, quality of life impact of weight loss, practical aspects of participation including materials received and clinic attendance. Healthcare professionals reported challenges with recruitment, however, overall it was a positive experience for them and for participants. Conclusion Liraglutide appears to be an acceptable therapy for obesity in this population with limited side effects. The quality of life benefits realised by several intervention participants reinforce the biomedical benefits of achieved weight loss.