Sex versus gender associations with brain structure.

In contrast to sex (a biological distinction), little is known about the associations between gender (a societal construct) and brain structure in the general population. In response to this knowledge gap, we examined the associations of sex vs. gender with FreeSurfer-generated cortical thickness and proportion-adjusted subcortical brain volume regions-of-interest (ROIs) in healthy adults (n = 88) screened for general medical conditions, mental illness, substance abuse, and intracranial pathologies. Gender role endorsement was assessed using the well-established and validated Bem Sex Role Inventory. For our main objectives, we calculated a continuum score as a composite measure of gender. For our secondary objectives, we examined sex-specific associations of the masculine vs. feminine gender role endorsement domains with brain structural outcomes. We found that female sex, independent of continuum scores, was associated with larger proportion-adjusted volumes for the basal ganglia, hippocampus, and ventral diencephalon. Higher continuum scores, independent of sex, were associated with thicker cortical thickness for the left and right superior frontal cortex, caudal and rostral middle frontal cortex, and right pars orbitalis. Female sex and higher continuum scores were independently associated with larger corpus callosum volumes. Post-hoc testing showed sex-specific associations between higher femininity scores and thicker prefrontal cortical thickness for the ROIs in females, but not in males. In conclusion, sex and gender showed semi-independent associations with brain structure in a general population sample. Our research supports the disaggregation of sex and gender to provide a more nuanced perspective on brain structural differences between men and women.

Relapse in schizophrenia: The role of factors other than non-adherence to treatment.

AIM: Relapse rates are very high in schizophrenia. However, little is known about the predictors of the time to relapse other than treatment non-adherence. We investigated possible risk factors for the time to relapse in patients with first-episode schizophrenia (n = 107) who received assured treatment by way of long-acting injectable antipsychotic over 24 months and who underwent regular clinical, cognitive, and metabolic assessments. METHODS: Using Cox regression analyses we assessed selected premorbid and baseline potential predictors of time to relapse. Relapse was defined using operationally defined relapse criteria. RESULTS: In the primary analysis only neurological soft signs total score retained significance, with higher scores predicting shorter time to relapse (HR = 1.05, 95% CI = 1.01-1.10, p = .029). In a more detailed secondary analysis poorer social relationships predicted shorter time to relapse (HR = 0.85, 95% CI = 0.76-0.95, p = .003). CONCLUSION: Our predominantly negative findings suggest that many of the previously implicated risk factors for the time to relapse are mediated by non-adherence rather than having a direct effect on relapse-proneness. Neurological soft signs, and perhaps quality of life in social relationships appear to play a role and merit further investigation.

Sex, gender, and outcome in first-episode psychosis: The role of premorbid functioning.

We examined the associations of sex (biological distinction) and gender (societal distinction) with psychopathology, depressive symptoms and social and occupational functioning over 24 months. We found that lower masculinity scores were associated with worse psychopathology outcomes, independent of sex and other neurodevelopmental factors. These effects were mediated by poor premorbid adjustment, which also mediated the relationship between childhood trauma and masculinity scores as predictors of disorganized symptom outcomes. Our findings highlight the importance of considering gender as a separate construct and the need for further research to understand the clinical implications of sex and gender differences in schizophrenia.

Associations between BMI and brain structures involved in food intake regulation in first-episode schizophrenia spectrum disorders and healthy controls.

Structural brain differences have been described in first-episode schizophrenia spectrum disorders (FES), and often overlap with those evident in the metabolic syndrome (MetS). We examined the associations between body mass index (BMI) and brain structures involved in food intake regulation in minimally treated FES patients (n = 117) compared to healthy controls (n = 117). The effects of FES diagnosis, BMI and their interactions on our selected prefrontal cortical thickness and subcortical gray matter volume regions of interest (ROIs) were investigated with hierarchical multivariate regressions, followed by post-hoc regressions for the individual ROIs. In a secondary analysis, we examined the relationships of other MetS risk factors and psychopathology with the brain ROIs. Both illness and BMI significantly predicted the grouped prefrontal cortical thickness ROIs, whereas only BMI predicted the grouped subcortical volume ROIs. For the individual ROIs, schizophrenia diagnosis predicted thinner left and right frontal pole and right lateral OFC thickness, and increased BMI predicted thinner left and right caudal ACC thickness. There were no significant main or interaction effects for diagnosis and BMI on any of the individual subcortical volume ROIs. Secondary analyses suggest associations between several brain ROIs and individual MetS risk factors, but not with psychopathology. Our findings indicate differential, independent effects for FES diagnosis and BMI on brain structures. Limited evidence suggests that the BMI effects are more prominent in FES. Exploratory analyses suggest associations between other MetS risk factors and some brain ROIs.

Cannabis use and hippocampal subfield volumes in males with a first episode of a schizophrenia spectrum disorder and healthy controls.

BACKGROUND: Both schizophrenia and cannabis use are associated with structural brain changes. The hippocampus is a region of particular interest due to its role in memory and select cognitive functions, impairment of which is a core feature of schizophrenia and has also been observed in substance abuse. This study aimed to explore the effects of recent/current cannabis use on hippocampal subfield volumes in male patients with first-episode schizophrenia spectrum disorders and matched controls. METHODS: This cross-sectional, case-control study included 63 patients and 58 controls scanned on 3T MRI scanners, with hippocampal segmentation performed using recently validated Freesurfer v6.0 software. Cannabis use status was determined by self and carer report together with urine toxicology screening, and patients were categorised as recent/current users or non-users. We used multivariate analysis of covariance (MANCOVA) with age, scan sequence, scan quality, and total intracranial volume as covariates, with subsequent analysis of variance (ANOVA) to test the effects of diagnosis and cannabis use status on individual hippocampal subfields. RESULTS: We found a group (patient/control) by cannabis use interaction effect in the subiculum, with decreased volumes observed in the cannabis non-using patients compared to the cannabis using patients, and decreased volumes in the cannabis using controls compared to the cannabis non-using controls. CONCLUSION: The increased subiculum volume in cannabis using patients compared to cannabis non-using patients raises important questions regarding the pathophysiology of schizophrenia and the role of cannabis use therein.

Gender role endorsement in first-episode schizophrenia spectrum disorders.

Sex (a biological distinction) and gender (a social construct) are inter-related, but semi-independent measures. The aim of our research was to compare gender role endorsement between first-episode schizophrenia spectrum disorder patients (n=77) and matched controls (n=64). The Bem Sex Role Inventory (BSRI) was used to assess masculinity and femininity scores as separate linear measures. This well-known research instrument also allowed us to examine gender as a categorical measure based on sex-specific cut-off scores calculated for controls as our normative reference sample using a median-split technique. First, we found that both masculinity and femininity scores differed between patients and controls. The distribution of gender as a categorical measure also differed between the two groups. Post-hoc testing with correction for multiple comparisons identified masculinity scores in particular as being lower in both male and female patients compared to controls of the corresponding sex. In conclusion, lower masculinity scores reported for chronic schizophrenia also affects first-episode patients with minimal prior treatment exposure irrespective of their biological sex. Future studies would do well to examine the associations of sex and gender with clinical and treatment outcomes from the perspective of the neurodevelopmental model of schizophrenia as a proposed "disorder of the self".

Fronto-limbic white matter fractional anisotropy and body mass index in first-episode schizophrenia spectrum disorder patients compared to healthy controls.

In this diffusion tensor imaging study, we explored the associations of body mass index (BMI) with white matter microstructure in first-episode schizophrenia spectrum disorder patients (n = 69) versus healthy controls (n = 93). We focused on fractional anisotropy (FA) measures for fronto-limbic white matter tracts known to connect brain regions which form part of a "core eating network". Secondary objectives included the associations of body mass with global illness severity, psychopathology and depressive symptoms. In a multivariate analysis of covariance (MANCOVA) model, there was a significant interaction between BMI and group (patient versus control) across the fronto-limbic white matter tracts of interest (F(1,155)= 4.91, p = 0.03). In a sub-analysis, BMI was significantly inversely correlated with FA measures for the genu and body of the corpus callosum, left and right tapetum, and left superior fronto-occipital fasciculus in controls. In patients, BMI was significantly positively correlated with white matter FA for the genu of the corpus callosum and left tapetum. Lower BMI was significantly correlated with more severe negative symptoms, as was earlier age of illness onset. Body mass may be differentially associated with fronto-limbic white matter microstructure in first-episode schizophrenia spectrum disorder compared to controls.

Hippocampal subfield volumes and change in body mass over 12 months of treatment in first-episode schizophrenia spectrum disorders.

In this study, we explored the relationship between baseline hippocampal subfield volumes and change in body mass over 12 months of treatment in 90 first-episode schizophrenia spectrum disorder patients (66 males, 24 females; mean age= 24.7 ± 6.8 years). Body mass index was assessed in patients at baseline, and at months 3, 6, 9 and 12. Hippocampal subfields of interest were assessed at baseline using a segmentation algorithm included in the FreeSurfer 6.0 software program. Linear regression revealed a significant interactive effect between sex and anterior hippocampus size as predictors of change in body mass over 12 months, adjusting for age, substance use, and treatment duration. In an exploratory post-hoc sub-analysis, partial correlations showed a significant association between weight gain and smaller CA1, CA3 and subiculum volumes in females, but not males, adjusting for age and substance use, with similar trends evident for the CA4 and presubiculum subfields. In conclusion, our findings suggest that smaller anterior hippocampal subfields at baseline are associated with the development of weight gain over the course of treatment in first-episode schizophrenia spectrum disorders in a sex-specific fashion. This may be related to the greater increase in body mass evident for female patients in our study.

Relationship between changes in metabolic syndrome constituent components over 12 months of treatment and cognitive performance in first-episode schizophrenia.

Few studies have investigated the longitudinal effects of treatment-emergent metabolic syndrome changes on cognitive performance in first-episode psychosis. The aim of the present study was to determine the associations between changes in metabolic syndrome constituent component over 12 months of treatment and end-point cognitive performance in schizophrenia spectrum disorders. This single site-cohort study included 72 minimally treated or antipsychotic-naïve first-episode patients. Cognitive performance was evaluated using the MATRICS Consensus Cognitive Battery (MCCB). Our primary objective of interest was the relationship between metabolic syndrome constituent component changes over 12 months of treatment and end-point cognitive performance. Secondary objectives included investigating whether this relationship was affected by age, sex, antipsychotic dose, treatment duration and substance use. Weight gain predicted better overall cognition (p = 0.02) at end-point, adjusting for age, sex, substance use, baseline cognitive score and BMI, modal antipsychotic dose and treatment duration. Weight loss (p = 0.04) and substance use (p = 0.01) were both associated with poorer working memory performance at end-point. Low baseline BMI showed differential effects on end-point working memory performance in substance users (unfavorable) compared to non-users (favorable) (p < 0.05). In conclusion, weight gain over the course of antipsychotic treatment is associated with better overall cognitive performance and the working memory domain in first-episode schizophrenia spectrum disorder patients. In contrast, low baseline BMI may represent an unfavorable marker in substance users, who demonstrated weight loss compared to non-users.

Weight gain and metabolic change as predictors of symptom improvement in first-episode schizophrenia spectrum disorder patients treated over 12 months.

BACKGROUND: Treatment-emergent weight gain is associated with antipsychotic efficacy in schizophrenia patients treated with clozapine and olanzapine. However, few studies have investigated this relationship in first-episode patients treated with other antipsychotics, in particular those with a lower obesogenic potential. Aim To investigate the relationships between weight gain and associated metabolic changes with psychopathology improvement in relation to age, sex, ethnicity, substance use, treatment duration and antipsychotic dose in first-episode schizophrenia spectrum disorder patients. METHODS: This single site cohort study included 106 minimally treated or antipsychotic-naive patients treated with flupenthixol decanoate over 12 months. Psychopathology was evaluated using the Positive and Negative Syndrome Scale (PANSS) and BMI, fasting blood lipids and glucose were assessed at regular intervals. Linear regression models were constructed to determine the effects of socio-demographic, clinical and metabolic factors as predictors of change in total PANSS score and factor-derived domains. RESULTS: BMI change scores were inversely correlated with change in PANSS total (R = -0.25; p = 0.011), positive (R = -0.23; p = 0.019), depressive anxiety (R = -0.21; p = 0.031) and disorganized symptoms (R = -0.32; p < 0.001). Linear regression analysis showed that increased BMI and treatment duration both predicted improvement in global psychopathology and disorganized symptoms independent of age, sex, ethnicity, substance use, co-medication with antidepressants and/or anticholinergics, as well as the dose and duration of antipsychotic exposure. CONCLUSIONS: Our findings suggest that the relationship between treatment-emergent weight gain and psychopathology improvement is not limited to patients treated with antipsychotics most associated with weight gain, and is not confounded by treatment duration and dose.

Effects of cannabis use on body mass, fasting glucose and lipids during the first 12 months of treatment in schizophrenia spectrum disorders.

While acute cannabis use stimulates appetite, general population studies suggest that chronic use is associated with reduced risk of obesity and other cardiometabolic risk factors. In this study we investigated changes in body mass index (BMI), fasting blood glucose and lipids, and rates of metabolic syndrome risk factors in cannabis users vs. non-users in 109 minimally treated patients with first-episode schizophrenia, schizophreniform or schizo-affective disorder who were treated according to a standardized treatment regime with depot antipsychotic medication over 12 months. Participants underwent repeated urine toxicology tests for cannabis and those testing positive at any time during the study (n = 40), were compared with those who tested negative at all time points (n = 69). There was a significant group*time interaction effect (p = 0.002) with the cannabis negative group showing a greater increase in BMI than the cannabis positive group, after adjusting for age, sex, methamphetamine use and modal dose of antipsychotic. There were no group*time interaction effects for fasting blood glucose or lipids. Post hoc tests indicated significant increases in fasting blood glucose and triglycerides and a decrease in high-density lipoprotein cholesterol for the cannabis negative group, with no significant changes in the cannabis positive group. Rates of metabolic syndrome did not differ significantly between groups, although more cannabis negative patients had elevated waist-circumference at endpoint (p = 0.003). It may be that chronic cannabis use directly suppresses appetite, thereby preventing weight gain in users. However, other indirect effects such as dietary neglect and smoking may be contributory and could explain our findings.

Childhood adversity and cognitive function in schizophrenia spectrum disorders and healthy controls: evidence for an association between neglect and social cognition.

BACKGROUND: Childhood adversity is associated with cognitive impairments in schizophrenia. However, findings to date are inconsistent and little is known about the relationship between social cognition and childhood trauma. We investigated the relationship between childhood abuse and neglect and cognitive function in patients with a first-episode of schizophrenia or schizophreniform disorder (n = 56) and matched healthy controls (n = 52). To the best of our knowledge, this is the first study assessing this relationship in patients and controls exposed to similarly high levels of trauma. METHODS: Pearson correlational coefficients were used to assess correlations between Childhood Trauma Questionnaire abuse and neglect scores and cognition. For the MCCB domains displaying significant (p < 0.05) correlations, within group hierarchical linear regression, was done to assess whether abuse and neglect were significant predictors of cognition after controlling for the effect of education. RESULTS: Patients and controls reported similarly high levels of abuse and neglect. Cognitive performance was poorer for patients compared with controls for all cognitive domains except working memory and social cognition. After controlling for education, exposure to childhood neglect remained a significant predictor of impairment in social cognition in both patients and controls. Neglect was also a significant predictor of poorer verbal learning in patients and of attention/vigilance in controls. However, childhood abuse did not significantly predict cognitive impairments in either patients or controls. CONCLUSION: These findings are cross sectional and do not infer causality. Nonetheless, they indicate that associations between one type of childhood adversity (i.e. neglect) and social cognition are present and are not illness-specific.

Brain volume changes over the first year of treatment in schizophrenia: relationships to antipsychotic treatment.

BACKGROUND: Progressive brain volume reductions have been described in schizophrenia, and an association with antipsychotic exposure has been reported. METHODS: We compared percentage changes in grey and white matter volume from baseline to month 12 in 23 previously antipsychotic-naïve patients with a first episode of schizophrenia or schizophreniform disorder who were treated with the lowest effective dose of flupenthixol decanoate depot formulation, with 53 matched healthy individuals. Total antipsychotic dose was precisely calculated and its relationship with brain volume changes investigated. Relationships between volumetric changes and treatment were further investigated in terms of treatment response (changes in psychopathology and functionality) and treatment-related adverse-events (extrapyramidal symptoms and weight gain). RESULTS: Excessive cortical volume reductions were observed in patients [-4.6 (6.6)%] v. controls [-1.12 (4.0)%] (p = 0.009), with no significant group differences for changes in subcortical grey matter and white matter volumes. In a multiple regression model, the only significant predictor of cortical volume change was total antipsychotic dose received (p = 0.04). Cortical volume change was not significantly associated with the changes in psychopathology, functionality, extrapyramidal symptoms and body mass index or age, gender and duration of untreated psychosis. CONCLUSIONS: Brain volume reductions associated with antipsychotic treatment are not restricted to poor outcome patients and occur even with the lowest effective dose of antipsychotic. The lack of an association with poor treatment response or treatment-related adverse effects counts against cortical volume reductions reflecting neurotoxicity, at least in the short term. On the other hand, the volume reductions were not linked to the therapeutic benefits of antipsychotics.