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Objective: Both cognitive impairment and alterations in white matter tissue microstructure are well recognised in schizophrenia. We investigated whether differences in white matter microstructure underpin cognitive impairments in patients with first-episode schizophrenia spectrum disorders when controlling for multiple confounding factors., Methods: We employed a cross-sectional study design and compared fractional anisotropy (FA) between individuals diagnosed with first- episode schizophrenia spectrum disorders (FES) (n = 68) and matched healthy controls (n = 120). We conducted multiple analyses of covariance (ANCOVAs) to compare the mean FA values for patients and controls across 27 white matter tracts. We conducted exploratory correlation analyses to determine if white matter tract differences were associated with global cognitive impairment as well as deficits across seven cognitive domains., Results: We found widespread reductions in FA in patients compared to controls, after controlling for confounding variables, such as age, biological sex, education, substances, and childhood adversities. We found a significant positive correlation between the attention/vigilance domain and the splenium of the corpus collosum and external capsule after correction for multiple comparisons. In the control group we found no significant correlations between FA and cognition., Conclusion: Our findings provide a neurobiological basis for attentional cognitive deficits in schizophrenia, highlighting a potential role for the splenium of the corpus collosum and external capsule., Competing Interests: Declaration of competing interest SK, LA, SDP, FS, AMS, LP, HLK, LS, RO and CB declare no conflict of interests. RAE has received honoraria from AstraZeneca, Bristol-Myers Squibb, Janssen, Lilly, Lundbeck, Organon, Pfizer, Servier, Otsuka and Wyeth for participating in advisory boards and speaking at educational meetings, and has received research funding from Janssen, Lundbeck and AstraZeneca., (Copyright © 2022. Published by Elsevier B.V.)

Background: Recent studies suggest a two-factor structure for negative symptoms as assessed by the Positive and Negative Syndrome Scale (PANSS) in schizophrenia, namely experiential and expressive subdomains. Little is known about their clinical correlates and treatment trajectories., Objectives: We sought to replicate the two factor-analysis derived subdomains for PANSS negative symptoms in schizophrenia and to assess their independent demographic, premorbid and treatment-related characteristics., Methods: This was a longitudinal study of 106 minimally treated participants with a first episode of a schizophrenia spectrum disorder who received treatment with flupenthixol decanoate 2-weekly injections over two years. Factor analysis was used to characterize the PANSS negative symptom subdomains and linear mixed-effect models for continuous repeated measures were constructed to assess the temporal relations between the negative symptom subdomains and premorbid and treatment related variables., Results: Factor analysis confirmed a two-factor solution for experiential and expressive subdomains of negative symptoms, although they were strongly correlated. The treatment response trajectories for the two subdomains did not differ significantly, and neither subdomain was significantly associated with our premorbid variables. We found significant main effects for disorganised symptoms and extrapyramidal symptoms on the expressive subdomain, and for disorganised symptoms and depressive symptoms on the experiential subdomain. Post-hoc testing indicated that reductions in HDL-cholesterol levels were associated with less improvement in both expressive and experiential subdomain scores., Conclusion: The two negative symptom subdomains are closely related, have similar premorbid correlates and respond similarly to antipsychotic treatment. Depression affects the experiential subdomain, whereas extrapyramidal symptoms affect the expressive subdomain., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: It has been proposed that sex and gender differences described in schizophrenia can be explained from a neurodevelopmental perspective., Aim: In this study, we examined the associations of biological sex and gender role endorsement with putative indicators of neurodevelopmental compromise., Methods: We used the Bem Sex Role Inventory to calculate masculinity scores in 77 patients with a first episode of a schizophrenia spectrum disorder, and selected the following indicators of neurodevelopmental compromise: family history of schizophrenia, obstetric complications, premorbid functioning, neurological soft signs, and cognitive function. Secondary objectives included the moderating effects of age of onset of illness, substance use and negative symptoms on these associations., Results: There were no significant sex differences across any of the indicators of neurodevelopmental compromise. However, lower masculinity scores correlated significantly with poorer premorbid adjustment, sensory integration deficits and worse overall cognitive performance. Stepwise linear regression identified poorer premorbid adjustment in early adolescence and lower verbal learning scores as independent predictors of lower masculinity scores. In contrast to sex, gender showed several associations with indicators of neurodevelopmental compromise., Conclusions: Lower masculinity scores may represent part of a phenotype for a neurodevelopmental anomaly that places some individuals on a pathway to schizophrenia., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest FS, SdP, LA, SK, LP, and HKL have no conflict of interest to declare. RE has participated in speakers/advisory boards and received honoraria from Janssen, Lundbeck, Servier and Otsuka, and has received research funding from Janssen and Lundbeck., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Childhood trauma and schizophrenia are both associated with neuroanatomical abnormalities in the hippocampus, a stress-sensitive structure vulnerable to developmental insults. However, few studies have evaluated the effects of childhood trauma exposure on hippocampal morphometry in minimally treated first-episode schizophrenia patients. Here we aim to investigate the associations of childhood trauma with hippocampal subfield volumes in a cohort of antipsychotic-naive or minimally treated first-episode schizophrenia spectrum disorder patients and matched controls. 79 patients with first-episode schizophrenia spectrum disorder and 82 matched controls completed the childhood trauma questionnaire and underwent MRI assessment. Hippocampal subfields were reconstructed using FreeSurfer 6.0. We considered inter-correlations between the various subfields, by entering them as dependent variables into a multivariate analysis of co-variance (MANCOVA), modeling for interactions between diagnosis, childhood trauma total score and gender while controlling for substance use, scanner sequence and age. MANCOVA revealed a significant interaction between sex, childhood trauma total scores and diagnosis across hippocampal sub-regions (p = 0.012). Bonferroni corrected post-hoc analysis revealed a significant sex*diagnosis*childhood trauma score interaction for the hippocampal fissure (F(1,161) = 9.485,p = .002). Hippocampal fissure size showed a positive relationship with CA structures as well as whole hippocampal size in the larger sample. Findings from the present study suggest that childhood trauma exposure exerts illness-specific effects on hippocampal structures in female patients with first-episode schizophrenia, consistent with increased stress sensitivity in this group., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: While insight in schizophrenia improves with treatment, significant impairments often persist. The degree of persistence is not well characterised., Aims: We assessed patient and clinician-rated changes in insight in acutely ill, minimally treated first-episode schizophrenia spectrum disorder patients over 24 months of standardised treatment with a depot antipsychotic., Method: This single arm open label longitudinal cohort study included 105 participants with first-episode schizophrenia, schizophreniform or schizoaffective disorder. Insight was assessed at months 0, 6, 12 and 24 using the patient-rated Birchwood Insight Scale (BIS) and clinician-rated global insight item of the Positive and Negative Syndrome Scale (PANSS). Changes in insight over time were assessed using linear mixed-effect models for continuous repeated measures. Relationships between insight and psychopathology, functionality, cognition and quality of life were assessed with regression models., Results: There was significant improvement over time for the PANSS insight item (p < 0.0001). However, the only significant improvement for the BIS was with the Need for Treatment subscale (p = 0.01). There were no significant improvements noted for the Symptom Attribution (p = 0.7) and Illness Awareness (p = 0.2) subscales, as well as the BIS Total score (p = 0.6). Apart from depressive symptoms at baseline, there were no significant predictors of patient-rated insight., Conclusions: Clinicians should note that, even when treatment is assured and response is favourable, fundamental impairments in patient-rated insight persist., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Impaired insight is a hallmark feature of schizophrenia. Structural studies implicate predominantly prefrontal, cingulate, cuneus/precuneus, and inferior temporal brain regions. The cortical midline structures (CMS) are also implicated in functional studies primarily through self-reflective processing tasks. However, few studies have explored the relationship between white matter tracts and insight in schizophrenia, and none in first-episode schizophrenia (FES). Here, we examined for fractional anisotropy (FA) differences in 89 minimally treated FES patients and 98 matched controls, and identified those FA differences associated with impaired clinical insight in patients. We found widespread FA reduction in FES patients compared to controls. Poorer insight in patients was predicted by lower FA values in a number of white matter tracts with a predilection for tracts associated with cortical midline structures (fronto-occipital, cingulate, cingulate hippocampus, uncinate, anterior corona radiata), and more severe depressive symptoms. The association between FA abnormalities and insight was most robust for the awareness of symptoms and illness awareness domains. Our study implicates a network of tracts involved in impaired insight in schizophrenia with a predilection for the CMS. This study is a first step in delineating the white matter tracts involved in insight impairment in schizophrenia prior to chronicity., (Copyright © 2016. Published by Elsevier B.V.)

Background: Studies of pre-and post-treatment striatal volume in schizophrenia have reported conflicting results., Materials and Methods: We assessed dorsal striatal (caudate and putamen) volumes bilaterally in 22 never-treated, non-substance-abusing patients with first-episode schizophrenia or schizophreniform disorder and 23 healthy controls matched for age, sex and educational status. Patients received either risperidone or flupenthixol long acting injection and were compared by structural MRI with controls at weeks 0, 4 and 13. T1-weighted data on a 3T MRI scanner were obtained and images were reconstructed using FreeSurfer. Treatment outcome was assessed by changes in psychopathology, insight, functionality, cognitive performance and motor symptoms., Results: Caudate, but not putamen volumes was significantly larger in patients bilaterally at baseline (P=0.01). Linear mixed effects repeated measures found no significant group × time interactions for any of the regions. Caudate volume was not significantly associated with improvements in psychotic symptoms. Also, the findings of a regression model were inconsistent insofar as larger caudate volume was associated with less improvement in depression scores, greater improvement in functionality and greater improvement in verbal learning but less improvement in reasoning and problem solving (left caudate) and composite cognitive score (right caudate)., Conclusions: The increased caudate volumes prior to treatment are contrary to previous reports in never-treated patients with first-episode schizophrenia, and together with our failure to demonstrate volume changes related to acute treatment, call into question previous proposals that enlarged caudate volume is a consequence of antipsychotic treatment., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: While antipsychotics are effective in the maintenance treatment of schizophrenia they have safety and tolerability risks. We investigated whether a combination of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) and a metabolic antioxidant, alpha-lipoic acid (α-LA), is effective in preventing relapse after antipsychotic discontinuation in subjects who were successfully treated for 2-3 years after a first-episode of schizophrenia, schizo-affective or schizophreniform disorder., Methods: In this randomized, double-blind, placebo controlled study antipsychotic treatment was tapered and discontinued and participants received either ω-3 PUFAs (eicosapentaenoic acid 2g/day and docosahexaenoic acid 1g/day)+α-LA 300 mg/day or placebo. Subjects were followed up for two years, or until relapse., Results: Recruitment was terminated prematurely due to the high relapse rates in both treatment groups as well as the severity of some of the relapse episodes. Of the 33 participants, 19/21(90%) randomized to ω-3 PUFAs+α-LA relapsed and one (5%) completed two years without relapse (p=0.6); and 9/12 (75%) randomized to placebo relapsed and none completed two years without relapse. Mean times to relapse were 39.8 ± 25.4 and 38.3 ± 26.6 weeks for the ω-3 PUFAs+α-LA and placebo groups, respectively (p=0.9). There were no significant differences between the groups in relapse symptom severity., Conclusions: We found no evidence that ω-3 PUFAs+α-LA could be a suitable alternative to maintenance antipsychotic treatment in relapse prevention, in this small study. Antipsychotic discontinuation after a single episode of schizophrenia carries a very high risk of relapse, and treatment guidelines endorsing this practice should be revised., (Copyright © 2014 Elsevier B.V. All rights reserved.)