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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.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.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.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.

Background and Hypothesis Two machine learning derived neuroanatomical signatures were recently described. Signature 1 is associated with widespread grey matter volume reductions and signature 2 with larger basal ganglia and internal capsule volumes. We hypothesized that they represent the neurodevelopmental and treatment-responsive components of schizophrenia respectively. Study Design We assessed the expression strength trajectories of these signatures and evaluated their relationships with indicators of neurodevelopmental compromise and with antipsychotic treatment effects in 83 previously minimally treated individuals with a first episode of a schizophrenia spectrum disorder who received standardized treatment and underwent comprehensive clinical, cognitive and neuroimaging assessments over 24 months. Ninety-six matched healthy case–controls were included. Study Results Linear mixed effect repeated measures models indicated that the patients had stronger expression of signature 1 than controls that remained stable over time and was not related to treatment. Stronger signature 1 expression showed trend associations with lower educational attainment, poorer sensory integration, and worse cognitive performance for working memory, verbal learning and reasoning and problem solving. The most striking finding was that signature 2 expression was similar for patients and controls at baseline but increased significantly with treatment in the patients. Greater increase in signature 2 expression was associated with larger reductions in PANSS total score and increases in BMI and not associated with neurodevelopmental indices. Conclusions These findings provide supporting evidence for two distinct neuroanatomical signatures representing the neurodevelopmental and treatment-responsive components of schizophrenia.

The association between childhood trauma exposure and risk of developing psychopathology may in part be mediated by the effects of chronic stress on dopaminergic neurotransmission. However, little is known about the differential effects of distinct trauma types on reward processing, particularly in adults without concurrent medical or psychiatric disorders. We examined the association of childhood trauma exposure, including the differential effects of abuse and neglect, with reward processing in healthy adults (n = 114). Functional magnetic resonance imaging during a monetary incentive delay task was used to assess neural activity in the ventral striatum and orbitofrontal cortex in relation to reward anticipation and reward outcome, respectively. Exposure to childhood trauma, including abuse and neglect, was assessed using the Childhood Trauma Questionnaire-Short Form. We found a significant effect for abuse on ventral striatal activation during reward anticipation, adjusting for age, sex, scanner site, educational level, and household monthly income. There were no effects for abuse or neglect, independently or combined, on orbitofrontal cortex activation during reward outcome. Our findings suggest differential effects of childhood abuse on ventral striatum activation during reward anticipation in healthy adults.

Cognitive deficits are a core feature of schizophrenia, and comorbid substance use may be a contributory factor. Methamphetamine use has been associated with cognitive impairment in schizophrenia, while associations with cannabis use are less clear-cut. This study aimed to investigate the associations of cannabis and methamphetamine use with cognitive performance in first-episode schizophrenia spectrum disorders over the first 2 years of treatment.This was a longitudinal cohort study in 81 patients treated with flupenthixol decanoate according to a standardized protocol over 24 months. Cognitive performance was assessed with the Measurement and Treatment Research to Improve Cognition in Schizophrenia Cognitive Consensus Battery at four time points, and urine testing for cannabis and methamphetamine was conducted at six time points. We used linear mixed-effect models for repeated measures to assess visit-wise changes in composite cognitive scores in patients (n = 91) compared to matched controls without psychiatric or medical disorders (n = 100). Linear regression models were constructed to examine pre-treatment and end-point effects in patients.Compared to controls, patients exhibited greater cognitive impairments at baseline, which improved with treatment, but remained significantly lower throughout. The number of positive methamphetamine, but not cannabis, tests predicted less cognitive improvement in patients.Our findings suggest a negative association between methamphetamine and cognition, but not cannabis.

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.

It has been proposed that sex and gender differences described in schizophrenia can be explained from a neurodevelopmental perspective.In this study, we examined the associations of biological sex and gender role endorsement with putative indicators of neurodevelopmental compromise.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.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.Lower masculinity scores may represent part of a phenotype for a neurodevelopmental anomaly that places some individuals on a pathway to schizophrenia.

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.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.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.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.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.

First-episode psychosis (FEP) patients are more sensitive to neuroleptic side-effects such as hyperprolactinemia. We examined the prolactin levels of previously minimally treated patients with first episode schizophrenia over their first year of treatment with flupenthixol decanoate and the relationship between prolactin levels, gender and clinical features of schizophrenia. Prolactin levels were assessed at three monthly intervals in 126 patients with first-episode schizophrenia in a single-site study conducted over 12 months during treatment with flupenthixol decanoate according to a fixed protocol. The mean prolactin level for the total sample was 11.91 ng/ml (standard deviation [SD]15.52) at baseline. Women had higher levels of prolactin than men at month 3, 6 and 12, reaching statistical significance at month 12 (p = 0.02). At 12 months more women than men had hyperprolactinemia (defined as more than 20 ng/ml for males, and as more than 25 ng/ml for females (p = 0.007). Using a mixed effect model, there was a significant association between prolactin change scores over 12 months and gender (p = 0.025) as well as Positive and Negative Syndrome Scale (PANSS) total scores (p = 0.001). In addition female gender (p = 0.04) and age (p = 0.02) correlated with the risk of hyperprolactinemia as categorical variable. In this study treatment with flupenthixol decanoate was associated with relatively low levels of hyperprolactinemia, likely owing to flupenthixol's relatively atypical mode of action, as well as to the low doses used in our study. We found an inverse correlation between total PANSS scores and prolactin levels, which could support the suggested theory of prolactin having antipsychotic properties. Our study confirms the importance of gender on the prolactin raising effects of antipsychotic treatment.

While insight in schizophrenia improves with treatment, significant impairments often persist. The degree of persistence is not well characterised.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.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.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.Clinicians should note that, even when treatment is assured and response is favourable, fundamental impairments in patient-rated insight persist.

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-naive 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

Cannabis use is associated with an unfavourable course of illness in schizophrenia, although several factors may confound this association. In this longitudinal study, we explored the influence of cannabis use on baseline symptom severity and treatment outcomes in 98 patients with first-episode schizophrenia spectrum disorders treated with a long acting injectable antipsychotic over 24 months. Using mixed models for repeated measures, we compared visit-wise changes in psychopathology, social and occupational functioning and quality of life between recent/current cannabis users (n=45) and non-users (n=53). There were no significant group by time interactions for any of our outcomes, and with the exception of poorer functionality in cannabis users at baseline, no significant differences in these domains at baseline or month 24. Also, remission rates were similar. However, more cannabis users met our operationally defined relapse criteria compared to non-users, and more frequent cannabis use over the course of treatment, as assessed by positive urine toxicology testing, predicted relapse. Our results suggest that cannabis users do not have poorer treatment response than non-users in terms of symptom reduction over the 24 months of treatment. However, dose-related risk of relapse remains with ongoing cannabis use, possibly by directly reducing the threshold for psychotic breakthrough.

Background: Prevention of new episodes during the first 2 years after a first episode of schizophrenia (FES) may delay treatment refractoriness and brain morphological changes over time. However, adherence to treatment is characteristically poor in these patients. Aim: The aim of this study was to examine clinical and sociodemographic factors associated with patient dropout in patients with FES. Setting: This study was set at inpatient and outpatient services at a psychiatric hospital in the Western Cape, between 2007 and 2011. Methods: Data were collected as part of a prospective longitudinal study, which followed up patients with FES treated with flupenthixol decanoate. We examined the relationship between treatment adherence and sociodemographic and clinical factors at baseline and at 24 months. Unadjusted and adjusted logistic regression models were used to determine adherence variables. Results: A total of 62% of patients completed the 24 months of treatment. Participants with FES and a substance use disorder (dual diagnosis) were at greater risk of dropout (p = 0.01). On univariate analysis, dual diagnosis participants who dropped out were older (p = 0.04) had completed more years of schooling (p = 0.001), older age of onset (p = 0.02) and higher baseline positive symptoms (p = 0.05). On regression analysis, non-completer substance users achieved a higher level of education (odds ratio [OR]: 3.87, confidence interval [CI]: 1.34–11.11, p = 0.01). Conclusion: Substance use disorder was associated with non-adherence to follow up in a cohort of FES patients treated with flupenthixol decanoate. Interventions that take into account age, education and baseline positive symptoms may afford the opportunity to influence adherence and patient outcome.&nbsp

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".

Depressive symptoms are common in schizophrenia and have been associated with both favourable and unfavourable outcomes. We studied the longitudinal course of depressive symptoms and explored their temporal relationships with other manifestations of the illness and its treatment. This longitudinal cohort study included 126 antipsychotic naive or only briefly treated patients with first-episode schizophrenia spectrum disorders treated with a long-acting antipsychotic over 24 months. Depressive symptoms were assessed at three monthly intervals using the Calgary Depression Scale for Schizophrenia and changes over time were assessed using linear mixed-effect models for continuous repeated measures. Depressive symptoms were most prominent at baseline with highly significant reductions during the first three months of treatment and maintenance of improvement thereafter. Most improvement occurred with antipsychotic treatment alone, with few patients requiring additional antidepressants. We also found that depressive symptoms were associated with positive symptoms, better insight and poorer quality of life, but not with negative symptoms, extrapyramidal symptoms, substance use or cumulative antipsychotic dose.There were few differences between patients who met criteria for depression during the acute phase of treatment and those in the post-acute phase.

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.

Studies assessing the treatment outcomes in first-episode schizophrenia have reported mixed results. While symptom improvement is frequently robust, when other domains are considered outcomes are generally poorer. We explored response trajectories, rates and predictors of recovery in the domains of core psychopathology, clinician-rated social and occupational functioning and patient-rated quality of life over 24 months of treatment in 98 patients with first-episode schizophrenia spectrum disorders who were treated with a long-acting antipsychotic medication. There was robust improvement in core psychopathology (effect size d = 3.36) and functionality (d = 1.78), with most improvement occurring within the first six months of treatment. In contrast, improvement in subjective quality of life was less marked (d = 0.37) and slower, only reaching significance after 12 months of treatment. Symptom remission was achieved by 70% of patients and over half met our criteria for functional remission and good quality of life. However, only 29% met the full criteria for recovery. Patients who met the recovery criteria had better premorbid adjustment, were less likely to be of mixed ethnicity and substance use emerged as the only modifiable predictor of recovery. Only 9% of our sample achieved both functional remission and good quality of life despite not being in symptom remission. We found high rates of symptom remission, functional remission and good quality of life in patients, although relatively few achieved recovery by meeting all three of the outcome criteria. Symptom remission is not a necessary prerequisite for functional remission and good quality of life, although few non-remitters achieve other recovery criteria.

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.

BackgroundChildhood 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.MethodsPearson 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.ResultsPatients 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.ConclusionThese 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.

Background Neurological soft signs (NSS) are proposed to represent both state- and trait-related features of schizophrenia. Method We assessed the course of NSS with the Neurological Evaluation Scale (NES) over 12 months of standardised treatment in 126 patients with first-episode schizophrenia, schizophreniform or schizoaffective disorder, and evaluated their state- and trait-related associations with psychopathology, functionality, cognition and antipsychotic treatment. We considered change scores from baseline to be state-related and endpoint scores to be trait-related. Results Significant effects for time were recorded for all NSS domains. For state-related change-scores greater improvements in sensory integration were predicted by more improvement in working memory ( p = 0.01); greater improvements in motor sequencing scores were predicted by more improvement in working memory ( p = 0.005) and functionality ( p = 0.005); and greater improvements in NES Total score were predicted by more improvement in disorganised symptoms ( p = 0.02). There were more substantial associations between trait-related endpoint scores than for state-related change scores. For endpoint scores lower composite cognitive score predicted poorer sensory integration ( p = 0.001); higher Parkinsonism score predicted poorer motor co-ordination ( p = 0.0001); lower composite cognitive score ( p = 0.001) and higher Parkinsonism score ( p = 0.005) predicted poorer motor sequencing; higher Parkinsonism score ( p = 0.0001) and disorganised symptoms ( p = 0.04), and lower composite cognitive score ( p = 0.0007) predicted higher NES total score. Conclusions NSS improved with treatment, but were weakly associated with improvements in psychopathology. Studies investigating NSS as trait-markers should ensure that patients have been optimally treated at the time of testing, and should take possible effects of extrapyramidal symptoms into account.

BackgroundProgressive brain volume reductions have been described in schizophrenia, and an association with antipsychotic exposure has been reported.MethodsWe 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).ResultsExcessive 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.ConclusionsBrain 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.

Background The relationship between schizophrenia and depression is complex. Longitudinal studies on the course of depression in first episode schizophrenia populations are scarce and there are conflicting results on the predictive value of some baseline measures. Methods We conducted an open label longitudinal cohort study which included 126 patients with first-episode schizophrenia spectrum disorders treated with long-acting antipsychotic medication over 24 months. Depression was assessed at three monthly intervals using the Calgary Depression Scale for Schizophrenia. Changes in depression over time were assessed using the linear mixed-effect models for continuous repeated measures. The relationship between depression and other clinical parameters was assessed with regression models. Results Depressive symptoms were most prominent at baseline and showed highly significant reductions in the first three months (p Discussion Our findings suggest that depression in schizophrenia is common and generally responds well to treatment. The relationship between depression and insight has implications for further treatment considerations

Childhood trauma exposure has been associated with poorer treatment outcomes in schizophrenia. Most studies to date have been conducted in naturalistic settings in which the outcome may have been mediated by factors such as poor adherence and substance abuse. We compared the effects of high vs low childhood trauma exposure on the treatment response over 24 months in 78 patients with first-episode schizophrenia spectrum disorders who received standardised treatment with a long acting injectable antipsychotic. Compared to the low childhood trauma group (n = 37), the high childhood trauma group (n = 41) received higher doses of antipsychotic medication and were less likely to achieve remission. When age, sex and cannabis use were controlled for, patients with high levels of childhood trauma had a slower treatment response for positive and disorganized symptom domains, although differences did not differ significantly at 24 months. While there were no differences in functional outcomes, self-rated quality of life was the domain that most clearly differentiated the high and low childhood trauma groups. High childhood trauma exposure was associated with lower quality of life scores at baseline, a lesser degree of improvement with treatment, and lower quality of life scores at 24 months.

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.

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.

BACKGROUND: 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 first-episode treatment-naive 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. METHODS: 79 first-episode schizophrenia spectrum disorder patients 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 abuse, scanner sequence and age. RESULTS: MANCOVA revealed a significant interaction between sex, childhood trauma questionnaire 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. In addition, larger fissures were significantly associated with higher childhood trauma exposure in females (r=.607,p=.008). DISCUSSION: Findings from the present study suggest that childhood trauma exposure exerts illness-specific effects on hippocampal structures in female first-episode patients, consistent with increased stress sensitivity in this group. Our study supports a unique association of early life trauma with biological changes in stress-sensitive brain regions.

BACKGROUND: Childhood trauma is likely to interfere with normal neurodevelopment. Evidence is also accumulating for the effect of childhood trauma on cognitive functioning and treatment outcomes. Firstly, to investigate the relationship between childhood trauma and neurodevelopment we studied the association between childhood trauma and premorbid adjustment, which may be a manifestation of neurodevelopmental compromise. We also explored the moderating role of a family history of schizophrenia/psychiatric illness, substance abuse, obstetric complications, and neurological soft signs. Next, we assessed the impact of childhood trauma on cognitive functioning, as little is known about the relationship between social cognition and childhood trauma. Lastly, we studied the effect of childhood trauma on clinical outcomes and functionality over the course of 2 years. Schizophrenia is an illness characterized by poor outcomes and this may be ascribed to a history of childhood adversity. METHODS: Our sample consisted of First Episode Schizophrenia (FES) patients and healthy controls. Patients received a fixed treatment regimen of long-acting decanoate injections. We used hierarchical regression to assess the relationship between childhood trauma and premorbid adjustment in 77 patients. We included interaction terms in the model. We also used hierarchical regression to explore the relationship between childhood trauma and cognition in patients (n = 56) and controls (n = 52). We used linear mixed effect models for continuous repeated measures to assess changes in clinical outcomes and functionality in 78 patients. RESULTS: We found a relationship between childhood trauma and premorbid adjustment from childhood to late adolescence. There were no moderating effects for family history of schizophrenia/psychiatric disorder. History of obstetric complications, substance abuse and poor motor coordination weakened the association between childhood trauma and premorbid adjustment, while poor sequencing of motor acts strengthened the association. Childhood neglect was a predictor of poor 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. Childhood abuse did not predict cognitive impairments in either group. Then we found no pronounced differences pre-treatment when comparing patients with high and low childhood trauma. Over time patients with high childhood trauma scores had more severe positive and disorganized symptoms and at the end of 2 years they had higher overall symptom severity and disorganized symptoms and poorer social and occupational functioning and quality of life. DISCUSSION: Our results confirm an association between childhood trauma and premorbid adjustment and indicate a general rather than specific association, apparent with different types of trauma, and affecting both social and academic premorbid adjustment. Our results suggest an interplay of risk factors, supporting the notion of different pathways to psychosis. We found that childhood adversity is associated with cognitive impairment. It seems that the association between neglect and social cognition is not illness-specific and found in both patients and controls. Although we did not find pronounced differences pre-treatment, the effect of early adversity was clearly visible over time and at the end of the 2-year follow-up period. Our findings regarding the effect of childhood trauma on premorbid adjustment, cognitive functioning, and treatment outcomes suggest that early adversity is an important environmental factor that can no longer be ignored when we treat patients with schizophrenia.

Purpose of review In this article, recent publications addressing the pros and cons of antipsychotic maintenance treatment are reviewed and some recommendations formulated. Recent findings On one hand, relapse rates are extremely high when antipsychotic treatment is discontinued, even after a single episode of psychosis; there are no reliable predictors of relapse; and there are serious psychosocial and biological consequences of relapse. On the other hand, in addition to the well recognised side-effect burden of antipsychotics, a few recent publications suggest an association between greater exposure to antipsychotic treatment and poorer long-term outcome. Summary There is more evidence in favour of maintaining patients on antipsychotics than on stopping them. There is an urgent need for more and better research before the question of duration of maintenance after a single episode of schizophrenia can be answered with confidence. Until such studies have been conducted, clinicians should prioritize relapse prevention, particularly in the early years of illness, by encouraging indefinite, continuous antipsychotic treatment, and avoid unnecessary side-effects by using the lowest possible effective dose and selecting the best tolerated antipsychotic.

Background Cannabis use is generally associated with an unfavourable course of illness in first-episode schizophrenia, including non-remission of psychopathology symptoms, higher rates of relapse and re-hospitalization, and poorer functioning. The aim of this study was to explore the influence of cannabis use on clinical and treatment outcomes in first-episode schizophrenia spectrum disorder patients over 24 months of assured antipsychotic treatment. Methods The present longitudinal study included 123 minimally treated or antipsychotic-naive first-episode patients assessed over 24 months of treatment with flupenthixol decanoate according to a standardized regimen. Time to relapse, rates of symptomatic and functional remission, as well as recovery were compared between cannabis users (n=41) and non-users (n=82) stratified based on a combination of self-report and urine toxicology results over the course of treatment. In addition, visit-wise changes in psychopathology severity and overall functioning were compared between these two study groups. We hypothesized that 1) ongoing cannabis use would present with more severe psychopathology and poorer overall level of functioning, and 2) rates of remission and recovery would be lower in cannabis users compared to their non-using counterparts. Results At study entry, cannabis-using patients were younger, more likely to be male and to use methamphetamine, and scored lower in social and occupational functioning. Moreover, while cannabis users were more likely to relapse at any point over 24 months of treatment, cannabis non-users were more likely to achieve remission within the first six months, although this effect was not statistically significant. However, our most important finding was the interaction between cannabis use and time for total psychopathology as well as for the PANSS positive factor. While differences were not evident at either study entry or endpoint, cannabis users recovered at a slower rate than non-users. Discussion These results suggest a poorer treatment response in cannabis users compared to non-users in the context of assured adherence to antipsychotic medication. Therefore, regardless of the neurobiological impact of cannabis use in schizophrenia, the behaviour of substance use itself needs to be targeted as part of first-line treatment in order to improve the treatment outcomes of substance-using patients.

Background: The association between caregiver burden, quality of life and depression in patients with mental illness in a resource-limited setting is underresearched. Factors associated with caregiver burden may be amenable to intervention. Aim: To describe the level of caregiver burden and its association with quality of life and depression. Methods: The cross-sectional study was carried out in a psychiatric hospital in the Cape Flats, which is an urban area on the periphery of Cape Town. Data were collected from 104 caregivers of patients attending the outpatients service. Caregiver burden was measured using the Zarit Burden Interview questionnaire. The PHQ-9 questionnaire was to screen and measure severity of symptoms of depression. The WHOQOL-BREF was used to measure the subjective evaluation of the quality of life. Results: Most caregivers were female (76.92%), and caregivers were mild to moderately stressed (mean ZBS score 33.38 ± 21.59) and experienced moderate depression (mean PHQ-9 score). These effects were significantly associated with quality of life in psychological and social domains. Conclusion: Caring for patients with mental illness can lead to immense physical and psychological distress, leading to poor quality of life. Strategies that may reduce the burden of care may include improving the patients’ quality of life and addressing psychosocial support, and clinicians should consider screening for symptoms of depression in caregivers.

Objective The goals of this study were to (i) estimate the rate of non-response to first-line treatment in first-episode schizophrenia, (ii) evaluate other outcomes associated with symptom non-response and (iii) identify demographic, baseline clinical and early treatment response predictors of non-response. Methods This was a single-site, longitudinal cohort study assessing the effects of treatment with flupenthixol decanoate according to a standardised protocol over 12 months in patients with schizophrenia, schizophreniform and schizo-affective disorders. Results Of 126 patients who received at least one dose of study medication, 84 (67%) completed the study. Fifteen (12%) met our predefined criteria for non-response. Non-responders were younger and at baseline had more prominent disorganised symptoms, poorer social and occupational functioning, poorer quality of life for psychological, social and environmental domains, more prominent neurological soft signs (NSS) and lower body mass index. At endpoint, the non-responders were characterised by higher levels of symptomatology in all domains, poorer functional outcome, poorer quality of life and greater cognitive impairments. They also had more prominent NSS and lower body mass index. The strongest predictors of non-response were more prominent baseline NSS and poor early (7 weeks) treatment response. Conclusions Results are consistent with a lower rate of refractoriness to treatment in first-episode schizophrenia compared with multi-episode samples. Copyright © 2015 John Wiley & Sons, Ltd.

Background This research aimed to identify and explore the experiences of Black registrars in their training in the Western Cape’s academic hospitals in order to identify structures, practices, attitudes and ideologies that may promote or impede the advancement of Black doctors into specialist medicine. This is justified by the requirement for universities to work towards monitoring and evaluating efforts to create non-discriminatory and inclusive training environments. Methods This study employed qualitative research methods. Ten Black African medical specialists were interviewed about their training experiences in two university training hospitals in the Western Cape Province, South Africa. Interview data was collected using open-ended questions and coded and analysed using thematic and critical discursive analysis techniques. Results Four experiential themes emerged from the interview data, they included: 1) experiences of everyday racism during work hours, 2) the physical and psychological effects of tokenism and an increased need to perform, 3) institutional racism as a result of inconsistent and unclear methods of promotion and clinical competence building, and 4) an organisational culture that was experienced as having a race and gender bias. Conclusion This is a pilot study and there are limits on the generalizability of the data due to the small sample. What is clear from our participants, though, is the strong experiential component of finding it challenging to be a Black trainee in a White-dominated profession. We are undertaking further research to explore the issues raised in more detail.

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. The aim of this study was to explore the effects of cannabis use on hippocampal subfield volumes in male first-episode schizophrenia spectrum disorder patients 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 the recently validated Freesurfer 6.0. Urine toxicology screening was done on the day of the MRI scan. We used multivariate analysis of covariance (MANCOVA) with age and scan sequence 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 diagnosis by cannabis use interaction effect in the subiculum (F=7,832; p=0,006), with smaller volumes observed in the cannabis non-using patients than the cannabis-using patients, and smaller volumes in the cannabis-using controls than the cannabis non-using controls. DISCUSSION: The larger subiculum volume in cannabis-using patients compared to both cannabis non-using patients and cannabis using controls was unexpected, and raises important questions regarding the pathophysiology of schizophrenia and the role of cannabis use therein. Future studies should investigate the effects of dose and composition of cannabis, as well as moderating genetic and other environmental effects, on hippocampal subfields in first episode schizophrenia.

Background Acute cannabis use stimulates appetite, while general population studies suggest that chronic use is associated with reduced risk of obesity and other cardiometabolic risk factors. Methods 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). Results 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. However, more cannabis negative patients had elevated waist-circumference at endpoint (p=0.003). Discussion Although other indirect effects such as dietary neglect and smoking may be contributory and could explain our findings, it may be that chronic cannabis use directly suppresses appetite, thereby preventing weight gain in users.

Background The course of schizophrenia is characterised by episodes of psychotic symptoms and enduring deficits of negative symptoms, cognition and functioning. We investigated the relationship between global brain measures and trait-related symptoms (endpoint scores), and global brain measures and state-related symptoms (change scores). Methods We examined global cortical, subcortical and white matter volume, and global cortical thickness in 54 first-episode schizophrenia patients at baseline. We performed clinical, cognitive, and neurological assessments at baseline and twelve month follow-up. We used hierarchical multiple regression to predict baseline brain measures. Results State-related clinical predictors accounted for 8% of variance in white matter volume, trait-related clinical predictors accounted for 7% of variance in subcortical volume. Trait-related cognitive scores accounted for 15% of variance in subcortical volume and 13% of variance in cortical volume. Baseline subcortical gray matter volume was significantly associated with sensory integration (0.02) and verbal learning (0.04) trait scores, cortical volume with verbal learning (0.04) trait scores, cortical thickness with social and occupational functioning (0.03) trait scores, and white matter volume with motor coordination (0.007) state scores. Discussion Impaired verbal learning may be the cognitive domain that is particularly trait-related, and possibly closest to the neurodevelopmental deficit underlying schizophrenia. State and trait components of neurological soft signs may be differentially related to brain structure. Mediators of the relationship between trait functional deficits and cortical thickness needs consideration.

Background Impairment of insight is a prominent feature of schizophrenia and is associated with poor adherence and poor outcomes. While many studies have investigated the nature of insight impairment in schizophrenia, few have charted its course longitudinally. In this study we investigated changes in different components of insight during the first 12 months of antipsychotic treatment. Methods The sample comprised 107 never or minimally treated patients with a first episode of schizophrenia, schizophreiform or schizoaffective disorder. They were treated according to a fixed protocol with flupenthixol decanoate. Insight was assessed with the self-rating Birchwood Insight Scale and the investigator rated global insight item of the PANSS scale.Psychopathology was assessed with the PANSS and CDSS. Cognitive performance was assessed with the MATRICS. We performed evaluations at baseline, month 6 and month 12. Linear mixed effects mixed models for repeated measures were conducted to assess changes over time, adjusting for age, gender and educational status. Results There were no significant changes in the BIS subscales of symptom awareness, awareness of illness or total BIS score. The need for treatment subscale improved slightly (p=0.02) while the PANSS global insight improved considerably (p

The goals of this study were to (i) estimate the rate of non-response to first-line treatment in first-episode schizophrenia, (ii) evaluate other outcomes associated with symptom non-response and (iii) identify demographic, baseline clinical and early treatment response predictors of non-response.This was a single-site, longitudinal cohort study assessing the effects of treatment with flupenthixol decanoate according to a standardised protocol over 12 months in patients with schizophrenia, schizophreniform and schizo-affective disorders.Of 126 patients who received at least one dose of study medication, 84 (67%) completed the study. Fifteen (12%) met our predefined criteria for non-response. Non-responders were younger and at baseline had more prominent disorganised symptoms, poorer social and occupational functioning, poorer quality of life for psychological, social and environmental domains, more prominent neurological soft signs (NSS) and lower body mass index. At endpoint, the non-responders were characterised by higher levels of symptomatology in all domains, poorer functional outcome, poorer quality of life and greater cognitive impairments. They also had more prominent NSS and lower body mass index. The strongest predictors of non-response were more prominent baseline NSS and poor early (7 weeks) treatment response.Results are consistent with a lower rate of refractoriness to treatment in first-episode schizophrenia compared with multi-episode samples.

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 2 g/day and docosahexaenoic acid 1 g/day) + α-LA 300 mg/day or placebo. Subjects were followed up for two years, or until relapse. Results: Recruitmentwas 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 Stanley Medical Research Institute (Grant #09T-1281)