A Neuroanatomical Signature for Schizophrenia Across Different Ethnic Groups

Schizophrenia is a disabling clinical syndrome found across the world. While the incidence and clinical expression of this illness are strongly influenced by ethnic factors, it is unclear whether patients from different ethnicities show distinct brain deficits. In this multicentre study, we used structural Magnetic Resonance Imaging to investigate neuroanatomy in 126 patients with first episode schizophrenia who came from 4 ethnically distinct cohorts (White Caucasians, African-Caribbeans, Japanese, and Chinese). Each patient was individually matched with a healthy control of the same ethnicity, gender, and age (±1 year). We report a reduction in the gray matter volume of the right anterior insula in patients relative to controls (P < .05 corrected); this reduction was detected in all 4 ethnic groups despite differences in psychopathology, exposure to antipsychotic medication and image acquisition sequence. This finding provides evidence for a neuroanatomical signature of schizophrenia expressed above and beyond ethnic variations in incidence and clinical expression. In light of the existing literature, implicating the right anterior insula in bipolar disorder, depression, addiction, obsessive-compulsive disorder, and anxiety, we speculate that the neuroanatomical deficit reported here may represent a transdiagnostic feature of Axis I disorders

White matter integrity as a predictor of response to treatment in first episode psychosis

The integrity of brain white matter connections is central to a patient's ability to respond to pharmacological interventions. This study tested this hypothesis using a specific measure of white matter integrity, and examining its relationship to treatment response using a prospective design in patients within their first episode of psychosis. Diffusion tensor imaging data were acquired in 63 patients with first episode psychosis and 52 healthy control subjects (baseline). Response was assessed after 12 weeks and patients were classified as responders or non-responders according to treatment outcome. At this second time-point, they also underwent a second diffusion tensor imaging scan. Tract-based spatial statistics were used to assess fractional anisotropy as a marker of white matter integrity. At baseline, non-responders showed lower fractional anisotropy than both responders and healthy control subjects (P < 0.05; family-wise error-corrected), mainly in the uncinate, cingulum and corpus callosum, whereas responders were indistinguishable from healthy control subjects. After 12 weeks, there was an increase in fractional anisotropy in both responders and non-responders, positively correlated with antipsychotic exposure. This represents one of the largest, controlled investigations of white matter integrity and response to antipsychotic treatment early in psychosis. These data, together with earlier findings on cortical grey matter, suggest that grey and white matter integrity at the start of treatment is an important moderator of response to antipsychotics. These findings can inform patient stratification to anticipate care needs, and raise the possibility that antipsychotics may restore white matter integrity as part of the therapeutic response

Incidence of schizophrenia and other psychoses in ethnic minority groups: results from the MRC AESOP Study

Background. The incidence of schizophrenia in the African-Caribbean population in England is reported to be raised. We sought to clarify whether (a) the rates of other psychotic disorders are increased, (b) whether psychosis is increased in other ethnic minority groups, and (c) whether particular age or gender groups are especially at risk. Method. We identified all people (n=568) aged 16-64 years presenting to secondary services with their first psychotic symptoms in three well-defined English areas (over a 2-year period in Southeast London and Nottingham and a 9-month period in Bristol). Standardized incidence rates and incidence rate ratios (IRR) for all major psychosis syndromes for all main ethnic groups were calculated. Results. We found remarkably high IRRs for both schizophrenia and manic psychosis in both African-Caribbeans (schizophrenia 9.1, manic psychosis 8.0) and Black Africans (schizophrenia 5.8, manic psychosis 6.2) in men and women. IRRs in other ethnic minority groups were modestly increased as were rates for depressive psychosis and other psychoses in all minority groups. These raised rates were evident in all age groups in our study. Conclusions. Ethnic minority groups are at increased risk for all psychotic illnesses but African- Caribbeans and Black Africans appear to be at especially high risk for both schizophrenia and mania. These findings suggest that (a) either additional risk factors are operating in African- Caribbeans and Black Africans or that these factors are particularly prevalent in these groups, and that (b) such factors increase risk for schizophrenia and mania in these groups

Diagnostic change 10 years after a first episode of psychosis

Background. A lack of an aetiologically based nosology classification has contributed to instability in psychiatric diag-noses over time. This study aimed to examine the diagnostic stability of psychosis diagnoses using data from an inci-dence sample of psychosis cases, followed up after 10 years and to examine those baseline variables which were associated with diagnostic change. Method. Data were examined from the ÆSOP and ÆSOP-10 studies, an incidence and follow-up study, respectively, of a population-based cohort of first-episode psychosis cases from two sites. Diagnosis was assigned using ICD-10 and DSM-IV-TR. Diagnostic change was examined using prospective and retrospective consistency. Baseline variables asso-ciated with change were examined using logistic regression and likelihood ratio tests. Results. Slightly more (59.6%) cases had the same baseline and lifetime ICD-10 diagnosis compared with DSM-IV-TR (55.3%), but prospective and retrospective consistency was similar. Schizophrenia, psychotic bipolar disorder and drug-induced psychosis were more prospectively consistent than other diagnoses. A substantial number of cases with other diagnoses at baseline (ICD-10, n = 61; DSM-IV-TR, n = 76) were classified as having schizophrenia at 10 years

Grey matter abnormalties in first episode schizophrenia and affective psychosis

Background: Grey matter and other structural brain abnormalities are consistently reported in first-onset schizophrenia, but less is known about the extent of neuroanatomical changes in first-onset affective psychosis. Aims: To determine which brain abnormalities are specific to (a) schizophrenia and (b) affective psychosis. Method: We obtained dual-echo (proton density/T2-weighted) MR images and carried out voxel-based analysis on the images of 73 first-episode psychosis patients (schizophrenia=44, affective psychosis=29) and 58 healthy controls. Results: Both patients with schizophrenia and patients with affective psychosis had enlarged lateral and third ventricle volumes. Regional cortical grey matter reductions (including bilateral anterior cingulate gyrus, left insula and left fusiform gyrus) were evident in affective psychosis but not in schizophrenia, although patients with schizophrenia displayed decreased hippocampal grey matter and increased striatal grey matter at a more liberal statistical threshold. Conclusions: Both schizophrenia and affective psychosis are associated with volumetric abnormalities at the onset of frank psychosis, with some of these evident in common brain areas

Predicting onset of early- and late-treatment resistance in first-episode schizophrenia patients using advanced shrinkage statistical methods in a small sample

Evidence suggests there are two treatment-resistant schizophrenia subtypes (i.e. early treatment resistant (E-TR) and late-treatment resistant (L-TR)). We aimed to develop prediction models for estimating individual risk for these outcomes by employing advanced statistical shrinkage methods. 239 first-episode schizophrenia (FES) patients were followed-up for approximately 5 years after first presentation to psychiatric services; of these, n=56 (25.2%) were defined as E-TR and n=24 (12.6%) were defined as L-TR. Using known risk factors for poor schizophrenia outcomes, we developed prediction models for E-TR and L-TR using LASSO and RIDGE logistic regression models. Models’ internal validation was performed employing Harrell's optimism-correction with repeated cross-validation; their predictive accuracy was assessed through discrimination and calibration. Both LASSO and RIDGE models had high discrimination, good calibration. While LASSO had moderate sensitivity for estimating an individual risk for E-TR and L-TR, sensitivity estimated for RIDGE model for these outcomes was extremely low, which was due to having a very large estimated optimism. Although it was possible to discriminate with sufficient accuracy who would meet criteria for E-TR and L-TR during the 5-year follow-up after first contact with mental health services for schizophrenia, further work is necessary to improve sensitivity for these models

Biological and psychosocial risk factors for psychotic major depression

AIMS: Few studies have investigated risk factors for psychotic major depression (PMD). We aimed to investigate the biological and psychosocial risk factors associated with PMD compared with other psychotic disorders. METHODS: Based on the aetiology and ethnicity in schizophrenia and other psychoses (ÆSOP) study, we used a case-control study to identify and recruit, at baseline and 10-year follow-up, all first episode cases of psychosis, presenting for the first time to specialist mental health services in defined catchment areas in the UK. Population-based controls were recruited from the same areas. Data were collected on: sociodemographics; social isolation; childhood adversity; life events; minor physical anomalies; and neurological soft signs. RESULTS: Living alone (aOR = 2.26, CI = 1.21-4.23), basic level qualification (aOR = 2.89, CI = 1.08-7.74), being unemployed (aOR = 2.12, CI = 1.13-3.96), having contact with friends less than monthly (aOR = 4.24, CI = 1.62-11.14), having no close confidants (aOR = 4.71, CI = 2.08-10.68), having experienced childhood adversity (aOR = 2.57, CI = 1.02-6.44), family history of mental illness (aOR = 10.68, CI = 5.06-22.52), family history of psychosis (aOR = 12.85, CI = 5.24-31.51), and having more neurological soft signs (aOR = 1.15, CI = 1.07-1.24) were all associated with a follow-up diagnosis of PMD and schizophrenia. Few variables associated with PMD were also associated with a diagnosis of bipolar disorder. Minor physical anomalies were associated with a follow-up diagnosis of schizophrenia and bipolar disorder, but not PMD. CONCLUSIONS: Risk factors associated with PMD appear to overlap with those for schizophrenia, but less so for bipolar disorder. Future work on the differential aetiology of PMD, from other psychoses is needed to find the 'specifier' between PMD and other psychoses. Future research on aetiology in PMD, and perhaps other psychoses, should account for diagnostic change.status: publishe

Utilising symptom dimensions with diagnostic categories improves prediction of time to first remission in first-episode psychosis

There has been much recent debate concerning the relative clinical utility of symptom dimensions versus conventional diagnostic categories in patients with psychosis. We investigated whether symptom dimensions rated at presentation for first-episode psychosis (FEP) better predicted time to first remission than categorical diagnosis over a four-year follow-up. The sample comprised 193 FEP patients aged 18–65 years who presented to psychiatric services in South London, UK, between 2006 and 2010. Psychopathology was assessed at baseline with the Positive and Negative Syndrome Scale and five symptom dimensions were derived using Wallwork/Fortgang's model; baseline diagnoses were grouped using DSM-IV codes. Time to start of first remission was ascertained from clinical records. The Bayesian Information Criterion (BIC) was used to find the best fitting accelerated failure time model of dimensions, diagnoses and time to first remission. Sixty percent of patients remitted over the four years following first presentation to psychiatric services, and the average time to start of first remission was 18.3 weeks (SD = 26.0, median = 8). The positive (BIC = 166.26), excited (BIC = 167.30) and disorganised/concrete (BIC = 168.77) symptom dimensions, and a diagnosis of schizophrenia (BIC = 166.91) predicted time to first remission. However, a combination of the DSM-IV diagnosis of schizophrenia with all five symptom dimensions led to the best fitting model (BIC = 164.35). Combining categorical diagnosis with symptom dimension scores in FEP patients improved the accuracy of predicting time to first remission. Thus our data suggest that the decision to consign symptom dimensions to an annexe in DSM-5 should be reconsidered at the earliest opportunity

Relationship Between Serum NMDA Receptor Antibodies and Response to Antipsychotic Treatment in First-Episode Psychosis

Background: When psychosis develops in NMDA receptor (NMDAR) antibody encephalitis, it usually has an acute or subacute onset, and antipsychotic treatment may be ineffective and associated with adverse effects. Serum NMDAR antibodies have been reported in a minority of patients with first-episode psychosis (FEP), but their role in psychosis onset and response to antipsychotic treatment is unclear. Methods: Sera from 387 patients with FEP (duration of psychosis <2 years, minimally or never treated with antipsychotics) undergoing initial treatment with amisulpride as part of the OPTiMiSE (Optimization of Treatment and Management of Schizophrenia in Europe) trial (ClinicalTrials.gov number NCT01248195) were tested for NMDAR IgG antibodies using a live cell–based assay. Symptom severity was assessed using the Positive and Negative Syndrome Scale and the Clinical Global Impressions Scale at baseline and again after 4 weeks of treatment with amisulpride. Results: At baseline, 15 patients were seropositive for NMDAR antibodies and 372 were seronegative. The seropositive patients had similar symptom profiles and demographic features to seronegative patients but a shorter duration of psychosis (median 1.5 vs. 4.0 months; p =.031). Eleven seropositive and 284 seronegative patients completed 4 weeks of amisulpride treatment: after treatment, there was no between-groups difference in improvement in Positive and Negative Syndrome Scale scores or in the frequency of adverse medication effects. Conclusions: These data suggest that in FEP, NMDAR antibody seropositivity alone is not an indication for using immunotherapy instead of antipsychotic medications. Further studies are required to establish what proportion of patients with FEP who are NMDAR antibody seropositive have coexisting cerebrospinal fluid inflammatory changes or other paraclinical evidence suggestive of a likely benefit from immunotherapy