Cortical morphology in patients with the deficit and non-deficit syndrome of schizophrenia: a worldwide meta- and mega-analyses.

Converging evidence suggests that schizophrenia (SZ) with primary, enduring negative symptoms (i.e., Deficit SZ (DSZ)) represents a distinct entity within the SZ spectrum while the neurobiological underpinnings remain undetermined. In the largest dataset of DSZ and Non-Deficit (NDSZ), we conducted a meta-analysis of data from 1560 individuals (168 DSZ, 373 NDSZ, 1019 Healthy Controls (HC)) and a mega-analysis of a subsampled data from 944 individuals (115 DSZ, 254 NDSZ, 575 HC) collected across 9 worldwide research centers of the ENIGMA SZ Working Group (8 in the mega-analysis), to clarify whether they differ in terms of cortical morphology. In the meta-analysis, sites computed effect sizes for differences in cortical thickness and surface area between SZ and control groups using a harmonized pipeline. In the mega-analysis, cortical values of individuals with schizophrenia and control participants were analyzed across sites using mixed-model ANCOVAs. The meta-analysis of cortical thickness showed a converging pattern of widespread thinner cortex in fronto-parietal regions of the left hemisphere in both DSZ and NDSZ, when compared to HC. However, DSZ have more pronounced thickness abnormalities than NDSZ, mostly involving the right fronto-parietal cortices. As for surface area, NDSZ showed differences in fronto-parietal-temporo-occipital cortices as compared to HC, and in temporo-occipital cortices as compared to DSZ. Although DSZ and NDSZ show widespread overlapping regions of thinner cortex as compared to HC, cortical thinning seems to better typify DSZ, being more extensive and bilateral, while surface area alterations are more evident in NDSZ. Our findings demonstrate for the first time that DSZ and NDSZ are characterized by different neuroimaging phenotypes, supporting a nosological distinction between DSZ and NDSZ and point toward the separate disease hypothesis.

The prevalence and clinical correlates of substance use disorders in patients with psychotic disorders from an Upper-Middle-Income Country.

BACKGROUND: Substance use disorders (SUDs) occur frequently in patients with psychotic disorders and have been associated with various demographic and clinical correlates. There is an absence of research on the prevalence and clinical correlates of SUDs in psychotic disorders in low-and-middle-income countries (LMICs). AIM: We aimed to determine the prevalence and correlates of SUDs in psychotic disorders. SETTING: Patients attending a large secondary-level psychiatric hospital in Cape Town South Africa. METHODS: We used the Structured Clinical Interview for DSM-IV (SCID-I) to determine psychiatric and substance use diagnoses, depressive, anxiety, obsessive-compulsive and post-traumatic symptoms. We used logistic regression models to determine significant predictors of SUDs. RESULTS: In total sample (N = 248), 55.6% of participants had any SUD, 34.3% had cannabis use disorders, 30.6% alcohol use disorders, 27.4% methamphetamine use disorders, 10.4% methaqualone use disorders and 4.8% had other SUDs. There were significant associations with male sex for most SUDs, with younger age and Coloured ethnicity for methamphetamine use disorders, and with lower educational attainment for cannabis use disorders. Anxiety symptoms and suicide attempts were significantly associated with alcohol use disorders; a diagnosis of a substance induced psychosis with cannabis and methamphetamine use disorders. Across most SUDs legal problems and criminal involvement were significantly increased. CONCLUSION: This study found a high prevalence and wide distribution of SUDs in patients with psychotic disorders, consistent with previous work from high income countries. Given clinical correlates, in individuals with psychotic disorders and SUDs it is important to assess anxiety symptoms, suicidality and criminal involvement.

Methamphetamine Use and Antipsychotic-related Extrapyramidal Side-effects in Patients with Psychotic Disorders.

Objective: Extrapyramidal side-effects (EPSE) are frequent in patients treated with antipsychotics and comorbid substance use disorders (SUDs). Methamphetamine has been shown to act as a dopaminergic neurotoxin. We aimed to determine whether EPSE occur more often in patients with psychotic disorders and co-occurring methamphetamine (MA) use disorders, and we examined the relationship between MA use, antipsychotic type, dose and EPSE. Methods: This study was a secondary analysis of data from three separate primary studies. Across all studies, psychiatric and SUD diagnoses were determined using the SCID-I for DSM-IV. EPSE were determined using the Simpson-Angus Scale (SAS) for Parkinsonism, the Barnes Akathisia Rating scale (BARS), and the Abnormal Involuntary Movement Scale (AIMS) for tardive dyskinesia. Participants were classified as having any EPSE if they scored above the cutoff on any of the EPSE scales (SAS, BARS, AIMS). We analyzed data using multivariable logistic regression analysis. Results: The sample included 102 patients with non-affective or affective psychotic disorders. Of the total sample, 65.7% were male, 54.9% had schizophrenia spectrum disorders, 20.5% bipolar type I disorder with psychotic features, 11.7% schizoaffective disorder and 12.7% had substance-induced psychosis. A diagnosis of a methamphetamine use disorder (abuse or dependence) was present in 25.5% of participants. EPSE occurred in 38.2% of patients and were significantly associated with MA use in the unadjusted and adjusted analysis, ORadj = 4.01, 95% CI [1.07, 14.98], p = .039. Patients with MA dependence and MA use >3 years were significantly more likely to have EPSE. We found a significant interaction effect between MA use disorders and standardized antipsychotic dose on the occurrence of EPSE, ORadj = 1.01, 95% CI [1.00, 1.01], p = .042, with MA users having a disproportionally higher likelihood of having EPSE compared to MA non-users as antipsychotic dosage increased. There were no significant associations of EPSE with comorbid alcohol, cannabis, or methaqualone use disorders. Conclusions: Patients with a MA use disorder were significantly more likely to have EPSE with evidence for a dose-response effect. Clinicians should carefully titrate antipsychotic dosage from lower to higher doses to avoid EPSE in patients with MA use disorders.

Correction: Widespread white matter microstructural abnormalities in bipolar disorder: evidence from mega- and meta-analyses across 3033 individuals.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Widespread white matter microstructural abnormalities in bipolar disorder: evidence from mega- and meta-analyses across 3033 individuals.

Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD); however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3033 (1482 BD and 1551 HC). Mean fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega- and meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum (R2 = 0.041, Pcorr < 0.001) and cingulum (right: R2 = 0.041, left: R2 = 0.040, Pcorr < 0.001). Lithium medication, later onset and short disease duration were related to higher FA along multiple ROIs. Results of the meta-analysis showed similar effects. We demonstrated widespread WM abnormalities in BD and highlighted that altered WM connectivity within the corpus callosum and the cingulum are strongly associated with BD. These brain abnormalities could represent a biomarker for use in the diagnosis of BD. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Risperidone versus other antipsychotics for people with severe mental illness and co-occurring substance misuse.

BACKGROUND: Up to 75% of people with serious mental illness (SMI) such as schizophrenia and bipolar disorder have co-occurring substance use disorders (dual diagnosis). Dual diagnosis can have an adverse effect on treatment and prognosis of SMI. OBJECTIVES: To evaluate the effects of risperidone compared to treatment with other antipsychotics (first-generation and other second-generation antipsychotics) used in people with serious mental illness and co-occurring substance misuse. SEARCH METHODS: On 6 January 2016 and 9 October 2017, we searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (including trial registers). SELECTION CRITERIA: We selected randomised trials of risperidone versus any other antipsychotic in people with SMI and substance abuse (dual diagnosis). We included trials meeting our inclusion criteria and reporting useable data. We excluded trials that either did not meet our inclusion criteria or met our inclusion criteria but did not report any useable data. DATA COLLECTION AND ANALYSIS: We independently inspected citations and selected studies. For included studies, we independently extracted data and appraised study quality. For binary outcomes we calculated the risk ratios (RRs) and their 95% confidence intervals. For continuous outcomes we calculated the mean differences (MDs) and their 95% confidence intervals. We pooled data using random-effects meta-analyses and assessed the quality of evidence, creating a 'Summary of findings' table using the GRADE approach. MAIN RESULTS: We identified eight randomised trials containing a total of 1073 participants with SMI and co-occurring substance misuse. Seven of these contributed useable data to the review. There was heterogeneity in trial design and measurement. Risperidone was compared to clozapine, olanzapine, perphenazine, quetiapine and ziprasidone. Few trials compared risperidone with first-generation agents. Few trials examined participants with a dual diagnosis from the outset and most trials only contained separate analyses of subgroups with a dual diagnosis or were secondary data analyses of subgroups of people with a dual diagnosis from existing larger trials.For risperidone versus clozapine we found no clear differences between these two antipsychotics in the reduction of positive psychotic symptoms (1 randomised controlled trial (RCT), n = 36, mean difference (MD) 0.90, 95% CI -2.21 to 4.01, very low quality evidence), or reduction in cannabis use (1 RCT, n = 14, risk ratio (RR) 1.00, 95% CI 0.30 to 3.35, very low quality evidence), improvement in subjective well-being (1 RCT, n = 36, MD -6.00, 95% CI -14.82 to 2.82, very low quality evidence), numbers discontinuing medication (1 RCT, n = 36, RR 4.05, 95% CI 0.21 to 78.76, very low quality evidence), extrapyramidal side-effects (2 RCTs, n = 50, RR 2.71, 95% CI 0.30 to 24.08; I² = 0%, very low quality evidence), or leaving the study early (2 RCTs, n = 45, RR 0.49, 95% CI 0.10 to 2.51; I² = 34%, very low quality evidence). Clozapine was associated with lower levels of craving for cannabis (1 RCT, n = 28, MD 7.00, 95% CI 2.37 to 11.63, very low quality evidence).For risperidone versus olanzapine we found no clear differences in the reduction of positive psychotic symptoms (1 RCT, n = 37, MD -1.50, 95% CI -3.82 to 0.82, very low quality evidence), reduction in cannabis use (1 RCT, n = 41, MD 0.40, 95% CI -4.72 to 5.52, very low quality evidence), craving for cannabis (1 RCT, n = 41, MD 5.00, 95% CI -4.86 to 14.86, very low quality evidence), parkinsonism (1 RCT, n = 16, MD -0.08, 95% CI -1.21 to 1.05, very low quality evidence), or leaving the study early (2 RCT, n = 77, RR 0.68, 95% CI 0.34 to 1.35; I² = 0%, very low quality evidence).For risperidone versus perphenazine, we found no clear differences in the number of participants leaving the study early (1 RCT, n = 281, RR 1.05, 95% CI 0.92 to 1.20, low-quality evidence).For risperidone versus quetiapine, we found no clear differences in the number of participants leaving the study early (1 RCT, n = 294, RR 0.96, 95% CI 0.86 to 1.07, low-quality evidence).For risperidone versus ziprasidone, we found no clear differences in the number of participants leaving the study early (1 RCT, n = 240, RR 0.96, 95% CI 0.85 to 1.10, low-quality evidence).For many comparisons, important outcomes were missing; and no data were reported in any study for metabolic disturbances, global impression of illness severity, quality of life or mortality. AUTHORS' CONCLUSIONS: There is not sufficient good-quality evidence available to determine the effects of risperidone compared with other antipsychotics in people with a dual diagnosis. Few trials compared risperidone with first-generation agents, leading to limited applicability to settings where access to second-generation agents is limited, such as in low- and middle-income countries. Moreover, heterogeneity in trial design and measurement of outcomes precluded the use of many trials in our analyses. Future trials in this area need to be sufficiently powered but also need to conform to consistent methods in study population selection, use of measurement scales, definition of outcomes, and measures to counter risk of bias. Investigators should adhere to CONSORT guidelines in the reporting of results.