Sandra Matheson

Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis

Brain-derived neurotrophic factor (BDNF) regulates the survival and growth of neurons, and influences synaptic efficiency and plasticity. Several studies report reduced peripheral (blood) levels of BDNF in schizophrenia, but findings are inconsistent. We undertook the first systematic review with meta-analysis of studies examining blood BDNF levels in schizophrenia compared with healthy controls, and examined potential effects of age, gender and medication. Included are individual studies of BDNF blood (serum or plasma) levels in schizophrenia (including schizoaffective disorder, or first episode psychosis), compared with age-matched healthy controls, obtained by electronic Medline and Embase searches, and hand searching. The decision to include or exclude studies, data extraction and quality assessment were completed by two independent reviewers. The initial search revealed 378 records, of which 342 were excluded on reading the Abstract, because they did not examine BDNF blood levels in schizophrenia compared with healthy controls. Of 36 papers screened in full, 17 were eligible for inclusion, but one was subsequently removed as an outlier. The remaining 16 studies provided moderate quality evidence of reduced blood BDNF levels in schizophrenia (Hedges g=−0.458, 95% confidence interval=−0.770 to −0.146, P<0.004, random effects model). Subgroup analyses reveal reduced BDNF in both drug-naïve and medicated patients, and in males and females with schizophrenia. Meta-regressions showed an association between reduced BDNF in schizophrenia and increasing age, but no effects of medication dosage. Overall, blood levels of BDNF are reduced in medicated and drug-naïve patients with schizophrenia; this evidence is of moderate quality, that is, precise but with considerable, unexplained heterogeneity across study results.

Systematic meta-review and quality assessment of the structural brain alterations in schizophrenia

BACKGROUND The large quantity of systematic reviews of magnetic resonance imaging studies in schizophrenia challenges their meaningful interpretation. This meta-review synthesises the available information from systematic reviews of structural alteration in both chronic and first-episode schizophrenia. METHODS Systematic reviews were identified using electronic databases. Review methodological quality was assessed according to the Assessment of Multiple Systematic Reviews checklist. Data were extracted in duplicate and quality assessed for consistency and precision, guided by Grading of Recommendations Assessment, Development and Evaluation recommendations. RESULTS Integration of volumetric and voxel-based estimates allowed critical assessment of the magnitude and location of anatomical differences. There is evidence for grey matter reductions of anterior cingulate, frontal (particularly medial and inferior) and temporal lobes, hippocampus/amygdala, thalamus, and insula that may be magnified over time. Other regional alterations appear specific to illness stage or medication status. CONCLUSIONS There is limited high quality evidence supporting grey or white matter changes in schizophrenia, which has previously been obscured by a large volume of conflicting lower quality evidence.

Childhood adversity in schizophrenia: a systematic meta-analysis

BACKGROUND Childhood adversity is a putative risk factor for schizophrenia, although evidence supporting this suggestion is inconsistent and controversial. The aim of this review was to pool and quality assess the current evidence pertaining to childhood adversity in people with schizophrenia compared to other psychiatric disorders and to non-psychiatric controls. METHOD Included were case-control, cohort and cross-sectional studies. Medline, EMBASE and PsycINFO databases were searched. Study reporting was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist and pooled evidence quality was assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS Twenty-five studies met inclusion criteria. Moderate to high quality evidence suggests increased rates of childhood adversity in schizophrenia compared to controls [odds ratio (OR) 3.60, p < 0.00001]. Increased childhood adversity was also reported in schizophrenia compared to anxiety disorders (OR 2.54, p = 0.007), although the effect was not significant in the subgroup analysis of five studies assessing only sexual abuse. No differences in rates of childhood adversity were found between schizophrenia and affective psychosis, depression and personality disorders whereas decreased rates of childhood adversity were found in schizophrenia relative to dissociative disorders and post-traumatic stress disorder (OR 0.03, p < 0.0001). CONCLUSIONS This is the first meta-analysis to report a medium to large effect of childhood adversity in people with schizophrenia and to assess specificity for schizophrenia. Further research is required that incorporates longitudinal design and other potentially causal variables to assess additive and/or interactive effects.

A systematic meta-review grading the evidence for non-genetic risk factors and putative antecedents of schizophrenia

INTRODUCTION Identifying the relative strength of evidence associated with non-genetic risk factors and putative antecedents of schizophrenia will guide research and may inform the design of early detection and intervention strategies. AIMS To present and quality assess current evidence for non-genetic risk factors and putative antecedents derived from well-conducted systematic reviews that report pooled data. METHOD Medline, Embase, CINAHL, Current Contents, and PsycINFO databases were searched systematically, and supplemented by hand searching. Review reporting quality was assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, review methodology was assessed using the Assessment of Multiple Systematic Reviews (AMSTAR) checklist, and evidence quality was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS Twenty-four reviews met inclusion criteria. The risk factors with the highest quality evidence, reporting medium effect sizes, were advanced paternal age, obstetric complications, and cannabis use. The strongest evidence among the putative antecedents was identified for motor dysfunction and low IQ. CONCLUSIONS More research is required that applies sound methodological practices, taking into consideration specificity for schizophrenia and possible confounding factors, to robustly identify the non-genetic risk factors and putative antecedents of schizophrenia.

Psychosocial treatments for people with co‐occurring severe mental illness and substance misuse: systematic review

AIM This study is a report of a systematic review to assess current evidence for the efficacy of psychosocial interventions for reducing substance use, as well as improving mental state and encouraging treatment retention, among people with dual diagnosis. BACKGROUND Substance misuse by people with a severe mental illness is common and of concern because of its many adverse consequences and lack of evidence for effective psychosocial interventions. DATA SOURCES Several electronic databases were searched to identify studies published between January 1990 and February 2008. Additional searches were conducted by means of reference lists and contact with authors. REVIEW METHODS Results from studies using meta-analysis, randomized and non-randomized trials assessing any psychosocial intervention for people with a severe mental illness and substance misuse were included. RESULTS Fifty-four studies were included: one systematic review with meta-analysis, 30 randomized controlled trials and 23 non-experimental studies. Although some inconsistencies were apparent, results showed that motivational interviewing had the most quality evidence for reducing substance use over the short term and, when combined with cognitive behavioural therapy, improvements in mental state were also apparent. Cognitive behavioural therapy alone showed little consistent support. Support was found for long-term integrated residential programmes; however, the evidence is of lesser quality. Contingency management shows promise, but there were few studies assessing this intervention. CONCLUSION These results indicate the importance of motivational interviewing in psychiatric settings for the reduction of substance use, at least in the short term. Further quality research should target particular diagnoses and substance use, as some interventions may work better for some subgroups.

Systematic Meta-Analysis of Insula Volume in Schizophrenia

BACKGROUND Volume reduction in insular cortex may constitute an important neuropathology in schizophrenia. We provide the first meta-analysis of studies that conducted region-of-interest analyses of the magnitude of effect and pattern of insula volume reduction in schizophrenia compared with healthy control subjects. METHODS Included studies examined insula volume in schizophrenia relative to healthy control subjects. Studies were located via electronic database searches and hand searching. Study selection, data extraction, and quality assessment were completed by two independent reviewers. Hedges g effect sizes were calculated using Comprehensive Meta-Analysis (v.2) to quantify volumetric differences between people with and without schizophrenia, accounting for moderating influences of age, sex, illness duration, medication, whole brain volume, and potential differences in hemispheric and anatomical subregions. RESULTS Random-effects analysis showed reductions of bilateral insula (n = 945, g = -.446, 95% confidence interval -.639 to -.252, p = .00001), with moderate heterogeneity apparent (I² = 76%). This effect was consistent across left and right insula and not influenced by illness stage or sex. Additional analyses revealed larger reductions of anterior (n = 605, g = -.643, p < 0.001; I² = 52%) than of posterior insula (n = 453, g = -.321, p = .028; I² = 55%). Meta-regression analyses did not identify any significant predictors of reduced insula volume. CONCLUSIONS This meta-analysis indicates medium-sized reduction of insula volume in schizophrenia, of greatest magnitude in the anterior subregion. Cellular distinctions across anterior and posterior insula may contribute to understanding the neuropathology and functional significance of the observed volumetric differences.

Common or distinct pathways to psychosis? A systematic review of evidence from prospective studies for developmental risk factors and antecedents of the schizophrenia spectrum disorders and affective psychoses

BackgroundIdentifying the unique and shared premorbid indicators of risk for the schizophrenia spectrum disorders (SSD) and affective psychoses (AP) may refine aetiological hypotheses and inform the delivery of universal versus targeted preventive interventions. This systematic review synthesises the available evidence concerning developmental risk factors and antecedents of SSD and AP to identify those with the most robust support, and to highlight remaining evidence gaps.MethodsA systematic search of prospective birth, population, high-risk, and case-control cohorts was conducted in Medline and supplemented by hand searching, incorporating published studies in English with full text available. Inclusion/exclusion decisions and data extraction were completed in duplicate. Exposures included three categories of risk factors and four categories of antecedents, with case and comparison groups defined by adult psychiatric diagnosis. Effect sizes and prevalence rates were extracted, where available, and the strength of evidence synthesised and evaluated qualitatively across the study designs.ResultsOf 1775 studies identified by the search, 127 provided data to the review. Individuals who develop SSD experience a diversity of subtle premorbid developmental deficits and risk exposures, spanning the prenatal period through early adolescence. Those of greatest magnitude (or observed most consistently) included obstetric complications, maternal illness during pregnancy (especially infections), other maternal physical factors, negative family emotional environment, psychopathology and psychotic symptoms, and cognitive and motor dysfunctions. Relatively less evidence has accumulated to implicate this diversity of exposures in AP, and many yet remain unexamined, with the most consistent or strongest evidence to date being for obstetric complications, psychopathology, cognitive indicators and motor dysfunction. Among the few investigations affording direct comparison between SSD and AP, larger effect sizes and a greater number of significant associations are commonly reported for SSD relative to AP.ConclusionsShared risk factors for SSD and AP may include obstetric complications, childhood psychopathology, cognitive markers and motor dysfunction, but the capacity to distinguish common versus distinct risk factors/antecedents for SSD and AP is limited by the scant availability of prospective data for AP, and inconsistency in replication. Further studies considering both diagnoses concurrently are needed. Nonetheless, the prevalence of the risk factors/antecedents observed in cases and controls helps demarcate potential targets for preventative interventions for these disorders.

Quality assessment and comparison of evidence for electroconvulsive therapy and repetitive transcranial magnetic stimulation for schizophrenia: A systematic meta-review

BACKGROUND Randomized studies directly comparing the effects of electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) for depression generally favour ECT. ECT and rTMS have also been investigated for chronic symptoms of schizophrenia although there are no direct comparisons available. AIMS We sought to determine the relative benefits and adverse outcomes of ECT and rTMS by comparing effect sizes reported in systematic reviews and to quality assess this evidence using GRADE and QUOROM guidelines. METHOD Included are systematic reviews with meta-analysis published since 2000, reporting results for people with a diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder or first episode schizophrenia. Medline, Embase, CINAHL, Current Contents, PsycINFO and the Cochrane library were searched and hand searching was conducted. Data extraction and quality assessment were completed by two independent reviewers. RESULTS Fifty-three of 58 reviews were excluded as they did not meet inclusion criteria. The remaining five have a low probability of reporting bias and show that high quality evidence suggests a short-term, medium to large treatment effect of rTMS for auditory hallucinations (d=0.88) but not other symptoms, for people treated with concurrent antipsychotics. For ECT, high quality evidence suggests a short-term small, significant effect for improvement in global symptoms, for people with or without concurrent antipsychotics (RR=0.76). There is no evidence for longer-term therapeutic or adverse effects of either treatment. CONCLUSIONS It is worthwhile considering rTMS in cases where auditory hallucinations have not responded to antipsychotic medications and ECT where overall symptoms have not responded to antipsychotic medications.

Stimulant use disorders in people with psychosis: A meta-analysis of rate and factors affecting variation

Objective: Stimulant abuse and dependence often complicate the care of people with psychotic disorders. This study systematically reviews the prevalence estimates reported for stimulant abuse and dependence in people with psychotic disorders, and examines personal, clinical, regional and methodological factors which explain variation in these rates. Methods: PsychINFO, EMBASE and MEDLINE (1946–2013) were searched systematically for studies reporting on stimulant drug use disorders in representative samples of people with psychotic disorders. Random effects models estimated the pooled rate of a stimulant use disorder, defined to include stimulant abuse and stimulant dependence. Study characteristics associated with heterogeneity in rates of stimulant use disorder were examined by subgroup analyses for categorical variables, by meta-regression for continuous independent variables and by multiple meta-regression. Results: Sixty-four studies provided 68 estimates of lifetime or recent stimulant use disorders in 22,500 people with psychosis. The pooled rate of stimulant use disorder was 8.9% (95% CI 7.4%, 10.5%). Higher rates of stimulant use disorders were reported in studies of affective psychosis, studies from inpatient settings, studies from the USA and Australia, and studies with higher rates of cannabis disorder; in multiple meta-regression analysis these factors explained 68% of between-study variance. Rates of stimulant use disorder were stable over time, and unrelated to age, sex, stage of psychosis, type of stimulant drug or study methodology factors. Conclusions: Reported rates of stimulant use disorder in people with psychosis are much higher than in the general population but vary widely and are associated with regional, service setting and clinical differences between studies. It is likely that stimulants contribute to the overall burden of psychosis, and that social and environmental factors combine with drug and illness-related factors to influence stimulant use in psychosis.

How much do we know about schizophrenia and how well do we know it? Evidence from the Schizophrenia Library

BACKGROUND True findings about schizophrenia remain elusive; many findings are not replicated and conflicting results are common. Well-conducted systematic reviews have the ability to make robust, generalizable conclusions, with good meta-analyses potentially providing the closest estimate of the true effect size. In this paper, we undertake a systematic approach to synthesising the available evidence from well-conducted systematic reviews on schizophrenia. METHOD Reviews were identified by searching Medline, EMBASE, CINAHL, Current Contents and PsycINFO. The decision to include or exclude reviews, data extraction and quality assessments were conducted in duplicate. Evidence was graded as high quality if reviews contained large samples and robust results; and as moderate quality if reviews contained imprecision, inconsistency, smaller samples or study designs that may be prone to bias. RESULTS High- and moderate-quality evidence shows that numerous psychosocial and biomedical treatments are effective. Patients have relatively poor cognitive functioning, and subtle, but diverse, structural brain alterations, altered electrophysiological functioning and sleep patterns, minor physical anomalies, neurological soft signs, and sensory alterations. There are markers of infection, inflammation or altered immunological parameters; and there is increased mortality from a range of causes. Risk for schizophrenia is increased with cannabis use, pregnancy and birth complications, prenatal exposure to Toxoplasma gondii, childhood central nervous system viral infections, childhood adversities, urbanicity and immigration (first and second generation), particularly in certain ethnic groups. Developmental motor delays and lower intelligence quotient in childhood and adolescence are apparent. CONCLUSIONS We conclude that while our knowledge of schizophrenia is very substantial, our understanding of it remains limited.