People with severe mental illness (SMI) -schizophrenia, bipolar disorder and major depressive disorder -appear at risk for cardiovascular disease (CVD), but a comprehensive meta-analysis is lacking. We conducted a large-scale meta-analysis assessing the prevalence and incidence of CVD; coronary heart disease; stroke, transient ischemic attack or cerebrovascular disease; congestive heart failure; peripheral vascular disease; and CVD-related death in SMI patients (N53,211,768) versus controls (N5113,383,368) (92 studies). The pooled CVD prevalence in SMI patients (mean age 50 years) was 9.9% (95% CI: 7.4-13.3). Adjusting for a median of seven confounders, patients had significantly higher odds of CVD versus controls in cross-sectional studies (odds ratio, OR51.53, 95% CI: 1.27-1.83; 11 studies), and higher odds of coronary heart disease (OR51.51, 95% CI: 1.47-1.55) and cerebrovascular disease (OR51.42, 95% CI: 1.21-1.66). People with major depressive disorder were at increased risk for coronary heart disease, while those with schizophrenia were at increased risk for coronary heart disease, cerebrovascular disease and congestive heart failure. Cumulative CVD incidence in SMI patients was 3.6% (95% CI: 2.7-5.3) during a median follow-up of 8.4 years (range 1.8-30.0). Adjusting for a median of six confounders, SMI patients had significantly higher CVD incidence than controls in longitudinal studies (hazard ratio, HR51.78, 95% CI: 1.60-1.98; 31 studies). The incidence was also higher for coronary heart disease (HR51.54, 95% CI: 1.30-1.82), cerebrovascular disease (HR51.64, 95% CI: 1.26-2.14), congestive heart failure (HR52.10, 95% CI: 1.64-2.70), and CVDrelated death (HR51.85, 95% CI: 1.53-2.24). People with major depressive disorder, bipolar disorder and schizophrenia were all at increased risk of CVD-related death versus controls. CVD incidence increased with antipsychotic use (p50.008), higher body mass index (p50.008) and higher baseline CVD prevalence (p50.03) in patients vs. controls. Moreover, CVD prevalence (p50.007), but not CVD incidence (p50.21), increased in more recently conducted studies. This large-scale meta-analysis confirms that SMI patients have significantly increased risk of CVD and CVD-related mortality, and that elevated body mass index, antipsychotic use, and CVD screening and management require urgent clinical attention.Key words: Cardiovascular disease, severe mental illness, schizophrenia, bipolar disorder, major depression, coronary heart disease, cerebrovascular disease, congestive heart failure, premature mortality (World Psychiatry 2017;16:163-180) People with severe mental illness (SMI) -including schizophrenia, bipolar disorder, major depressive disorder, and their related spectrum disorders -have a life expectancy shortened of 10-17.5 years compared to the general population 1,2 . While suicide explains some of this reduced life expectancy 3 , it is now established that physical diseases account for the overwhelming majority of premature mortality 4,5 . Among physical conditions, c...

The literature on non-genetic peripheral biomarkers for major mental disorders is broad, with conflicting results. An umbrella review of meta-analyses of non-genetic peripheral biomarkers for Alzheimer's disease, autism spectrum disorder, bipolar disorder (BD), major depressive disorder, and schizophrenia, including first-episode psychosis. We included meta-analyses that compared alterations in peripheral biomarkers between participants with mental disorders to controls (i.e., between-group meta-analyses) and that assessed biomarkers after treatment (i.e., withingroup meta-analyses). Evidence for association was hierarchically graded using a priori defined criteria against several biases. The Assessment of Multiple Systematic Reviews (AMSTAR) instrument was used to investigate study quality. 1161 references were screened. 110 met inclusion criteria, relating to 359 meta-analytic estimates and 733,316 measurements, on 162 different biomarkers. Only two estimates met a priori defined criteria for convincing evidence (elevated awakening cortisol levels in euthymic BD participants relative to controls and decreased pyridoxal levels in participants with schizophrenia relative to controls). Of 42 estimates which met criteria for highly suggestive evidence only five biomarker aberrations occurred in more than one disorder. Only 15 meta-analyses had a power >0.8 to detect a small effect size, and most (81.9%) meta-analyses had high heterogeneity. Although some associations met criteria for either convincing or highly suggestive evidence, overall the vast literature of peripheral biomarkers for major mental disorders is affected by bias and is underpowered. No convincing evidence supported the existence of a transdiagnostic biomarker. Adequately powered and methodologically sound future large collaborative studies are warranted.

Catatonia is an independent syndrome that co-occurs with several mental and medical conditions. We performed a systematic literature review in PubMed/Scopus until February 2017 and meta-analyzed studies reporting catatonia prevalence. Across 74 studies (cross-sectional = 32, longitudinal = 26, retrospective = 16) providing data collected from 1935 to 2017 across all continents, mean catatonia prevalence was 9.0% (k = 80, n = 110764; 95% CI = 6.9-11.7, I2 = 98%, publication bias P < .01), decreasing to 7.8% (k = 19, n = 7612, 95% CI = 7-8.7, I2 = 38.9%) in a subgroup with low heterogeneity. Catatonia prevalence was 23.9% (k = 8, n = 1168, 95% CI = 10-46.9, I2 = 96%) in patients undergoing ECT/having elevated creatinine phosphokinase. Excluding ECT samples, the catatonia prevalence was 8.1% (k = 72, n = 109606, 95% CI = 6.1-10.5, I2 = 98%, publication bias P < .01), with sensitivity analyses demonstrating that country of study origin (P < .001), treatment setting (P = .003), main underlying condition (P < .001), and sample size (P < .001)moderated catatonia prevalence, being highest in Uganda (48.5%, k = 1) and lowest in Mexico (1.9%, 95% CI = 0.4-8.8, I2 = 67%, k = 2), highest in nonpsychiatric out- or inpatient services (15.8%, 95% CI = 8.1-28.4, I2 = 97%, k = 15)and lowest in psychiatric outpatients services (3.2%, 95% CI = 1.7-6.1, I2 = 50%, k = 3), highest in presence of medical or neurological illness with no comorbid psychiatric condition (20.6%, 95% CI = 11.5-34.2, I2 = 95%, k = 10)and lowest in mixed psychiatric samples (5.7%, 95% CI = 4.2-7.7, I2 =98%, k = 43), highest in studies with sample sizes <100 (20.7%, 95% CI = 12.8-31.6, I2 = 90%, k = 17) and lowest in studies with sample sizes >1000 (2.3%, 95% CI = 1.3-3.9, I2 = 99%, k = 16). Meta-regression showed that smaller sample size (P < .01) and less major depressive disorder (P = .02) moderated higher catatonia prevalence. Year of data collection did not significantly moderate the results. Results from this first meta-analysis of catatonia frequencies across time and disorders suggest that catatonia is an epidemiologically and clinically relevant condition that occurs throughout several mental and medical conditions, whose prevalence has not decreased over time and does not seem to depend on different rating scales/criteria. However, results were highly heterogeneous, calling for a cautious interpretation.

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AimThe aim of this study was to summarize the characteristics, efficacy, and safety of vesicular monoamine transporter-2 (VMAT-2) inhibitors for treating tardive dyskinesia (TD).Materials and methodsWe conducted a literature search in PubMed, Cochrane Database, and ClinicalTrials.gov, screening for systematic reviews, meta-analyses or double-blind, randomized, placebo-controlled trials (DBRPCTs) reporting efficacy or safety data of VMAT-2 inhibitors (tetrabenazine, deutetrabenazine, and valbenazine) in patients with TD. A random effects meta-analysis of efficacy and safety data from DBRPCTs was performed.ResultsTwo acute, 12-week DBRPCTs with deutetrabenazine 12–48 mg/day (n=413) and 4 acute, 4–6-week double-blind trials with valbenazine 12.5–100 mg/day (n=488) were meta-analyzable, without meta-analyzable, high-quality data for tetrabenazine. Regarding reduction in total Abnormal Involuntary Movement Scale (AIMS) scores (primary outcome), both deutetrabenazine (k=2, n=413, standardized mean difference [SMD] =−0.40, 95% confidence interval [CI] =−0.19, −0.62, p<0.001; weighted mean difference (WMD) =−1.44, 95% CI =−0.67, −2.19, p<0.001) and valbenazine (k=4, n=421, SMD =−0.58, 95% CI =−0.26, −0.91, p<0.001; WMD =−2.07, 95% CI =−1.08, −3.05, p<0.001) significantly outperformed placebo. Results were confirmed regarding responder rates (≥50% AIMS total score reduction; deutetrabenazine: risk ratio [RR] =2.13, 95% CI =1.10, 4.12, p=0.024, number-needed-to-treat [NNT] =7, 95% CI =3, 333, p=0.046; valbenazine: RR =3.05, 95% CI =1.81, 5.11, p<0.001, NNT =4, 95% CI =3, 6, p<0.001). Less consistent results emerged from patient-rated global impression-based response (p=0.15) and clinical global impression for deutetrabenazine (p=0.088), and for clinical global impression change for valbenazine (p=0.67). In an open-label extension (OLE) study of deutetrabenazine (≤54 weeks) and a dose-blinded valbenazine study (≤48 weeks), responder rates increased over time. With valbenazine, discontinuation effects were studied, showing TD symptom recurrence towards baseline severity levels within 4 weeks after valbenazine withdrawal. No increased cumulative or specific adverse (AEs) events versus placebo (acute trials) in extension versus acute trial data were observed.ConclusionThe 2 VMAT-2 inhibitors, valbenazine and deutetrabenazine, are effective in treating TD, both acutely and long-term, without concerns about increased risk of depression or suicide in the TD population. No head-to-head comparison among VMAT-2 inhibitors and no high-quality, meta-analyzable data are available for tetrabenazine in patients with TD.