Marc De Hert

Prevalence of Metabolic Syndrome and Metabolic Abnormalities in Schizophrenia and Related Disorders—A Systematic Review and Meta-Analysis

Individuals with schizophrenia have high levels of medical comorbidity and cardiovascular risk factors. The presence of 3 or more specific factors is indicative of metabolic syndrome, which is a significant influence upon future morbidity and mortality. We aimed to clarify the prevalence and predictors of metabolic syndrome (MetS) in adults with schizophrenia and related disorders, accounting for subgroup differences. A PRISMA systematic search, appraisal, and meta-analysis were conducted of 126 analyses in 77 publications (n = 25,692). The overall rate of MetS was 32.5% (95% CI = 30.1%-35.0%), and there were only minor differences according to the different definitions of MetS, treatment setting (inpatient vs outpatient), by country of origin and no appreciable difference between males and females. Older age had a modest influence on the rate of MetS (adjusted R(2) = .20; P < .0001), but the strongest influence was of illness duration (adjusted R(2) = .35; P < .0001). At a study level, waist size was most useful in predicting high rate of MetS with a sensitivity of 79.4% and a specificity of 78.8%. Sensitivity and specificity of high blood pressure, high triglycerides, high glucose and low high-density lipoprotein, and age (>38 y) are shown in supplementary appendix 2 online. Regarding prescribed antipsychotic medication, highest rates were seen in those prescribed clozapine (51.9%) and lowest rates of MetS in those who were unmedicated (20.2%). Present findings strongly support the notion that patients with schizophrenia should be considered a high-risk group. Patients with schizophrenia should receive regular monitoring and adequate treatment of cardio-metabolic risk factors.

A genome-wide search for schizophrenia susceptibility genes

We completed a systematic genome-wide search for evidence of loci linked to schizophrenia using a collection of 70 pedigrees containing multiple affected individuals according to three phenotype classifications: schizophrenia only (48 pedigrees; 70 sib-pairs); schizophrenia plus schizoaffective disorder (70 pedigrees; 101 sib-pairs); and a broad category consisting of schizophrenia, schizoaffective disorder, paranoid or schizotypal personality disorder, psychosis not otherwise specified (NOS), delusional disorder, and brief reactive psychosis (70 pedigrees; 111 sib-pairs). All 70 families contained at least one individual affected with chronic schizophrenia according to DSM-III-R criteria. Three hundred and thirty-eight markers spanning the genome were typed in all pedigrees for an average resolution of 10.5 cM (range, 0-31 cM) and an average heterozygosity of 74.3% per marker. The data were analyzed using multipoint nonparametric allele-sharing and traditional two-point lod score analyses using dominant and recessive, affecteds-only models. Twelve chromosomes (1, 2, 4, 5, 8, 10, 11, 12, 13, 14, 16, and 22) had at least one region with a nominal P value <0.05, and two of these chromosomes had a nominal P value <0.01 (chromosomes 13 and 16), using allele-sharing tests in GENEHUNTER. Five chromosomes (1, 2, 4, 11, and 13) had at least one marker with a lod score >2.0, allowing for heterogeneity. These regions will be saturated with additional markers and investigated in a new, larger set of families to test for replication.

Risk of metabolic syndrome and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder: a systematic review and meta-analysis

Metabolic syndrome (MetS) and its components are highly predictive of cardiovascular diseases. The primary aim of this systematic review and meta‐analysis was to assess the prevalence of MetS and its components in people with schizophrenia and related psychotic disorders, bipolar disorder and major depressive disorder, comparing subjects with different disorders and taking into account demographic variables and psychotropic medication use. The secondary aim was to compare the MetS prevalence in persons with any of the selected disorders versus matched general population controls. The pooled MetS prevalence in people with severe mental illness was 32.6% (95% CI: 30.8%‐34.4%; N = 198; n = 52,678). Relative risk meta‐analyses established that there was no significant difference in MetS prevalence in studies directly comparing schizophrenia versus bipolar disorder, and in those directly comparing bipolar disorder versus major depressive disorder. Only two studies directly compared people with schizophrenia and major depressive disorder, precluding meta‐analytic calculations. Older age and a higher body mass index were significant moderators in the final demographic regression model (z = −3.6, p = 0.0003, r2 = 0.19). People treated with all individual antipsychotic medications had a significantly (p<0.001) higher MetS risk compared to antipsychotic‐naïve participants. MetS risk was significantly higher with clozapine and olanzapine (except vs. clozapine) than other antipsychotics, and significantly lower with aripiprazole than other antipsychotics (except vs. amisulpride). Compared with matched general population controls, people with severe mental illness had a significantly increased risk for MetS (RR = 1.58; 95% CI: 1.35‐1.86; p<0.001) and all its components, except for hypertension (p = 0.07). These data suggest that the risk for MetS is similarly elevated in the diagnostic subgroups of severe mental illness. Routine screening and multidisciplinary management of medical and behavioral conditions is needed in these patients. Risks of individual antipsychotics should be considered when making treatment choices.

TYPICAL AND ATYPICAL ANTIPSYCHOTICS DIFFERENTIALLY AFFECT LONG-TERM INCIDENCE RATES OF THE METABOLIC SYNDROME IN FIRST-EPISODE PATIENTS WITH SCHIZOPHRENIA: A RETROSPECTIVE CHART REVIEW

UNLABELLED The presence of the metabolic syndrome (MetS) is an important risk factor for cardiovascular disease and diabetes. There are limited data on the prevalence of MetS in patients with schizophrenia at the onset of the disorder and specifically no data on patients treated in the era when only first-generation antipsychotics were available. METHODS Data from a historic cohort of consecutively admitted first-episode patients with schizophrenia treated with first-generation antipsychotics (FGAs) were compared with an age and sex matched series of consecutive first-episode patients treated only with second-generation antipsychotics (SGAs). Rates of MetS were compared at baseline and after on average 3 years of treatment exposure. RESULTS At first episode there was no difference in the prevalence of MetS between the historic and the current cohort. Rates of MetS increased over time in both groups, but patients started on SGAs had a three times higher incidence rate of MetS (Odds Ratio 3.6, CI 1.7-7.5). The average increase in weight and body mass index was twice as high in patients started on SGA. The difference between the FGA and SGA group was no longer significant when patients started on clozapine and olanzapine were excluded. CONCLUSION Rates of MetS at the first episode of schizophrenia today are not different from those of patients 15 to 20 years ago. This finding counters the notion that the high rates of metabolic abnormalities in patients with schizophrenia currently reported are mainly due to lifestyle changes over time in the general population. Some SGAs have a significantly more negative impact on the incidence of MetS compared to FGAs in first-episode patients.

Risk factors for suicide in young people suffering from schizophrenia: a long-term follow-up study

Ten per cent of patients with schizophrenia commit suicide, but assessment of risk is difficult. Large case-control studies with a long follow-up period are needed. These should focus on patients from one age group to give clinicians the details required to identify those at highest risk.We present a case-control study of 63 patients who committed suicide and 63 controls from a consecutive admission series of patients with a diagnosis of schizophrenia. All patients were under the age of 30 at admission.Risk factors for suicide were male gender, chronic illness with frequent relapses (OR 6.0), frequent short hospitalisation, a negative attitude towards treatment (OR non-compliance 7.0), impulsive behaviour (OR acting out 6.4, OR involuntary commitment 17), parasuicide (OR suicide attempt 4.8, OR highly lethal suicide attempt 11), high pre-morbid IQ (OR 4.3), psychosis (OR 7.0) and depression (OR 36). However, early onset of a defect state (OR 6.3) and a daily activity (OR 4.2) were protective factors. Identified risk factors could help clinicians to target high-risk patients and form the basis for interventions aimed at reducing suicide.

Prevalence of diabetes and the metabolic syndrome in a sample of patients with bipolar disorder

OBJECTIVES The presence of metabolic abnormalities is an important risk factor for cardiovascular disease and diabetes. There are limited data on the prevalence of the metabolic abnormalities in disorders other than schizophrenia in which antipsychotic medication is part of routine treatment. METHODS Sixty consecutive patients with bipolar disorder (BD) at our university psychiatric hospital and affiliate services were entered in an extensive prospective metabolic study including an oral glucose tolerance test. The prevalence of the metabolic syndrome was assessed based on the National Cholesterol Education Program Adult Treatment Protocol (ATP-III) criteria, the adapted ATP-III criteria using a fasting glucose threshold of 100 mg/dL, and the recently proposed criteria from the International Diabetes Federation (IDF). RESULTS The analysis of 60 patients showed a prevalence of the metabolic syndrome of 16.7% (ATP-III), 18.3% (adapted ATP-III) and 30.0% (IDF), respectively. A total of 6.7% of the patients met criteria for diabetes and 23.3% for pre-diabetic abnormalities. CONCLUSIONS The metabolic syndrome and glucose abnormalities are highly prevalent among patients with BD. They represent an important risk for cardiovascular and metabolic disorders. Assessment of the presence and monitoring of metabolic abnormalities and its associated risks should be part of the clinical management of patients with BD.

Is the Prevalence of Metabolic Syndrome and Metabolic Abnormalities Increased in Early Schizophrenia? A Comparative Meta-Analysis of First Episode, Untreated and Treated Patients

UNLABELLED We aimed to discover whether metabolic complications of schizophrenia (SZ) are present in first episode (FE) and unmedicated (UM) patients, in comparison with patients established on antipsychotic medication (AP). METHOD A systematic search, critical appraisal, and meta-analysis were conducted of studies to December 2011 using Medline, PsycINFO, Embase and experts. Twenty-six studies examined FE SZ patients (n = 2548) and 19 included UM SZ patients (n = 1325). For comparison we identified 78 publications involving 24 892 medicated patients who had chronic SZ already established on AP. RESULTS In UM, the overall rate of metabolic syndrome (MetS) was 9.8% using any standardized criteria. Diabetes was found in only 2.1% and hyperglycaemia (>100 mg/dl) in 6.4%. In FE, the overall MetS rate was 9.9%, diabetes was found in only 1.2%, and hyperglycaemia in 8.7%. In UM and FE, the rates of overweight were 26.6%, 22%; hypertriglyceridemia 16.9%, 19.6%; low HDL 20.4%, 21.9%; high blood pressure 24.3%, 30.4%; smoking 40.2%, 46.8%, respectively. In both groups all metabolic components and risk factors were significantly less common in early SZ than in those already established on AP. Waist size, blood pressure and smoking were significantly lower in UM compared with FE. CONCLUSION There is a significantly lower cardiovascular risk in early SZ than in chronic SZ. Both diabetes and pre-diabetes appear uncommon in the early stages, especially in UM. However, smoking does appear to be elevated early after diagnosis. Clinicians should focus on preventing initial cardiometabolic risk because subsequent reduction in this risk is more difficult to achieve, either through behavioral or pharmacologic interventions.

Diabetes mellitus in people with schizophrenia, bipolar disorder and major depressive disorder: a systematic review and large scale meta-analysis

Type 2 diabetes mellitus (T2DM) is highly predictive of cardiovascular diseases and can have particularly deleterious health impacts in people with severe mental illness (SMI), i.e. schizophrenia, bipolar disorder or major depressive disorder. This meta‐analysis aimed: a) to describe pooled frequencies of T2DM in people with SMI; b) to analyze the influence of demographic, illness and treatment variables as well as T2DM assessment methods; and c) to describe T2DM prevalence in studies directly comparing persons with each specific SMI diagnosis to general population samples. The trim and fill adjusted pooled T2DM prevalence among 438,245 people with SMI was 11.3% (95% CI: 10.0%‐12.6%). In antipsychotic‐naïve participants, the prevalence of T2DM was 2.9% (95% CI: 1.7%‐4.8%). There were no significant diagnostic subgroup differences. A comparative meta‐analysis established that multi‐episode persons with SMI (N=133,470) were significantly more likely to have T2DM than matched controls (N=5,622,664): relative risk, RR=1.85, 95% CI: 1.45‐2.37, p<0.001. The T2DM prevalence was consistently elevated in each of the three major diagnostic subgroups compared to matched controls. Higher T2DM prevalences were observed in women with SMI compared to men (RR=1.43, 95% CI: 1.20‐1.69, p<0.001). Multi‐episode (versus first‐episode) status was the only significant predictor for T2DM in a multivariable meta‐regression analysis (r2=0.52, p<0.001). The T2DM prevalence was higher in patients prescribed antipsychotics, except for aripriprazole and amisulpride. Routine screening and multidisciplinary management of T2DM is needed. T2DM risks of individual antipsychotic medications should be considered when making treatment choices.

A meta-analysis of cardio-metabolic abnormalities in drug naïve, first-episode and multi-episode patients with schizophrenia versus general population controls

A meta‐analysis was conducted to explore the risk for cardio‐metabolic abnormalities in drug naïve, first‐episode and multi‐episode patients with schizophrenia and age‐ and gender‐ or cohort‐matched general population controls. Our literature search generated 203 relevant studies, of which 136 were included. The final dataset comprised 185,606 unique patients with schizophrenia, and 28 studies provided data for age‐ and gender‐matched or cohort‐matched general population controls (n=3,898,739). We found that multi‐episode patients with schizophrenia were at increased risk for abdominal obesity (OR=4.43; CI=2.52‐7.82; p<0.001), hypertension (OR=1.36; CI=1.21‐1.53; p<0.001), low high‐density lipoprotein cholesterol (OR=2.35; CI=1.78‐3.10; p<0.001), hypertriglyceridemia (OR=2.73; CI=1.95‐3.83; p<0.001), metabolic syndrome (OR=2.35; CI=1.68‐3.29; p<0.001), and diabetes (OR=1.99; CI=1.55‐2.54; p<0.001), compared to controls. Multi‐episode patients with schizophrenia were also at increased risk, compared to first‐episode (p<0.001) and drug‐naïve (p<0.001) patients, for the above abnormalities, with the exception of hypertension and diabetes. Our data provide further evidence supporting WPA recommendations on screening, follow‐up, health education and lifestyle changes in people with schizophrenia.

Evidence that the COMTVal158Met polymorphism moderates sensitivity to stress in psychosis: An experience‐sampling study

Gene–environment interactions involving the catechol‐O‐methyltransferase Val158Met polymorphism (COMTVal158Met) have been implicated in the causation of psychosis. Evidence from general population studies suggests that Met/Met subjects are sensitive to stress, a trait associated with psychosis. We hypothesized that the Met allele would moderate the effects of stress on negative affect (NA) in controls, and on NA and psychosis in patients with a psychotic disorder. Thirty‐one patients with a psychotic disorder and comorbid cannabis misuse and 25 healthy cannabis users were studied with the experience sampling method (ESM), a structured diary technique assessing current context and emotional and psychotic experiences in daily life. A significant interaction between COMTVal158Met genotype and ESM stress in the model of NA was found for patients (interaction χ2 = 7.4, P = 0.02), but not for controls (interaction χ2 = 3.8, P = 0.15). In the model of ESM psychosis, a significant interaction between COMTVal158Met genotype and ESM stress was also apparent (interaction χ2 = 11.6, P < 0.01), with Met/Met patients showing the largest increase in psychotic experiences as well as NA in reaction to ESM stress. The findings suggest that the COMTVal158Met polymorphism moderates affective and psychotic responses to stress in patients with psychosis, providing evidence for gene–environment interaction mechanisms in the formation of psychotic symptoms.