Ruud van Winkel

Metabolic and cardiovascular adverse effects associated with antipsychotic drugs

Antipsychotic medications can induce cardiovascular and metabolic abnormalities (such as obesity, hyperglycemia, dyslipidemia and the metabolic syndrome) that are associated with an increased risk of type 2 diabetes mellitus and cardiovascular disease. Controversy remains about the contribution of individual antipsychotic drugs to this increased risk and whether they cause sudden cardiac death through prolongation of the corrected QT interval. Although some drug receptor-binding affinities correlate with specific cardiovascular and metabolic abnormalities, the exact pharmacological mechanisms underlying these associations remain unclear. Antipsychotic agents with prominent metabolic adverse effects might cause abnormalities in glucose and lipid metabolism via both obesity-related and obesity-unrelated molecular mechanisms. Despite existing guidelines and recommendations, many antipsychotic-drug-treated patients are not assessed for even the most easily measurable metabolic and cardiac risk factors, such as obesity and blood pressure. Subsequently, concerns have been raised over the use of these medications, especially pronounced in vulnerable pediatric patients, among whom their use has increased markedly in the past decade and seems to have especially orexigenic effects. This Review outlines the metabolic and cardiovascular risks of various antipsychotic medications in adults and children, defines the disparities in health care and finally makes recommendations for screening and monitoring of patients taking these agents.

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.

Metabolic syndrome in people with schizophrenia: a review

Metabolic syndrome and other cardiovascular risk factors are highly prevalent in people with schizophrenia. Patients are at risk for premature mortality and overall have limited access to physical health care. In part these cardio-metabolic risk factors are attributable to unhealthy lifestyle, including poor diet and sedentary behaviour. But over recent years it has become apparent that antipsychotic agents can have a negative impact on some of the modifiable risk factors. The psychiatrist needs to be aware of the potential metabolic side effects of antipsychotic medication and to include them in the risk/benefit assessment when choosing a specific antipsychotic. He should also be responsible for the implementation of the necessary screening assessments and referral for treatment of any physical illness. Multidisciplinary assessment of psychiatric and medical conditions is needed. The somatic treatments offered to people with severe and enduring mental illness should be at par with general health care in the non-psychiatrically ill population.

Prevalence of the metabolic syndrome in patients with schizophrenia treated with antipsychotic medication

UNLABELLED The presence of the metabolic syndrome is an important risk factor for cardiovascular disease and diabetes. There are limited data on the prevalence of the metabolic syndrome in European patients suffering from schizophrenia. METHODS All consecutive patients with schizophrenia 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 criteria (NCEP, Adult Treatment Protocol, ATP-III), adapted ATP-III criteria using a fasting glucose threshold of 100 mg/dl (AHA) and on the recently proposed criteria from the International Diabetes Federation (IDF). RESULTS The analysis of 430 patients showed a prevalence of the metabolic syndrome of 28.4% (ATP-III), 32.3% (ATP-III A) and 36% (IDF), respectively. The prevalence of the metabolic syndrome in our sample of patients with schizophrenia is at least twice as high compared to an age-adjusted community sample in Belgium. CONCLUSION The metabolic syndrome is highly prevalent among treated patients with schizophrenia. It represents an important risk for cardiovascular and metabolic disorders. Assessment of the presence and monitoring of the associated risks of the metabolic syndrome should be part of the clinical management of patients treated with antipsychotics.

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.

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.

Common Variants at VRK2 and TCF4 Conferring Risk of Schizophrenia

Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10(-9)).

Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: evidence for a common genetic vulnerability?

Past analyses examining the relationship between genetic variation in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene and psychiatric disorders have provided mixed and largely inconclusive findings. MTHFR is involved in the one-carbon metabolic pathway which is essential for DNA biosynthesis and the epigenetic process of DNA methylation. We conducted a meta-analysis of all published case-control studies investigating associations between two common MTHFR single nucleotide polymorphisms (SNPs), MTHFR C677T (sample size 29,502) and A1298C (sample size 7934), and the major psychiatric disorders (i) schizophrenia (SZ), (ii) bipolar disorder (BPD), and (iii) unipolar depressive disorder (UDD). In order to examine possible shared genetic vulnerability, we also tested for associations between MTHFR and all of these major psychiatric disorders (SZ, BPD and UDD) combined. MTHFR C677T was significantly associated with all of the combined psychiatric disorders (SZ, BPD and UDD); random effects odds ratio (OR)=1.26 for TT versus CC genotype carriers; confidence interval (CI) 1.09-1.46); meta-regression did not suggest moderating effects of psychiatric diagnosis, sex, ethnic group or year of publication. Although MTHFR A1298C was not significantly associated with the combination of major psychiatric disorders, nor with SZ, there was evidence for diagnostic moderation indicating a significant association with BPD (random effects OR=2.03 for AA versus CC genotype carriers, CI: 1.07-3.86). Meta-analysis on UDD was not possible due to the small number of studies available. This study provides evidence for shared genetic vulnerability for SZ, BPD and UDD mediated by MTHFR 677TT genotype, which is in line with epigenetic involvement in the pathophysiology of these psychiatric disorders.

Considering a frame of reference for physical activity research related to the cardiometabolic risk profile in schizophrenia

This article reviews evidence that researchers and mental health service providers need to take into account four modifiable factors that affect the prevalence of the metabolic syndrome in people with schizophrenia: (a) physical activity as part of a health-related lifestyle, (b) physical fitness, (c) mental health status and (d) antipsychotic medication. The implementation of physical activity in order to prevent and treat cardiometabolic risk factors in people with schizophrenia is discussed. English language articles published until July 2009 were identified by PubMed, CINAHL, PsychINFO, and Cochrane Central Register of Controlled Trials. The search terms schizophrenia and metabolic syndrome, physical activity, health, fitness, and lifestyle were used. Physical activity interventions result in positive effects on metabolic outcomes, physical fitness, health-related behavior and mental health. Considering present knowledge, physical therapists should take into account the emotional (negative symptoms, self-esteem, self-efficacy, and stress) and physiological (cardiometabolic parameters) components of mental illness when offering physical activity interventions. The physical activity stimulus should be adapted to the individuals physical fitness level and the side effects of the antipsychotic medications. More research is needed to assist in the practical development of effective evidence-based preventive and curative strategies in psychiatric services for metabolic syndrome in persons with schizophrenia.

Remission criteria for schizophrenia: Evaluation in a large naturalistic cohort

BACKGROUND Recently, remission criteria for schizophrenia have been proposed, based on low symptom severity of core symptoms (severity criterion), sustained over minimally 6 months (time criterion). Little is known, however, about the added value of the time criterion in addition to the cross-sectional severity criterion. METHODS In order to evaluate whether remission is a valid concept for daily clinical practice, the cumulative incidence of patients meeting remission criteria was evaluated in a large naturalistic prospective study of patients with schizophrenia or schizoaffective disorder in different treatment settings in Belgium. The impact of being in remission on global and daily functioning was evaluated. RESULTS Over time, nearly 1 out of 3 patients with a diagnosis of schizophrenia or schizoaffective disorder (29%) met criteria for remission at study endpoint. Patients in remission had better insight in their disorder, a higher level of global functioning and functioned better with respect to daily living tasks, both compared to patients never meeting remission criteria and to patients only meeting the severity criterion but not the time criterion. Of the patients not meeting remission criteria at baseline, 21% attained remission at study endpoint. CONCLUSION The remission severity and time criteria appear to combine into a valid concept for daily clinical practice and should be a target for treatment.