Tony Cohn

Characterizing coronary heart disease risk in chronic schizophrenia: high prevalence of the metabolic syndrome.

Objective: To determine the prevalence and characteristics of coronary heart disease (CHD) risk factors in patients with chronic schizophrenia or schizoaffective disorder. Method: We compared individual CHD risk factors and Framingham risk predictions in a group of 240 patients with a large national sample (Canadian Heart Health Survey) matched for age and sex. In addition, we compared rates of the metabolic syndrome (syndrome X) with recently published rates in the US adult population. Results: Compared with the reference population, Framingham 10-year risk of myocardial infarction was greater in the male patients (t3091 = 4.35, P < 0.001) but not in the female patients. Prevalence rates of the metabolic syndrome in the patients (42.6% of men and 48.5% of women) were approximately 2 times published rates in the US adult population. Further, the syndrome appears to occur at a younger age than in the general population. Conclusions: These long-term patients have increased CHD risks best captured by the metabolic syndrome conceptualization coupled with a high rate of cigarette smoking. This characterization is consistent with increased cardiovascular morbidity and decreased life expectancy in both men and women. We underscore the importance of both screening for and treating potentially reversible CHD risk factors in schizophrenia patients.

Validation of a physical activity assessment tool for individuals with schizophrenia

OBJECTIVE Increasing physical activity must be one component of lifestyle interventions designed to prevent or treat obesity in schizophrenia and there is now a need to develop low cost, practical and accurate measures of physical activity in this population to identify the prevalence of physical (in)activity and to assess the effectiveness of physical activity interventions. The objective of this study was to provide preliminary validation of the Short-Form International Physical Activity Questionnaire (IPAQ), a measurement tool that could prove useful for both clinicians and researchers in the field. METHOD Reliability and validity data were collected from a sample of 35 outpatients with a DSM-IV diagnosis of schizophrenia. Test-retest repeatability was assessed within the same week and criterion validity was assessed against an RT3 accelerometer. Spearmans correlation coefficients are reported based on the total reported physical activity (minutes) and estimated energy expenditure. RESULT We found a correlation coefficient of 0.68 for reliability and 0.37 for criterion validity based on total reported minutes of physical activity. There was a nonsignificant correlation (0.30; p>0.05) between the RT3 data and estimated energy expenditure derived from the IPAQ. CONCLUSION Although not without limitations, the Short-Form IPAQ, when used with individuals with schizophrenia, exhibits measurement properties that are comparable to those reported in the general population and can be considered as a surveillance tool to assess levels of physical activity.

Insulin resistance and adiponectin levels in drug-free patients with schizophrenia: A preliminary report.

Objective: To compare the insulin sensitivity and adiponectin levels of medication-free patients suffering from schizophrenia or schizoaffective disorder with that of matched healthy volunteers. Method: We evaluated 9 nondiabetic patients aged 26.6 years (median 26 years, range 17 to 41 years) and matched volunteers, using the frequently sampled intravenous glucose tolerance test, minimal model analysis, and fasting adiponectin levels. Results: The mean insulin sensitivity index of the patients was 42% lower than that of the healthy volunteers (P = 0.026), with inadequate compensation in insulin secretion. Patients with schizophrenia tended to have reduced adiponectin levels (P = 0.055). Conclusions: By direct measurement, this study provides evidence of insulin resistance and susceptibility to type 2 diabetes in patients with schizophrenia who are free of antipsychotic drugs.

Pharmacologic and Nonpharmacologic Strategies for Weight Gain and Metabolic Disturbance in Patients Treated With Antipsychotic Medications

Objectives: To provide an overview of pharmacologic and nonpharmacologic strategies for antipsychotic-associated weight gain and metabolic disturbance, to identify important areas for future research, and to make practice recommendations based on current knowledge. Methods: We undertook a selective review of interventions for weight gain and metabolic disturbance in the general population and in individuals treated with antipsychotic medications, focusing on randomized controlled trials in schizophrenia. Results: Pharmacologic strategies include medication choice, medication dosage and formulation, choice of concomitant psychotropic medications, medication switching, medication addition to effect weight loss or prevent weight gain, and medications to increase insulin sensitivity. Medication choice and medication switching may have the most potent influence on weight and metabolic parameters. Modest short-term weight loss can occur with the addition of selective medications and (or) lifestyle interventions. However, more rigorous and longer-term studies are needed. Conclusions: Although difficult, the prevention of weight gain and the promotion of weight loss are possible for individuals treated with antipsychotic medications. Further research, including diabetes prevention studies, is required. We suggest a pathway for the management of weight gain and emerging metabolic disturbance.

Insulin Resistance and Decreased Glucose-stimulated Insulin Secretion After Acute Olanzapine Administration

The newer atypical antipsychotics, as a class, have been associated with an increased risk of weight gain and metabolic abnormalities. The mechanisms underlying this phenomenon are currently unclear, but there are data to suggest the possibility of an immediate (as opposed to chronic) effect of these drugs. The aim of the present study was to assess the acute effects of olanzapine on specific measures of insulin sensitivity and secretion. Healthy animals were tested in either the hyperinsulinemic-euglycemic or the hyperglycemic clamp. After reaching steady state in the hyperinsulinemic-euglycemic clamp, rats were injected with olanzapine (3 mg/kg sc) and monitored for an additional 130 minutes. In the hyperglycemic clamp, olanzapine was injected approximately 90 minutes before receiving a glucose bolus, and hyperglycemia was maintained via exogenous glucose infusion for an additional 90 minutes. Insulin and C-peptide levels were monitored throughout this clamp. Acute administration of olanzapine significantly lowered the glucose infusion rate due to an increase in hepatic glucose production and a decrease in glucose utilization. Olanzapine pretreatment induced hyperglycemia and markedly decreased plasma insulin and C-peptide in response to the glucose challenge. These findings indicate that olanzapine can directly induce metabolic changes that occur rapidly and well in advance of the changes that might be anticipated as a result of its weight-gain liability. We present novel findings highlighting an olanzapine-induced deficit in beta-cell functioning.

Body mass index, waist circumference and quality of life in individuals with schizophrenia ☆

OBJECTIVE The primary objective was to examine the differential relationship between waist circumference, body mass index, and self-reported quality of life in patients with schizophrenia. METHOD Individuals with DSM-IV schizophrenia (n=90) were interviewed to obtain sociodemographic data, complete a Quality of Life questionnaire (the MOS SF-12) and have measurements taken of height, weight (kg), and waist circumference (cm). Multiple regression analysis was used to assess the associations between adiposity measures (BMI, WC) and quality of life outcomes (PCS, MCS). RESULTS Mental component score (MCS) was not significantly related to either of the weight related measures. After adjustment for gender and age, both BMI alone and WC alone were significant predictors of PCS. When both BMI and WC were included in the same regression model, only WC remained a significant predictor of PCS. CONCLUSIONS Quality of life in schizophrenic patients is related to measures of body weight. The relationship is strongest using waist circumference as the primary measure. This provides further support for routinely incorporating this measure within research and clinical assessments.

Atypical antipsychotics and effects of muscarinic, serotonergic, dopaminergic and histaminergic receptor binding on insulin secretion in vivo: An animal model

The atypical antipsychotics (AAPs) have been associated with increased risk of type-2 diabetes. Evidence suggests direct, drug-related effects independent of weight gain and although mechanisms underlying this phenomenon are unclear, it has been suggested that the heterogeneous receptor binding profile of the AAPs may influence receptors implicated in glucose metabolism. This study aimed to clarify weight gain-independent mechanisms of AAP-induced changes in insulin secretion by deconstructing their binding profile with representative antagonists. Healthy rats were pretreated with a single subcutaneous dose of darifenacin 6 mg/kg (n=10), a selective M(3) muscarinic antagonist; ketanserin 2mg/kg (n=10), a 5HT(2A) antagonist; raclopride 0.3mg/kg (n=11) a selective D(2)/D(3) antagonist; terfenadine 20mg/kg (n=9) a selective H(1) antagonist; or, vehicle (n=11). Hyperglycemic clamps were employed following injection, providing an index of secretory capacity of pancreatic β-cells. Acute treatment with darifenacin and ketanserin significantly decreased insulin response to glucose challenge as compared to controls, which was confirmed in the darifenacin group by reduced C-peptide levels. Treatment with raclopride resulted in an increased insulin response and a strong tendency to increased C-peptide levels. H(1) blockade did not result in effects on insulin or C-peptide. Results suggest that the effects of antipsychotics on glucose dysregulation may be related to direct inhibitory effects of muscarinic (M(3)) and serotonergic (5HT(2)) antagonism on insulin secretion. Based on the expression of D(2)-like receptors in β-cells, which mediate inhibition of insulin secretion, we propose that prolonged D(2) blockade with antipsychotics may predispose to depletion of insulin stores and an eventual defect in pancreatic compensation.

Exploring the Construct Validity of the Transtheoretical Model to Structure Physical Activity Interventions for Individuals with Serious Mental Illness

OBJECTIVE Physical activity intervention research involving individuals with serious mental illness are often not based on any theoretical framework. This study examined the construct validity of the Transtheoretical Model (TTM) in individuals with serious mental illness to guide future physical activity interventions. METHODS Fifty-four individuals completed surveys that asked about their current stage of change for physical activity, self-efficacy, and perceived advantages and disadvantages of being more physically active. RESULTS Most individuals reported being in the preparation stage of the TTM. As individuals approached the action and maintenance stages, self-efficacy and perceived benefits of physical activity increased significantly. Although perceived disadvantages decreased with each successive stage, this change was not significant. CONCLUSIONS This studys findings support the TTMs application in this population to structure physical activity interventions given that self-efficacy, perceived benefits of and barriers to physical activity differed across stages and changes were in the direction predicted by theory.

Schizophrenia and the incidence of cardiovascular morbidity: A population-based longitudinal study in Ontario, Canada

OBJECTIVE Despite the high rates of cardiovascular mortality among people with schizophrenia, little is known about the incidence of cardiovascular morbidity in this population. We assessed whether individuals diagnosed with schizophrenia, in comparison to a population-proxy comparison group (comprised of individuals receiving an appendicitis-related primary diagnosis), would have a significantly greater risk of subsequent readmission to an inpatient or Emergency Department setting with a cardiovascular condition. DESIGN Using inpatient hospital discharge records from April 1, 2002 to March 31, 2006 in Ontario, Canada, we constructed a population-based cohort study of patients who were followed for a period up to 4 years. Individuals with a primary ICD-10 (F20) schizophrenia diagnosis (n=9815) were matched with persons with a primary ICD-10 appendicitis-related diagnosis (K35-37) on sex, age, average neighbourhood income level, and amount of follow-up time available. We used a Cox regression procedure to estimate group differences in time-to-readmission with a cardiovascular-related diagnosis. RESULTS Individuals in the Schizophrenia group had a significantly greater adjusted risk of readmission for a cardiovascular event in comparison to individuals in the Appendicitis group [adjusted hazard ratio (AHR)=1.43, 95% CI, 1.22-1.69]. CONCLUSIONS Given the elevated risk of cardiovascular morbidity among individuals with schizophrenia, our findings add to the importance of screening and intervention programs for metabolic disorders and known cardiovascular risk factors among patients with schizophrenia.

Acute effects of single-dose olanzapine on metabolic, endocrine, and inflammatory markers in healthy controls.

Abstract Atypical antipsychotics may “directly” influence glucose homeostasis, increasing risk of type 2 diabetes independently of changes in adiposity. Animal models suggest direct effects after even a single dose of certain atypical antipsychotics on glucose dysregulation. Here, we investigated effects of a single-dose olanzapine (OLA) on glucose metabolism in healthy volunteers, thereby minimizing confounding effects of the illness of schizophrenia and adiposity. In a randomized double-blind crossover design, 15 subjects were administered 10 mg of OLA or placebo at 7:00 A.M. on separate study dates. A frequently sampled intravenous glucose tolerance test was initiated 4.25 hours later to assess changes in glucose homeostasis, including an index of insulin sensitivity, disposition index, glucose effectiveness, and acute insulin response to glucose. We also examined effects on cortisol, prolactin, fasting free fatty acids (FFAs), insulin-mediated suppression of FFAs, and adipocytokines (leptin, adiponectin, C-reactive protein, interleukin 6, and tumor necrosis factor &agr;). Complete data for both visits were analyzed for 12 subjects. Olanzapine treatment significantly decreased glucose effectiveness (P = 0.041) and raised fasting glucose over 4.25 hours (P = 0.03) as compared to placebo. Olanzapine was associated with lower serum cortisol (P = 0.003), lower fasting FFA (P = 0.042), and increased prolactin levels (P < 0.0001). We therefore suggest that a single dose of OLA may invoke early changes in some parameters of glucose and lipid metabolism, as well as endocrine indices.