Jonathan M. Meyer

Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III.

UNLABELLED One important risk factor for cardiovascular disease is the metabolic syndrome (MS), yet limited data exist on its prevalence in US patients with schizophrenia. METHODS Using baseline data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial, assessment of MS prevalence was performed based on National Cholesterol Education Program (NCEP) criteria, and also using a fasting glucose threshold of 100 mg/dl (AHA). Subjects with sufficient anthropometric data, data on use of antihypertensives, hypoglycemic medications or insulin, and fasting glucose and lipid values >8 h from last meal were included in the analysis. Comparative analyses were performed using a randomly selected sample from NHANES III matched 1:1 on the basis of age, gender and race/ethnicity. RESULTS Of 1460 CATIE baseline subjects, 689 met analysis criteria. MS prevalence was 40.9% and 42.7%, respectively using the NCEP and AHA derived criteria. In females it was 51.6% and 54.2% using the NCEP and AHA criteria, compared to 36.0% (p = .0002) and 36.6% (p = .0003), respectively for males. 73.4% of all females (including nonfasting subjects) met the waist circumference criterion compared to 36.6% of males. In a logistic regression model with age, race and ethnicity as covariates, CATIE males were 138% more likely to have MS than the NHANES matched sample, and CATIE females 251% more likely than their NHANES counterparts. Even when controlling for differences in body mass index, CATIE males were still 85% more likely to have MS than the NHANES male sample, and CATIE females 137% more likely to have MS than females in NHANES. CONCLUSIONS The metabolic syndrome is highly prevalent in US schizophrenia patients and represents an enormous source of cardiovascular risk, especially for women. Clinical attention must be given to monitoring for this syndrome, and minimizing metabolic risks associated with antipsychotic treatment.

Low rates of treatment for hypertension, dyslipidemia and diabetes in schizophrenia: Data from the CATIE schizophrenia trial sample at baseline

UNLABELLED Persons diagnosed with schizophrenia have higher morbidity and mortality rates from cardiovascular disease, yet often have limited access to appropriate primary care screening or treatment. Metabolic disorders such as diabetes, hyperlipidemia and hypertension are highly prevalent in populations with schizophrenia, exceeding 50% in some studies; however, there have been few published studies on treatment rates among schizophrenia patients screened for these disorders. METHODS Using the baseline data from subjects (N=1460) recruited into the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study, we examined the point prevalence of diabetes, hyperlipidemia and hypertension treatment at the time of enrollment for the entire cohort and those with fasting laboratory values obtained 8 or more hours since last meal. RESULTS Rates of non-treatment ranged from 30.2% for diabetes, to 62.4% for hypertension, and 88.0% for dyslipidemia. Nonwhite men were more likely to be treated for DM and dyslipidemia than nonwhite women. CONCLUSIONS These data indicate the high likelihood that metabolic disorders are untreated in patients with schizophrenia, with particularly high rates of non-treatment for hypertension and dyslipidemia. Nonwhite women may be especially vulnerable to undertreatment of dyslipidemia and diabetes compared to nonwhite men. The findings here support the need for increased attention to basic monitoring and treatment of cardiovascular risk factors in this vulnerable and often underserved psychiatric population.

A comparison of ten-year cardiac risk estimates in schizophrenia patients from the CATIE study and matched controls

OBJECTIVE Standardized mortality rates are elevated in schizophrenia compared to the general population. The incidence of coronary heart disease (CHD) and the relative contribution of CHD to increased mortality in schizophrenia patients are not clear, despite recent concerns about metabolic complications of certain atypical antipsychotics. METHOD Ten-year risk for CHD was calculated for 689 subjects who participated in the Clinical Trials of Antipsychotic Treatment Effectiveness (CATIE) Schizophrenia Trial at baseline using the Framingham CHD risk function and were compared with age-, race- and gender-matched controls from the National Health and Nutrition Examination Survey (NHANES) III. RESULTS Ten-year CHD risk was significantly elevated in male (9.4% vs. 7.0%) and female (6.3% vs. 4.2%) schizophrenia patients compared to controls (p = 0.0001). Schizophrenia patients had significantly higher rates of smoking (68% vs. 35%), diabetes (13% vs. 3%), and hypertension (27% vs. 17%) and lower HDL cholesterol levels (43.7 vs. 49.3 mg/dl) compared to controls (p < 0.001). Only total cholesterol levels did not differ between groups. Ten-year CHD risk remained significantly elevated in schizophrenia patients after controlling for body mass index (p = 0.0001). CONCLUSIONS These results are consistent with recent evidence of increased cardiac mortality in schizophrenia patients. While the impact of cigarette smoking is clear, the relative contributions to cardiac risk of specific antipsychotic agents, diet, exercise, and quality of medical care remain to be clarified.

The effects of antipsychotic therapy on serum lipids: a comprehensive review

OBJECTIVES The purpose of this paper is to review the literature since 1970 documenting the effects of antipsychotic agents on serum lipids, including a discussion of possible mechanisms for the observed phenomena, the clinical significance and recommendations for monitoring hyperlipidemia during antipsychotic therapy. RESULTS High-potency conventional antipsychotics (e.g., haloperidol) and the atypical antipsychotics, ziprasidone, risperidone and aripiprazole, appear to be associated with lower risk of hyperlipidemia. Low-potency conventional antipsychotics (e.g., chlorpormazine, thioridazine) and the atypical antipsychotics, quetiapine, olanzapine and clozapine, are associated with higher risk of hyperlipidemia. Possible hypotheses for lipid dysregulation include weight gain, dietary changes and the development of glucose intolerance. CONCLUSIONS Given the multiple cardiovascular risk factors seen in patients with schizophrenia, great care must be exercised in the choice of antipsychotic therapy to minimize the medical burden of additional risk imposed by hyperlipidemia. It is recommended that a lipid panel be obtained at baseline in all patients with schizophrenia, annually thereafter for patients on agents associated with lower risk of hyperlipidemia and quarterly in patients on agents associated with higher risk for hyperlipidemia. All patients with persistent dyslipidemia should be referred for lipid-lowering therapy or switched to a less lipid-offending antipsychotic agent.

Phenomenology of and risk factors for new-onset diabetes mellitus and diabetic ketoacidosis associated with atypical antipsychotics: an analysis of 45 published cases.

Case reports and small retrospective studies suggest that atypical antipsychotic agents may be associated with new-onset Type II diabetes mellitus (DM) or diabetic ketoacidosis (DKA); however, these reports often provide limited or no information on demographic variables such as age, gender, ethnicity, relationship to weight gain, and time course. We analyzed 45 published cases of new-onset DM or DKA for which followed initiation of atypical antipsychotic treatment. Of the 45 patients, 20 had received clozapine, 19 olanzapine, 3 quetiapine, and 3 risperidone. Eighty-seven percent patients were male, and 47% African American. Forty-two percent of these patients presented as DKA, and 50% manifested no weight gain at time of presentation with DM or DKA, although 84% were overweight before antipsychotic therapy. Eighty-four percent presented within 6 months and 59% within 3 months of commencing atypical antipsychotics. The DKA cohort had significantly younger age, less overweight at baseline, and higher proportion of women than did those with DM alone, without significant differences in distribution of ethnicity, weight gain, family history of DM, or duration of exposure to atypical agents. Clinicians should be aware of the potential risks of new-onset DM and DKA in patients taking atypical antipsychotics, and utilize appropriate clinical and laboratory monitoring to prevent serious adverse events.

Change in metabolic syndrome parameters with antipsychotic treatment in the CATIE Schizophrenia Trial: Prospective data from phase 1

BACKGROUND The metabolic syndrome (MS) is associated with increased risk for diabetes mellitus and coronary heart disease, and is highly prevalent among schizophrenia patients. Given concerns over antipsychotic metabolic effects, this analysis explored MS status and outcomes in phase 1 of the CATIE Schizophrenia Trial. METHODS The change in proportion of subjects with MS and individual criteria was compared between antipsychotic treatment groups, along with mean changes for individual criteria. Primary analyses examined subjects with fasting laboratory assessments at baseline and 3 months. Other analyses examined 3-month changes in MS status, waist circumference (WC), HDL cholesterol and blood pressure in all subjects, metabolic changes at the end of phase 1 participation (EOP), and repeated measures changes in HDL, blood pressure (BP) and WC over phase 1. RESULTS At 3 months, there were no significant between-drug differences for the change in proportion of subjects meeting MS status or individual MS criteria in the smaller fasting cohort (n = 281) or for those meeting criteria for parameters not dependent on fasting status (BP, HDL, WC) among all subjects (n=660). Among all subjects whose MS status could be determined at 3 months (n=660), MS prevalence increased for olanzapine (from 34.8% to 43.9%), but decreased for ziprasidone (from 37.7% to 29.9%) (p=.001). Although effect sizes varied across subgroups, at 3 months olanzapine and quetiapine had the largest mean increase in waist circumference (0.7 in. for both) followed by risperidone (0.4 in.), compared to no change for ziprasidone (0.0 in.) and a decrease in waist circumference for perphenazine (-0.4 in.). Olanzapine also demonstrated significantly different changes in fasting triglycerides at 3 months (+21.5 mg/dl) compared to ziprasidone (-32.1 mg/dl). EOP exposure data was obtained, on average, nine months from baseline for all metabolic variables. Results from EOP and repeated measures analyses were consistent with those at 3 months for mean changes in WC and fasting triglycerides, but between group differences emerged for HDL and SBP. CONCLUSIONS This large non-industry sponsored study confirms the differential metabolic effects between antipsychotics. Clinicians are advised to monitor all metabolic parameters, including WC, HDL and serum triglycerides, during antipsychotic treatment.

The metabolic syndrome and schizophrenia.

Objective:  To summarize the accumulated data on metabolic syndrome prevalence in patients with schizophrenia, examine evidence for a biological contribution of the mental illness to metabolic risk and review novel options available for management of prediabetic states.

Which comes first: atypical antipsychotic treatment or cardiometabolic risk?

Objective:  To provide an overview for practicing clinicians on the pharmacological basis of cardiometabolic risk induced by antipsychotic drugs in patients with serious mental illness, to propose hypotheses to explain these risks and to give tips for managing cardiometabolic risk during antipsychotic treatment.

Antipsychotic effects on estimated 10-year coronary heart disease risk in the CATIE schizophrenia study.

OBJECTIVE Persons with schizophrenia die earlier than the general population, in large part due to cardiovascular disease. The study objective was to examine effects of different antipsychotic treatments on estimates of 10-year coronary heart disease (CHD) risk calculated by the Framingham Heart Study formula. METHOD Change in 10-year risk for CHD was compared between treatment groups in 1125 patients followed for 18 months or until treatment discontinuation in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial. RESULTS The covariate-adjusted mean change in 10-year CHD risk differed significantly between treatments. Olanzapine was associated with a 0.5% (SE 0.3) increase and quetiapine, a 0.3% (SE 0.3) increase; whereas risk decreased in patients treated with perphenazine, -0.5% (SE 0.3), risperidone, -0.6% (SE 0.3), and ziprasidone -0.6% (SE 0.4). The difference in 10-year CHD risk between olanzapine and risperidone was statistically significant (p=0.004). Differences in estimated 10-year CHD risk between drugs were most marked in the tertile of subjects with a baseline CHD risk of at least 10%. Among individual CHD risk factors used in the Framingham formula, only total and HDL cholesterol levels differed between treatments. CONCLUSIONS These results indicate that the impact on 10-year CHD risk differs significantly between antipsychotic agents, with olanzapine producing the largest elevation in CHD risk of the agents studied in CATIE.

Atypical antipsychotics and glucose dysregulation: a systematic review

Atypical antipsychotics (AAP) have been widely used for the management of patients with schizophrenia and other psychotic disorders since they were introduced during the past decade. AAP, as a class, have demonstrated a significant advantage over conventional antipsychotics in clinical efficacy and lower incidence of extrapyramidal symptoms (EPS) and tardive dyskinesia (TD). However, there have been numerous case reports, retrospective studies, epidemiological and clinical data suggesting that certain AAP may be associated with a greater risk of metabolic abnormalities than others, including weight gain, hyperlipidemia, and new-onset type 2 diabetes mellitus (DM) or diabetic ketoacidosis (DKA). In this article, we review and evaluate recent findings addressing the issue of glucose dysregulation associated with AAP therapy along with the recommendations with a recent consensus conference on this issue. Rational patient monitoring guidelines are also elucidated, particularly for high-risk populations that need more intensive scrutiny during treatment of AAP.