Results of a 2-year lifestyle intervention for type 2 diabetes: the Reach Ahead for Lifestyle and Health-Diabetes randomized controlled trial.

OBJECTIVE: The Reach Ahead for Lifestyle and Health (REAL HEALTH)-Diabetes study assessed the comparative effectiveness of two Look AHEAD (Action for Health in Diabetes)-adapted lifestyle intervention (LI) arms targeting weight loss in type 2 diabetes compared with medical nutrition therapy (MNT) referral. At 1 year, LI had greater weight loss than MNT. This study reports outcomes at 24 (end of LI) and 36 months. METHODS: Participants (N = 211) with type 2 diabetes and BMI > 25 kg/m2 were randomly assigned to in-person LI, telephone conference call LI, or MNT. The primary outcome was percentage weight change. Secondary outcomes included 5% and 10% weight loss, glycated hemoglobin (HbA1c), and patient-reported outcomes. RESULTS: Participants were 61.7 (SD 10.2) years old; 55% were female; 77% were non-Hispanic White; and had mean (SD) weight of 98 (18.9) kg and mean (SD) HbA1c of 7.7% (1.2%). Mean (SD) weight change at 24 and 36 months was -4.4% (5.9%) and -4.4% (5.4%) in in-person LI, -4.0% (5.8%) and -5.3% (6.4%) in telephone LI, and -3.1% (5.2%) and -5.8% (7.1%) in MNT, with no statistically significant difference in weight or HbA1c at 24 and 36 months. Compared with MNT, LI arms had favorable changes in patient-reported outcomes related to learned dietary skills. CONCLUSIONS: There were no differences in weight outcomes among LI participants compared with referral to MNT at the end of intervention or 1 year after its conclusion.

Clozapine, Diabetes Mellitus, Cardiovascular Risk and Mortality: Results of a 21-Year Naturalistic Study in Patients with Schizophrenia and Schizoaffective Disorder.

The goal of this 21-year naturalistic study of clozapine-treated patients was to examine the cardiovascular risk factors following clozapine initiation and resultant mortality estimates from cardiovascular disease. Data were collected from January 1992 to February 2012 medical records from clozapine-treated patients with schizophrenia or schizoaffective disorder. Demographics, clozapine dosage and laboratory results were extracted at 12-month intervals. At clozapine initiation, the mean age of the 96 patients was 36.4 years±7.6 years; n=27 (28%) were women. The mean duration of clozapine use was 13 years. The Kaplan-Meier estimate for 21-year cardiovascular events was 29%, while the Kaplan-Meier estimate for 21-year mortality from cardiovascular disease was 10%. The mean cardiovascular risk increased during the first ten years (p<.01), while a slight decrease occurred beyond ten years (p<.01). Patients involved in cardiometabolic research showed a greater decrease in cardiovascular risk factors over 21 years (p=.05). The Kaplan-Meier estimate for 21-year all-cause mortality was 22%. Forty-one patients were diagnosed with diabetes (42.7%), compared to a nationwide prevalence of 13.7% in a similar age group. These results support the hypothesis that clozapine-treated patients are at risk for cardiovascular events and death secondary to an increased risk of medical disorders. Interventions that target weight loss, smoking cessation, and lipid profile improvement may alleviate the increased risk of cardiovascular mortality.

Pathophysiological mechanisms of increased cardiometabolic risk in people with schizophrenia and other severe mental illnesses.

Patients with schizophrenia have increased mortality and morbidity compared with the general population. These patients have a 20-year shorter lifespan than peers without schizophrenia, mainly due to premature cardiovascular disease, suicide, and cancer. Patients with severe mental illness are at increased risk for cardiovascular disease related to increased incidence of diabetes, hypertension, smoking, poor diet, obesity, dyslipidaemia, metabolic syndrome, low physical activity, and side-effects of antipsychotic drugs. Some second-generation antipsychotics (eg, clozapine, olanzapine, quetiapine, and risperidone) are associated with an increased risk of weight gain and obesity, impaired glucose tolerance and new-onset diabetes, hyperlipidaemia, and cardiovascular disease. The mechanisms by which schizophrenia and patients with severe mental illness are susceptible to cardiometabolic disorders are complex and include lifestyle risks and direct and indirect effects of antipsychotic drugs. An understanding of these risks might lead to effective interventions for prevention and treatment of cardiometabolic disorders in schizophrenia and severe mental illness.

A randomized placebo-controlled pilot study of pravastatin as an adjunctive therapy in schizophrenia patients: effect on inflammation, psychopathology, cognition and lipid metabolism.

OBJECTIVE: The aim of this study was to investigate the role of pravastatin, as an adjunctive therapy, on inflammatory markers, lipid and glucose metabolism, psychopathology, and cognition in subjects with schizophrenia and schizoaffective disorder. METHODS: Schizophrenia or schizoaffective subjects (N=60) were randomized to receive either a 12-week supply of pravastatin 40 mg/day or placebo treatment. Anthropometric measures, lipids and glucose metabolism, inflammatory markers, psychopathology and cognitive performance were assessed at baseline, 6 weeks and 12 weeks. RESULTS: Pravastatin use was associated with a significant decrease in total cholesterol, low density lipoprotein (LDL) cholesterol and LDL particle number levels, but was not associated with any significant changes in cognition or psychopathology in the participants, except a significant decrease in the Positive and Negative Syndrome Scale (PANSS) positive symptom score from baseline to week 6. However, this decrease failed to remain significant at 12 weeks. Interestingly, triglycerides, LDL-cholesterol, total cholesterol, LDL particle number, small LDL particle number, large very low density lipoprotein (VLDL) particle number and C-reactive protein (CRP) followed a similar pattern at 6 and 12 weeks as psychopathology. CONCLUSIONS: These results suggest that a randomized trial with a larger sample size and a higher dosage of pravastatin would be helpful in further evaluating the anti-inflammatory properties of pravastatin, its association with improvements in cognitive symptoms, and its potential to reduce positive and negative symptoms associated with schizophrenia or schizoaffective disorders.

An exploratory study examining lipid-lowering medications in reducing fasting serum lipids in schizophrenia patients treated with atypical antipsychotics.

BACKGROUND: We present a retrospective study examining response to treatment with fibrates or statins in schizophrenia patients. METHODS: We identified the patient population using the Research Patient Data Registry. Demographic data, total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and non-HDL cholesterol (non-HDL-C) levels were obtained before initiation of treatment with lipid-lowering medication (LLM) and after LLM treatment was initiated (N = 183). RESULTS: Treatment with LLMs resulted in a statistically significant decrease in total cholesterol, triglycerides, LDL-C, and non-HDL-C. An independent-samples t test comparing the statin treatment-alone group with the fibrate treatment-alone group showed a significant reduction in triglyceride levels from baseline to 1-year follow-up in the fibrate treatment-alone group. CONCLUSIONS: The results of this study indicate that schizophrenia patients respond to LLMs in a manner consistent with the general population. Future studies would benefit from a larger sample, as well as comparisons between more specific treatment groups, such as those defined by type of statin or fibrate, to observe differential effects on specific markers of dyslipidemia in this population.

Placebo-controlled pilot study of ramelteon for adiposity and lipids in patients with schizophrenia.

OBJECTIVE: Few interventions have been successful to prevent or reverse the medical complications associated with antipsychotic agents in the schizophrenia population. In particular, no single agent can correct multiple metabolic abnormalities such as insulin resistance, hyperlipidemia, inflammation, obesity, and fat distribution. We now report a randomized placebo-controlled pilot study to examine the effects of ramelteon on obesity and metabolic disturbances among subjects with schizophrenia. METHODS: A double-blind, placebo-controlled, 8-week pilot trial was conducted, adding ramelteon 8 mg/d to stable outpatients with schizophrenia. Vital signs and anthropometric measurements, including height, weight, waist circumference, and body fat were assessed, and laboratory assays were tracked to monitor changes in metabolic markers. RESULTS: Twenty-five subjects were randomly assigned to treatment with study drug or placebo, and 20 subjects were included in the final analysis. Ramelteon did not improve anthropometric measurements, glucose metabolism, and inflammatory markers. There was, however, a significant decrease in total cholesterol and ratio of cholesterol to high-density lipoprotein in the ramelteon group. Although the standard anthropometric measures did not show significant change, the dual-energy x-ray absorptiometry scan showed a trend toward reduction in fat in the abdominal and trunk areas with a moderate effect size. CONCLUSIONS: Although ramelteon decreased cholesterol, treatment may have to be longer than 8 weeks and with a higher dose for maximal effect of ramelteon for body fat and lipid changes. Future studies are needed for patients with schizophrenia with a larger sample size to fully understand ramelteon's effects on abdominal adiposity and lipids.

Effects of modafinil on weight, glucose and lipid metabolism in clozapine-treated patients with schizophrenia.

RATIONALE: Sedation is a common side effect of clozapine treatment and may exacerbate metabolic consequences of poor diet and exercise habits that are common in patients with schizophrenia. Modafinil has been proposed as a treatment for clozapine-induced sedation and metabolic abnormalities. OBJECTIVE: To estimate the effect sizes and person-to-person variation in anthropometric measures, glucose and lipid metabolism, and diet on modafinil treatment for future randomized control trials. METHODS: A double-blind, placebo-controlled, flexible-dosed 8-week pilot trial was conducted, adding modafinil up to 300 mg/day to stabilized schizophrenia outpatients receiving clozapine. Blood pressure, weight, BMI, laboratory assays, and dietary intake were tracked to monitor changes in metabolic markers. RESULTS: Thirty-five participants were randomly assigned to treatment with study drug or placebo and were included in the analysis. Modafinil did not improve blood pressure, weight, BMI, glucose or lipid metabolism compared to placebo. Modafinil was well tolerated and did not worsen psychosis. CONCLUSIONS: Results of this pilot trial do not support routine use of modafinil to counteract increased weight and metabolic diseases in patients taking clozapine. However, the effects of modafinil on weight and insulin regulation warrant further investigation with effect sizes of 0.4 to 0.6.

No effect of single-dose intranasal insulin treatment on verbal memory and sustained attention in patients with schizophrenia.

BACKGROUND: Impairments in verbal memory and attention are among the most severe and disabling cognitive deficits in patients with schizophrenia. Whereas efficacy for cognition has not yet been established for any pharmacologic strategy in schizophrenia, an accumulating body of evidence suggests a possible beneficial role of insulin. METHODS: We conducted a double-blind, placebo-controlled trial to examine the effect of single-dose intranasal insulin treatment on cognition in nondiabetic patients with schizophrenia. After fasting for 12 hours, subjects received either 40 IU regular human insulin or placebo administered by intranasal pump. The Hopkins Verbal Learning Test and the Continuous Performance Test-Identical Pairs were administered before and 30 minutes after intranasal treatment. RESULTS: Thirty patients were enrolled and completed the study. The 2 treatment groups (insulin vs placebo, n = 15 in each group) did not differ on any demographic or general clinical variable (P > 0.40). There was no significant difference between the 2 treatment groups in change on Hopkins Verbal Learning Test immediate recall total score and delayed recall score, or on CPT d', hits rate, reaction time of hits, or false-alarm rate (P > 0.1). CONCLUSIONS: Results of the present study suggest that single-dose intranasal insulin treatment does not have a large-enough effect on verbal memory or sustained attention to be detected by a sample of this size in patients with schizophrenia but was safe and well tolerated. Longitudinal studies to explore cognitive benefits of repeated dosing of intranasal insulin treatment are needed.

Dietary saturated fat intake and glucose metabolism impairments in nondiabetic, nonobese patients with schizophrenia on clozapine or risperidone.

BACKGROUND: High dietary saturated fat (SF) intake is strongly linked to metabolic disturbances. The goal of this study was to understand the relationship between clozapine and risperidone with glucose and lipid metabolism and dietary fat intake in patients with schizophrenia. METHODS: Thirty-one clozapine-treated patients and 15 risperidone-treated patients were assessed using a 4-day dietary record, an IV glucose tolerance test, and lipid profiles. RESULTS: Clozapine-treated patients consumed a significantly higher percentage of SF than did risperidone-treated patients (13.7% +/- 3.4% vs 10.6% +/- 3.0 % of total energy; P = .007). Compared with the risperidone group, the clozapine group also had a significantly higher percentage of total fat in their diet (36% +/- 6.7% vs 30.9% +/- 5.7% of total energy; P = .007). Similarly, the clozapine group had a significant impairment in insulin sensitivity index (SI), glucose effectiveness (SG), and disposition index (DI) compared with the risperidone group (P < .05). Pearson correlation analysis of both groups showed that dietary SF was significantly correlated with impairment in glucose homeostasis (SG: r = -0.43; P = .004; DI: r = -0.35; P = .02). CONCLUSION: Abnormal glucose homeostasis in atypical clozapine-treated patients with schizophrenia may be associated with or aggravated by high dietary SF consumption.

Waist circumference is the best anthropometric predictor for insulin resistance in nondiabetic patients with schizophrenia treated with clozapine but not olanzapine.

OBJECTIVE: The goal of this study was to evaluate which anthropometric measure (human body measurement) best predicts insulin resistance measured by the insulin sensitivity index (SI) and the homeostasis model of assessment of insulin resistance (HOMA-IR) in nondiabetic patients with schizophrenia treated with clozapine or olanzapine. METHODS: We conducted a cross-sectional study of nondiabetic subjects with schizophrenia being treated with olanzapine or clozapine using a frequently sampled intravenous glucose tolerance test, nutritional assessment, and anthropometric measures, to assess the relationship between anthropometric measures and insulin resistance. RESULTS: No difference was found between the groups treated with clozapine and olanzapine in age, gender, race, body mass index (BMI), waist circumference (WC), lipid levels, HOMA-IR, or SI. The disposition index (SI x the acute insulin response to glucose), which measures how the body compensates for insulin resistance to maintain a normal glucose level, was significantly lower in the group treated with clozapine than in the group treated with olanzapine (1067+/-1390 vs. 2521+/-2805; P=0.013), suggesting that the subjects treated with clozapine had a reduced compensatory response to IR compared with the subjects treated with olanzapine. In the clozapine group, both higher WC and BMI were significantly associated with elevated HOMA-IR and lower SI; however, WC was a stronger correlate of IR than BMI, as measured by SI (-0.50 vs. -0.40). In the olanzapine group, neither WC nor BMI was significantly associated with any measure of glucose metabolism. CONCLUSIONS: In this study, WC was the single best anthropometric surrogate for predicting IR in patients treated with clozapine but not olanzapine. The results suggest that WC may be a valuable screening tool for predicting IR in patients with schizophrenia being treated with clozapine who are at relatively higher risk of developing the metabolic syndrome, type 2 diabetes mellitus, and associated cardiovascular disease.

Aripiprazole added to overweight and obese olanzapine-treated schizophrenia patients.

Olanzapine treatment has been associated with clinically meaningful weight increases, hypertriglyceridemia, insulin resistance, and diabetes mellitus. There are few options for olanzapine responders who fail other antipsychotic agents. Aripiprazole is a potent (high-affinity) partial agonist at D2 and 5-HT1A receptors and a potent antagonist at 5-HT2A receptor and is associated with less weight gain than olanzapine. We report the results of a 10-week placebo-controlled, double-blind crossover study that examined 15 mg/d aripiprazole's effects on weight, lipids, glucose metabolism, and psychopathology in overweight and obese schizophrenia and schizoaffective disorder subjects treated with a stable dose of olanzapine. During the 4 weeks of aripiprazole treatment, there were significant decreases in weight (P = 0.003) and body mass index (P = 0.004) compared with placebo. Total serum cholesterol (P = 0.208), high-density lipoprotein cholesterol (HDL-C; P = 0.99), HDL-2 (P = 0.08), HDL-3 (P = 0.495), and low-density lipoprotein cholesterol (P = 0.665) did not change significantly comparing aripiprazole treatment to placebo treatment. However, total serum triglycerides (P = 0.001), total very low-density lipoprotein cholesterol (VLDL-C; P = 0.01), and VLDL-1C and VLDL-2C (P = 0.012) decreased significantly during the aripiprazole treatment phase. The VLDL-3C tended lower during aripiprazole, but the decrease was not significant (P = 0.062). There was a decrease in C-reactive protein comparing aripiprazole treatment to placebo, although it did not reach significance (P = 0.087). The addition of aripiprazole to a stable dose of olanzapine was well tolerated and resulted in significant improvements on several outcome measures that predict risk for medical morbidity.

Ziprasidone as an adjuvant for clozapine- or olanzapine-associated medical morbidity in chronic schizophrenia.

OBJECTIVE: This study sought to examine the effect of ziprasidone on olanzapine or clozapine-associated medical morbidity such as insulin resistance, diabetes mellitus (DM) and impaired fasting glucose, obesity, and hyperlipidemia in patients with schizophrenia or schizoaffective disorder. METHOD: This was a 6-week, open label trial of ziprasidone 160 mg/day added to a stable dose of olanzapine or clozapine in 21 schizophrenia or schizoaffective patients with DM, impaired fasting glucose, or insulin resistance. RESULTS: Ten olanzapine-treated subjects and 11 clozapine-treated subjects were enrolled in the study. There were no significant differences between the two groups at baseline for age, gender, education, ethnicity, BMI, cholesterol levels, or fasting glucose. At week 6, there were no significant changes in weight, BMI, cholesterol levels, or fasting glucose. There was no significant difference in psychotic, negative, or depressive symptoms. QTc significantly increased at week 2 but not at week 6. CONCLUSIONS: The addition of 160 mg/day of ziprasidone was well tolerated but did not produce significant improvement in fasting glucose, insulin resistance, hyperlipidemia or lead to weight loss in olanzapine- or clozapine-treated subjects with schizophrenia or schizoaffective disorder.

Elevated hemoglobin A1c as a possible indicator of diabetes mellitus and diabetic ketoacidosis in schizophrenia patients receiving atypical antipsychotics.

OBJECTIVE: We conducted a retrospective epidemiologic study assessing the incidence of new-onset diabetes mellitus presenting as diabetic ketoacidosis in patients with schizophrenic disorders (ICD-9 295.0-295.9; referred to as "schizophrenia patients" hereafter) treated with atypical antipsychotic agents. METHOD: The identification of patients and the review of records were achieved by using an electronic database linking administrative and clinical laboratory data between January 1, 1995, and December 31, 2001. The main outcome measure was the incidence of diabetic ketoacidosis or hyperosmolar hyperglycemic syndrome per 10,000 patient years in patients with new-onset or existing diabetes mellitus. We also determined the incidence of diabetic ketoacidosis associated with the use of atypical antipsychotics and calculated the mean hemoglobin A1c (HbA1c) level for all patients. RESULTS: During the 7-year period, 18.4% of schizophrenia patients were diagnosed with diabetes mellitus, compared with 6.6% in the general hospital population (p < .001). After chart review, 23 schizophrenia patients were identified with diabetic ketoacidosis: 11 had diabetes presenting as diabetic ketoacidosis, 8 had diabetic ketoacidosis with known diabetes mellitus, 2 had new-onset diabetes mellitus-hyperosmolar hyperglycemic syndrome, and 2 had hyperosmolar hyperglycemic syndrome with known diabetes mellitus. The incidence of diabetes presenting as diabetic ketoacidosis in schizophrenia patients was more than 10-fold higher than that reported in the general population: 14.93 per 10,000 patient years in schizophrenia patients versus 1.4 per 10,000 patient years in the general population (p < .000001) and versus the 1.98 per 10,000 patient years in the general hospital population (p < .000001). The incidence of diabetic ketoacidosis for each of atypical antipsychotic drugs over the 7-year period was as follows: clozapine, 2.2%; olanzapine, 0.8%; and risperidone, 0.2% (no incidence with ziprasidone or quetiapine). Of the 11 patients with diabetes presenting as diabetic ketoacidosis, the mean HbA1c level at admission was 13.3% +/- 1.9% (10.4%-16.9%). CONCLUSIONS: The incidence of diabetes mellitus presenting as diabetic ketoacidosis in schizophrenia patients is higher than in the general hospital population and differs across atypical antipsychotic agents. Elevated HgbA1c levels observed suggests that patients had undiagnosed diabetes mellitus for at least several weeks before the diabetic ketoacidosis episode.

Higher fasting serum insulin is associated with increased resting energy expenditure in nondiabetic schizophrenia patients.

BACKGROUND: Insulin has emerged as an important determinant of food intake, energy expenditure, and weight control. This study examined the relationship between fasting serum insulin level and resting energy expenditure (REE) in a cross-sectional sample of nondiabetic schizophrenia patients. METHODS: Subjects were recruited from an urban community mental health clinic. Each subject underwent a series of anthropometric measures and an indirect calorimetry measure. A fasting blood sample was taken for plasma glucose, serum insulin, and lipid profile. RESULTS: Seventy-one subjects (54 male, 17 female) were included in the study. There was a significant positive relationship between REE and fasting serum insulin level (r = .39, p = .001). Stepwise multiple regression analysis was performed with various characteristics such as age, race, antipsychotic agent used, fat-free mass, BMI, waist circumference, waist-hip ratio, physical activity level, and fasting serum insulin as candidate predictors for REE. Only fat-free mass and insulin were able to enter into the regression model, which indicates that higher fat-free mass and higher fasting serum insulin level predict increased REE. CONCLUSIONS: A higher fasting serum insulin level is associated with an increased REE, which may prevent further weight gain in nondiabetic patients with schizophrenia.

Glucose metabolism in patients with schizophrenia treated with olanzapine or quetiapine: a frequently sampled intravenous glucose tolerance test and minimal model analysis.

OBJECTIVE: Clozapine and olanzapine treatment has been associated with insulin resistance in non-obese schizophrenia patients. Much less is known regarding other agents such as quetiapine. The objective of this study was to compare matched olanzapine- and quetiapine-treated schizophrenia patients and normal controls on measures of glucose metabolism. METHOD: A cross-sectional comparison of quetiapine-treated and olanzapine-treated non-obese (body mass index < 30.0 kg/m2) schizophrenia subjects (DSM-IV) with matched normal controls using a frequently sampled intravenous glucose tolerance test and nutritional assessment was conducted from April 2002 to October 2004. Data from 24 subjects were included in the analysis (7 quetiapine, 8 olanzapine, 9 normal controls). RESULTS: There was a significant difference among groups for fasting baseline plasma glucose concentrations (p = .02), with olanzapine greater than normal controls (p = .01). The insulin sensitivity index (SI) differed significantly among groups (p = .039); olanzapine subjects exhibited significant insulin resistance compared to normal controls (p = .01), but there was no significant difference for quetiapine versus olanzapine (p = .1) or quetiapine versus normal controls (p = .40). SI inversely correlated with quetiapine dose (p = .0001) and waist circumference (p = .03) in quetiapine-treated subjects. Insulin resistance calculated by the homeostasis model assessment of insulin resistance (HOMA-IR) also differed significantly among groups (p = .03). The olanzapine group had a higher HOMA-IR level than normal controls (p = .01). There was a significant difference in glucose effectiveness (SG) among the groups (p = .049). SG was lower in the olanzapine group than in the quetiapine group (p = .03) and in the olanzapine group compared to normal controls (p = .049). CONCLUSIONS: Our findings are consistent with our previous report that nonobese olanzapine-treated subjects showed insulin resistance, measured by both HOMA-IR and SI, and reduction in SG. Studies that include larger samples, unmedicated patients, and varying durations of antipsychotic exposure are necessary to confirm these results.

Adrenocortical carcinoma: contrast washout characteristics on CT.

OBJECTIVE: The purpose of this study was to characterize pathologically proven adrenocortical carcinoma by examination of washout attenuation characteristics on contrast-enhanced CT images. CONCLUSION: Adrenocortical carcinoma has relative contrast retention on delayed contrast-enhanced CT. All tumors in this series had a relative percentage washout less than 40%, a finding consistent with malignant disease.

Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular risks and mortality: results of a 10-year naturalistic study.

OBJECTIVE: The goal of this 10-year naturalistic study was to examine, in clozapine-treated patients, the change in cardiovascular risk factors following clozapine initiation and the mortality estimates from cardiovascular disease. METHOD: Data were collected from medical records from January 1992 to December 2003 and included age, gender, race, diagnosis, family history of diabetes, and age at clozapine initiation for clozapine-treated patients with schizophrenia or schizoaffective disorder (DSM-IV criteria). Clozapine dosage and laboratory results were recorded at 12-month intervals. RESULTS: At the time of clozapine initiation, the mean +/-?SD age of the 96 patients studied was 36.5 +/- 7.9 years; 28% (N = 27) were women. The Kaplan-Meier estimate for 10-year mortality from cardiovascular disease was 9%. African American and Hispanic American patients exhibited elevated risk of cardiovascular disease-related mortality (odds ratio [OR] = 7.2, p = .09; OR = 11.3, p = .04, respectively) compared to white patients. Body mass index (BMI) significantly increased the odds ratio of mortality (OR = 1.2, p < .01). The Kaplan-Meier estimate for new-onset diabetes mellitus was approximately 43%, and Hispanic American (OR = 4.3, p = .027) and African American (OR = 11.5, p = .0001) patients showed elevated risks of developing diabetes mellitus compared to white patients. Additionally, BMI (OR = 1.11, p = .0006), total cholesterol level (OR = 1.006, p = .04), and serum triglyceride level (OR = 1.002, p = .04) modestly increased the odds ratio for the development of diabetes mellitus. CONCLUSIONS: These results support the hypothesis that clozapine-treated patients appear to be at risk for death from cardiovascular disease secondary to clozapine-associated medical disorders such as obesity, diabetes, hypertension, and hyperlipidemia.

A double-blind, placebo-controlled trial of sibutramine for olanzapine-associated weight gain.

OBJECTIVE: Weight gain is commonly observed with olanzapine treatment and can increase the risk for obesity, cardiovascular disease, hypertension, and diabetes mellitus. This study examined the effectiveness of sibutramine, an approved weight loss agent, in overweight and obese subjects taking olanzapine for schizophrenia or schizoaffective disorder. METHOD: Each subject had a DSM-IV diagnosis of schizophrenia or schizoaffective disorder, had been taking a stable dose of olanzapine for at least 4 months, and had a body mass index of >/=30 kg/m(2) or >/=27 kg/m(2) plus at least one cardiovascular risk factor. In a 12-week double-blind, randomized, placebo-controlled study, 37 subjects received placebo or sibutramine (up to 15 mg/day). For the first 8 weeks all subjects participated in weekly group sessions focused on nutrition and behavioral modification. RESULTS: The sibutramine and placebo groups had no significant baseline differences on age, gender, education, ethnicity, diagnosis, weight, body mass index, and blood pressure. At week 12 the sibutramine group had significantly greater losses than the placebo group in weight (mean=8.3 lb, SD=2.4, versus mean=1.8 lb, SD=1.6), waist circumference, body mass index, and hemoglobin A(1c). There were no significant differences on most side effects, although the sibutramine group exhibited a mean increase in systolic blood pressure of 2.1 mm Hg (SD=8.5), and anticholinergic side effects and sleep disturbances were at least twice as common in the sibutramine group. CONCLUSIONS: Sibutramine was an effective and well-tolerated adjunct to behavior modification for weight loss in patients with schizophrenia and schizoaffective disorder being treated with olanzapine.