Sibutramine May Help Control Weight Gain Associated With Olanzapine Treatment
Sibutramine may be effective in controlling the weight gain associated with olanzapine, according to the results of a randomized trial published in the May issue of the American Journal of Psychiatry.
"Weight gain is commonly observed with olanzapine treatment and can increase the risk for obesity, cardiovascular disease, hypertension, and diabetes mellitus," write David C. Henderson, MD, from the Massachusetts General Hospital in Boston, and colleagues. "Sibutramine hydrochloride, a weight loss agent affecting both serotonin and norepinephrine reuptake, was introduced into the U.S. Market in 1997. The hypophagic effect of sibutramine is thought to be mediated, in part, through activation of the serotonin 5-HT2C receptor."
In this 12-week, double-blind trial, 37 persons were randomized to receive placebo or sibutramine, up to 15 mg per day. All study subjects had schizophrenia or schizoaffective disorder meeting criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision, treated with a stable dose of olanzapine for at least four months, and had a body mass index (BMI) of at least 30 kg/m2 or at least 27 kg/m2 plus at least one cardiovascular risk factor. During the first eight weeks, all study subjects participated in weekly group sessions dealing with nutrition and behavior modification.
At baseline, both groups were similar in age, sex, education, ethnicity, diagnosis, weight, BMI, and blood pressure. Although the difference between groups was not significant at weeks 4 and 8, by week 12, the sibutramine group fared significantly better than the placebo group in terms of reductions in weight (mean, 8.3 ± 2.4 lb vs 1.8 ± 1.6 lb), waist circumference, BMI, and hemoglobin A1C. These reductions were not sustained at three months after study completion; the study subjects who had received sibutramine gained weight and returned to near their baseline weight.
Most adverse effects were similar in both groups. However, the sibutramine group had a mean increase in systolic blood pressure of 2.1 ± 8.5 mm Hg, and anticholinergic adverse effects and sleep disturbances were at least twice as frequent in the sibutramine group.
"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," the authors write. "As expected, the benefits of sibutramine do not continue after discontinuation of the drug."
Study limitations may include lack of generalizability to other populations, particularly in the absence of a nutritional counseling program, such as patients taking serotonergic agents, selective serotonin reuptake inhibitors, or other medications that cause significant weight gain (e.g., clozapine). Other limitations include short duration and inability to determine whether the observed weight reductions could be maintained with long-term use of sibutramine.
"Sibutramine treatment improved several health status markers that are predictive of cardiovascular disease," the authors conclude. "This degree of weight loss in obese schizophrenia patients could, if sustained, substantially reduce morbidity and mortality.... "Additional studies are necessary to establish the long-term weight loss effectiveness and safety in schizophrenia patients whose weight gain from antipsychotic medications jeopardizes their cardiovascular health."
The National Alliance for Research on Schizophrenia and Depression and an investigator-initiated independent research grant from Eli Lilly and Co., maker of Zyprexa, supported this study. Knoll Pharmaceuticals (Abbott Laboratories) provided the study drug and placebo.
Am J Psychiatry. 2005;162:954-962
Learning Objectives for This Educational Activity
Upon completion of this activity, participants will be able to:
"Weight gain is commonly observed with olanzapine treatment and can increase the risk for obesity, cardiovascular disease, hypertension, and diabetes mellitus," write David C. Henderson, MD, from the Massachusetts General Hospital in Boston, and colleagues. "Sibutramine hydrochloride, a weight loss agent affecting both serotonin and norepinephrine reuptake, was introduced into the U.S. Market in 1997. The hypophagic effect of sibutramine is thought to be mediated, in part, through activation of the serotonin 5-HT2C receptor."
In this 12-week, double-blind trial, 37 persons were randomized to receive placebo or sibutramine, up to 15 mg per day. All study subjects had schizophrenia or schizoaffective disorder meeting criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision, treated with a stable dose of olanzapine for at least four months, and had a body mass index (BMI) of at least 30 kg/m2 or at least 27 kg/m2 plus at least one cardiovascular risk factor. During the first eight weeks, all study subjects participated in weekly group sessions dealing with nutrition and behavior modification.
At baseline, both groups were similar in age, sex, education, ethnicity, diagnosis, weight, BMI, and blood pressure. Although the difference between groups was not significant at weeks 4 and 8, by week 12, the sibutramine group fared significantly better than the placebo group in terms of reductions in weight (mean, 8.3 ± 2.4 lb vs 1.8 ± 1.6 lb), waist circumference, BMI, and hemoglobin A1C. These reductions were not sustained at three months after study completion; the study subjects who had received sibutramine gained weight and returned to near their baseline weight.
Most adverse effects were similar in both groups. However, the sibutramine group had a mean increase in systolic blood pressure of 2.1 ± 8.5 mm Hg, and anticholinergic adverse effects and sleep disturbances were at least twice as frequent in the sibutramine group.
"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," the authors write. "As expected, the benefits of sibutramine do not continue after discontinuation of the drug."
Study limitations may include lack of generalizability to other populations, particularly in the absence of a nutritional counseling program, such as patients taking serotonergic agents, selective serotonin reuptake inhibitors, or other medications that cause significant weight gain (e.g., clozapine). Other limitations include short duration and inability to determine whether the observed weight reductions could be maintained with long-term use of sibutramine.
"Sibutramine treatment improved several health status markers that are predictive of cardiovascular disease," the authors conclude. "This degree of weight loss in obese schizophrenia patients could, if sustained, substantially reduce morbidity and mortality.... "Additional studies are necessary to establish the long-term weight loss effectiveness and safety in schizophrenia patients whose weight gain from antipsychotic medications jeopardizes their cardiovascular health."
The National Alliance for Research on Schizophrenia and Depression and an investigator-initiated independent research grant from Eli Lilly and Co., maker of Zyprexa, supported this study. Knoll Pharmaceuticals (Abbott Laboratories) provided the study drug and placebo.
Am J Psychiatry. 2005;162:954-962
Learning Objectives for This Educational Activity
Upon completion of this activity, participants will be able to:
- Describe the relationship between antipsychotic agents and weight gain.
- Identify outcomes improved with the use of sibutramine in the management of olanzapine-associated weight gain.
Clinical Context
Although all antipsychotic agents may produce weight gain, newer unconventional agents may increase the risk of weight gain to a greater extent than do older drugs. Patients who are underweight at the initiation of therapy appear to carry the biggest risk of weight gain related to antipsychotic therapy, but patients who are overweight at baseline are most likely to experience the consequences of antipsychotic-associated weight gain, including diabetes.
Because improved response to antipsychotics has been associated with higher amounts of weight gain, treatment discontinuation or dosage reduction is less attractive for many patients and physicians who can witness the positive psychotropic effects of the medication. The authors of the current study examined the efficacy of sibutramine, which can reduce weight through activation of central serotonin receptors, in the management of weight gain associated with the newer antipsychotic olanzapine.
Study Highlights
- Patients who were receiving olanzapine for schizophrenia or schizoaffective disorder at stable doses for at least 4 months were eligible for study participation. All study subjects had experienced weight gain associated with olanzapine and had a BMI of at least 30 kg/m2 or 27 kg/m2 plus 1 or more cardiovascular risk factors. Patients with significant medical problems or substance abuse were excluded from study participation.
- The study intervention consisted of two to three 5-mg sibutramine tablets daily or matching placebo. The research was double-blinded. All participants attended 8 weekly sessions focused on weight education.
- The main study outcome was weight loss during the 12-week treatment period. Subjects were also followed for BMI, waist-to-hip ratio, and percentage of body fat, which was assessed using skinfold measurements. Psychiatric disease activity was monitored, as were lipid profiles and glycosylated hemoglobin.
- 37 study subjects participated in the trial. Baseline characteristics were similar between the sibutramine and placebo groups. The mean ages of participants were 43.2 and 40.7 years, respectively, and the mean baseline BMIs were 34.3 and 38.4 kg/m2, respectively. Estimated body fat was 38.4% in the sibutramine group and 34% in the placebo group.
- Both groups exhibited nonsignificant decreases in total calories consumed during the study period. Intake of polyunsaturated fats was lower in the sibutramine group at 12 weeks compared with baseline intake.
- There was no significant difference in weight loss between the 2 groups at weeks 4 and 8, but at week 12 a growing difference became statistically relevant. The average weight loss was 2 pounds in the placebo group at 12 weeks compared with 8 pounds in the sibutramine group.
- Both BMI and waist-to-hip ratio were improved in the sibutramine group compared with the placebo group at 12 weeks. However, the percentage of body fat did not differ between groups.
- Glycosylated hemoglobin values decreased from 5.6% at baseline to 5.3% at 12 weeks in the sibutramine group; the respective values for the placebo cohort were 5.7% and 6.0%. The difference in these values at 12 weeks between groups was statistically significant.
- Lipid profiles were not significantly different between groups at 12 weeks. Compared with baseline values, levels of low-density lipoprotein cholesterol decreased in the sibutramine group, but triglyceride levels increased.
- Sibutramine was associated with a mean increase in systolic blood pressure of 2.1 mm Hg. Anticholinergic adverse effects were also more common with sibutramine. Rates of study discontinuation were similar between the 2 treatment groups.
- In a follow-up of 22 study subjects 3 months after study termination, the benefits of sibutramine were no longer evident; patients from the 2 treatment groups exhibited similar weights, BMIs, and waist-to-hip ratios.
Pearls for Practice
- Newer antipsychotic agents may be more likely to increase patients' weight than are older agents, particularly for underweight patients and patients whose psychiatric symptoms respond well to treatment. Patients who are overweight at baseline, however, are more likely to experience negative health consequences as a result of antipsychotic-associated weight gain.
- Sibutramine can reduce weight, BMI, and waist-to-hip ratio after 12 weeks in patients with weight gain related to olanzapine. However, these benefits do not seem to persist after cessation of treatment with sibutramine.
Saludos Cordiales
Dr. José Manuel Ferrer Guerra
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