Appropriate intervention strategies for weight gain induced by olanzapine: A randomized controlled study
ABSTRACT Weight gain induced by antipsychotics is the second most frequently given reason for noncompliance with pharmacologic therapy; excessive sedative effects rank first, with extrapyramidal side effects ranking third. Frequently, weight gain leads to inconsistent pharmacologic treatment; this exposes patients to the risk of recurrent symptoms. In fact, one of the key contributors to good clinical outcomes in schizophrenic patients is compliance with pharmacologic treatment. The goals of this study were to evaluate weight gain in a group of patients treated with olanzapine, diet modifications, and moderate physical activity and to compare the findings with those from a second group of patients who were given only olanzapine treatment. For 8 wk, investigators followed 2 groups of patients suffering from schizophrenia and hypomania in bipolar disorder, according to the nosographic criteria of The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). The first group (A) of 18 patients (9 female, 9 male) affected by manic episodes in bipolar disorder received olanzapine (10-20 mg/d), jogged lightly for 30 min 3 times a week, and complied with a diet that consisted of 500 kcal/d less than usual. The second group (B) of 10 patients (4 female, 6 male) with schizophrenia received only olanzapine (10-20 mg/d). All patients from both groups were weighed at the beginning of the observation period and weekly thereafter for 2 mo. After 2 mo of observation, group A showed a mean weight gain of 1.47 kg, whereas group B exhibited a mean weight gain of 3.5 kg; the difference between the 2 groups was almost 2 kg (P<.005). Group A showed a statistically significant reduction in weight gain compared with group B, clearly demonstrating the effectiveness of moderate physical activity and diet therapy in reducing weight gain in atypical antipsychotic treatment. Therefore, patient weight and body mass index must be monitored during the first weeks of antipsychotic treatment, with the goals of avoiding significant weight gain and treatment interruption.
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ABSTRACT: There is an increase in the prevalence of obesity among people with schizophrenia thought to be due in part to the weight enhancing side-effects of medications commonly used to treat the symptoms of schizophrenia. Despite the deleterious health effects associated with obesity and its impact on quality of life and medication compliance, little is known about body composition and energy expenditure in this clinical group. The primary purpose of this thesis was to enhance understanding of body composition and energy expenditure, particularly resting energy expenditure in men with schizophrenia who take atypical antipsychotic medications. Unique to this investigation is the evaluation of clinical tools used to predict body composition and energy expenditure against reference methodologies in men with schizophrenia. Further, given the known links between obesity and physical activity, an additional but less comprehensive component of the thesis was a consideration of total and activity energy expenditure in addition to the interaction between psychiatric symptoms, side-effects of antipsychotic medications and physical activity also occurred as part of this thesis. Collectively, the goals of this thesis were addressed through a series of studies – the first two studies were related to the measurement and characteristics of body composition in men with schizophrenia, while the third and fourth studies were related to the measurement and characteristics of resting energy expenditure in men with schizophrenia. The fifth and sixth studies the utilised doubly labelled water technique to quantify activity and total energy expenditure in a small group of men with schizophrenia and explored the use of accelerometry in this cohort. The final study briefly considered the impact of psychiatric symptoms and self-reported medication side-effects on objectively measured physical activity. In the first study, thirty-one male adults previously diagnosed with schizophrenia and sixteen healthy male controls were recruited. Estimates of body composition derived from an anthropometry-based equation and from bioelectric impedance analysis (BIA) using deuterium dilution as the reference methodology to determine total body water were compared. The study also determined the validity of equations commonly used to predict body composition from BIA in the men with schizophrenia. A further aim was to determine the superiority of either BIA or body mass index (BMI) as an indicator of obesity in this cohort. The inclusion of the control group, closely matched for age, body size and body composition demonstrated that there was no difference in the ability of body composition prediction methods to distinguish between fat and fat-free mass (FFM) in controls and men with schizophrenia when both groups had similar body composition. However this study indicated that an anthropometry-based equation previously used in people with schizophrenia was a poor predictor of body composition in this cohort, as evidenced by wide limits of agreement (25%) and systematic variation of the bias. In comparison, the best predictor of percentage body fat (%BF) in this group was gained when impedance values were used to predict percentage body fat via the equation published by Lukaski et al (1986). Although percentage body fat was underpredicted using the Lukaski et al. (1986) equation, the mean magnitude was relatively small (1.3%), with the limits of agreement approximately 13%. Linear regression analysis revealed that %BF predicted using the Lukaski et al. (1986) equation explained 25% more of the variance in percentage body fat than BMI. Further, this study also indicated that BIA was more sensitive than BMI in distinguishing between overweight and obesity in this cohort of men with schizophrenia. Because of the almost exclusive use of BMI as an indicator of obesity in people with schizophrenia, the level of excess body fat may be in excess of that previously indicated. The second study extended the examination of body composition in men with schizophrenia. In this study, the thirty-one participants with schizophrenia (age, 34.2 ± 5.7 years; BMI, 30.2 ± 5.7 kg/m2) were individually matched with sedentary controls by age, weight and BMI. Deuterium dilution was used to distinguish between FFM and fat mass. The previous study had indicated that while BIA was a suitable group measure for obesity, on an individual level the technique lacked the precision required for investigating body composition in men with schizophrenia. Waist circumference was used as an indicator of body fat distribution. The findings of this study indicated that in comparison with healthy sedentary controls of similar body size and age, men with schizophrenia had higher levels of body fat which was more centrally distributed. Percentage body fat was on average 4% higher and waist circumference, on average 5 cm greater in men with schizophrenia than the sedentary controls of the same age and BMI. Further, this study indicates that the use of BMI to predict body fat in men with schizophrenia will result in greater bias than when it is used to predict body fat in other sedentary men. Commonly used regression equations to predict energy requirements at rest are based on the relationships between weight and resting energy expenditure (REE) and in such equations, weight acts as a surrogate measure of FFM. The objectives of study three were to measure REE in a small group of men with schizophrenia who were taking the antipsychotic medication clozapine and to determine whether REE can be predicted with sufficient accuracy to substitute for the measurement of REE in the clinical and/or research settings. Body composition was determined using deuterium dilution and REE was measured using a Deltatrac Metabolic Cart via a ventilated hood. The male participants, (aged 28.0 ± 6.7 yrs, BMI 29.8 ± 6.8 kg/m2) were weight stable at the time of the study and had been taking clozapine for 20.5 ± 12.8 months, with doses of 450 ± 140 mg/day. Of the six prediction equations evaluated, the equation of Mifflin et al. (1990) with no systematic bias, the lowest bias and the lowest limits of agreement proved to be the most suitable equation to predict REE in this cohort. The overestimation of REE can be corrected for by deducting 160 kcal/day from the predicted REE value when using the Mifflin et al. (1990) equations. However, the magnitude of the error associated with the prediction of REE for an individual is 370 kcal/day. The findings of this study indicate that REE cannot be predicted with sufficient individual accuracy in men with schizophrenia, therefore it was necessary to measure rather than predict REE in subsequent studies. In the fourth study, indirect calorimetry (Deltatrac Metabolic Cart via ventilated hood) and deuterium dilution were used to accurately determine REE, respiratory quotient (RQ) and FFM in 31 men with schizophrenia and healthy sedentary controls individually matched for age and BMI. Data from this study indicated that gross REE was lower in men with schizophrenia than in healthy sedentary controls of a similar age and body size. However, there was no difference between the groups in REE when REE was adjusted for FFM using the mathematically correct method (analysis of covariance with FFM as the covariate). There was however a statistically and clinically significant difference in resting, fasted RQ between men with schizophrenia and controls, suggesting that RQ rather than REE may be an important correlate worthy of further investigation in men with schizophrenia who take antipsychotic medications. Studies five and six involved the application of the doubly labelled water (DLW) technique to accurately determine total energy expenditure (TEE) and activity energy expenditure (AEE) in a small group of men with schizophrenia who had been taking the atypical antipsychotic medication clozapine. The participants were those who took part in study three. The purpose of these studies was to assess the validity of a commercially available tri-axial accelerometer (RT3) for predicting free-living AEE and to investigate TEE and AEE in men with schizophrenia. There was poor agreement between AEE measured using DLW and AEE predicted using the RT3. However, using the RT3 to measure inactivity explained over two-thirds of the variance in AEE. This study found that the relationship between current AEE per kilogram of body weight and change from baseline weight in men taking clozapine was strong although not significant. The sedentary nature of the group of participants in this study was reflected in physical activity levels, (PAL, 1.39 ± 0.27), AEE (435 ±352 kcal/day) and TEE (2511 ± 606 kcal/day) that fell well short of values recommended by WHO (2000) for optimal health and to prevent weight gain. Given the increasing recognition of the importance of sedentary behaviour to weight gain in the general community, further examination of the unique contributing factors such as medication side effects and symptoms of mental illness to activity levels in this clinical group is warranted. The final study used accelerometry (RT3) to objectively measure activity in a group of 31 men with schizophrenia who had been taking atypical antipsychotic medications for more than four months. The purpose of this study was to explore the relationships between psychiatric symptomatology, side-effects of medication and physical activity. Accelerometry output was analysed to provide a measure of inactivity and moderate intensity activity (MIA). The well-validated and reliable standardised clinical interview, the Positive and Negative Syndrome Scale (PANSS) was used as a measure of psychiatric symptoms. Perceived side-effects of medication were assessed using the Liverpool University Neuroleptic Rating Side-Effects Scale (LUNSER). Surprisingly, there was no relationship reported between any measures of negative symptoms and physical inactivity. However, self-reported measures of medication side-effects relating to fatigue, sleepiness during the day and extrapyramidal symptoms explained 40% of the variance in inactivity. This study found significant relationships between some negative symptoms and moderate intensity activity. Despite the expectation that as symptoms of mental illness reduce, inactivity may diminish and moderate intensity activity will increase, it may not be surprising that in practice this is an overly simplistic view. It may be that measures of social functioning and possibly therefore cognition may be better predictors of physical activity than psychiatric symptomatology per se.
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ABSTRACT: Since experiments regarding a possible relation between olanzapine and orexin A has been scarcely reported in international literature, this experiment tested the effect of olanzapine on the sympathetic and thermogenic effects induced by orexin A. The firing rates of the sympathetic nerves to interscapular brown adipose tissue (IBAT), along with IBAT, colonic temperatures and heart rate were monitored in urethane-anesthetized male Sprague-Dawley rats before an injection of orexin A (1.5 nmol) into the lateral cerebral ventricle and over a period of 150 min after the injection. The same variables were monitored in rats with an intraperitoneal administration of olanzapine (10mg/kg bw), injected 30 min before the orexin administration. The results show that orexin A increases the sympathetic firing rate, IBAT, colonic temperatures and heart rate. This increase is blocked by the injection of olanzapine. These findings indicate that olanzapine affects the complex reactions related to activation of orexinergic system.Peptides 02/2008; 29(1):120-6. DOI:10.1016/j.peptides.2007.10.016 · 2.61 Impact Factor
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ABSTRACT: This study focuses on exploring the relationship between changes in appetite or eating behaviors and subsequent weight change for adult patients with schizophrenia or bipolar disorder treated with olanzapine and adjunctive potential weight mitigating pharmacotherapy. The aim is not to compare different weight mitigating agents, but to evaluate patients' characteristics and changes in their eating behaviors during treatment. Identification of patient subgroups with different degrees of susceptibility to the effect of weight mitigating agents during olanzapine treatment may aid clinicians in treatment decisions. Data were obtained from 3 randomized, double-blind, placebo-controlled, 16-week clinical trials. Included were 158 patients with schizophrenia or bipolar disorder and a body mass index (BMI) > or = 25 kg/m2 who had received olanzapine treatment in combination with nizatidine (n = 68), sibutramine (n = 42), or amantadine (n = 48). Individual patients were analyzed for categorical weight loss > or= 2 kg and weight gain > or = 1 kg. Variables that were evaluated as potential predictors of weight outcomes included baseline patient characteristics, factors of the Eating Inventory, individual items of the Eating Behavior Assessment, and the Visual Analog Scale. Predictors/correlates of weight loss > or = 2 kg included: high baseline BMI, low baseline interest in food, and a decrease from baseline to endpoint in appetite, hunger, or cravings for carbohydrates. Reduced cognitive restraint, increase in hunger, and increased overeating were associated with a higher probability of weight gain > or = 1 kg. The association between weight gain and lack of cognitive restraint in the presence of increased appetite suggests potential benefit of psychoeducational counseling in conjunction with adjunctive pharmacotherapeutic agents in limiting weight gain during antipsychotic drug therapy. This analysis was not a clinical trial and did not involve any medical intervention.BMC Psychiatry 04/2009; 9:12. DOI:10.1186/1471-244X-9-12 · 2.24 Impact Factor