Olanzapine, weight change and metabolic effects: a naturalistic 12-month follow up

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1 507738TPP / Therapeutic Advances in PsychopharmacologyMS Balbão, JE Cecílio Therapeutic Advances in Psychopharmacology Original Research Olanzapine, weight change and metabolic effects: a naturalistic 12-month follow up Marina Salviato Balbão, Jaime Eduardo Cecílio Hallak, Emerson Arcoverde Nunes, Mauricio Homem de Mello, Andresa de Toledo Triffoni-Melo, Flavia Isaura de Santi Ferreira, Cristiano Chaves, Ana Maria Sertori Durão, Adriana Pelegrino Pinho Ramos, José Alexandre de Souza Crippa and Regina Helena Costa Queiroz Abstract Objective: Olanzapine is an atypical antipsychotic drug used to treat schizophrenia. Some of the adverse effects related to its use are obesity, hyperlipidemia, type 2 diabetes and hypertension, which may result in development of metabolic syndrome. This study aimed to investigate a possible increase in some anthropometric and biochemical parameters, and the existence of any correlation between them in Brazilian patients with schizophrenia treated with olanzapine in the mid term. Methods: Thirty subjects with schizophrenia were evaluated, 16 women and 14 men, aged between 18 and 47 years. All patients underwent blood collection and anthropometric measurements at four different times during 12 months of follow up; thus each patient was his or her own control. Results: Evaluation of some anthropometric measurements showed significant differences when comparing the mean values obtained in each of the different data collection times (p < 0.05). However, the biochemical indicators of development of metabolic syndrome measured in our study did not show the same rate of increment, with only the total cholesterol and glucose levels presenting statistically significant changes (p < 0.05), but without the same magnitude of weight change. Conclusion: We conclude that medium-term treatment with olanzapine promoted a substantial weight gain and increased visceral fat, while the metabolic profile did not show the same magnitude of change, suggesting a dissociation between weight gain and blood parameters, despite the severe weight gain observed among subjects evaluated. Keywords: Anthropometric measurements, biochemical parameters, olanzapine, schizophrenia, weight gain Introduction Olanzapine is a drug from the class of atypical antipsychotics used in the short-term treatment of acute psychosis, psychotic and manic-depressive disorders and agitated states in delirium and dementia, as well as in the long-term treatment of chronic psychotic disorders such as schizophrenia [Gardner et al. 2005]. When compared with conventional antipsychotics, atypical medication has a lower incidence of extrapyramidal side effects such as tremors, dystonia, hypokinesia, akathisia and extrapyramidal syndrome, most of them caused by the blockade of dopamine D 2 receptors in nigrostriatal dopaminergic neurons [Matsui-Sakata et al. 2005]. However, there are some adverse effects associated with the use of olanzapine that deserve to be mentioned: weight gain, insulin resistance, hyperglycemia, dyslipidemia and diabetes mellitus type II. Among these effects, weight gain is of great significance because it is associated with obesity [Newcomer, 2004]. A common and well known consequence of obesity is the increased risk of developing cardiovascular diseases, particularly disorders of insulin and visceral fat deposition Ther Adv Psychopharmacol 2014, Vol. 4(1) DOI: / The Author(s), Reprints and permissions: journalspermissions.nav Correspondence to: Marina Salviato Balbão, PhD Department of Clinical Analyses, Toxicology and Food Sciences, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Bandeirantes Avenue, 3900, , Ribeirão Preto, SP, Brazil. marinarpo@yahoo.com.br Jaime Eduardo Cecílio Hallak, PhD Emerson Arcoverde Nunes, MD José Alexandre de Souza Crippa, PhD Department of Neuroscience and Behavioral Sciences, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, and National Science and Technology Institute for Translational Medicine (INCT-TM), Rio Grande do Sul, Brazil Mauricio Homem de Mello, PhD Flavia Isaura de Santi Ferreira, MSc Regina Helena Costa Queiroz, PhD Department of Clinical Analyses, Toxicology and Food Sciences, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil Andresa de Toledo Triffoni-Melo, PhD Department of Internal Medicine, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil Cristiano Chaves, MD, MSc Ana Maria Sertori Durão, MSc National Science and Technology Institute for Translational Medicine (INCT-TM), Rio Grande do Sul, Brazil Adriana Pelegrino Pinho Ramos, PhD Department of Pharmaceutical Sciences, University of Ribeirão Preto, Ribeirão Preto, Brazil 30

2 MS Balbão, JE Cecílio et al. [Meyer and Stahl, 2009]. This relationship also occurs in patients with psychiatric disorders, and this may be due to multiple factors, including the induction or exacerbation of effects related to antipsychotic treatment [Smith et al. 2010]. It is suggested that a significant number of cases of diabetes occurring after initiation of antipsychotics is due to factors independent of weight gain [Scheen and De Hert, 2007]. Newcomer and colleagues conducted a review of blood glucose levels using the glucose tolerance test in 79 subjects comprising 48 with schizophrenia and 31 healthy subjects without treatment [matched for body mass index (BMI), fat mass and age] [Newcomer et al. 2002]. This study showed a significant increase in glucose levels in patients receiving atypical antipsychotics, particularly olanzapine and clozapine. However, there is still a lack of well controlled studies to assess the direct effects of olanzapine on glucose metabolism. In addition to the importance of weight gain and diabetes associated with the use of antipsychotics, it is also important to diagnose and treat dyslipidemia in patients using this class of drugs, considering the long-term impact of dyslipidemia on the risk of cardiovascular death. The possible direct effect of antipsychotics on lipid profiles may partly be a reflection of insulin resistance, which leads to increased lipolysis. This direct effect of insulin resistance causes an increase in levels of free fatty acids that are sequentially processed by the liver into triglycerides [Meyer and Stahl, 2009]. However many patients develop dyslipidemia without producing glucose intolerance. Thus, there is a need for more controlled studies to assess the effects of antipsychotics on lipid metabolism. Some anthropometric parameters, such as BMI, waist and hip circumferences (WC and HC, respectively) and waist-to-hip ratio (WHR), may also be used as risk markers for metabolic abnormalities, such as those associated with the use of second-generation antipsychotics [Bray, 1989; De Hert et al. 2006; Janssen et al. 2002; World Health Organization, 1998]. Thus, the objective of this study was to investigate a possible increase in some anthropometric and biochemical parameters, and the existence of a correlation between them, in Brazilian patients with schizophrenia in a 12-month follow up during olanzapine treatment. Materials and methods Subjects The longitudinal study was conducted in 30 patients, 16 women and 14 men aged between 18 and 47 years (mean = 27.83, SD = 8.34). The subjects were selected among inpatients in the psychiatric ward of the Clinical Hospital of the Medical School of Ribeirão Preto, University of São Paulo (EPQU-HCFMRP) who were medically indicated for initiation of treatment with olanzapine (10 35 mg/day). The diagnosis of schizophrenia was performed following the criteria of the Diagnostic and Statistic Manual of Mental Disorders, fourth edition (DSM-IV). All patients and family members signed an informed consent form to take part in this study, which was approved by the Ethics Research Committee of the Clinical Hospital (HCFMRP-USP). Study design This was a prospective experimental study carried out at HCFMRP-USP for 5 years ( ). The 30 patients underwent blood collection and anthropometric measurements at four different time points. Time zero (or T0) refers to the measurements before the treatment with olanzapine. After that, the subsequent measurements were performed 1 month (time one or T1), 2 months (time two or T2), 9 months (time three or T3) and 12 months (time four or T4) after time zero respectively. Thus, each patient was his or her own control. All collections and assessments occurred during the hospitalization period and routine follow up post discharge of these patients. Anthropometric assessment Anthropometric evaluation consisted of determining the parameters height, weight (measured in the morning after fasting for 12 h), BMI calculated by dividing the body weight (kg) by the square of the height (m), arm circumference, WC, HC, WHR (dividing the value of WC by HC), bicep and tricep circumference, subscapular and suprailiac skinfold, resistance, body fat percentage and basal metabolic rate. Biochemical indicators and assay methods Blood samples were collected after 12 h of fasting for analysis of total cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein 31

3 Therapeutic Advances in Psychopharmacology 4 (1) Table 1. Statistical analysis of anthropometric parameters at different times of data collection (n = 30). Variable T0 T1 T2 T3 T4 p Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Weight (kg) 66.6 (9.73) 70.6 (11.2) 74.0 (11.5) 75.9 (12.9) 77.3 (13.4) BMI (kg/m 2 ) 24.4 (4.01) 25.9 (4.20) 27.1 (4.47) 28.0 (5.16) 28.1 (5.21) WC (cm) 76.2 (8.74) 79.8 (8.45) 83.0 (8.28) 84.1 (8.99) 84.7 (10.0) HC (cm) 91.5 (8.54) 94.7 (6.45) 96.6 (7.23) 98.1 (8.10) 98.4 (9.45) WHR 0.84 (0.08) 0.85 (0.07) 0.87 (0.07) 0.86 (0.07) 0.87 (0.09) BMI, body mass index; HC, hip circumference; WC, waist circumference; WHR, waist-to-hip ratio. (LDL) cholesterol, triglycerides, glucose, insulin and cortisol. Statistical analysis The quantitative and qualitative variables were described as means, standard deviation and p value. Anthropometric and biochemical data were analyzed statistically using the Statistical Package for the Social Sciences (SPSS), version The different parameters were tested individually by analysis of variance for repeated measures unifactorial, analyzing the factor time and the simple contrast of the initial measure with each of the subsequent analyses. The significance level was 5% (p < 0.05) for all analyses. Results Clinical and demographic data showed no differences among the subjects, which suggests that they were homogeneous for age (χ 2 = 3.59, p = 0.94) and sex (χ 2 = 1.47, p = 0.26). The mean age of the subjects was 26.8 years, and the mean duration of the disorder was 67.8 weeks. Anthropometric measurements showed significant differences when comparing the mean values obtained in each of the different periods of data collection. The difference between the mean values for weight, BMI, WC and HC among the studied subjects showed significant increase (Table 1). The mean weight observed among our subjects increased from 66.9 kg ± 9.73 (mean ± SD) at T0 to 77.3 kg ± 13.4 (p = 0.002) 12 months after initiating treatment, when we performed our last evaluation. The prevalence of substantial weight gain (SWG) (subjects with weight gain greater than 7% of initial BMI) also showed prominent and progressive increase across each time point. Among our subjects, 30% showed SWG after 1 month of olanzapine use (T1 T0). A drastic increase in this percentage was observed during the second evaluation (T2 T0), when 63.3% of the participants presented SWG, which represents a twofold increase when compared with the first measures (T1 T0). The SWG among our subjects reached its highest prevalence after 9 months of olanzapine use, which was during the third time point (T3), when 70% of the subjects showed SWG. Finally, the last time point showed that after 12 months of antipsychotic use, 67% of the participants presented with SWG. The mean BMI values increased from 24.4 ± 4.01 (mean ± SD) to 28.1 ± 5.21 kg/m 2 (p = 0.003) after 12 months. It is worth noting the significant increase in the average WC (T1 T0 = 3.388, T2 T0 = 6.571, T3 T0 = and T4 T0 = cm), suggesting increased visceral fat. For the parameter WHR, even with the observation of an increase in the difference of means, its results were not statistically significant (p > 0.05). Regarding biochemical parameters, total cholesterol was one of the few that showed significant change (Table 2), with an increase of 30.1 mg/dl (18.7%) (p = 0.049) in the mean cholesterol levels after 12 months of treatment, leading to 20% of the subjects ending up with total cholesterol levels higher than 200mg/dl (above the optimal/ near optimal concentration) [Jellinger et al. 2012]. HDL and LDL cholesterol levels showed no significant difference along all time points. We observed some difference in triglyceride levels along the study, but without statistical significance (Table 2). During the first 2 months of treatment their levels showed a tendency to decrease followed by an augmentation, which occurred between the third and the ninth month of the study (between T2 and T3). 32

4 MS Balbão, JE Cecílio et al. Table 2. Statistical analysis of biochemical indicators at different times of sample collection (n = 30). Variable T0 T1 T2 T3 T4 p Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD) Total cholesterol (mg/dl) (44.1) (36.6) (73.5) (69.7) (69.0) Triglycerides (mg/dl) (93.5) (73.0) (75.4) (76.0) (77.5) HDL cholesterol (mg/dl) 41.6 (8.84) 40.3 (8.66) 40.8 (10.4) 41.1 (10.2) 41.3 (10.1) LDL cholesterol (mg/dl) 98.1 (34.6) (30.9) (32.9) (31.3) (32.2) Glucose (mg/dl) 79.2 (9.3) 80.4 (8.3) 82.9 (9.4) 82.6 (8.6) 84.9 (9.3) Insulin (µu/ml) 7.6 (5.3) 10.7 (19.4) 7.1 (3.8) 7.3 (3.7) 7.2 (3.9) Cortisol (µg/dl) 14.3 (6.9) 13.1 (5.7) 13.9 (5.8) 14.7 (5.9) 14.6 (6.2) HDL, high-density lipoprotein; LDL, low-density lipoprotein. Blood glucose levels showed small but statistically significant augmentation in the first two months (T1 and T2), as well as in the last months of olanzapine use (T4) (Table 2), when we could observe the final increase of 5.7 mg/dl in the mean fasting glucose level, which represented an increase of 7.1%. Despite not showing statistical significance, insulin levels decreased along the whole evaluation period (Table 2). Cortisol levels increased, although without statistical significance from the second month of olanzapine therapy (Table 2). Discussion Antipsychotics represent an important component in clinical management of many psychotic conditions like schizophrenia. However, most of the patients present weight gain as one of the main adverse effects. Our results are partially consistent with previous studies that showed the relationship between the short- and mid-term use of olanzapine and metabolic alterations [Allison et al. 1999; Lieberman et al. 2005; Mackin et al. 2005; Meyer and Koro, 2004; Newcomer, 2005], even though some of our results point to different outcomes compared with previous studies. While conventional antipsychotics produce a modest increase in weight, it has already been well established that atypical antipsychotics, such as olanzapine and clozapine, among others, are associated with more marked weight gain [Graham et al. 2005]. The weight gain with the use of such medications is considerably higher, as shown in a meta-analysis of over 80 studies on weight change during antipsychotic treatment, which showed a mean weight gain of 4.15 kg after 10 weeks of olanzapine use, 4.45 kg increase with clozapine use and 2.10 kg with risperidone compared with 1.08 kg with the typical antipsychotic haloperidol [Davis et al. 2003]. In our study, the weight gain after 8 weeks of olanzapine use was almost twice as high (7.9 kg) as the value mentioned above. Also, the observed SWG among our patients (reaching 63.3% after 2 months and 67% of the patients after 12 months) was considerably higher compared with previously published data concerning both short- and long-term use of olanzapine that point to a SWG ( 7%) affecting 15 50% of patients [Bobes et al. 2003; Jaton et al. 2003; Kinon et al. 2005]. This magnitude of weight change is not usual with patients already using other antipsychotics previously, but such a higher rate of weight gain has already been observed in a drug-naive young population (mean age 26.7 years), in which 77.1% presented with SWG after 1 year [Perez-Iglesias et al. 2008]. In that study the authors argued that the greater weight change was probably due to patients characteristics (drug-naive young people with a low prevalence of obesity, 4%) and to good treatment compliance (low dropout rates, good family support), reflecting regular use of the drug. Some of these characteristics were similar in our population; they were also young (mean age 26.8 years), with a low prevalence of obesity (13.3%), and presented good treatment compliance because the initial treatment occurred while they were inpatients in our ward. Still, only 20% of our subjects were drug naive, which lead us to other possible reasons for the greater weight gain. One reasonable explanation for this could be the higher doses administered to our patients (mean 20.5 mg in the first month and 24 mg in the last measure after 12 months), which means 33

5 Therapeutic Advances in Psychopharmacology 4 (1) that we surpassed the labeled maximum recommended dose. Although some of the literature data indicate a dose-dependent effect of olanzapine on weight gain [Simon et al. 2009], our population was too homogeneous to make this analysis possible. Almost all participants ended up using similar high doses of olanzapine, with no significant dosedependent effect being observed in our study. The majority of the subjects included in our study were already using another antipsychotic without good response (80%), with all of them being acutely ill and needing treatment as inpatients in our ward, which generally demands fast titration and higher end doses of antipsychotics, and therefore they are more likely to present with greater side effects. The use of olanzapine doses above those established on the medication label has been supported by cumulative data, but only for patients with severe or refractory symptoms, and also with the warning of increased risk of weight gain and elevated prolactin [Citrome and Kantrowitz, 2009]. Furthermore, it is important to highlight that there was a significant increase in the mean measures of the other parameters during the 12-month monitoring of individuals, indicating a rise in body fat and, consequently, an increase in cardiac risk. Another important result was the increase in the average WC, clearly indicating an increase in visceral fat (abdominal), which is related to a high risk of morbidity and mortality, mainly cardiovascular [Egger, 1995]. Several studies have identified a high prevalence of dyslipidemia in patients treated with olanzapine and clozapine. A cross-sectional study of 62 patients with schizophrenia found that increased BMI was associated with dyslipidemia [Kato et al. 2005]. Furthermore, Leitão-Azevedo and colleagues showed a significant decrease in HDL cholesterol levels in patients treated with clozapine compared with those treated with first-generation antipsychotics [Leitão-Azevedo et al. 2006]. Likewise, for the other metabolic parameters (LDL cholesterol and triglycerides), the study failed to show significant difference between the treatments. Other clinical studies showed that olanzapine has significant adverse effects on the lipid profile, especially in triglyceride levels, which increased by about 38%, with minimal changes in total cholesterol levels (6%) [Wirshing et al. 2002]. Unlike the anthropometric measurements, the biochemical indicators of development of metabolic syndrome measured in our study, cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, glucose and insulin, did not show the same rate of increment as the BMI and weight, for example. Even with the total cholesterol and glucose levels presenting with statistically significant changes, the magnitude of this change did not happen at the same pace as the weight change, given that even with 67% of the subjects presenting with a SWG after 1 year, only 20% of our patients ended up with a total cholesterol above 200 mg/dl (dyslipidemia), and only 6.6% with a glucose level above the normal range of 100 mg/dl. Despite the believed relationship between weight gain and metabolic alterations with the use of olanzapine, a lack of correlation between increasing BMI and metabolic parameters with the use of olanzapine in selected populations has already been described in the literature [Ader et al. 2008; Krakowski et al. 2009], and perhaps this was the case in our study, since this is the first mid-term study to evaluate weight gain and alterations in metabolic parameters in Brazilian patients with schizophrenia. It can be argued that a larger follow up could have shown bigger changes in the metabolic parameters, and we agree that an evaluation beyond the 12-month period may show larger differences in the metabolic parameters, since we observed a regular increase in these parameters along the time points, although at a different pace compared with the weight gain. Our results showed that mid-term treatment with olanzapine promoted substantial weight gain and increased visceral fat, while the metabolic profile did not show the same magnitude of change in HDL cholesterol, triglycerides, cortisol and insulin levels, with the only laboratory alterations being observed with statistical significance in total cholesterol and blood glucose levels. However, the glucose alterations were not clinically relevant in characterizing a metabolic disorder, which suggests a dissociation between the increased weight and the blood parameters, despite the severe weight gain observed among our subjects. Funding The study was supported in part by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). 34

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