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Differential effects of olanzapine and clozapine on plasma levels of adipocytokines and total ghrelin
Progress in Neuro-Psychopharmacology & Biological Psychiatry 58 (2015) 47–50
Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp
Differential effects of olanzapine and clozapine on plasma levels of adipocytokines and total ghrelin Mong-Liang Lu a,1, Tsu-Nai Wang b,1, Tsang-Yaw Lin c, Wen-Chuan Shao c, Sheng-Huang Chang c, Jen-Yu Chou d, Yi-Feng Ho e, Yin-To Liao e,f,g, Vincent Chin-Hung Chen e,f,g,⁎ a
Department of Psychiatry, Wan-Fang Hospital and School of Medicine, Taipei Medical University, Taipei, Taiwan Department of Public Health, College of Health Science, Kaohsiung Medical University, Kaohsiung, Taiwan Tsaotun Psychiatric Center Department of Health, Nan-Tou, Taiwan d Graduate Institute of Humanities in Medicine, Taipei Medical University, Taipei, Taiwan e Institute of Medicine, Chung Shan Medical University Taichung, Taiwan f Department of Psychiatry, Chung Shan Medical University Hospital, Taichung, Taiwan g School of Medicine, Chung Shan Medical University, Taichung, Taiwan b c
a r t i c l e
i n f o
Article history: Received 15 September 2014 Received in revised form 16 November 2014 Accepted 2 December 2014 Available online 9 December 2014 Keywords: Adiponectin Clozapine Ghrelin Leptin Olanzapine Schizophrenia
a b s t r a c t Second-generation antipsychotics (SGAs) have been associated with an increased liability for weight gain and metabolic side effects. Among SGAs, clozapine and olanzapine had great liability to induce weight gain and metabolic adverse reactions. Leptin, adiponectin, and total ghrelin play important roles in energy homeostasis and are suggested to be biomarkers of metabolic disturbances. The purpose of the present study was to investigate the differential effects of antipsychotics (olanzapine and clozapine) on the levels of adipocytokines (leptin and adiponectin) and total ghrelin. Three hundred and thirty-three patients with schizophrenia under clozapine or olanzapine monotherapy were recruited. Control participants were recruited from a healthy community population based on a health investigation (N = 119). Fasting blood samples for glucose, cholesterol, triglycerides, leptin, adiponectin, and total ghrelin were analyzed. There were significant differences in the levels of cholesterol, triglycerides, and glucose between these three groups. Post hoc comparisons showed that the olanzapine group had the highest levels of cholesterol and triglycerides. The levels of leptin, adiponectin, and total ghrelin were also significantly different between the three groups after controlling age and body mass index (BMI). Post hoc comparisons showed that the olanzapine group had the lowest levels of adiponectin and total ghrelin. The present study found that the uses of olanzapine and clozapine were associated with changes in adipocytokines and total ghrelin, even after adjusting potential confounding factors. Olanzapine had greater influences on adiponectin and total ghrelin than clozapine. The changes in adipocytokines and total ghrelin were a direct effect of antipsychotics on hormonal pathways of energy homeostasis, rather than the result of weight gain. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Schizophrenia is one of the top causes of long-term disability in the world, and its symptoms can cause impairments in social and occupational functioning as well as self-care. Schizophrenia also has a large economic impact on the cost of medical resources and lost working potential (Rice, 1999). People with schizophrenia have a mortality risk two Abbreviations: BMI, body mass index; CVD, cardiovascular diseases; SGAs, secondgeneration antipsychotics ⁎ Corresponding author at: Doctor Vincent Chin-Hung Chen, Chung Shan Medical University Hospital, No. 110, Sec. 1, Jianguo N. Rd., Taichung City 40201, Taiwan. Tel.: +886 4 24739595x38824. E-mail address: [email protected] (V.C.-H. Chen). 1 Tsu-Nai Wang contributed equally to Mong-Liang Lu.
http://dx.doi.org/10.1016/j.pnpbp.2014.12.001 0278-5846/© 2014 Elsevier Inc. All rights reserved.
to three times greater than the general population. Specifically, there is an apparent increase in cardiovascular mortality relative to the general population (Brown et al., 2010). People with schizophrenia also have a higher prevalence of risk factors for cardiovascular diseases (CVD) such as diabetes, metabolic syndrome, and obesity compared with the general population (Casey, 2005; Huang et al., 2009). Patients with schizophrenia store more visceral fat than control participants (Ryan et al., 2004). Second-generation antipsychotics (SGAs) have been increasingly used for patients with schizophrenia due to their increased efficacy and reduced risk of extrapyramidal side effects compared with firstgeneration antipsychotics (Leucht et al., 2009). Among SGAs, clozapine and olanzapine had great liability to induce weight gain and metabolic adverse reactions (Allison et al., 1999; Newcomer, 2007). These
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sequelae exacerbate the already elevated risk for CVD and diabetes in this population (Casey, 2005). Because the prominent problem of antipsychotics is related to weight gain, understanding the underlying mechanism is important. Leptin is mainly produced by adipocytes and exerts an anorexigenic effect (Gautron and Elmquist, 2011). Leptin is a mediator of long-term regulation of energy balance, suppressing food intake and thereby inducing weight loss (Friedman and Halaas, 1998). Several studies report that leptin levels are increased during long-term antipsychotic treatment and the increases are highly correlated with weight changes (Jin et al., 2008). Adiponectin, an adipocyte-derived plasma protein, plays important roles in fat and carbohydrate metabolism and the endocrine system. Adiponectin might protect against insulin resistance and the adverse consequences of obesity (Yamauchi et al., 2001). Adiponectin is negatively associated with hypertriglyceridemia (Yu et al., 2012) and abnormal glucose metabolism (Jalovaara et al., 2008). The relationship between the use of antipsychotics and the levels of adiponectin remained conflicted (Jin et al., 2008). Ghrelin, a gut–brain hormone, is primarily synthesized in the stomach and involved in energy homeostasis. Ghrelin increases food intake, and the concentration of serum ghrelin is negatively correlated with insulin resistance and body fat (Leidy et al., 2004). Ghrelin stimulates weight gain and may play an important role in the etiology of obesity (Horvath et al., 2001). Previous studies report inconsistent findings regarding the association between antipsychotic use and ghrelin levels. Some studies have shown decreased ghrelin levels (Hosojima et al., 2006; Togo et al., 2004), some have found increased ghrelin levels (Murashita et al., 2007; Palik et al., 2005), and other studies do not find significant changes in ghrelin levels (Himmerich et al., 2005; Theisen et al., 2005). The relationship between SGA treatments and serum ghrelin levels remains unclear. The major limitations of previous studies on the association between antipsychotics and the levels of leptin, adiponectin, and ghrelin were small sample sizes, short treatment durations, and lack of healthy controls. Possible explanations for the discrepancies between previous studies included the lack of control for potentially confounding variables such as age and adiposity. The current study explores the differences in the levels of leptin, adiponectin, and total ghrelin between healthy controls and subjects with schizophrenia being treated with clozapine or olanzapine. The differential effects of olanzapine and clozapine on the levels of adipocytokines and total ghrelin were also examined after controlling age and body mass index (BMI). 2. Methods 2.1. Participants and procedure This study was performed at Taipei Medical University-Wan Fang Hospital and Tsaotun Psychiatric Center in Taiwan. This study was approved by the Institutional Review Board of both hospitals. All participants gave written informed consent after receiving a detailed explanation of the study. Patients diagnosed with schizophrenia (according to the DSM-IV criteria) who were undergoing clozapine or olanzapine monotherapy for at least 6 months were recruited. Participants in the healthy control group were recruited from the general population in southern Taiwan using a health survey. Following our previous study (Chen et al., 2011), control participants were excluded if they 1) had a substance-related disorder, 2) had diabetes mellitus, 3) had hyperlipidemia, 4) had mental retardation, or 5) were pregnant. 2.2. Phenotype measurements All participants agreed to receive a clinical interview and an anthropometrical parameter assessment, as well as to provide blood
samples. A trained research assistant interviewed patients to collect demographic and psychiatric information. 2.3. Plasma leptin, adiponectin, and total ghrelin levels Blood samples were collected after at least 8 h of fasting. Plasma was stored at −70 °C before measuring the biochemical markers as well as the leptin, adiponectin, and total ghrelin levels. We detected plasma concentrations of leptin, adiponectin and total ghrelin using an RIA assay. This assay uses 125I-labeled murine adiponectin and total ghrelin as well as a multispecies rabbit antiserum via the double antibody/PEG technique (human ghrelin and adiponectin RIA Kit, Linco Research Inc., St. Charles, Missouri, USA). The sensitivity limits for the human adiponectin and total ghrelin RIA assays were 1 ng/ml and 100 pg/ml, respectively. The fasting levels of total cholesterol, triglycerides and glucose were determined using standard laboratory methods. 2.4. Statistical analyses We collected descriptive statistics (mean ± standard deviation, frequency, and percent) of the demographics and biochemical markers as well as the ghrelin and adiponectin levels. An ANOVA was used to compare the mean differences among the three groups. The chi-square test was used to explore the associations among categorical variables. Oneway analyses of variance (ANOVA) were employed to analyze data between groups followed by Tukey–Kramer post-hoc comparisons. Analysis of covariance (ANCOVA) was applied to analyze the medication effect on the levels of leptin, adiponectin, and total ghrelin after controlling for the confounding factors of age and BMI. All analyses were performed with the statistical software SPSS 19.0. 3. Results Three hundred and thirty-three subjects with schizophrenia and 119 control subjects were recruited for the present study. These participants with schizophrenia were classified into an olanzapine group (n = 167) and a clozapine group (n = 166). There was no group difference with regard to sex distribution (Table 1). Subjects in the control group had smaller waist circumference than the other two groups. Subjects in the clozapine group had older age, heavier body weight, and a larger BMI than the other two groups. Table 2 presents the biochemical markers as well as the levels of leptin, adiponectin, and total ghrelin for the olanzapine, clozapine and control groups. There were significant differences in the levels of cholesterol, triglycerides, and glucose between these three groups. Post hoc comparisons showed that the olanzapine group had the highest levels of cholesterol, triglycerides, and glucose. The levels of leptin, adiponectin, and total ghrelin also had significant differences between the three groups. Post hoc comparisons showed that the olanzapine group had the highest level of leptin, and lowest levels of adiponectin and total ghrelin. Using ANCOVA with age and BMI adjustment, there were significant differences in the serum levels of leptin (F = 15.24, df = 2, p b 0.001),
Table 1 Characteristics of the olanzapine, clozapine, and control groups.
Sex Men Women Age Weight Waist circumference BMI
Control N = 119
Olanzapine N = 167
Clozapine N = 166
56 63 38.9 ± 9.3 62.6 ± 11.4 78.5 ± 9.7 23.0 ± 3.3
82 85 38.5 ± 11.3 65.7 ± 13.8 88.1 ± 12.4 24.5 ± 4.8
94 72 45.5 ± 8.7 61.5 ± 11.7 86.3 ± 10.1 23.2 ± 3.8
P value
0.216 b0.001 0.009 b0.001 0.002
M.-L. Lu et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 58 (2015) 47–50
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Table 2 The differences in biochemical markers, leptin, adiponectin, and total ghrelin levels among the olanzapine, clozapine and control groups.
Cholesterol (mg/dl) Triglyceride (mg/dl) Glucose (mg/dl) Leptin (ng/ml) Adiponectin (ng/ml) Total Ghrelin (pg/ml)
Control N = 119
Olanzapine N = 167
Clozapine N = 166
A
B
C
182.2 ± 29.6 90.2 ± 38.3 88.2 ± 10.1 5.4 ± 4.1 22.5 ± 14.3 1261.2 ± 1639.7
191.7 ± 36.6 156.3 ± 105.7 99.2 ± 31.6 15.6 ± 18.5 12.6 ± 10.4 618.3 ± 399.3
169.7 ± 33.4 128.6 ± 86.3 94.9 ± 22.0 10.8 ± 10.7 16.6 ± 12.4 863.5 ± 332.3
P value
b0.001 b0.001 0.001 b0.001 b0.001 b0.001
Tukey–Kramer post-hoc comparison, P-values A/B
A/C
B/C
0.048 b0.001 0.001 b0.001 b0.001 b0.001
0.007 0.001 0.061 0.002 b0.001 0.001
b0.001 0.01 0.231 0.004 0.005 0.039
ANOVAs were used for continuous variables. Multiple comparisons were determined using Tukey–Kramer post-hoc tests.
adiponectin (F = 17.67, df = 2, p b 0.001), and total ghrelin (F = 14.30, df = 2, p b 0.001) between the three groups. Post hoc Bonferroni multiple comparisons showed that the olanzapine group had the lowest level of adiponectin (vs. control group, p b 0.001; vs. clozapine group, p = 0.042) and total ghrelin (vs. control group, p b 0.001; vs. clozapine group, p = 0.039). Compared with the control group, the clozapine group had higher levels of leptin (vs. control group, p b 0.001), and lower levels of adiponectin (vs. control group, p b 0.001) and total ghrelin (vs. control group, p = 0.004). There was no significant difference in leptin levels between the clozapine and olanzapine groups. 4. Discussion The present study found that the use of olanzapine and clozapine was associated with changes in the levels of leptin, adiponectin, and total ghrelin, even after adjusting for potential confounding factors. Olanzapine had a greater influence on adipocytokines and total ghrelin than clozapine. Among the peptide hormones affecting metabolism, research of the relationship between leptin and antipsychotics is relatively well developed. The results of our study showed that leptin levels were significantly higher in olanzapine or clozapine treated subjects with schizophrenia than in healthy controls. This finding was consistent with previous studies. The data about the effects of different antipsychotics on the leptin levels are limited and controversial. Previous studies reported no significant differences in leptin levels between olanzapine and clozapine groups (Esen-Danaci et al., 2008; Kluge et al., 2009; Melkersson and Dahl, 2003; Tsai et al., 2011). However, Herran et al. (2001) reported that antipsychotics tended to exert different effects on leptin levels, and olanzapine induced a greater increase among SGAs. Our results showed the difference in leptin level between olanzapine and clozapine group disappeared after adjusting age and BMI. It might imply leptin changes were directly related to the weight gain liability of antipsychotics (Jin et al., 2008). Our results showed that olanzapine-treated subjects had the lowest adiponectin levels, followed by clozapine-treated subjects, and then healthy controls. In fact, the effects of antipsychotics on adiponectin changes are still inconclusive in the literature. Earlier studies did not find significant changes in adiponectin levels after antipsychotic treatment (Jin et al., 2008; Tsai et al., 2011). However, in a large cohort study including 567 patients with schizophrenia, the results showed that the adiponectin level was negatively correlated with BMI increase after initiation of antipsychotic treatment (Bai et al., 2009). Bai et al. (2009) also reported that the clozapine group had lower levels of adiponectin than did the olanzapine group, which was inconsistent with our findings. Our results showed that healthy controls had the highest total ghrelin levels, followed by clozapine-treated subjects, and then olanzapinetreated subjects. Relatively few studies investigated the association between antipsychotics use and ghrelin level, and their findings were inconsistent. However, the treatment duration of antipsychotics might have an important impact on ghrelin levels (Jin et al., 2008; Sentissi et al., 2008). Zhang et al. (2013) suggest a triphasic effect of SGAs on ghrelin levels:
an initial increase exerted by the acute up-regulatory effect of SGAs on ghrelin production; followed by a secondary decrease possibly due to the negative feedback from the SGA-induced increased body weight and food intake; and a final recovery of ghrelin levels back to the baseline levels or above to reach the new equilibrium. Furthermore, previous studies reported no differences in ghrelin levels among olanzapine-treated and clozapine-treated subjects (Esen-Danaci et al., 2008; Tsai et al., 2011). In our study, the group differences in adiponectin and total ghrelin levels remained significant after adjusting age and BMI. It might imply that the changes in adiponectin and total ghrelin levels appeared to be more the direct effect of antipsychotics on adiponectin and ghrelin pathway of energy homeostasis, rather than the result of weight gain. Our study results showed that olanzapine group had higher levels of cholesterol and triglycerides than the clozapine group. Among SGAs, clozapine and olanzapine had the highest potential to induce hyperlipidemia (Newcomer, 2007). In a 12-week randomized double-blind study it was reported that clozapine had the greater increases in cholesterol, triglyceride, and glucose than olanzapine (Krakowski et al., 2009). An 8-year prospective study showed both olanzapine and clozapine long-term treatments cause development of hyperglycemia and hyperlipidemia (Feng and Melkersson, 2012). Recent meta-analysis study showed no differences in metabolic side effects between clozapine and olanzapine (Rummel-Kluge et al., 2010). The presence of differences in adiponectin, total ghrelin, and lipid levels between patients treated with clozapine and olanzapine is an unexpected finding. One possible explanation is that clozapine and olanzapine had various receptor-binding profiles, and consequently different metabolic adversity potentials. It is the heterogeneous receptor binding pharmacology of the different antipsychotic medications that has been implicated in their varied risk of weight gain and related metabolic side effects. Histamine, dopamine, serotonin, glutamate, adrenergic and muscarinic receptor affinities have been suggested as possible factors associated with metabolic disturbances. (Deng et al., 2010; Nasrallah, 2008; Reynolds and Kirk, 2010). Clozapine and olanzapine have broad receptor-binding profiles of these receptors, and these multiple bindings have a cumulative effect on the metabolic adversity (Starrenburg and Bogers, 2009). Another possible explanation is that clozapine-treated patients had reached a plateau of metabolic changes before they received the current treatment regimen. Clozapine is often reserved to treat patients with refractory schizophrenia (Kane et al., 1988). Our subjects received other antipsychotic drugs before initiation of clozapine treatment. In chronic schizophrenic patients treated with multiple antipsychotics in the past, SGAs might not induce further changes in metabolic disturbances (Smith et al., 2012). These observations indicate that the effects of clozapine and olanzapine on adiponectin and ghrelin secretions still await more clarification. The current study also has some limitations. First, it is a crosssectional study. We could not interpret the causal relationships between antipsychotic use and adipocytokines in the cross-sectional design. Second, patients were not randomly assigned to treatment arms. Third, we failed to include other parameters, such as visceral fat assessment, dietary habits, physical activity levels and other metabolic parameters.
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5. Conclusion In conclusion, our study revealed that patients with schizophrenia receiving olanzapine and clozapine treatment had higher leptin levels and lower levels of total ghrelin and adiponectin than healthy controls. Olanzapine had greater influences on the levels of adiponectin and total ghrelin than clozapine. The changes in adipocytokines and total ghrelin levels were more directly related to antipsychotic effects on these hormonal pathways of energy homeostasis, rather than the result of weight gain. Acknowledgments This study was supported by grants from the Central Region Hospital Alliance, Department of Health (no. 9916), Taipei Medical UniversityWan Fang Hospital (103-wf-eva-01), and the National Science Council (NSC 102-2314-B-038-047-MY2), Taipei, Taiwan. References Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, et al. Antipsychoticinduced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999;156: 1686–96. Bai YM, Chen TT, Yang WS, Chi YC, Lin CC, Liou YJ, et al. Association of adiponectin and metabolic syndrome among patients taking atypical antipsychotics for schizophrenia: a cohort study. Schizophr Res 2009;111:1–8. Brown S, Kim M, Mitchell C, Inskip H. Twenty-five year mortality of a community cohort with schizophrenia. Br J Psychiatry 2010;196:116–21. Casey DE. Metabolic issues and cardiovascular disease in patients with psychiatric disorders. Am J Med 2005;118(Suppl. 2):15S–22S. Chen VC, Wang TN, Lu ML, Chou JY, Ju PC, Wu JY, et al. Weight gain and ghrelin level after olanzapine monotherapy. Prog Neuropsychopharmacol Biol Psychiatry 2011;35:632–5. Deng C, Weston-Green K, Huang XF. The role of histaminergic H1 and H3 receptors in food intake: a mechanism for atypical antipsychotic-induced weight gain? Prog Neuropsychopharmacol Biol Psychiatry 2010;34:1–4. Esen-Danaci A, Sarandol A, Taneli F, Yurtsever F, Ozlen N. Effects of second generation antipsychotics on leptin and ghrelin. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:1434–8. Feng S, Melkersson K. Metabolic parameters and long-term antipsychotic treatment: a comparison between patients treated with clozapine or olanzapine. Neuro Endocrinol Lett 2012;33:493–8. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998;395:763–70. Gautron L, Elmquist JK. Sixteen years and counting: an update on leptin in energy balance. J Clin Invest 2011;121:2087–93. Herran A, Garcia-Unzueta MT, Amado JA, de La Maza MT, Alvarez C, Vazquez-Barquero JL. Effects of long-term treatment with antipsychotics on serum leptin levels. Br J Psychiatry 2001;179:59–62. Himmerich H, Fulda S, Kunzel HE, Pfennig A, Dzaja A, Cummings DE, et al. Ghrelin plasma levels during psychopharmacological treatment. Neuropsychobiology 2005;52:11–6. Horvath TL, Diano S, Sotonyi P, Heiman M, Tschop M. Minireview: ghrelin and the regulation of energy balance—a hypothalamic perspective. Endocrinology 2001;142:4163–9. Hosojima H, Togo T, Odawara T, Hasegawa K, Miura S, Kato Y, et al. Early effects of olanzapine on serum levels of ghrelin, adiponectin and leptin in patients with schizophrenia. J Psychopharmacol 2006;20:75–9. Huang MC, Lu ML, Tsai CJ, Chen PY, Chiu CC, Jian DL, et al. Prevalence of metabolic syndrome among patients with schizophrenia or schizoaffective disorder in Taiwan. Acta Psychiatr Scand 2009;120:274–80. Jalovaara K, Santaniemi M, Timonen M, Jokelainen J, Kesaniemi YA, Ukkola O, et al. Low serum adiponectin level as a predictor of impaired glucose regulation and type 2 diabetes mellitus in a middle-aged Finnish population. Metabolism 2008;57:1130–4.
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Contents lists available at ScienceDirect
Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp
Differential effects of olanzapine and clozapine on plasma levels of adipocytokines and total ghrelin Mong-Liang Lu a,1, Tsu-Nai Wang b,1, Tsang-Yaw Lin c, Wen-Chuan Shao c, Sheng-Huang Chang c, Jen-Yu Chou d, Yi-Feng Ho e, Yin-To Liao e,f,g, Vincent Chin-Hung Chen e,f,g,⁎ a
Department of Psychiatry, Wan-Fang Hospital and School of Medicine, Taipei Medical University, Taipei, Taiwan Department of Public Health, College of Health Science, Kaohsiung Medical University, Kaohsiung, Taiwan Tsaotun Psychiatric Center Department of Health, Nan-Tou, Taiwan d Graduate Institute of Humanities in Medicine, Taipei Medical University, Taipei, Taiwan e Institute of Medicine, Chung Shan Medical University Taichung, Taiwan f Department of Psychiatry, Chung Shan Medical University Hospital, Taichung, Taiwan g School of Medicine, Chung Shan Medical University, Taichung, Taiwan b c
a r t i c l e
i n f o
Article history: Received 15 September 2014 Received in revised form 16 November 2014 Accepted 2 December 2014 Available online 9 December 2014 Keywords: Adiponectin Clozapine Ghrelin Leptin Olanzapine Schizophrenia
a b s t r a c t Second-generation antipsychotics (SGAs) have been associated with an increased liability for weight gain and metabolic side effects. Among SGAs, clozapine and olanzapine had great liability to induce weight gain and metabolic adverse reactions. Leptin, adiponectin, and total ghrelin play important roles in energy homeostasis and are suggested to be biomarkers of metabolic disturbances. The purpose of the present study was to investigate the differential effects of antipsychotics (olanzapine and clozapine) on the levels of adipocytokines (leptin and adiponectin) and total ghrelin. Three hundred and thirty-three patients with schizophrenia under clozapine or olanzapine monotherapy were recruited. Control participants were recruited from a healthy community population based on a health investigation (N = 119). Fasting blood samples for glucose, cholesterol, triglycerides, leptin, adiponectin, and total ghrelin were analyzed. There were significant differences in the levels of cholesterol, triglycerides, and glucose between these three groups. Post hoc comparisons showed that the olanzapine group had the highest levels of cholesterol and triglycerides. The levels of leptin, adiponectin, and total ghrelin were also significantly different between the three groups after controlling age and body mass index (BMI). Post hoc comparisons showed that the olanzapine group had the lowest levels of adiponectin and total ghrelin. The present study found that the uses of olanzapine and clozapine were associated with changes in adipocytokines and total ghrelin, even after adjusting potential confounding factors. Olanzapine had greater influences on adiponectin and total ghrelin than clozapine. The changes in adipocytokines and total ghrelin were a direct effect of antipsychotics on hormonal pathways of energy homeostasis, rather than the result of weight gain. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Schizophrenia is one of the top causes of long-term disability in the world, and its symptoms can cause impairments in social and occupational functioning as well as self-care. Schizophrenia also has a large economic impact on the cost of medical resources and lost working potential (Rice, 1999). People with schizophrenia have a mortality risk two Abbreviations: BMI, body mass index; CVD, cardiovascular diseases; SGAs, secondgeneration antipsychotics ⁎ Corresponding author at: Doctor Vincent Chin-Hung Chen, Chung Shan Medical University Hospital, No. 110, Sec. 1, Jianguo N. Rd., Taichung City 40201, Taiwan. Tel.: +886 4 24739595x38824. E-mail address: [email protected] (V.C.-H. Chen). 1 Tsu-Nai Wang contributed equally to Mong-Liang Lu.
http://dx.doi.org/10.1016/j.pnpbp.2014.12.001 0278-5846/© 2014 Elsevier Inc. All rights reserved.
to three times greater than the general population. Specifically, there is an apparent increase in cardiovascular mortality relative to the general population (Brown et al., 2010). People with schizophrenia also have a higher prevalence of risk factors for cardiovascular diseases (CVD) such as diabetes, metabolic syndrome, and obesity compared with the general population (Casey, 2005; Huang et al., 2009). Patients with schizophrenia store more visceral fat than control participants (Ryan et al., 2004). Second-generation antipsychotics (SGAs) have been increasingly used for patients with schizophrenia due to their increased efficacy and reduced risk of extrapyramidal side effects compared with firstgeneration antipsychotics (Leucht et al., 2009). Among SGAs, clozapine and olanzapine had great liability to induce weight gain and metabolic adverse reactions (Allison et al., 1999; Newcomer, 2007). These
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sequelae exacerbate the already elevated risk for CVD and diabetes in this population (Casey, 2005). Because the prominent problem of antipsychotics is related to weight gain, understanding the underlying mechanism is important. Leptin is mainly produced by adipocytes and exerts an anorexigenic effect (Gautron and Elmquist, 2011). Leptin is a mediator of long-term regulation of energy balance, suppressing food intake and thereby inducing weight loss (Friedman and Halaas, 1998). Several studies report that leptin levels are increased during long-term antipsychotic treatment and the increases are highly correlated with weight changes (Jin et al., 2008). Adiponectin, an adipocyte-derived plasma protein, plays important roles in fat and carbohydrate metabolism and the endocrine system. Adiponectin might protect against insulin resistance and the adverse consequences of obesity (Yamauchi et al., 2001). Adiponectin is negatively associated with hypertriglyceridemia (Yu et al., 2012) and abnormal glucose metabolism (Jalovaara et al., 2008). The relationship between the use of antipsychotics and the levels of adiponectin remained conflicted (Jin et al., 2008). Ghrelin, a gut–brain hormone, is primarily synthesized in the stomach and involved in energy homeostasis. Ghrelin increases food intake, and the concentration of serum ghrelin is negatively correlated with insulin resistance and body fat (Leidy et al., 2004). Ghrelin stimulates weight gain and may play an important role in the etiology of obesity (Horvath et al., 2001). Previous studies report inconsistent findings regarding the association between antipsychotic use and ghrelin levels. Some studies have shown decreased ghrelin levels (Hosojima et al., 2006; Togo et al., 2004), some have found increased ghrelin levels (Murashita et al., 2007; Palik et al., 2005), and other studies do not find significant changes in ghrelin levels (Himmerich et al., 2005; Theisen et al., 2005). The relationship between SGA treatments and serum ghrelin levels remains unclear. The major limitations of previous studies on the association between antipsychotics and the levels of leptin, adiponectin, and ghrelin were small sample sizes, short treatment durations, and lack of healthy controls. Possible explanations for the discrepancies between previous studies included the lack of control for potentially confounding variables such as age and adiposity. The current study explores the differences in the levels of leptin, adiponectin, and total ghrelin between healthy controls and subjects with schizophrenia being treated with clozapine or olanzapine. The differential effects of olanzapine and clozapine on the levels of adipocytokines and total ghrelin were also examined after controlling age and body mass index (BMI). 2. Methods 2.1. Participants and procedure This study was performed at Taipei Medical University-Wan Fang Hospital and Tsaotun Psychiatric Center in Taiwan. This study was approved by the Institutional Review Board of both hospitals. All participants gave written informed consent after receiving a detailed explanation of the study. Patients diagnosed with schizophrenia (according to the DSM-IV criteria) who were undergoing clozapine or olanzapine monotherapy for at least 6 months were recruited. Participants in the healthy control group were recruited from the general population in southern Taiwan using a health survey. Following our previous study (Chen et al., 2011), control participants were excluded if they 1) had a substance-related disorder, 2) had diabetes mellitus, 3) had hyperlipidemia, 4) had mental retardation, or 5) were pregnant. 2.2. Phenotype measurements All participants agreed to receive a clinical interview and an anthropometrical parameter assessment, as well as to provide blood
samples. A trained research assistant interviewed patients to collect demographic and psychiatric information. 2.3. Plasma leptin, adiponectin, and total ghrelin levels Blood samples were collected after at least 8 h of fasting. Plasma was stored at −70 °C before measuring the biochemical markers as well as the leptin, adiponectin, and total ghrelin levels. We detected plasma concentrations of leptin, adiponectin and total ghrelin using an RIA assay. This assay uses 125I-labeled murine adiponectin and total ghrelin as well as a multispecies rabbit antiserum via the double antibody/PEG technique (human ghrelin and adiponectin RIA Kit, Linco Research Inc., St. Charles, Missouri, USA). The sensitivity limits for the human adiponectin and total ghrelin RIA assays were 1 ng/ml and 100 pg/ml, respectively. The fasting levels of total cholesterol, triglycerides and glucose were determined using standard laboratory methods. 2.4. Statistical analyses We collected descriptive statistics (mean ± standard deviation, frequency, and percent) of the demographics and biochemical markers as well as the ghrelin and adiponectin levels. An ANOVA was used to compare the mean differences among the three groups. The chi-square test was used to explore the associations among categorical variables. Oneway analyses of variance (ANOVA) were employed to analyze data between groups followed by Tukey–Kramer post-hoc comparisons. Analysis of covariance (ANCOVA) was applied to analyze the medication effect on the levels of leptin, adiponectin, and total ghrelin after controlling for the confounding factors of age and BMI. All analyses were performed with the statistical software SPSS 19.0. 3. Results Three hundred and thirty-three subjects with schizophrenia and 119 control subjects were recruited for the present study. These participants with schizophrenia were classified into an olanzapine group (n = 167) and a clozapine group (n = 166). There was no group difference with regard to sex distribution (Table 1). Subjects in the control group had smaller waist circumference than the other two groups. Subjects in the clozapine group had older age, heavier body weight, and a larger BMI than the other two groups. Table 2 presents the biochemical markers as well as the levels of leptin, adiponectin, and total ghrelin for the olanzapine, clozapine and control groups. There were significant differences in the levels of cholesterol, triglycerides, and glucose between these three groups. Post hoc comparisons showed that the olanzapine group had the highest levels of cholesterol, triglycerides, and glucose. The levels of leptin, adiponectin, and total ghrelin also had significant differences between the three groups. Post hoc comparisons showed that the olanzapine group had the highest level of leptin, and lowest levels of adiponectin and total ghrelin. Using ANCOVA with age and BMI adjustment, there were significant differences in the serum levels of leptin (F = 15.24, df = 2, p b 0.001),
Table 1 Characteristics of the olanzapine, clozapine, and control groups.
Sex Men Women Age Weight Waist circumference BMI
Control N = 119
Olanzapine N = 167
Clozapine N = 166
56 63 38.9 ± 9.3 62.6 ± 11.4 78.5 ± 9.7 23.0 ± 3.3
82 85 38.5 ± 11.3 65.7 ± 13.8 88.1 ± 12.4 24.5 ± 4.8
94 72 45.5 ± 8.7 61.5 ± 11.7 86.3 ± 10.1 23.2 ± 3.8
P value
0.216 b0.001 0.009 b0.001 0.002
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Table 2 The differences in biochemical markers, leptin, adiponectin, and total ghrelin levels among the olanzapine, clozapine and control groups.
Cholesterol (mg/dl) Triglyceride (mg/dl) Glucose (mg/dl) Leptin (ng/ml) Adiponectin (ng/ml) Total Ghrelin (pg/ml)
Control N = 119
Olanzapine N = 167
Clozapine N = 166
A
B
C
182.2 ± 29.6 90.2 ± 38.3 88.2 ± 10.1 5.4 ± 4.1 22.5 ± 14.3 1261.2 ± 1639.7
191.7 ± 36.6 156.3 ± 105.7 99.2 ± 31.6 15.6 ± 18.5 12.6 ± 10.4 618.3 ± 399.3
169.7 ± 33.4 128.6 ± 86.3 94.9 ± 22.0 10.8 ± 10.7 16.6 ± 12.4 863.5 ± 332.3
P value
b0.001 b0.001 0.001 b0.001 b0.001 b0.001
Tukey–Kramer post-hoc comparison, P-values A/B
A/C
B/C
0.048 b0.001 0.001 b0.001 b0.001 b0.001
0.007 0.001 0.061 0.002 b0.001 0.001
b0.001 0.01 0.231 0.004 0.005 0.039
ANOVAs were used for continuous variables. Multiple comparisons were determined using Tukey–Kramer post-hoc tests.
adiponectin (F = 17.67, df = 2, p b 0.001), and total ghrelin (F = 14.30, df = 2, p b 0.001) between the three groups. Post hoc Bonferroni multiple comparisons showed that the olanzapine group had the lowest level of adiponectin (vs. control group, p b 0.001; vs. clozapine group, p = 0.042) and total ghrelin (vs. control group, p b 0.001; vs. clozapine group, p = 0.039). Compared with the control group, the clozapine group had higher levels of leptin (vs. control group, p b 0.001), and lower levels of adiponectin (vs. control group, p b 0.001) and total ghrelin (vs. control group, p = 0.004). There was no significant difference in leptin levels between the clozapine and olanzapine groups. 4. Discussion The present study found that the use of olanzapine and clozapine was associated with changes in the levels of leptin, adiponectin, and total ghrelin, even after adjusting for potential confounding factors. Olanzapine had a greater influence on adipocytokines and total ghrelin than clozapine. Among the peptide hormones affecting metabolism, research of the relationship between leptin and antipsychotics is relatively well developed. The results of our study showed that leptin levels were significantly higher in olanzapine or clozapine treated subjects with schizophrenia than in healthy controls. This finding was consistent with previous studies. The data about the effects of different antipsychotics on the leptin levels are limited and controversial. Previous studies reported no significant differences in leptin levels between olanzapine and clozapine groups (Esen-Danaci et al., 2008; Kluge et al., 2009; Melkersson and Dahl, 2003; Tsai et al., 2011). However, Herran et al. (2001) reported that antipsychotics tended to exert different effects on leptin levels, and olanzapine induced a greater increase among SGAs. Our results showed the difference in leptin level between olanzapine and clozapine group disappeared after adjusting age and BMI. It might imply leptin changes were directly related to the weight gain liability of antipsychotics (Jin et al., 2008). Our results showed that olanzapine-treated subjects had the lowest adiponectin levels, followed by clozapine-treated subjects, and then healthy controls. In fact, the effects of antipsychotics on adiponectin changes are still inconclusive in the literature. Earlier studies did not find significant changes in adiponectin levels after antipsychotic treatment (Jin et al., 2008; Tsai et al., 2011). However, in a large cohort study including 567 patients with schizophrenia, the results showed that the adiponectin level was negatively correlated with BMI increase after initiation of antipsychotic treatment (Bai et al., 2009). Bai et al. (2009) also reported that the clozapine group had lower levels of adiponectin than did the olanzapine group, which was inconsistent with our findings. Our results showed that healthy controls had the highest total ghrelin levels, followed by clozapine-treated subjects, and then olanzapinetreated subjects. Relatively few studies investigated the association between antipsychotics use and ghrelin level, and their findings were inconsistent. However, the treatment duration of antipsychotics might have an important impact on ghrelin levels (Jin et al., 2008; Sentissi et al., 2008). Zhang et al. (2013) suggest a triphasic effect of SGAs on ghrelin levels:
an initial increase exerted by the acute up-regulatory effect of SGAs on ghrelin production; followed by a secondary decrease possibly due to the negative feedback from the SGA-induced increased body weight and food intake; and a final recovery of ghrelin levels back to the baseline levels or above to reach the new equilibrium. Furthermore, previous studies reported no differences in ghrelin levels among olanzapine-treated and clozapine-treated subjects (Esen-Danaci et al., 2008; Tsai et al., 2011). In our study, the group differences in adiponectin and total ghrelin levels remained significant after adjusting age and BMI. It might imply that the changes in adiponectin and total ghrelin levels appeared to be more the direct effect of antipsychotics on adiponectin and ghrelin pathway of energy homeostasis, rather than the result of weight gain. Our study results showed that olanzapine group had higher levels of cholesterol and triglycerides than the clozapine group. Among SGAs, clozapine and olanzapine had the highest potential to induce hyperlipidemia (Newcomer, 2007). In a 12-week randomized double-blind study it was reported that clozapine had the greater increases in cholesterol, triglyceride, and glucose than olanzapine (Krakowski et al., 2009). An 8-year prospective study showed both olanzapine and clozapine long-term treatments cause development of hyperglycemia and hyperlipidemia (Feng and Melkersson, 2012). Recent meta-analysis study showed no differences in metabolic side effects between clozapine and olanzapine (Rummel-Kluge et al., 2010). The presence of differences in adiponectin, total ghrelin, and lipid levels between patients treated with clozapine and olanzapine is an unexpected finding. One possible explanation is that clozapine and olanzapine had various receptor-binding profiles, and consequently different metabolic adversity potentials. It is the heterogeneous receptor binding pharmacology of the different antipsychotic medications that has been implicated in their varied risk of weight gain and related metabolic side effects. Histamine, dopamine, serotonin, glutamate, adrenergic and muscarinic receptor affinities have been suggested as possible factors associated with metabolic disturbances. (Deng et al., 2010; Nasrallah, 2008; Reynolds and Kirk, 2010). Clozapine and olanzapine have broad receptor-binding profiles of these receptors, and these multiple bindings have a cumulative effect on the metabolic adversity (Starrenburg and Bogers, 2009). Another possible explanation is that clozapine-treated patients had reached a plateau of metabolic changes before they received the current treatment regimen. Clozapine is often reserved to treat patients with refractory schizophrenia (Kane et al., 1988). Our subjects received other antipsychotic drugs before initiation of clozapine treatment. In chronic schizophrenic patients treated with multiple antipsychotics in the past, SGAs might not induce further changes in metabolic disturbances (Smith et al., 2012). These observations indicate that the effects of clozapine and olanzapine on adiponectin and ghrelin secretions still await more clarification. The current study also has some limitations. First, it is a crosssectional study. We could not interpret the causal relationships between antipsychotic use and adipocytokines in the cross-sectional design. Second, patients were not randomly assigned to treatment arms. Third, we failed to include other parameters, such as visceral fat assessment, dietary habits, physical activity levels and other metabolic parameters.
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