Hai-Yan Yuan1, Hai-Xia Liang1, Guang-Rong Liang2, Gui-Xiang Zhang3, Huan-De Li1. 1. Clinical Pharmacy and Pharmacology Research Institute, Second Xiangya Hospital, Central South University, Changsha, China. 2. Department of Pharmacy, Nanhua Hospital, Nanhua University, Hengyang, China. 3. School of Pharmaceutical Sciences, Central South University, Changsha, China.
Abstract
BACKGROUND: Clozapine has been associated with metabolic adverse events (AEs) (eg, elevated body weight, blood glucose concentrations, cholesterol, triglycerides [TG]), all of which have deleterious effects on health and medication compliance. However, little focus has been directed toward finding a suitable experimental model to study the metabolic AEs associated with clozapine. OBJECTIVE: The aim of this study was to assess the effects of clozapine administration for 28 days on body weight, glucose tolerance, blood glucose concentrations, plasma lipids, and insulin in C57BL/6 mice. METHODS: C57BL/6 mice were grouped and treated with clozapine 2 or 10 mg/kg or vehicle intraperitoneally QD for 28 days. Body weight was assessed on days 0 (baseline), 7, 14, 21, and 28, and glucose tolerance, blood glucose concentrations, insulin (calculated by insulin resistance index [IRI]), and plasma lipids (including total cholesterol, TG, high-density lipoprotein cholesterol [HDL-C], and low-density lipoprotein cholesterol) were assessed on day 29. RESULTS: Sixty 10-week-old, male C57BL/6 mice were included in the study and were divided into 3 groups (20 mice per group). The body weight significantly decreased in the clozapine 10-mg-treated group on days 14, 21, and 28 compared with the vehicle group (mean [SD] body weight: 21.61 [1.05] vs 22.79 [1.11], 22.53 [1.05] vs 24.17 [1.24], and 22.21 [1.07] vs 24.99 [1.39] g, respectively; all, P < 0.05). In the clozapine 10-mg/kg group, blood glucose concentrations significantly increased 0, 30, 60, and 120 minutes after glucose administration compared with the vehicle group (mean [SD]: 6.67 [1.25], 25.34 [5.85], 12.68 [3.39], and 7.52 [1.45] mmol/L, respectively, vs 4.61 [0.78], 21.54 [6.55], 11.46 [3.46], and 6.55 [1.42] mmol/L, respectively; all P < 0.05). The clozapine 10-mg/kg group also had significant increases in plasma insulin concentrations compared with the vehicle group (12.70 [5.27] vs 7.62 [4.54] μIU/mL; P < 0.05) and IRI (3.01 [1.26] vs 1.51 [0.96]; P < 0.05). Plasma HDL-C concentration also significantly decreased in the clozapine 10-mg/kg group compared with the vehicle group (1.23 [0.25] vs 1.47 [0.16]; P < 0.05). CONCLUSION: Clozapine 10 mg/kg was associated with significant decreases in body weight and significant increases in fasting blood glucose and glucose tolerance in these male C57BL/6 mice.
BACKGROUND:Clozapine has been associated with metabolic adverse events (AEs) (eg, elevated body weight, blood glucose concentrations, cholesterol, triglycerides [TG]), all of which have deleterious effects on health and medication compliance. However, little focus has been directed toward finding a suitable experimental model to study the metabolic AEs associated with clozapine. OBJECTIVE: The aim of this study was to assess the effects of clozapine administration for 28 days on body weight, glucose tolerance, blood glucose concentrations, plasma lipids, and insulin in C57BL/6 mice. METHODS: C57BL/6 mice were grouped and treated with clozapine 2 or 10 mg/kg or vehicle intraperitoneally QD for 28 days. Body weight was assessed on days 0 (baseline), 7, 14, 21, and 28, and glucose tolerance, blood glucose concentrations, insulin (calculated by insulin resistance index [IRI]), and plasma lipids (including total cholesterol, TG, high-density lipoprotein cholesterol [HDL-C], and low-density lipoprotein cholesterol) were assessed on day 29. RESULTS: Sixty 10-week-old, male C57BL/6 mice were included in the study and were divided into 3 groups (20 mice per group). The body weight significantly decreased in the clozapine 10-mg-treated group on days 14, 21, and 28 compared with the vehicle group (mean [SD] body weight: 21.61 [1.05] vs 22.79 [1.11], 22.53 [1.05] vs 24.17 [1.24], and 22.21 [1.07] vs 24.99 [1.39] g, respectively; all, P < 0.05). In the clozapine 10-mg/kg group, blood glucose concentrations significantly increased 0, 30, 60, and 120 minutes after glucose administration compared with the vehicle group (mean [SD]: 6.67 [1.25], 25.34 [5.85], 12.68 [3.39], and 7.52 [1.45] mmol/L, respectively, vs 4.61 [0.78], 21.54 [6.55], 11.46 [3.46], and 6.55 [1.42] mmol/L, respectively; all P < 0.05). The clozapine 10-mg/kg group also had significant increases in plasma insulin concentrations compared with the vehicle group (12.70 [5.27] vs 7.62 [4.54] μIU/mL; P < 0.05) and IRI (3.01 [1.26] vs 1.51 [0.96]; P < 0.05). Plasma HDL-C concentration also significantly decreased in the clozapine 10-mg/kg group compared with the vehicle group (1.23 [0.25] vs 1.47 [0.16]; P < 0.05). CONCLUSION:Clozapine 10 mg/kg was associated with significant decreases in body weight and significant increases in fasting blood glucose and glucose tolerance in these male C57BL/6 mice.
Authors: Donna A Wirshing; Jennifer A Boyd; Laura R Meng; Jacob S Ballon; Stephen R Marder; William C Wirshing Journal: J Clin Psychiatry Date: 2002-10 Impact factor: 4.384
Authors: David C Henderson; Enrico Cagliero; Paul M Copeland; Christina P Borba; Anne Eden Evins; Doug Hayden; Mary T Weber; Ellen J Anderson; David B Allison; Tara B Daley; David Schoenfeld; Donald C Goff Journal: Arch Gen Psychiatry Date: 2005-01