A Double Blind, Placebo-Controlled, Randomized Crossover Study of the Acute Metabolic Effects of Olanzapine in Healthy Volunteers

Background and RationaleAtypical antipsychotics exhibit metabolic side effects including diabetes mellitus and obesity. The adverse events are preceded by acute worsening of oral glucose tolerance (oGTT) along with reduced plasma free fatty acids (FFA) and leptin in animal models. It is unclear whether the same acute effects occur in humans. Methodology/Principal FindingsA double blind, randomized, placebo-controlled crossover trial was conducted to examine the potential metabolic effects of olanzapine in healthy volunteers. Participants included male (8) and female (7) subjects [18–30 years old, BMI 18.5–25]. Subjects received placebo or olanzapine (10 mg/day) for three days prior to oGTT testing. Primary endpoints included measurement of plasma leptin, oral glucose tolerance, and plasma free fatty acids (FFA). Secondary metabolic endpoints included: triglycerides, total cholesterol, high- and low-density lipoprotein cholesterol, heart rate, blood pressure, body weight and BMI. Olanzapine increased glucose Area Under the Curve (AUC) by 42% (2808±474 vs. 3984±444 mg/dl·min; P = 0.0105) during an oGTT. Fasting plasma leptin and triglycerides were elevated 24% (Leptin: 6.8±1.3 vs. 8.4±1.7 ng/ml; P = 0.0203) and 22% (Triglycerides: 88.9±10.1 vs. 108.2±11.6 mg/dl; P = 0.0170), whereas FFA and HDL declined by 32% (FFA: 0.38±0.06 vs. 0.26±0.04 mM; P = 0.0166) and 11% (54.2±4.7 vs. 48.9±4.3 mg/dl; P = 0.0184), respectively after olanzapine. Other measures were unchanged. Conclusions/SignificanceOlanzapine exerts some but not all of the early endocrine/metabolic changes observed in rodent models of the metabolic side effects, and this suggest that antipsychotic effects are not limited to perturbations in glucose metabolism alone. Future prospective clinical studies should focus on identifying which reliable metabolic alterations might be useful as potential screening tools in assessing patient susceptibility to weight gain and diabetes caused by atypical antipsychotics. Trial RegistrationClinicalTrials.gov NCT00741026

背景与研究依据
非典型抗精神病药（atypical antipsychotics）可引发包括糖尿病与肥胖在内的代谢不良反应。在动物模型中，此类不良事件发生前会出现口服葡萄糖耐量试验（oral glucose tolerance test, oGTT）急性恶化，同时血浆游离脂肪酸（plasma free fatty acids, FFA）与瘦素（leptin）水平降低。目前尚不清楚人类是否会出现相同的急性效应。

研究方法与主要结果
本研究采用双盲、随机、安慰剂对照交叉试验，探究奥氮平（olanzapine）对健康志愿者的潜在代谢影响。受试者包含8名男性与7名女性，年龄介于18至30岁，体重指数（body mass index, BMI）为18.5~25。受试者在进行oGTT检测前3日每日服用安慰剂或奥氮平（10mg/天）。主要终点指标包括血浆瘦素、口服葡萄糖耐量以及血浆游离脂肪酸（FFA）的检测。次要代谢终点指标涵盖：甘油三酯、总胆固醇、高密度脂蛋白胆固醇（high-density lipoprotein cholesterol, HDL）与低密度脂蛋白胆固醇（low-density lipoprotein cholesterol, LDL）、心率、血压、体重及BMI。

奥氮平可使oGTT过程中的葡萄糖曲线下面积（Area Under the Curve, AUC）升高42%（2808±474 vs. 3984±444 mg/dl·min; P = 0.0105）。空腹血浆瘦素与甘油三酯分别升高24%（瘦素：6.8±1.3 vs. 8.4±1.7 ng/ml; P = 0.0203）与22%（甘油三酯：88.9±10.1 vs. 108.2±11.6 mg/dl; P = 0.0170），而FFA与HDL分别下降32%（FFA：0.38±0.06 vs. 0.26±0.04 mM; P = 0.0166）与11%（54.2±4.7 vs. 48.9±4.3 mg/dl; P = 0.0184），其余检测指标无显著变化。

结论与意义
奥氮平可引发啮齿类动物代谢不良反应模型中观察到的部分而非全部早期内分泌/代谢变化，这提示抗精神病药物的影响并非仅局限于葡萄糖代谢紊乱。未来的前瞻性临床研究应聚焦于识别哪些可靠的代谢改变可作为潜在筛查工具，用于评估患者发生非典型抗精神病药所致体重增加与糖尿病的易感性。

试验注册
ClinicalTrials.gov NCT00741026