Effects of Low Dose Metformin on Metabolic Traits in Clozapine-Treated Schizophrenia Patients: An Exploratory Twelve-Week Randomized, Double-Blind, Placebo-Controlled Study

Background
Metformin has been used for alleviating metabolic abnormalities in patients with schizophrenia. The lowest dose of metformin to treat metabolic abnormalities in clozapine-treated patients is 1000 mg/d. This study was designed to determine whether metformin at 500 mg/d and 1000 mg/d is effective in improving the metabolic profiles of clozapine-treated patients with pre-existing metabolic abnormalities, and whether its effectiveness depends on metformin dosage.
Methods
In this 12-week, randomized, double-blind, placebo-controlled trial, metformin at 500 mg/d or 1000 mg/d was prescribed to clozapine-treated patients with schizophrenia who had pre-existing metabolic abnormalities. The recruited patients underwent physical and laboratory evaluations at weeks 4, 8, and 12. The outcomes were any changes in metabolic traits.
Results
Among the 96 clozapine-treated patients with schizophrenia screened for the trial, 55 patients with pre-existing metabolic abnormalities were randomly assigned to placebo (n = 18), metformin dosage at 500 mg/d (n = 18), and metformin dosage at 1000 mg/d (n = 19) groups. The body weight (BW) of patients in the metformin 1000 mg/d group significantly decreased, by a mean of 0.97 kg over the 12 week trial period. Moreover, patients in the metformin at 500 mg/d and 1000 mg/d groups had a significant decrease in body mass index (BMI) after 12 weeks, with the mean decrease being 0.70 and 0.50 kg/m2, respectively. No significant changes were observed in the other metabolic parameters of patients in the three groups.
Conclusions
Our results demonstrated that a low metformin dosage of either 500 mg/d or 1000 mg/d for 12 weeks slightly reduced the BW and BMI of clozapine-treated patients with pre-existing metabolic abnormalities. A longer period of treatment with a larger sample is warranted to determine the factors that influence the metformin treatment response.
Trial Registration
ClinicalTrials.gov NCT02751307

背景
二甲双胍（Metformin）已被用于缓解精神分裂症患者的代谢异常。针对接受氯氮平（Clozapine）治疗的患者，治疗代谢异常所需的二甲双胍最低剂量为1000 mg/d。本研究旨在探讨500 mg/d与1000 mg/d剂量的二甲双胍，能否改善接受氯氮平治疗且既往存在代谢异常的精神分裂症患者的代谢谱，并明确其疗效是否依赖于二甲双胍给药剂量。

方法
本研究为为期12周的随机双盲安慰剂对照试验，将500 mg/d或1000 mg/d剂量的二甲双胍，给予接受氯氮平治疗且既往存在代谢异常的精神分裂症患者。入组患者分别于第4、8、12周接受体格检查与实验室检测。研究结局指标为代谢特征的各项变化。

结果
本试验共筛查96例接受氯氮平治疗的精神分裂症患者，最终55例既往存在代谢异常的患者被随机分配至安慰剂组（n=18）、500 mg/d二甲双胍组（n=18）与1000 mg/d二甲双胍组（n=19）。在12周试验周期内，1000 mg/d二甲双胍组患者的体质量（Body Weight, BW）显著下降，平均降幅达0.97 kg。此外，500 mg/d与1000 mg/d二甲双胍组患者在12周后体质量指数（Body Mass Index, BMI）均显著降低，平均降幅分别为0.70 kg/m²与0.50 kg/m²。三组患者其余代谢参数均未观察到显著变化。

结论
本研究结果显示，对于接受氯氮平治疗且既往存在代谢异常的精神分裂症患者，500 mg/d或1000 mg/d低剂量二甲双胍连续治疗12周，可轻度降低其体质量与体质量指数。未来需开展更大样本量、更长治疗周期的研究，以明确影响二甲双胍治疗应答的相关因素。

试验注册
ClinicalTrials.gov 编号：NCT02751307