Metformin (MET) has been reported to have antidepressant effects in animal models and in diabetic patients with depression, owing to its anti-inflammatory, antioxidant, and neuroprotective activity. Accordingly, we proposed that MET would show antidepressant effects in patients with major depressive disorder (MDD) without other comorbidities. In this double-blind placebo-controlled study, 80 adult outpatients with MDD (DSM-IV criteria) and a Hamilton Depression Rating Scale (HAM-D) score >18 were randomized to receive fluoxetine 20 mg once daily plus placebo (n = 40) or fluoxetine 20 mg once daily plus MET 1000 mg once daily for 12 weeks. Patients were assessed by HAM-D score (weeks 0, 4, 8, and 12). The serum levels of TNF–α, IL-1β, IL-6, IGF-1, MDA, CRP, BDNF, and serotonin were measured before and after therapy. Mixed-effects model repeated-measures analysis of covariance was used to compare the HAM-D scores and the biological markers between the two groups. After 4, 8 and 12 weeks, patients in the MET group showed a statistically significant decline in HAM-D score relative to the placebo group (least squares mean difference [LSMD] –2.347, p = 0.000, LSMD –3.369, p = 0.000, and LSMD –3.454, p = 0.000, respectively). Response and remission rates were significantly higher in the MET group (89% and 81%, respectively) than in the placebo group (59% and 46%, respectively). Moreover, the MET group was superior in conserving the measured biological markers compared with the placebo group. Our findings suggest MET as a promising, effective, and safe short-term adjunctive approach in nondiabetic MDD patients. Trial registration ID: NCT04088448.

据报道，二甲双胍 (MET) 在动物模型和患有抑郁症的糖尿病患者中具有抗抑郁作用，因为它具有抗炎、抗氧化和神经保护活性。因此，我们提出 MET 将在没有其他合并症的重度抑郁症 (MDD) 患者中显示出抗抑郁作用。在这项双盲安慰剂对照研究中，80 名患有 MDD（DSM-IV 标准）且汉密尔顿抑郁评定量表（HAM-D）评分 >18 的成年门诊患者被随机分配接受氟西汀 20 mg 每日一次加安慰剂（n = 40) 或氟西汀 20 毫克，每天一次，加 MET 1000 毫克，每天一次，持续 12 周。通过 HAM-D 评分（第 0、4、8 和 12 周）对患者进行评估。治疗前后测定血清 TNF-α、IL-1β、IL-6、IGF-1、MDA、CRP、BDNF 和 5-羟色胺水平。使用协方差的混合效应模型重复测量分析来比较两组之间的HAM-D评分和生物标志物。4、8 和 12 周后，与安慰剂组相比，MET 组患者的 HAM-D 评分显着下降（最小二乘均值差 [LSMD] –2.347，p  = 0.000，LSMD –3.369，p  = 0.000 , 和 LSMD –3.454, p = 0.000，分别）。MET 组的缓解率和缓解率（分别为 89% 和 81%）显着高于安慰剂组（分别为 59% 和 46%）。此外，与安慰剂组相比，MET 组在保存测量的生物标志物方面更胜一筹。我们的研究结果表明 MET 是非糖尿病 MDD 患者的一种有前途、有效且安全的短期辅助方法。试用注册号：NCT04088448。