Feng Yaning, Wong Kenneth Chi-Yin, Leung Perry Bok-Man, Lee Benedict Ka-Wa, Sham Pak-Chung, Lui Simon Sai-Yu, So Hon-Cheong
School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, China.
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
Psychol Med. 2025 Apr 28;55:e123. doi: 10.1017/S0033291725000935.
Second-generation antipsychotics (SGAs) cause metabolic side effects. However, patients' metabolic profiles were influenced by time-invariant and time-varying confounders. Real-world evidence on the long-term, dynamic effects of SGAs (e.g. different treatment sequences) are limited. We employed advanced causal inference methods to evaluate the metabolic impact of SGAs in a naturalistic cohort.
We followed 696 Chinese patients with schizophrenia-spectrum disorders receiving SGAs. Longitudinal targeted maximum likelihood estimation (LTMLE) was used to estimate the average treatment effects (ATEs) of continuous SGA treatment versus 'no treatment' on metabolic outcomes, including total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), fasting glucose (FG), and body mass index (BMI), over 6-18 months at 3-month intervals. LTMLE accounted for time-invariant and time-varying confounders. Post-SGA discontinuation side effects were also assessed.
The ATEs of continuous SGA treatment on BMI and TG showed an inverted U-shaped pattern, peaking at 12 months and declining afterwards. Similar patterns were observed for TC and LDL, albeit the ATEs peaked at 15 months. For FG and HDL, the ATEs peaked at ~6 months. The adverse impact of SGAs on BMI persisted even after medication discontinuation, yet other metabolic parameters did not show such lingering side effects. Clozapine and olanzapine exhibited greater metabolic side effects compared to other SGAs.
Our real-world study suggests that metabolic side effects may stabilize with prolonged continuous treatment. Clozapine and olanzapine confer higher cardiometabolic risks than other SGAs. The side effects of SGAs on BMI may persist after drug discontinuation. These insights may guide antipsychotic choice and improve management of metabolic side effects.
第二代抗精神病药物（SGA）会引发代谢副作用。然而，患者的代谢状况受到时不变和时变混杂因素的影响。关于SGA长期动态影响（如不同治疗顺序）的真实世界证据有限。我们采用先进的因果推断方法，在一个自然队列中评估SGA对代谢的影响。
我们对696名接受SGA治疗的中国精神分裂症谱系障碍患者进行了随访。采用纵向靶向最大似然估计（LTMLE）来估计连续SGA治疗与“未治疗”相比，在6至18个月内每隔3个月对包括总胆固醇（TC）、高密度脂蛋白（HDL）、低密度脂蛋白（LDL）、甘油三酯（TG）、空腹血糖（FG）和体重指数（BMI）在内的代谢指标的平均治疗效果（ATE）。LTMLE考虑了时不变和时变混杂因素。还评估了停用SGA后的副作用。
连续SGA治疗对BMI和TG的ATE呈倒U形模式，在12个月时达到峰值，随后下降。TC和LDL也观察到类似模式，尽管ATE在15个月时达到峰值。对于FG和HDL，ATE在约6个月时达到峰值。即使停药后，SGA对BMI的不良影响仍然存在，但其他代谢参数未显示出这种持续的副作用。与其他SGA相比，氯氮平和奥氮平表现出更大的代谢副作用。
我们的真实世界研究表明，长期持续治疗可能使代谢副作用趋于稳定。氯氮平和奥氮平比其他SGA带来更高的心脏代谢风险。SGA对BMI的副作用在停药后可能持续存在。这些见解可能指导抗精神病药物的选择，并改善代谢副作用的管理。
