Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini (LC), 23842, Italy.
Department of Pharmacological Sciences, University of Padova (PD), 35131, Italy.
Trends Endocrinol Metab. 2019 Mar;30(3):189-210. doi: 10.1016/j.tem.2019.01.003. Epub 2019 Feb 1.
Antipsychotics frequently cause obesity and related metabolic disorders that current psychopharmacological/endocrinological theories do not explain consistently. An integrative/alternative theory implies metabolic alterations happening at the cellular level. Many observations in vitro and in vivo, and pivotal observations in humans, point towards chemical properties of antipsychotics, independent of receptor binding characteristics. Being amphiphilic weak bases, antipsychotics can disrupt lysosomal function, affecting cholesterol trafficking; moreover, by chemical mimicry, antipsychotics can inhibit cholesterol biosynthesis. These two molecular adverse effects may trigger a cascade of transcriptional and biochemical events, ultimately reducing available cholesterol while increasing cholesterol precursors and fatty acids. The macroscopic manifestation of these molecular alterations includes decreased high-density lipoprotein and increased very low-density lipoprotein and triglycerides that may translate into obesity and related metabolic disorders.
抗精神病药常导致肥胖和相关代谢紊乱，但目前的精神药理学/内分泌学理论并不能对此做出一致解释。一种综合/替代理论表明，代谢改变发生在细胞水平。许多体外和体内观察结果，以及人类的关键观察结果，都指向了抗精神病药的化学特性，而这些特性与受体结合特性无关。作为两亲性弱碱，抗精神病药可以破坏溶酶体功能，影响胆固醇转运；此外，通过化学模拟，抗精神病药可以抑制胆固醇的生物合成。这两种分子不良反应可能引发一连串的转录和生化事件，最终减少可用胆固醇，同时增加胆固醇前体和脂肪酸。这些分子改变的宏观表现包括高密度脂蛋白减少和极低密度脂蛋白和甘油三酯增加，这可能导致肥胖和相关代谢紊乱。
