Carli Marco, Kolachalam Shivakumar, Longoni Biancamaria, Pintaudi Anna, Baldini Marco, Aringhieri Stefano, Fasciani Irene, Annibale Paolo, Maggio Roberto, Scarselli Marco
Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy.
Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
Pharmaceuticals (Basel). 2021 Mar 8;14(3):238. doi: 10.3390/ph14030238.
Atypical antipsychotics (AAPs) are commonly prescribed medications to treat schizophrenia, bipolar disorders and other psychotic disorders. However, they might cause metabolic syndrome (MetS) in terms of weight gain, dyslipidemia, type 2 diabetes (T2D), and high blood pressure, which are responsible for reduced life expectancy and poor adherence. Importantly, there is clear evidence that early metabolic disturbances can precede weight gain, even if the latter still remains the hallmark of AAPs use. In fact, AAPs interfere profoundly with glucose and lipid homeostasis acting mostly on hypothalamus, liver, pancreatic β-cells, adipose tissue, and skeletal muscle. Their actions on hypothalamic centers via dopamine, serotonin, acetylcholine, and histamine receptors affect neuropeptides and 5'AMP-activated protein kinase (AMPK) activity, thus producing a supraphysiological sympathetic outflow augmenting levels of glucagon and hepatic glucose production. In addition, altered insulin secretion, dyslipidemia, fat deposition in the liver and adipose tissues, and insulin resistance become aggravating factors for MetS. In clinical practice, among AAPs, olanzapine and clozapine are associated with the highest risk of MetS, whereas quetiapine, risperidone, asenapine and amisulpride cause moderate alterations. The new AAPs such as ziprasidone, lurasidone and the partial agonist aripiprazole seem more tolerable on the metabolic profile. However, these aspects must be considered together with the differences among AAPs in terms of their efficacy, where clozapine still remains the most effective. Intriguingly, there seems to be a correlation between AAP's higher clinical efficacy and increase risk of metabolic alterations. Finally, a multidisciplinary approach combining psychoeducation and therapeutic drug monitoring (TDM) is proposed as a first-line strategy to avoid the MetS. In addition, pharmacological treatments are discussed as well.
非典型抗精神病药物（AAPs）是常用于治疗精神分裂症、双相情感障碍和其他精神障碍的药物。然而，它们可能会导致代谢综合征（MetS），表现为体重增加、血脂异常、2型糖尿病（T2D）和高血压，这些都会导致预期寿命缩短和依从性差。重要的是，有明确证据表明，即使体重增加仍是使用AAPs的标志，但早期代谢紊乱可能先于体重增加出现。事实上，AAPs主要通过作用于下丘脑、肝脏、胰腺β细胞、脂肪组织和骨骼肌，对葡萄糖和脂质稳态产生深远影响。它们通过多巴胺、5-羟色胺、乙酰胆碱和组胺受体作用于下丘脑中心，影响神经肽和5'AMP激活蛋白激酶（AMPK）的活性，从而产生超生理水平的交感神经输出，增加胰高血糖素水平和肝脏葡萄糖生成。此外，胰岛素分泌改变、血脂异常、肝脏和脂肪组织中的脂肪沉积以及胰岛素抵抗都成为MetS的加重因素。在临床实践中，在AAPs中，奥氮平和氯氮平与MetS的风险最高相关，而喹硫平、利培酮、阿塞那平和氨磺必利会引起中度改变。齐拉西酮、鲁拉西酮等新型AAPs以及部分激动剂阿立哌唑在代谢方面似乎更可耐受。然而，这些方面必须与AAPs在疗效方面的差异一起考虑，其中氯氮平仍然是最有效的。有趣的是，AAPs较高的临床疗效与代谢改变风险增加之间似乎存在相关性。最后，提出了一种将心理教育和治疗药物监测（TDM）相结合的多学科方法作为避免MetS的一线策略。此外，还讨论了药物治疗。
