Department of Psychiatry, Queen's University Belfast, Belfast BT9 7BL, UK.
Pharmacol Ther. 2010 Jan;125(1):169-79. doi: 10.1016/j.pharmthera.2009.10.010. Epub 2009 Nov 17.
Obesity and metabolic syndrome, with increased risk of eventual cardiovascular disease and type II diabetes, are significant problems for patients receiving antipsychotic drugs and are likely contribute to their decreased life expectancy. Several drug-related mechanisms may contribute to these problems, including effects both influencing food intake and on glucose and lipid metabolism. The metabolic consequences of different antipsychotic drugs vary substantially; these variations reflect differences in receptor pharmacology and provide clues as to the underlying pharmacological mechanisms. The two drugs with the greatest effects on body weight, olanzapine and clozapine, also have high affinity for the 5-HT2C and histamine H1 receptors, which implicate these receptors in antipsychotic-induced weight gain, while peripheral M3 muscarinic receptor antagonism as well as central 5-HT2C effects may contribute to obesity-independent diabetes. Other receptor mechanisms may have additive or synergistic effects; dopamine D2 receptor antagonism can enhance 5-HT2C-mediated effects on food intake, as well as influencing lipid and glucose metabolism via disinhibition of prolactin secretion. Pharmacogenetic associations of drug-induced weight gain with 5-HT2C receptor and leptin gene polymorphisms, among others, have provided further clues. Elevated leptin secretion in the absence of a decrease in food intake indicates drug-induced leptin insensitivity in the hypothalamus. The minimal weight gain seen with ziprasidone and aripiprazole may reflect their having further pharmacological effects that protect against changes in food intake and related metabolic factors. Understanding the pharmacology of metabolic consequences of current antipsychotic drug treatment is clearly the key to developing improved pharmacotherapies that avoid these problematic and limiting adverse effects.
肥胖和代谢综合征会增加患者患心血管疾病和 2 型糖尿病的风险，这对接受抗精神病药物治疗的患者来说是一个重大问题，可能导致他们的预期寿命缩短。一些与药物相关的机制可能导致这些问题，包括影响食物摄入以及葡萄糖和脂质代谢的作用。不同抗精神病药物的代谢后果有很大差异；这些差异反映了受体药理学的差异，并为潜在的药理学机制提供了线索。对体重影响最大的两种药物，奥氮平和氯氮平，也对 5-HT2C 和组胺 H1 受体具有高亲和力，这表明这些受体与抗精神病药引起的体重增加有关，而外周 M3 毒蕈碱受体拮抗作用以及中枢 5-HT2C 作用可能与肥胖无关的糖尿病有关。其他受体机制可能具有相加或协同作用；多巴胺 D2 受体拮抗作用可以增强 5-HT2C 介导的食物摄入作用，以及通过抑制催乳素分泌来影响脂质和葡萄糖代谢。药物引起的体重增加与 5-HT2C 受体和瘦素基因多态性等药物遗传学关联提供了进一步的线索。在没有减少食物摄入的情况下，瘦素分泌增加表明下丘脑存在药物诱导的瘦素不敏感。齐拉西酮和阿立哌唑的体重增加最小，这可能反映了它们具有进一步的药理学作用，可以防止食物摄入和相关代谢因素的变化。显然，了解当前抗精神病药物治疗代谢后果的药理学是开发避免这些有问题和限制不良影响的改良药物治疗的关键。
