Arch Gen Psychiatry：抗精神病药物治疗导致严重的体重增加的相关基因

抗精神病药物越来越多地在美国人群中运用，但抗精神病药物会带来一系列副作用包括体重迅速增加，尤其是对儿童而言在Zucker Hillside医院和Feinstein医学研究中心的研究人员发现了一种基因与常用的抗精神病药物治疗引发的体重增加有关。这些研究结果发表在Archives of General Psychiatry杂志上。

这项研究针对第二代抗精神病药物开展。对第二代抗精神病药物是常用来治疗许多精神病和非(患)精神病的障碍。然而，要注意的是这些第二代抗精神病药物会导致体重大幅增加，包括肥胖和其他心血管危险因素。

二代抗精神病药物增加体重的副作用是非常明显的，因为它常常导致那些患有慢性和严重的精神疾病患者减少寿命高达至30年。体重的增加也促使一些患者停止服药，并严重影响他们的生活质量。

通过全基因组关联研究（GWAS），研究人员首先计算美国一组儿童首次接受抗精神病药物治疗的患者。

然后，他们在在精神病医院重复了三个独立的实验研究。MC4R基因或黑皮素4受体基因被确定为增加体重的主要原因，早期研究发现MC4R基因或黑皮素4受体基因与肥胖和2型糖尿病有关。

doi:10.1001/archgenpsychiatry.2012.191
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Association Between Common Variants Near the Melanocortin 4 Receptor Gene and Severe Antipsychotic Drug–Induced Weight Gain

Anil K. Malhotra, MD; Christoph U. Correll, MD; Nabilah I. Chowdhury, BSc; Daniel J. Müller, MD; Peter K. Gregersen, MD; Annette T. Lee, PhD; Arun K. Tiwari, PhD; John M. Kane, MD; W. Wolfgang Fleischhacker, MD; Rene S. Kahn, MD; Roel A. Ophoff, PhD; Jeffrey A. Lieberman, MD; Herbert Y. Meltzer, MD; Todd Lencz, PhD; James L. Kennedy, MD

Context  Second-generation antipsychotics (SGAs) are increasingly used in the treatment of many psychotic and nonpsychotic disorders. Unfortunately, SGAs are often associated with substantial weight gain, with no means to predict which patients are at greatest risk.

Objective  To identify single-nucleotide polymorphisms associated with antipsychotic drug–induced weight gain.

Design  Pharmacogenetic association study.

Setting  The discovery cohort was from a US general psychiatric hospital. Three additional cohorts were from psychiatric hospitals in the United States and Germany and from a European antipsychotic drug trial.

Participants  The discovery cohort consisted of 139 pediatric patients undergoing first exposure to SGAs. The 3 additional cohorts consisted of 73, 40, and 92 subjects.

Intervention  Patients in the discovery cohort were treated with SGAs for 12 weeks. Additional cohorts were treated for 6 and 12 weeks.

Main Outcome Measures  We conducted a genome-wide association study assessing weight gain associated with 12 weeks of SGA treatment in patients undergoing first exposure to antipsychotic drugs. We next genotyped 3 independent cohorts of subjects assessed for antipsychotic drug–induced weight gain.

Results  Our genome-wide association study yielded 20 single-nucleotide polymorphisms at a single locus exceeding a statistical threshold of P < 10–5. This locus, near the melanocortin 4 receptor (MC4R) gene, overlaps a region previously identified by large-scale genome-wide association studies of obesity in the general population. Effects were recessive, with minor allele homozygotes gaining extreme amounts of weight during the 12-week trial. These results were replicated in 3 additional cohorts, with rs489693 demonstrating consistent recessive effects; meta-analysis revealed a genome-wide significant effect (P = 5.59 x 10–12). Moreover, we observed consistent effects on related metabolic indices, including triglyceride, leptin, and insulin levels.

Conclusions  These data implicate MC4R in extreme SGA-induced weight gain and related metabolic disturbances. A priori identification of high-risk subjects could lead to alternative treatment strategies in this population.