Antipsychotic drug-induced weight gain

抗精神病药物引起的体重增加

• 批准号: 6894031
• 负责人: TIMOTHY R NAGY
• 金额: $ 26.18万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6894031
• 关键词: antipsychotic agents; bioenergetics; body composition; calorimetry; dietary lipid; disease /disorder model; drug administration rate /duration; drug adverse effect; gene expression; glucose clamp technique; hyperinsulinism; hypothalamus; insulin sensitivity /resistance; laboratory mouse; microarray technology; nutrient intake activity; nutrition related tag; pharmacokinetics; photon absorptiometry; risperidone; serotonin inhibitor; weight gain

DESCRIPTION (provided by applicant): The new atypical antipsychotic drugs have proven to be very effective in the treatment of psychoses, however, one very alarming side effect of these drugs is excessive weight gain. In humans it has been shown that average weight gains of 4 to 4.5 kg can occur during a 10-week treatment period to nearly a 12 kg increase after one year of treatment. This increase in body weight is associated with an increase in impaired glucose tolerance and hypertension and therefore is likely to increase mortality rates. The mechanisms involved in the drug-induced weight gain are currently unknown. We have developed a mouse model in which we can induce weight gain with three of the currently available and commonly prescribed antipsychotic drugs (olanzapine, quetiapine, and risperidone). Weight gain in our model is reproducible and occurs within four weeks using twice-daily oral treatment. We hypothesize that olanzapine and quetiapine produce weight gain via increased food intake and risperidone produces weight gain by decreasing energy expenditure. We further hypothesize that these drug-induced changes in food intake and energy expenditure are due to differential changes in hypothalamic gene expression patterns relating to alternative mechanisms of regulating energy balance. Lastly, alterations either in food intake, body weight, and/or body composition, or the direct action of the drugs will produce decreases in insulin sensitivity in vivo. With the proposed studies, we will determine the mechanisms of drug-induced weight gain associated with these drugs. Once known, attempts could be made to avoid the deleterious side effects, or at least allow one to more accurately consider benefits versus risks dependent upon the presence of other confounding variables (family history of obesity, diabetes, and hypertension).

描述（申请人提供）：新型非典型抗精神病药物已被证明在治疗精神病方面非常有效，然而，这些药物的一个非常令人担忧的副作用是体重过度增加。研究表明，在人类中，10 周的治疗期间体重平均增加 4 至 4.5 公斤，治疗一年后体重增加近 12 公斤。体重的增加与糖耐量受损和高血压的增加有关，因此可能会增加死亡率。目前尚不清楚药物引起的体重增加的机制。我们开发了一种小鼠模型，在该模型中，我们可以使用三种目前可用的常用抗精神病药物（奥氮平、喹硫平和利培酮）诱导体重增加。我们的模型中的体重增加是可重复的，并且使用每日两次口服治疗可在四个星期内发生。我们假设奥氮平和喹硫平通过增加食物摄入来增加体重，而利培酮通过减少能量消耗来增加体重。我们进一步假设这些药物引起的食物摄入和能量消耗的变化是由于与调节能量平衡的替代机制相关的下丘脑基因表达模式的差异变化所致。最后，食物摄入量、体重和/或身体成分的改变，或药物的直接作用将导致体内胰岛素敏感性降低。通过拟议的研究，我们将确定与这些药物相关的药物引起的体重增加的机制。一旦知道，就可以尝试避免有害的副作用，或者至少允许人们根据其他混杂变量（肥胖、糖尿病和高血压的家族史）的存在，更准确地考虑收益与风险。