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（由申请人提供）：事实证明，新的非典型抗精神病药在治疗精神病方面非常有效，但是，这些药物的一种非常令人震惊的副作用是体重增加过多。在人类中，已经表明，在治疗一年后，在10周的治疗期间，平均体重增加4至4.5 kg可能会增加近12公斤。体重的这种增加与葡萄糖耐受性和高血压受损的增加有关，因此可能会提高死亡率。目前，药物诱导的体重增加的机制目前尚不清楚。我们已经开发了一种小鼠模型，其中我们可以使用三种当前可用和常规的抗精神病药（Olanzapine，Quetiapine和Risperpidone）诱导体重增加。我们模型的体重增加是可重现的，并且在每天两次的口服处理中发生在四个星期之内。我们假设奥氮平和喹硫平和喹硫平通过增加食物摄入而产生的体重增加，利培酮通过减少能量消耗而产生的体重增加。我们进一步假设，这些药物诱导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有关的下丘脑基因表达模式的变化差异。最后，食物摄入，体重和/或身体成分中的改变，或者药物的直接作用会在体内产生胰岛素敏感性的降低。通过拟议的研究，我们将确定与这些药物相关的药物诱导的体重增加的机制。一旦知道，就可以尝试避免有害的副作用，或者至少让一个人更准确地考虑福利与风险，取决于存在其他混杂变量（肥胖，糖尿病和高血压的家族史）。