Antipsychotic drug-induced weight gain

描述(申请人提供)：新的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。在人类中，已经表明，在10周的治疗期间，平均体重可以增加4到4.5公斤，而在治疗一年后，体重可以增加近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。药物导致体重增加的机制目前尚不清楚。我们已经开发了一个小鼠模型，在这个模型中，我们可以用目前可用的和常用的三种抗精神病药物(奥氮平、奎硫平和利培酮)来诱导体重增加。在我们的模型中，体重增加是可重复性的，每天两次口服治疗在四周内发生。我们假设奥氮平和奎硫平通过增加食物摄入量而增加体重，而利培酮通过减少能量消耗而增加体重。我们进一步假设，这些药物引起的食物摄入量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不同变化所致。最后，无论是食物摄入量、体重和/或身体成分的改变，还是药物的直接作用，都会导致体内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体重增加的机制。一旦知道，可以尝试避免有害的副作用，或者至少允许人们更准确地考虑益处与风险，这取决于其他混杂变量的存在(肥胖、糖尿病和高血压的家族病史)。

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).