METABOLIC EFFECTS OF ATYPICAL ANTIPSYCHOTICS

描述（由申请人提供）：在美国，非典型抗精神病药被广泛用于治疗精神分裂症、双相情感障碍和其他精神疾病。越来越多的证据表明，这些药物通常会导致体重大幅增加和空腹高血糖，并可能增加显性糖尿病和危及生命的糖尿病酮症酸中毒的风险。体重增加是糖尿病的已知风险因素，特别是如果体重增加反映了内脏肥胖的增加，但药物相关性糖尿病是在没有药物相关性肥胖的情况下发生的，或者是在药物相关性肥胖之前发生的。虽然这些药物可能会使许多人处于糖尿病的风险中，但人们对这些药物改变代谢以及肥胖和糖尿病发展的机制知之甚少。我们已经观察到，正常犬长期服用两种常用处方药会导致显著的代谢紊乱，包括肥胖，但未发生糖尿病。我们建议测试的假设，抗精神病药物引起糖尿病的诱导代谢紊乱的背景下增加的疾病的风险，如精神分裂症，在没有药物干预。将对已诱发糖尿病风险因素的犬给予药物-特别是中度胰岛素分泌缺陷或高脂肪饮食导致的内脏肥胖-以测试药物诱导的坦率糖尿病发展是否会在具有已知疾病风险因素的犬中发展。我们还建议进行研究，以确定这些药物导致体重增加的机制。我们将测试增加的热量摄入是否可以解释所有的体重增加，或者药物是否可以减少能量消耗，无论是在基础休息条件下还是通过减少与体力活动相关的能量输出。最后，虽然脑是非典型抗精神病药物的精神作用的明显部位，但介导这些药物引起的代谢紊乱的靶组织尚不清楚。我们提出了一系列的研究来确定非典型抗精神病药物是否通过中枢或外周机制来诱导肥胖、肝胰岛素抵抗和胰腺a细胞功能下降。研究这些药物的代谢效应对于了解接受精神药物治疗的患者患糖尿病的风险增加至关重要。

DESCRIPTION (provided by applicant): Atypical antipsychotics are widely prescribed to millions of people in the United States for treatment of schizophrenia, bipolar disorder and other psychiatric conditions. Evidence has been accumulating that these drugs often cause substantial weight gain and fasting hyperglycemia, and may confer increased risk for overt diabetes and life-threatening diabetic ketoacidosis. Weight gain is a known risk factor for diabetes, especially if increased weight reflects increase in visceral obesity, but drug-associated diabetes has occurred in the absence of, or develop prior to drug-related obesity. While these drugs may place many people at risk for diabetes, little is known about the mechanisms by which metabolism becomes altered by these drugs and obesity and diabetes develops. We have observed that chronic administration of two commonly prescribed drugs to normal dogs causes significant metabolic disturbances, including obesity, but diabetes did not develop. We propose to test the hypothesis that antipsychotics cause diabetes by inducing metabolic derangements over a backdrop of enhanced risk for the disease, such as that conferred by schizophrenia in the absence of pharmacologic intervention. Drugs will be given to dogs in which diabetic risk factors have been induced - specifically, modest insulin secretory defect or visceral adiposity resulting from high fat diet - to test whether that drug-induced development of frank diabetes would develop in dogs with known risk factors for the disease. We also propose studies to determine the mechanism by which these drugs cause weight gain. We will test whether increased caloric intake can account for all weight gain, or whether drugs act to decrease energy expenditure, either under basal resting conditions or by reducing energy output associated with physical activity. Finally, although the brain is the obvious site of the psychotropic action of atypical antipsychotics, the target tissues which mediate the metabolic disturbances caused by these drugs is not known. We propose a series of studies to determine whether atypical antipsychotics act via central or peripheral mechanisms to induce obesity, hepatic insulin resistance, and diminished pancreatic a-cell function. Studies of the metabolic effects of these agents are critical to understand the increased risk of diabetes in patients undergoing treatment with psychotropic medication.