METABOLIC EFFECTS OF ATYPICAL ANTIPSYCHOTICS

非典型抗精神病药的代谢作用

• 批准号: 6925031
• 负责人: MARILYN ADER
• 金额: $ 44.69万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6925031
• 关键词: antipsychotic agents; bioenergetics; caloric dietary content; diabetes risk; dogs; drug adverse effect; drug related diabetes mellitus; insulin sensitivity /resistance; pancreatic islet function; pharmacokinetics; weight gain

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.

描述(申请人提供)：非典型抗精神病药物在美国被广泛开给数百万人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，并可能增加患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在没有药物相关性肥胖的情况下发生，或在药物相关性肥胖之前发生。虽然这些药物可能会让许多人面临患糖尿病的风险，但人们对这些药物改变新陈代谢、导致肥胖和糖尿病的机制知之甚少。我们观察到，对正常狗长期服用两种常用的处方药会导致显著的代谢紊乱，包括肥胖，但没有发生糖尿病。我们建议测试这一假设，即抗精神病药物通过在疾病风险增加的背景下诱导代谢紊乱而导致糖尿病，例如在缺乏药物干预的情况下精神分裂症所致的疾病。药物将用于那些已经诱发糖尿病危险因素的狗，具体地说，是适度的胰岛素分泌缺陷或高脂肪饮食引起的内脏肥胖，以测试药物诱导的坦率糖尿病的发展是否会在具有已知疾病危险因素的狗身上发展。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。我们将测试增加的卡路里摄入量是否可以解释所有的体重增加，或者药物是否在基础休息条件下或通过减少与体力活动相关的能量输出来降低能量消耗。最后，尽管大脑是非典型抗精神病药物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。我们提出了一系列研究，以确定非典型抗精神病药物是否通过中枢或外周机制诱导肥胖、肝脏胰岛素抵抗和胰腺a细胞功能减弱。对这些药物的代谢影响的研究对于了解接受精神药物治疗的患者患糖尿病风险增加至关重要。