Secondary Research Project: Monoamine Transporter Occupancy

二级研究项目：单胺转运蛋白占用

• 批准号: 7892513
• 负责人: MICHAEL JOSEPH OWENS
• 金额: $ 21.44万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892513
• 关键词: Antidepressive Agents; Biological Assay; Blood specimen; Brain; Cells; Clinical; Data; Development; Dose; Emission-Computed Tomography; Escitalopram; Exhibits; Financial cost; Functional disorder; Goals; Human; Image; Imaging technology; Measures; Methods; Monitor; Norepinephrine; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Photons; Physicians; Positron-Emission Tomography; Research Project Grants; Selective Serotonin Reuptake Inhibitor; Serotonin; Serum; Techniques; Technology; Therapeutic; Validation; base; compliance behavior; dopamine transporter; dosage; experience; in vivo; molecular site; monoamine; response; serotonin transporter; tool; treatment response; uptake

Until now, determining whether patients were receiving an adequate dose of a given antidepressant medication was based almost exclusively upon the experience of the prescribing physician. Recently in vivo imaging technology with PET (positron emission tomography) and SPECT (single photon emission computed tomography) are emerging as new tools for assessment and optimization of pharmacological treatment (e.g. monitor adequacy of dosing), psychiatric medication development, and basic understanding of the pathophysiology of psychiatric illness. However, these techniques are associated with limited availability and significant financial costs that preclude the availability of this technology to the vast majority of clinicians. The goal of this project is to provide a valid and simpler alternative (an assay using a human blood sample) to PET imaging to furnish similar in vivo molecular site occupancy data. Briefly, it now appears that most SSRI antidepressants block approximately 80% of their target serotonin transporters (SERT) at standard clinical doses. This data suggests that appropriate clinical dosing might best be determined by assessing brain SERT occupancy. We have developed a unique method in which we are able to measure the magnitude of 5-HT, NE or dopamine (DA) transporter occupancy in antidepressanttreated patients by exposing cells transfected with the human SERT, NET or DAT to the patients' serum after steady-state is attained. Following validation of this technique using concomitant PET imaging we will determine what magnitude of serotonin and/or norepinephrine uptake blockade is required for an optimal treatment response. Simply stated, if a patient has not responded to a standard dose of an SSRI or SNRI, is it because they have not yet achieved a substantial occupancy of the SERT and/or norepinephrine (NET) transporter? These data may be extremely valuable in monitoring patient compliance, the need for dosage adjustment and, in the case of adequate occupancy without therapeutic response, information that provides a rational decision to switch medication class or initiate other treatment options.

到目前为止，确定患者是否接受了足够剂量的给定抗抑郁药 药物治疗几乎完全基于处方医生的经验。最近在 体内成像技术采用 PET（正电子发射断层扫描）和 SPECT（单光子发射 计算机断层扫描（CT）正在成为评估和优化药理学的新工具。 治疗（例如监测剂量是否充足）、精神科药物开发和基本治疗 了解精神疾病的病理生理学。然而，这些技术是相关的 由于可用性有限且财务成本高昂，阻碍了该技术的可用性 绝大多数临床医生。该项目的目标是提供一种有效且更简单的替代方案（一种分析方法） 使用人体血液样本）进行 PET 成像，以提供类似的体内分子位点占用数据。 简而言之，现在看来大多数 SSRI 抗抑郁药会阻断大约 80% 的目标血清素转运蛋白 (SERT) 标准临床剂量。该数据表明，适当的临床剂量可能最好是 通过评估大脑 SERT 占用率来确定。我们开发了一种独特的方法 能够测量抗抑郁药治疗中 5-HT、NE 或多巴胺 (DA) 转运蛋白占用的程度 将转染人 SERT、NET 或 DAT 的细胞暴露于患者血清中 达到稳态后。在使用伴随 PET 成像验证该技术后，我们将确定最佳治疗反应需要多大程度的血清素和/或去甲肾上腺素摄取阻断。 简单地说，如果患者对标准剂量的 SSRI 或 SNRI 没有反应，是否是因为他们 尚未大量占据 SERT 和/或去甲肾上腺素 (NET) 转运蛋白？ 这些数据对于监测患者依从性、剂量调整的需要可能非常有价值 并且，在充分占用而没有治疗反应的情况下，提供提供治疗反应的信息 理性决定更换药物类别或启动其他治疗选择。