Secondary Research Project: Monoamine Transporter Occupancy

到目前为止，确定患者是否接受了足够剂量的抗抑郁药， 药物治疗几乎完全基于处方医生的经验。最近在 PET（正电子发射断层扫描）和SPECT（单光子发射）体内成像技术 计算机断层扫描）正在成为评估和优化药理学的新工具。 治疗（例如监测剂量的充分性）、精神病药物开发和基本 了解精神疾病的病理生理学。然而，这些技术与 有限的可用性和巨大的财务成本，排除了这种技术的可用性， 绝大多数临床医生。本项目的目标是提供一种有效和简单的替代方法（测定 使用人血液样品）进行PET成像以提供相似的体内分子位点占有数据。 简而言之，现在看来，大多数SSRI抗抑郁药阻断了大约80%的目标血清素转运蛋白 （SERT）在标准临床剂量下。这些数据表明，适当的临床剂量可能是最好的， 通过评估大脑SERT占用来确定。我们开发了一种独特的方法， 能够测量5-HT，NE或多巴胺（DA）转运蛋白占有率的大小， 通过将用人SERT、NET或DAT转染的细胞暴露于患者血清 在达到稳定状态之后。在使用伴随PET成像对该技术进行验证后，我们将确定最佳治疗反应所需的5-羟色胺和/或去甲肾上腺素摄取阻滞的幅度。 简单地说，如果患者对标准剂量的SSRI或SNRI没有反应，是因为他们 还没有实现SERT和/或去甲肾上腺素（NET）转运蛋白的大量占用？ 这些数据在监测患者依从性、剂量调整的需要方面可能是极其有价值的 以及，在没有治疗反应的充分占用的情况下， 合理决定转换药物类别或开始其他治疗选择。

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.