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给定抗抑郁药物 用药几乎完全基于开处方的医生的经验。最近在 正电子发射断层扫描(PET)和单光子发射(SPECT)活体成像技术 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)、精神科药物开发和基本情况 对精神疾病的病理生理学的理解。然而，这些技术是相关联的 由于有限的可获得性和巨大的财务成本，使该技术无法在 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法(化验 使用人类血液样本)到PET成像，以提供类似的活体分子位置占据数据。 简而言之，现在看来，大多数SSRI抗抑郁药阻止了大约80%的目标5-羟色胺转运体 (SERT)按标准临床剂量。这一数据表明，适当的临床剂量可能是最好的 通过评估大脑SERT占有率来确定。我们已经开发出一种独特的方法，在这种方法中，我们 能够测量5-羟色胺、去甲肾上腺素或多巴胺(DA)转运体在抗抑郁治疗中的占有率 将转人SERT、Net或DAT的细胞暴露于患者血清中 在达到稳态后。在使用伴随的PET成像验证这项技术之后，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断的程度。 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 尚未实现SERT和/或去甲肾上腺素(净)转运体的大量占用？ 这些数据在监测患者的依从性、剂量调整的必要性方面可能非常有价值 在没有治疗反应的情况下，充分居住的情况下，提供 理性地决定更换药物类别或启动其他治疗方案。

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.