SPECT Brain Imaging as a Biomarker of Major Depression

SPECT 脑成像作为重度抑郁症的生物标志物

• 批准号: 6983491
• 负责人: JAY D AMSTERDAM
• 金额: $ 20.21万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6983491
• 关键词: biomarker; brain disorder diagnosis; brain imaging /visualization /scanning; citalopram; clinical research; clinical trials; dopamine receptor; dopamine transporter; drug screening /evaluation; human subject; human therapy evaluation; interview; major depression; mental disorder chemotherapy; occipital lobe /cortex; outcomes research; pathologic process; pharmacokinetics; radionuclide diagnosis; radiotracer; receptor binding; receptor expression; single photon emission computed tomography; statistics /biometry

DESCRIPTION (provided by applicant): Dopamine (DA) may play a key role in the pathophysiology of major depressive episode (MDE) and may, in part, mediate the therapeutic action of many antidepressant drugs. Recent animal and human studies suggest that DA transporter (DAT) activity may reflect the general state of DA neurotransmitter activity in the CNS, and alterations in normal DAT activity may reflect alteration in central DA function. A variety of antidepressants affect central DA activity, and this effect is not limited to 'DA-ergic' antidepressants. Studies have shown that repeated administration of antidepressants from all pharmacological classes result in enhanced D2-like receptor binding, and this enhanced sensitization has been suggested as a 'final common pathway' for antidepressant action. [99mTc]TRODAT-1 is a unique SPECT radioligand which is highly selective for the DAT with almost no SERT cross binding. Studies with [99mTc]TRODAT-1 conducted at Penn have shown it to be an effective tool for evaluating alterations in striatal DAT levels. Preliminary studies in patients with Parkinson's disease (compared to healthy controls) have shown [99mTc]TRODAT-1 to be effective for quantifying DAT levels. Preliminary studies from our group have shown a significant increase (12% - 36%) in [99mTc]TRODAT-1 binding to DAT sites in the putamen and caudate regions of patients with MDE compared to controls. We propose to conduct a preliminary study to examine whether increased striatal DAT levels in MDE represent a putative state-dependent biomarker of depression. For specific aim #1 we will ask: Do increased striatal DA T levels in MDE represent a state-dependent biomarker that is reduced after successful antidepressant treatment? We hypothesize that increased striatal DAT levels in MDE patients will decrease during successful antidepressant treatment, and will not appreciably decrease in patients who do not respond to treatment. For specific aim #2 we will ask: Do striatal DAT levels remain stable over time in non-depressed, healthy controls? To answer these questions, we will measure striatal DAT levels using [99mTc]TRODAT-1 SPECT with MRI co-localization, before and after 8 weeks of treatment with s-citalopram or placebo in 44 drug-naive MDE patients. We will compare these results to measurements of striatal DAT levels in 22 non-depressed, healthy subjects studied under similar conditions with [99mTc]TRODAT-1 SPECT on two separate occasions 8 weeks apart.

描述(申请人提供)：多巴胺(DA)可能在主要抑郁发作(MDE)的病理生理学中发挥关键作用，并可能在一定程度上介导许多抗抑郁药物的治疗作用。最近的动物和人类研究表明，DA转运体(DAT)活性可能反映了中枢DA神经递质活动的一般状态，而正常DAT活性的变化可能反映了中枢DA功能的变化。多种抗抑郁药影响中枢多巴胺的活性，这种影响并不局限于‘DA能’抗抑郁药。研究表明，重复使用所有药理类别的抗抑郁药都会导致D2样受体结合增强，这种增强的增敏作用被认为是抗抑郁作用的最终共同途径。[99mTC]TRODAT-1是一种独特的SPECT放射性配基，对DAT具有很高的选择性，几乎没有SERT交叉结合。在宾夕法尼亚大学进行的[99mTc]TRODAT-1研究表明，它是评估纹状体DAT水平变化的有效工具。对帕金森氏病患者(与健康对照组相比)的初步研究表明，[99mTC]TRODAT-1对DAT水平的量化是有效的。我们小组的初步研究显示，与对照组相比，MDE患者壳核和尾状体区DAT位点的[99mTc]TRODAT-1结合显著增加(12%-36%)。我们建议进行一项初步研究，以检验MDE患者纹状体DAT水平升高是否代表抑郁症的假定状态依赖生物标记物。对于特定的目标#1，我们会问：MDE中纹状体DA-T水平的升高是否代表了一种状态依赖的生物标记物，在成功的抗抑郁药物治疗后会降低？我们假设MDE患者纹状体DAT水平的升高在成功的抗抑郁药物治疗期间会降低，而在治疗无效的患者中不会明显降低。对于特定的目标2，我们将问：在非抑郁的健康对照组中，纹状体DAT水平是否随着时间的推移保持稳定？为了回答这些问题，我们将使用[99mTC]TRODAT-1 SPECT结合磁共振共定位技术，对44例未用药的MDE患者在服用S-西酞普兰或安慰剂治疗8周前和治疗后的纹状体DAT水平进行测量。我们将把这些结果与22名非抑郁的健康受试者的纹状体DAT水平进行比较，这些受试者在类似的条件下使用[99mTC]TRODAT-1 SPECT在两个不同的场合相隔8周进行研究。