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: 7124659
• 负责人: JAY D AMSTERDAM
• 金额: $ 19.73万
• 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/7124659
• 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（由申请人提供）：多巴胺（DA）可能在重度抑郁发作（MDE）的病理生理中发挥关键作用，并可能部分介导许多抗抑郁药物的治疗作用。最近的动物和人体研究表明，DA转运蛋白（DAT）活性可能反映了中枢神经系统中DA神经递质活性的一般状态，而正常DAT活性的改变可能反映了中枢DA功能的改变。多种抗抑郁药影响中枢DA活性，这种影响并不局限于“DA能”抗抑郁药。研究表明，反复服用所有药理学类别的抗抑郁药会导致d2样受体结合增强，这种增强的致敏性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放射配体，它对几乎没有SERT交叉结合的DAT具有高度选择性。宾夕法尼亚大学对[99mTc]TRODAT-1进行的研究表明，它是评估纹状体DAT水平变化的有效工具。对帕金森病患者的初步研究（与健康对照相比）表明[99mTc]TRODAT-1可有效量化DAT水平。我们组的初步研究显示，与对照组相比，MDE患者的[99mTc]TRODAT-1与壳核和尾状核区域DAT位点的结合显著增加（12% - 36%）。我们建议进行一项初步研究，以检验MDE中纹状体数据水平升高是否代表一种假定的状态依赖性抑郁症生物标志物。对于具体目标#1，我们将问：MDE患者纹状体DA - T水平升高是否代表一种状态依赖性的生物标志物，在成功的抗抑郁治疗后会降低？我们假设MDE患者纹状体数据水平的升高在抗抑郁药物治疗成功期间会降低，而在治疗无效的患者中不会明显降低。对于具体目标#2，我们将问：纹状体数据水平是否随时间保持稳定，在非抑郁的健康对照中？为了回答这些问题，我们将使用[99mTc]TRODAT-1 SPECT与MRI共定位测量纹状体数据水平，在44例未使用药物的MDE患者使用s-西酞普兰或安慰剂治疗8周前后。我们将把这些结果与22名非抑郁健康受试者的纹状体数据水平进行比较，这些受试者在相似的条件下使用[99mTc]TRODAT-1 SPECT在两个不同的时间间隔8周进行研究。