SPECT Brain Imaging as a Biomarker of Major Depression

描述（由申请人提供）：多巴胺（DA）可能在重度抑郁发作（MDE）的病理生理学中起关键作用，并可能部分介导许多抗抑郁药物的治疗作用。 最近的动物和人类研究表明，DA转运蛋白（DAT）的活动可能反映了一般状态的DA神经递质活动在中枢神经系统中，和正常DAT活动的改变可能反映中枢DA功能的改变。多种抗抑郁药影响中枢DA活性，并且这种作用不限于“DA能”抗抑郁药。 研究表明，重复给予所有药理学类别的抗抑郁药会导致D2样受体结合增强，这种增强的致敏作用被认为是抗抑郁作用的“最终共同途径”。[99 mTc]TRODAT-1是一种独特的SPECT放射性配体，对DAT具有高度选择性，几乎没有SERT交叉结合。在宾夕法尼亚大学进行的[99 mTc]TRODAT-1研究表明，它是评估纹状体DAT水平变化的有效工具。 帕金森病患者的初步研究（与健康对照组相比）显示[99 mTc]TRODAT-1可有效定量DAT水平。我们小组的初步研究表明，与对照组相比，MDE患者的壳核和尾状核区域的[99 mTc]TRODAT-1与DAT位点的结合显著增加（12% - 36%）。 我们建议进行一项初步研究，以检查是否增加纹状体DAT水平在MDE代表一个假定的状态依赖性抑郁症的生物标志物。 对于具体目标#1，我们会问：MDE中纹状体DA T水平的增加是否代表成功的抗抑郁药治疗后降低的状态依赖性生物标志物？ 我们假设MDE患者纹状体DAT水平的增加在成功的抗抑郁治疗过程中会降低，而在对治疗无反应的患者中不会明显降低。 对于具体的目标#2，我们会问：在非抑郁的健康对照组中，纹状体DAT水平是否随时间保持稳定？ 为了回答这些问题，我们将使用[99 mTc]TRODAT-1 SPECT与MRI共定位，在44名药物初治MDE患者中使用s-西酞普兰或安慰剂治疗8周之前和之后测量纹状体DAT水平。 我们将比较这些结果的纹状体DAT水平的测量在22个非抑郁症，健康受试者在类似的条件下研究[99 mTc]TRODAT-1 SPECT在两个不同的场合8周间隔。

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.