5HT Function /Rceptor Imaging In Mood/Anxiety Disorders

多种证据表明，5-HT 1A受体功能在惊恐障碍（PD）、创伤后应激障碍（PTSD）和抑郁症中异常。本方案通过应用正电子发射断层扫描（PET）和5-HT 1A受体放射性配体[F-18] FC-WAY 100635评估惊恐障碍、创伤后应激障碍以及单相和双相抑郁症中5-HT 1A的结合潜力，研究了体内5-HT 1A异常的药理学基础。由于中央5-HT 1A受体密度在啮齿动物中通过皮质酮给药和应激介导的皮质酮分泌下调，因此评估HPA轴活性以确定5-HT 1A受体的下调是否与PD、PTSD和MDD中的皮质醇分泌过多相关。在未用药的PD、PTSD和抑郁患者或健康志愿者中获得5-HT 1A结合的PET图像。在推注（[F-18]FCWAY）后，使用PET数据的双组织室模型计算5-HT 1A受体分布容积。5-HT 1A受体分布在海马体，杏仁核，腹侧ACC，和眶皮质的体积进行了比较之间的整个抑郁症和对照组样本。用直线回归分析法评价5-HT 1A受体分布容积与唾液皮质醇、脑脊液促肾上腺皮质激素释放激素（CRH）浓度的关系。 在过去的一年中，另外12例MDD受试者和6例BD受试者进入本研究进行5 HT 1A受体成像;其中4例BD受试者在情绪稳定剂治疗后重新扫描。我们已经开发出令人满意的房室模型，用于逐像素确定分布容积，并开发了一种用于定义感兴趣区域的方法，该方法将是半自动的，因此不受操作员偏倚的影响。分析图像数据以比较BD与对照。研究结果显示，双相情感障碍患者的前、后扣带皮层和海马中的5 HT 1A受体结合显著减少。这些区域的5 HT 1A受体在调节情绪行为中起着重要作用。在即将到来的一年中，5-羟色胺转运体基因多态性对这种反应的影响将得到表征。 此外，这项研究的神经心理学评估比较了抑郁症和健康受试者，结果显示未用药的单极和双相抑郁症患者存在缺陷，这与杏仁核、腹侧前扣带回皮质和眶皮质功能障碍一致。具体而言，未经药物治疗的抑郁症患者表现出缺陷，在抑制不适当的反应，情感刺激，这是不存在于健康的对照样本表明对这些刺激的注意力偏差。未经药物治疗的抑郁样本也需要更多的时间来考虑基于风险的任务，这与额叶损伤患者的研究结果一致。 此外，用5-羟色胺转运体放射性配体进行成像，以表征5-羟色胺系统的突触前部分。另外12名单相抑郁症患者，6名双相抑郁症患者和17名健康对照者使用这种新方法进行了研究。这些结果首次表明，在双相抑郁症的脑干中的5 HTT位点显着减少，而在前扣带回中的5 HTT结合增加。描述这些结果的手稿已准备出版。 最后，我们已经开始描述卵巢类固醇和5 HTT和5 HT 1A受体结合的妇女谁发展产后抑郁症和月经相关的情绪障碍之间的关系。这些数据表明，影像学措施是敏感的卵巢类固醇。这项工作是与美国国立卫生研究院的Peter施密特和大卫Rubinow博士以及匹兹堡大学的Eydie Moses和Walter Kaye博士合作进行的。

A variety of evidence suggests serotonin 1A (5-HT1A) receptor function is abnormal in panic disorder (PD), postraumatic stress disorder (PTSD), and depression. This protocol investigates the pharmacological basis for 5-HT1A abnormalities in vivo by applying positron emission tomography (PET) and the 5-HT1A receptor radioligand [F-18]FC-WAY100635 to assess 5-HT1A binding potential in panic disorder, postraumatic stress disorder, and unipolar and bipolar depression. Because central 5-HT1A receptor density is down-regulated in rodents by corticosterone administration and by stress-mediated corticosterone secretion, assessments of HPA-axis activity were assessed to determine whether down-regulation of 5-HT1A receptors correlates with cortisol hypersecretion in PD, PTSD, and MDD. PET images of 5-HT1A binding were acquired in subjects who are unmedicated PD, PTSD and depressed patients, or are healthy volunteers. The 5-HT1A receptor volume of distribution was calculated with a two tissue compartment model of PET data after a bolus infusion of ([F-18]FCWAY). The 5-HT1A receptor volume of distribution in the hippocampus, amygdala, ventral ACC, and orbital cortex were compared between the entire depressive and control samples. The relationships between 5-HT1A receptor volume of distribution and salivary cortisol and between 5-HT1A receptor volume of distribution and cerebrospinal fluid concentrations of corticotrophin releasing hormone (CRH), were assessed by linear regression analysis. During the past year, an additional 12 subjects with MDD and 6 with BD entered into this study for 5HT1A receptor imaging; 4 of the BD subjects were rescanned following mood stabilizer treatment. We have developed satisfactory compartmental models for pixelwise determination of volume of distribution and have developed a method for defining regions of interest that will be semi-automated and thus independent of operator bias. The image data were analyzed for the BD versus control comparisons. The results include showing prominent reductions in 5HT1A receptor binding in the anterior and posterior cingulate cortices and the insula in bipolar disorder. The 5HT1A receptors in these regions play important roles in regulating emotional behavior. During the upcoming year the effects of serotonin transporter gene polymorphisms on this response will be characterized. In addition, the neuropsychological assessments from this study comparing depressed and healthy subjects have shown deficits in the unmedicated unipolar and bipolar depressed patients that are consistent with dysfunction of the amygdala, ventral anterior cingulate cortex, and orbital cortex. Specifically, unmedicated depressed patients displayed deficits in inhibiting inappropriate responses to affective stimuli that was not present in the healthy control sample suggesting an attentional bias towards these stimuli. The unmedicated depressed sample also required more time to deliberate on a risk-based task, consistent with findings in frontal lesion patients. In addition, imaging with the serotonin transporter radioligand progressed to permit characterization of the presynaptic portion of the serotonin system. An additional 12 subjects with unipolar depression, 6 subjects with bipolar depression and 17 healthy controls have been studied using this new method. These results showed for the first time a marked reduction in 5HTT sites in the brainstem and an increase in 5HTT binding in the anterior cingulate in bipolar depression. A manuscript describing these results has been prepared for publication. Finally, we have begun to characterize the relationship between ovarian steroids and 5HTT and 5HT1A receptor binding in women who develop post partum depression and menstrual related mood disorders. These data have shown that the imaging measures are sensitive to ovarian steroids. This work is being conducted in collaboration with Drs. Peter Schmidt and David Rubinow at NIH and with Drs. Eydie Moses and Walter Kaye at University of Pittsburgh.