SEROTONIN 1A RECEPTOR & METABOLIC IMAGING IN DEPRESSION

描述：(申请人摘要)多条证据表明，在重度抑郁障碍(MDD)患者中，5-羟色胺1A(5HT1A)受体功能异常，躯体抗抑郁治疗会影响5HT1A受体功能的变化，这与治疗效果有关。支持这些假说的数据是通过评估MDD受试者对5HT1A激动剂的神经内分泌和温度反应，测量从MDD受试者死后获得的小样本脑组织中5HT1A受体结合，以及检测给予抗抑郁药物(AD)后大鼠5HT1A受体结合的变化来获得的。然而，还没有直接的证据表明中枢5HT1a受体异常或抗抑郁治疗对5HT1a受体药理的影响。最近，一种用于正电子发射断层扫描成像的高选择性5-HT1a受体放射配基的发展，使直接、非侵入性地探索MDD的中央5HT1a受体结合潜力(BP)成为可能。为了促进对MDD的神经生物学和AD治疗机制的认识，我们将使用正电子发射计算机断层扫描和[C11 C]Way-100635来比较MDD和健康对照组之间以及MDD受试者治疗前后的5HT1a受体BP。在同一扫描过程中将获得18F-脱氧葡萄糖(FDG)摄取的图像，以评估区域5HT1A受体BP与先前在MDD中发现的葡萄糖代谢异常的关系。在成像之前，也要检查皮质醇分泌离子的内分泌评估，以确定海马5HT1a受体的下调是否发生在与MDD相关的皮质醇过多反应中，就像在应激和糖皮质激素应用期间的实验动物一样。在抑郁症患者接受抗抑郁药物舍曲林治疗的8周间隔后，重复进行成像和内分泌测量。先导成像数据表明，未用药的抑郁症患者和对照组之间的5HT1a受体BP在近颞叶皮质以及腹外侧和腹内侧前额叶皮质(PFC)中的差异非常明显。如果MDD患者的中颞叶皮质(包括海马区)的5HT1a受体BP减少与皮质醇分泌异常之间建立了联系，那么在治疗过程中这种异常的正常化可能具有预后意义。在腹外侧部和腹内侧部，5HT1a受体BP的异常减少的幅度比以前在MDD这些区域显示的代谢异常和灰质体积的异常程度更大，提示5HT1a受体成像方法可能提供敏感的病理标记物，可以指导MDD的死后组织学和组织化学研究。

DESCRIPTION: (Applicant's abstract) Multiple lines of evidence suggest that serotonin1A (5HT1A) receptor function is abnormal in major depressive disorder (MDD) and that somatic antidepressant therapies effect changes in 5HT1A receptor function that are relevant to treatment efficacy. The data supporting these hypotheses have been obtained by assessing neuroendocrine and temperature responses to 5HT1A agonists in MDD subjects, measuring 5HT1A receptor binding in brain tissue acquired post mortem from small samples of MDD subjects, and examining changes in 5HT1A receptor binding in rats following antidepressant drug (AD) administration. However, there has been no direct demonstration of a central 5HT1A receptor abnormality or an effect of antidepressant treatment on 5HT1A receptor pharmacology in living depressed subjects. The development of a highly selective 5-HT1A receptor radioligand for positron emission tomography (PET) imaging, [carbonyl-11C]- WAY-100635, has recently made direct, noninvasive exploration of the central 5HT1A receptor binding potential (BP) possible in MDD. To advance knowledge regarding the neurobiology of MDD and the mechanisms of AD treatment, PET and [carbonyl-11C]WAY-100635 will be used to compare the 5HT1A receptor BP between MDD and healthy control subjects and between the pre-and post-treatment conditions in the MDD subjects. Images of 18F-fluorodeoxyglucose (FDG) uptake will be acquired in the same scan session to evaluate the relationship between regional 5HT1A receptor BP and the glucose metabolic abnormalities previously identified in MDD. Endocrine assessments of cortisol secret-ion are also examined prior to imaging to determine whether down-regulation of hippocampal 5HT1A receptors occurs in response to the hypercortisolism associated with MDD as it does in experimental animals during stress and glucocorticoid administration. The imaging and endocrine measures are repeated following an 8 week interval during which the depressives are treated with the antidepressant drug sertraline. Pilot imaging data suggest that the differences in the 5HT1A receptor BP between unmedicated depressives and controls are robust in the mesiotemporal cortex and the ventrolateral and ventromedial prefrontal cortex (PFC). If a link between reduced 5HT1A receptor BP in the mesiotemporal cortex (which includes the hippocampus) and abnormal cortisol secretion is established in MDD, then normalization of this abnormality during treatment may have prognostic implications. In the ventrolateral and ventromedial PFC, the magnitude of the abnormal reductions of 5HT1A receptor BP were proportionately larger than the abnormalities of metabolism and grey matter volume previously shown in these areas in MDD, suggesting the 5HT1A receptor imaging measures may provide sensitive markers of pathology that can guide future post mortem histological and histochemical studies of MDD.