Tryptophan Depletion in Remitted Depressed Patients

多种证据表明，重度抑郁症（MDD）与中枢神经系统功能异常降低有关。一个有益的范例，研究多巴胺能功能和抑郁症之间的关系，涉及色氨酸耗竭（TD）的情绪反应，通过口服负荷的所有必需氨基酸，除了5-HT前体，色氨酸。我们获得的初步证据表明，TD的情绪降低效果取决于基因型的5-HT转运蛋白（5-HTT）的启动子区域的功能多态性，指定5-HTTLPR，以及在家族史。在健康女性中，s-等位基因和积极的情绪障碍家族史似乎是TD期间抑郁症状发展的附加危险因素。 目前的研究采用定量PET脑血流（CBF）和葡萄糖代谢成像，以研究变异5-HTTLPR基因型对TD的神经生理反应的影响。我们还研究了5-HTTLPR基因型和TD对PFC代谢活性的影响之间的关系，以及在具有s/s等位基因的受试者和具有单一s等位基因加抑郁症家族史的受试者中，是否会在更大程度上减少PFC代谢。我们还研究了PFC代谢活性的这种降低是否是TD期间出现抑郁症状的受试者所独有的。 此外，基于5-HT抑制杏仁核神经元活动的证据，并调节从感觉皮层到杏仁核的情绪突出的感觉信息的传输，我们测试了这一假设，即在MDD中，与TD相关的5-羟色胺功能降低可能会抑制杏仁核对感觉刺激的反应。通过评估杏仁核对通常激活杏仁核的感官刺激的生理反应，即表现出恐惧或悲伤情绪表情的人脸图片，来探索这一假设。我们特别感兴趣的是，确定是否杏仁核CBF反应的情绪刺激在TD是最显着增加的受试者携带的5-HTTLPR的S-等位基因，以及是否是唯一的受试者在TD期间发展抑郁症状。 今年增加了一个新的项目，以研究基因型，MDD的历史和血清素消耗之间的关系，对情绪化的单词的处理。在色氨酸耗尽和对照条件下，有MDD病史的痴呆受试者和健康对照者在执行“情感转移任务”（受试者在检测悲伤和快乐单词之间交替注意）时进行功能性MRI扫描。 在前几年的一项双盲、安慰剂对照、随机（根据5-HTTLPR基因型）交叉研究中，对36例未用药缓解的MDD受试者和36例健康对照进行了研究。数据分析仍在继续，并已准备好一份手稿供提交，以描述基因型对大脑区域的影响，这些区域在5-羟色胺耗竭和抑郁复发期间改变其活性。

Major depressive disorder (MDD) has been associated with abnormally reduced function of central serotonergic systems by various types of evidence. One instructive paradigm for investigating the relationship between serotonergic function and depression has involved the mood response to tryptophan depletion (TD), achieved by oral loading with all essential amino acids excepting the 5-HT precursor, tryptophan. We obtained preliminary evidence that the mood lowering effect of TD depends upon the genotype for a functional polymorphism in the promoter region of the 5-HT transporter (5-HTT), designated 5-HTTLPR, as well as upon family history. In healthy females the s-allele and a positive family history for mood disorders appeared to be additive risk factors for the development of depressive symptoms during TD. The current study employed quantitative PET imaging of cerebral blood flow (CBF) and glucose metabolism to investigate the effect of variant 5-HTTLPR genotypes on the neurophysiological response to TD. We also examined the relationship between 5-HTTLPR genotypes and the TD effect on PFC metabolic activity and whether reduction in PFC metabolism in response to TD would occur to a greater extent in subjects with the s/s allele and in subjects with a single s allele plus a family history of depression. We also examined whether this reduction in PFC metabolic activity is unique to subjects who develop depressive symptoms during TD. In addition, based upon evidence that 5-HT inhibits neuronal activity in the amygdala, and modulates transmission of emotionally-salient sensory information from the sensory cortices to the amygdala, we tested the hypothesis that in MDD, reduced serotonin function associated with TD may disinhibit the amygdaloid response to sensory stimulation. This hypothesis was explored by assessing the physiological responses of the amygdala to sensory stimuli that normally activate the amygdala, namely pictures of human faces that show fearful or sad emotional expressions. We were particularly interested in determining whether the amygdala CBF response to emotional stimuli during TD is most prominently increased in subjects carrying the s-allele of the 5-HTTLPR, and whether it is unique to subjects who develop depressive symptoms during TD. A new project was added this year to examine the relationships between genotype, history of MDD, and serotonin depletion on the processing of emotionally valenced words. Recovered subjects with a history of MDD and healthy controls underwent functional MRI scanning while performing an "affective shift task" (in which subjects alternate attention between detecting sad versus happy words) in both the tryptophan depleted and the control condition. Thirty-six unmedicated-remitted subjects with MDD and 36 healthy controls were studied in previous years in a double-blind, placebo-controlled, randomized (according to 5-HTTLPR genotype) crossover study. The data analysis has continued and a manuscript has been prepared for submission to describe the effects of genotype on the brain regions that change their activity during serotonin depletion and during depressive relapse.