Tryptophan Depletion in Remitted Depressed Patients

各种证据表明，重度抑郁障碍(MDD)与中枢5-羟色胺能系统功能异常降低有关。一个研究5-羟色胺能功能与抑郁之间关系的指导性范例涉及色氨酸耗竭(TD)时的情绪反应，这是通过口服除5-羟色胺前体色氨酸以外的所有必需氨基酸来实现的。我们获得的初步证据表明，TD的情绪降压作用依赖于5-羟色胺转运体(5-HTT)启动子区5-HTTLPR功能多态性的基因型以及家族史。在健康女性中，S等位基因和情绪障碍阳性家族史似乎是TD期间抑郁症状发生的附加危险因素。 今年我们报道了TD下的糖代谢变化不仅可以区分健康对照组和MDD患者，而且在5-HTTLPR基因多态性上也可以区分S携带者和L纯合子。这些数据为S等位基因与大脑功能相关的文献提供了强有力的证据。阐明这一点很重要，因为S等位基因与在压力背景下患抑郁症的风险增加有关。 本研究采用脑血流量(CBF)和葡萄糖代谢的PET定量成像技术，探讨5-HTTLPR基因变异对TD神经生理学反应的影响。我们还研究了5-HTTLPR基因型与TD对PFC代谢活性的影响的关系，以及TD对PFC代谢活性的影响是否会在S/S等位基因携带者和S等位基因加抑郁症家族史的受试者中发生更大程度的降低。我们还检查了这种PFC代谢活动的减少是否是在TD期间出现抑郁症状的受试者所特有的。 此外，基于5-羟色胺抑制杏仁核神经元活动，并调节从感觉皮质到杏仁核的情绪显著感觉信息传递的证据，我们检验了这样的假设，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。这一假说是通过评估杏仁核对通常激活杏仁核的感觉刺激的生理反应来探索的，即表现出恐惧或悲伤情绪表情的人脸图片。我们特别感兴趣的是确定在TD期间杏仁核CBF对情绪刺激的反应是否在携带5-HTTLPR的S等位基因的受试者中显著增加，以及这是否是TD期间出现抑郁症状的受试者所独有的。 今年，我们报告了我们的研究结果，即基因、MDD病史和5-羟色胺耗竭之间的关系在情感配价词的加工上。有MDD病史的康复受试者和健康对照组接受了功能性核磁共振扫描，同时在色氨酸耗竭和对照组的情况下都执行了一项“情感转换任务”(受试者在检测悲伤和快乐的词之间切换注意力)。 36名未用药缓解的MDD患者和36名健康对照在前几年进行了双盲、安慰剂对照、随机(根据5-HTTLPR基因)交叉研究。数据分析仍在继续，一份手稿已经发表，描述了在5-羟色胺耗竭和抑郁症复发期间，基因对大脑区域的影响，这些区域改变了它们的活动。第二份手稿正在准备中，以表明在大多数情况下，根据色氨酸耗竭的代谢反应，可以正确地对基因(5-HTTLPR基因多态)和表型(健康对照组、抑郁症复发的MDD和保持恢复的MDD)进行正确分类。 此外，在这些病例中，对情绪面孔的脑血流(CBF)反应进行了评估，并与肾上腺素能受体的基因突变有关，该基因突变与抑郁症的发生风险增加有关。这项研究还显示，在MDD康复者中，对悲伤面孔的CBF反应异常。 在功能磁共振研究中，另外13名有MDD病史的康复患者和另外13名健康对照被研究并对结果进行了分析。一份手稿已经发表，描述了色氨酸枯竭对健康人类情绪处理的影响，另一份手稿报告了色氨酸枯竭对恢复的MDD组和对照组执行任务的行为和神经反应的不同影响。 在过去的一年里，我们扩大了样本量，并检查了5-羟色胺转运体基因多态对这些数据的影响。我们了解到，这种基因变异与抑郁的易感性有关，似乎对5-羟色胺能系统有功能影响，也影响大脑对情绪化词汇的反应。尤其是亚膝前扣带回，这一结构与抑郁症的病理生理学和抗抑郁药物治疗机制有关，它对悲伤词语的反应因其多态而不同，这特别增加了抑郁的易感性。

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. This year we reported that the glucose metabolic changes under TD not only differentiate healthy controls and subjects with MDD, but also can differentiate between s-carriers and l-homozygotes for the 5-HTTLPR polymorphism. These data added strong evidence to the literature that the s-allele is functionally relevant in the brain. This was important to elucidate, because the s-allele had been linked to an increased risk of developing depression within the context of stress. 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. This year we reported the results of our investigation of 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 one manuscript has been published to describe the effects of genotype on the brain regions that change their activity during serotonin depletion and during depressive relapse. A second manuscript is in preparation to show that genotype (for the 5-HTTLPR genotype polymorphism) and phenotype (healthy control, MDD in depressive relapse, and MDD with maintained recovery) can be classified correctly in most cases by their metabolic response to tryptophan depletion. In addition, the cerebral blood flow (CBF) response to emotional faces was assessed in these cases and associated with a gene mutation for an adrenergic receptor that had been associated with increasing the risk for developing depression. This study also demonstrated abnormalities in the CBF responses to sad faces that were abnormal in recovered cases with MDD. In the fMRI study, 13 additional recovered patients with a history of MDD and 13 additional healthy controls werestudied and the results analyzed. A manuscript has published which describes the effects of tryptophan depletion on emotional processing in healthy humans, and another manuscript has been published which reports the differential effects of tryptophan depletion on both the behavioral and the neural responses to performing the task between the recovered MDD and control groups. This past year we extended this sample size and also examined the effects of a genetic polymorphism in the serotonin transporter on these data. We learned that this genetic variant, which has been associated with the vulnerability to depression and appears to have a functional effect on the serotonergic system, also affects the brain's responses to emotional words. In particular the subgenual anterior cingulate, a structure implicated in both the pathophysiology of depression and the mechanisms of antidepressant treatment, shows responses to sad words that differ on the basis of the polymorphism which particularly increases the vulnerability to depression.