Neurobiology and Target validation of novel therapeutic agents in mood disorders

本报告涉及根据协议08-M-0196(NCT00759395)、08-M-0150(NCT00697268)、14-M-0085(NCT02122562)、14-M-0041(NCT02049385)和07-M-0152(NCT00472576)收集的工作。 过去一年的结果： 1)有终生自杀未遂史的重度抑郁障碍患者恐惧增强。我们发现，与那些没有终生自杀未遂史的抑郁症患者相比，有终生自杀未遂的抑郁症患者恐惧加剧的惊吓程度更高。自杀未遂者中恐惧增强的惊吓增加表明杏仁核在有自杀未遂病史的抑郁症患者中的作用。研究结果强调了焦虑症状在治疗自杀风险增加的患者中的重要性。 2)自然杀伤细胞和单核细胞中P11水平与慢性西酞普兰的抗抑郁反应。我们发现，自然杀伤细胞和单核细胞中的p11水平与西酞普兰的抗抑郁反应有关。 3)双相情感障碍患者抑郁发作时的锂和一氧化氮水平。我们发现，与双相抑郁患者的基线水平相比，锂治疗6周后血浆一氧化氮水平显著升高。与健康对照组匹配时，抑郁发作期间的基线氧化物水平没有差异。目前的研究结果表明，锂上调了病程较短的未用药BD患者的一氧化氮信号。 4)舍曲林和经颅直流电刺激抗抑郁治疗后血浆BDNF水平。我们测量了基线和终点的BDNF血浆水平，观察到治疗后BDNF水平没有显著变化。此外，在应答者和无应答者中没有观察到显著的变化，也没有观察到BDNF水平与抑郁症相关的临床和精神病理变量之间的关系。因此，在为数不多的评估抗抑郁药物治疗过程中BDNF变化的安慰剂对照试验中，我们没有观察到BDNF的增加，无论抑郁症患者的临床改善如何。 5)我们描述了在重度抑郁症患者和健康对照组中使用11C-罗利普兰的临床方案的方法学和有效性。我们发现，对于11C-Rolipram PET临床扫描，图像衍生输入函数是全动脉输入函数的良好替代。 6)心境障碍患者一级亲属中儿茶酚胺耗竭：(18)氟脱氧葡萄糖正电子发射断层扫描研究。我们的结果表明，对儿茶酚胺缺乏的敏感性可能是情绪障碍易感性的表型标志，在神经生理学水平上，纹状体及其由边缘-皮质-纹状体-苍白球-丘脑回路组成的传出投射的去抑制是其特征。 (7)躁狂、抑郁的家族遗传独立性。发现双相情感障碍(BP I；优势比(OR)=8.40；3.27~20.97；H2=0.83)和重度抑郁障碍(OR=2.26；1.58~3.22；H2=0.20)具有家族聚集性，而BP II无家族聚集性。BP I的家族聚集性主要归因于躁狂发作的家族特异性

This Report involves work collected under protocols 08-M-0196 (NCT00759395); 08-M-0150 (NCT00697268); 14-M-0085 (NCT02122562); 14-M-0041 (NCT02049385); and 07-M-0152 (NCT00472576). Results this past year: 1) Increased fear-potentiated startle in major depressive disorder patients with lifetime history of suicide attempt. We found that the magnitude of fear-potentiated startle was increased in depressed patients with lifetime suicide attempts compared to those without a lifetime history of suicide attempt. Increased fear-potentiated startle in suicide attempters suggests the role of amygdala in depressed patients with a suicide attempt history. Findings highlight the importance of anxiety symptoms in the treatment of patients at increased suicide risk. 2) P11 levels in natural killer cells and monocytes and antidepressant response to chronic citalopram. We found that p11 levels in natural killer cells and monocytes correlated with antidepressant response to citalopram. 3) Lithium and nitric oxide levels in subjects with bipolar disorder during depressive episodes. We found that lithium treatment significantly increased plasma nitric oxide levels after 6 weeks of treatment in comparison to baseline levels in bipolar depression. Baseline oxide levels during depressive episodes showed no difference when matching up to healthy controls. The present findings suggest that lithium upregulates nitric oxide signaling in unmedicated BD with short illness duration. 4) BDNF plasma levels after antidepressant treatment with sertraline and transcranial direct current stimulation. We measured BDNF plasma levels at baseline and endpoint, observing no significant changes of BDNF levels after treatment. In addition, no significant changes were observed in responders and non-responders as well as no relationships between BDNF levels and clinical and psychopathological variables related to depression. Thus, in one of the few placebo-controlled trials evaluating BDNF changes over an antidepressant treatment course, we did not observe BDNF increase regardless of clinical improvement in depressed patients. 5) We described the methodology and validation of a clinical protocol using 11C-rolipram in patients with major depression and healthy controls. We found that image-derived input function is a good alternative to full arterial input function for 11C-rolipram PET clinical scans. 6) Catecholamine depletion in first-degree relatives of individuals with mood disorders: An (18)Ffluorodeoxyglucose positron emission tomography study. Our results suggest that sensitivity to catecholamine depletion may be a phenotypic marker of vulnerability to mood disorders that is characterized at the neurophysiological level by disinhibition of the striatum and its efferent projections comprising the limbic-cortical-striatal-pallidal-thalamic circuitry. 7) Independence of familial transmission of mania and depression. We found that there was specificity of familial aggregation of bipolar I (BP I; odds ratio (OR)=8.40; 3.27-20.97; h2=0.83) and major depressive disorder (OR=2.26; 1.58-3.22; h2=0.20), but not BP II. The familial aggregation of BP I was primarily attributable to the familial specificity of manic episodes after