Neurobiology and Target validation of novel therapeutic agents in mood disorders

情绪障碍新型治疗药物的神经生物学和靶标验证

• 批准号: 8940006
• 负责人: Carlos Zarate
• 金额: $ 95.83万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8940006
• 关键词: Aftercare; Age; Alcohols; Amygdaloid structure; Antidepressive Agents; Anxiety; Anxiety Disorders; Beck depression inventory; Biological Markers; Bipolar Depression; Bipolar Disorder; Bipolar I; Brain; Brain imaging; Brain-Derived Neurotrophic Factor; Catecholamines; Chronic; Citalopram; Clinical; Clinical Protocols; Clinical Research; Corpus striatum structure; Databases; Depressed mood; Diagnosis; Diazoxide; Dimensions; Disease remission; Disinhibition; Dose; Double-Blind Method; Enhancers; Family history of; Female; First Degree Relative; Fright; Functional Magnetic Resonance Imaging; Genetic; Glutamate Transporter; Glutamates; Hamilton Rating Scale for Depression; Image; Individual; Infusion procedures; Inpatients; Intravenous; Investigation; Ketamine; Lithium; Magnetic Resonance Spectroscopy; Major Depressive Disorder; Manic; Measures; Mental Depression; Methodology; Montgomery and Asberg depression rating scale; Mood Disorders; National Institute of Mental Health; Natural Killer Cells; Neurobiology; Neuropsychological Tests; Nitric Oxide; Odds Ratio; Outcome Measure; Oxides; Patients; Pharmaceutical Preparations; Phase; Placebos; Plasma; Positron-Emission Tomography; Protocols documentation; Recording of previous events; Recruitment Activity; Reporting; Research; Research Domain Criteria; Resistance; Rest; Role; Rolipram; Scanning; Sertraline; Severities; Signal Transduction; Site; Specificity; Suicide; Suicide attempt; Symptoms; Syndrome; Thalamic structure; Therapeutic Agents; Validation; Visual; alcohol use disorder; analog; collected works; depressive symptoms; design; improved; male; monocyte; neurochemistry; neurophysiology; novel therapeutics; open label; peripheral blood; placebo controlled study; response; secondary outcome; suicidal risk; suicide attempter; transmission process; treatment effect; treatment response

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

本报告涉及根据方案08-M-0196（NCT 00759395）、08-M-0150（NCT 00697268）、14-M-0085（NCT 02122562）、14-M-0041（NCT 02049385）和07-M-0152（NCT 00472576）收集的工作。 过去一年的成果： 第一章 终生有自杀企图史的重性抑郁症患者的恐惧增强惊吓增加我们发现，与那些没有自杀企图的终身病史的抑郁症患者相比，有自杀企图的抑郁症患者的恐惧增强惊吓程度增加。 自杀未遂者的恐惧增强惊吓增加表明杏仁核在有自杀企图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。 （二） 自然杀伤细胞和单核细胞中P11水平与慢性西酞普兰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相关。 第三章 双相情感障碍受试者抑郁发作时锂和一氧化氮水平。我们发现，锂治疗显着增加血浆一氧化氮水平治疗6周后，与基线水平相比，双相抑郁症。抑郁发作期间的基线氧化物水平与健康对照组相比没有差异。目前的研究结果表明，锂上调一氧化氮信号在未经药物治疗的BD与短病程。 四、 舍曲林和经颅直流电刺激抗抑郁治疗后的BDNF血浆水平。我们测量了基线和终点时的BDNF血浆水平，观察到治疗后BDNF水平无显著变化。此外，在应答者和非应答者中没有观察到显著变化，BDNF水平与抑郁症相关的临床和精神病理学变量之间也没有关系。因此，在为数不多的评估抗抑郁治疗过程中BDNF变化的安慰剂对照试验中，无论抑郁症患者的临床改善如何，我们都没有观察到BDNF增加。 第五章） 我们描述了使用11 C-咯利普兰治疗重度抑郁症患者和健康对照的临床方案的方法学和验证。我们发现，图像衍生的输入功能是一个很好的替代全动脉输入功能的11 C-咯利普兰PET临床扫描。 六、 情绪障碍患者一级亲属中的儿茶酚胺耗竭：一项18氟脱氧葡萄糖正电子发射断层扫描研究我们的研究结果表明，敏感性儿茶酚胺耗竭可能是一个表型标志物的脆弱性情绪障碍的特点是在神经生理水平的纹状体和它的传出投射，包括边缘皮质-纹状体-苍白球-丘脑电路的去抑制。 第七章） 躁狂症和抑郁症家族传播的独立性。我们发现双相I型（BP I; OR =8.40; 3.27-20.97; h2=0.83）和重性抑郁障碍（OR=2.26; 1.58-3.22; h2=0.20）的家族聚集性具有特异性，而BP II型则无特异性。BP I的家族聚集性主要归因于躁狂发作的家族特异性，