Neurobiology of non-specific and specific treatment responses in Major Depression

重度抑郁症非特异性和特异性治疗反应的神经生物学

• 批准号: 9003106
• 负责人: Jon-Kar Zubieta
• 金额: $ 62.37万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9003106
• 关键词: Accounting; Acute; Affect; Affective; Amygdaloid structure; Anterior; Antidepressive Agents; Area; Back; Behavioral; Biological; Biological Markers; Brain; Chronic; Clinical; Clinical Medicine; Clinical Trials; Cognitive; Conduct Clinical Trials; Cues; Data; Development; Diagnosis; Dopamine; Double-Blind Method; Double-blind trial; Drug Targeting; Ego; Emotional; Expectancy; Genetic Polymorphism; Genetic Variation; Hydrocortisone; Individual; Intervention; Learning; Link; Maintenance; Major Depressive Disorder; Measurement; Measures; Medial; Mediating; Moods; Neurobiology; Neurotic Disorders; Neurotransmitters; Noise; Nucleus Accumbens; Opioid Receptor; Patients; Peripheral; Personality Traits; Personality inventories; Pharmaceutical Preparations; Placebo Effect; Placebos; Predictive Value; Process; Psychophysics; Randomized Controlled Trials; Recovery; Regulation; Reporting; Rewards; Science; Selective Serotonin Reuptake Inhibitor; Source; Stimulus; Stress; Structure; Symptoms; System; Testing; Thalamic structure; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Transcend; Treatment outcome; Variant; active method; antidepressant effect; arm; biomarker discovery; comparative effectiveness; design; effectiveness trial; emotion regulation; endogenous opioids; expectation; experience; inflammatory marker; inter-individual variation; neurochemistry; neurotransmission; novel; novel strategies; open label; predictive of treatment response; public health relevance; randomized placebo controlled trial; relating to nervous system; response; screening; symptomatic improvement; theories; trait; treatment response

 DESCRIPTION (provided by applicant): In science, profound changes in paradigm have emerged when previously unexplained phenomena, typically disregarded as noise or measurement error, are explained by a new theoretical structure. If a comparable phenomenon could be found in clinical medicine, an unexplained source of variance, it would be the so-called "placebo effect". It should be noted that placebo effects have a different meaning for clinical trials and for neurobiologists. In the former case, they are considered "non-specific", and contributing to the variability, "noise", in treatment responses. This effect is particularly prominent in Major Depressive Disorder (MDD), a chronic and disabling illness that nevertheless presents with ≈ 30-50% responses attributable to placebo. For the neurobiologists, however, there is now uncontroversial evidence that the cognitive-emotional integrative processes that take place in the context of positive expectations associated with a potential therapeutic intervention, induce changes in brain function and neurochemistry that are associated with symptom improvement and illness recovery. In that context, "true" neurobiological placebo responses represent potential mechanisms of resiliency and treatment response, as well as new treatment target opportunities, as will be described in this application and backed by convincing preliminary data. This application proposes to examine "non-specific" and "specific" neurobiological contributions to treatment response, objectively explaining variance by studying the function of a neurotransmitter system linked with the regulation of stress, affect and mood, but also placebo responses, the endogenous opioid system and µ-opioid receptors. We are to determine interindividual variations in the function of µ-opioid receptor-mediated neurotransmission in patients diagnosed with moderate-severe MDD and the effect of placebo and active antidepressant administrations on these mechanisms. The data acquired will determine neurobiological factors that are associated with symptom improvement across "non-specific" and "drug-specific" conditions. Contributing variables that would explain variability in these mechanisms, specifically genetic variation, biomarkers and personality trait variation will be examined and pooled to develop markers of treatment response and orient novel approaches to the conduct of clinical trials. Some of these markers, specifically those linked to functional genetic polymorphisms would also direct the examination of novel treatment approaches not currently contemplated in drug target screening.

 描述(申请人提供)：在科学中，当以前无法解释的现象，通常被忽略为噪声或测量误差，被新的理论结构解释时，范式发生了深刻的变化。如果可以在临床医学中发现类似的现象，这是一种无法解释的差异来源，那就是所谓的“安慰剂效应”。应该指出的是，安慰剂效应对临床试验和神经生物学家有不同的意义。在前一种情况下，它们被认为是“非特异性的”，并导致治疗反应中的变异性，即“噪音”。这种影响在严重抑郁障碍中尤其明显，这是一种慢性和致残性疾病，但≈30%-50%的反应可归因于安慰剂。然而，对于神经生物学家来说，现在有毋庸置疑的证据表明，在与潜在治疗干预相关的积极预期的背景下发生的认知-情绪整合过程会导致与症状改善和疾病康复相关的大脑功能和神经化学的变化。在这种情况下，“真正的”神经生物安慰剂反应代表了潜在的复原力和治疗反应机制，以及新的治疗靶点机会，如本申请中将描述的，并有令人信服的初步数据支持。这项应用建议检查治疗反应的“非特异性”和“特异性”神经生物学贡献，通过研究神经递质系统的功能来客观解释差异，神经递质系统与压力、情感和情绪的调节有关，但也与安慰剂反应、内源性阿片系统和µ-阿片受体有关。我们将确定被诊断为中重度MDD患者的µ-阿片受体介导的神经传递功能的个体间差异，以及安慰剂和积极的抗抑郁药物对这些机制的影响。获得的数据将确定与“非特定”和“药物特定”条件下症状改善相关的神经生物学因素。将检查和汇集解释这些机制中的变异性的贡献变量，特别是遗传变异性、生物标记物和个性特征变异性，以开发治疗反应的标记物，并指导进行临床试验的新方法。其中一些标记，特别是那些与功能性遗传多态有关的标记，也将指导目前在药物靶标筛选中没有考虑的新治疗方法的检查。