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: 9341382
• 负责人: Jon-Kar Zubieta
• 金额: $ 56.3万
• 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/9341382
• 关键词: 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; Neurotics; 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; resilience; 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.

 在科学中，当以前无法解释的现象（通常被视为噪声或测量误差）被新的理论结构解释时，范式发生了深刻的变化。如果在临床医学中可以找到一种类似的现象，一种无法解释的方差来源，那就是所谓的“安慰剂效应”。应该注意的是，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”，并有助于治疗反应的变异性，“噪音”。这种效应在重度抑郁症（MDD）中尤为突出，MDD是一种慢性致残性疾病，但安慰剂的应答率为30-50%。然而，对于神经生物学家来说，现在有无争议的证据表明，在与潜在的治疗干预相关的积极期望的背景下发生的认知-情绪整合过程会引起与症状改善和疾病恢复相关的脑功能和神经化学的变化。在这种情况下，“真正的”神经生物学安慰剂反应代表了弹性和治疗反应的潜在机制，以及新的治疗靶点机会，如本申请中所述，并得到令人信服的初步数据的支持。本申请提出检查对治疗反应的“非特异性”和“特异性”神经生物学贡献，通过研究与压力、情感和情绪调节相关的神经递质系统的功能以及安慰剂反应、内源性阿片系统和μ-阿片受体来客观地解释差异。我们将确定诊断为中重度MDD患者的μ-阿片受体介导的神经传递功能的个体间差异，以及安慰剂和活性抗抑郁药给药对这些机制的影响。所获得的数据将确定与“非特异性”和“药物特异性”条件下的症状改善相关的神经生物学因素。将检查并汇总解释这些机制中的变异性的贡献变量，特别是遗传变异、生物标志物和人格特质变异，以开发治疗反应的标志物，并确定开展临床试验的新方法。这些标记中的一些，特别是那些与功能性遗传多态性相关的标记，也将指导目前在药物靶点筛选中未考虑的新治疗方法的检查。