Niciu Mark J, Mathews Daniel C, Nugent Allison C, Ionescu Dawn F, Furey Maura L, Richards Erica M, Machado-Vieira Rodrigo, Zarate Carlos A
Experimental Therapeutics & Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, Maryland.
Depress Anxiety. 2014 Apr;31(4):297-307. doi: 10.1002/da.22224. Epub 2013 Dec 18.
An impediment to progress in mood disorders research is the lack of analytically valid and qualified diagnostic and treatment biomarkers. Consistent with the National Institute of Mental Health (NIMH)'s Research Domain Criteria (RDoC) initiative, the lack of diagnostic biomarkers has precluded us from moving away from a purely subjective (symptom-based) toward a more objective diagnostic system. In addition, treatment response biomarkers in mood disorders would facilitate drug development and move beyond trial-and-error toward more personalized treatments. As such, biomarkers identified early in the pathophysiological process are proximal biomarkers (target engagement), while those occurring later in the disease process are distal (disease pathway components). One strategy to achieve this goal in biomarker development is to increase efforts at the initial phases of biomarker development (i.e. exploration and validation) at single sites with the capability of integrating multimodal approaches across a biological systems level. Subsequently, resultant putative biomarkers could then undergo characterization and surrogacy as these latter phases require multisite collaborative efforts. We have used multimodal approaches - genetics, proteomics/metabolomics, peripheral measures, multimodal neuroimaging, neuropsychopharmacological challenge paradigms and clinical predictors - to explore potential predictor and mediator/moderator biomarkers of the rapid-acting antidepressants ketamine and scopolamine. These exploratory biomarkers may then be used for a priori stratification in larger multisite controlled studies during the validation and characterization phases with the ultimate goal of surrogacy. In sum, the combination of target engagement and well-qualified disease-related measures are crucial to improve our pathophysiological understanding, personalize treatment selection, and expand our armamentarium of novel therapeutics.
情绪障碍研究进展的一个阻碍是缺乏分析上有效且合格的诊断和治疗生物标志物。与美国国立精神卫生研究所（NIMH）的研究领域标准（RDoC）计划一致，诊断生物标志物的缺乏使我们无法从纯粹主观的（基于症状的）诊断系统转向更客观的诊断系统。此外，情绪障碍的治疗反应生物标志物将促进药物开发，并从试错法转向更个性化的治疗。因此，在病理生理过程早期识别出的生物标志物是近端生物标志物（靶点参与），而在疾病过程后期出现的生物标志物是远端生物标志物（疾病途径成分）。在生物标志物开发中实现这一目标的一种策略是，在能够整合生物系统水平多模态方法的单一研究点，加大生物标志物开发初始阶段（即探索和验证）的力度。随后，由于后期阶段需要多中心合作，由此产生的假定生物标志物可进行特征描述和替代验证。我们使用了多模态方法——遗传学、蛋白质组学/代谢组学、外周测量、多模态神经影像学、神经精神药理学激发范式和临床预测指标——来探索快速起效的抗抑郁药氯胺酮和东莨菪碱的潜在预测指标以及中介/调节生物标志物。这些探索性生物标志物随后可在验证和特征描述阶段用于更大规模的多中心对照研究中的先验分层，最终目标是进行替代验证。总之，靶点参与和合格的疾病相关测量指标的结合对于提高我们对病理生理学的理解、个性化治疗选择以及扩大我们的新型治疗手段至关重要。
