Department of Psychiatry, University of Pittsburgh, PA 15219, USA.
Int J Neuropsychopharmacol. 2013 Sep;16(8):1893-909. doi: 10.1017/S1461145713000436. Epub 2013 May 14.
Major depression is characterized by low mood, a reduced ability to experience pleasure and frequent cognitive, physiological and high anxiety symptoms. It is also the leading cause of years lost due to disability worldwide in women and men, reflecting a lifelong trajectory of recurring episodes, increasing severity and progressive treatment resistance. Yet, antidepressant drugs at best treat only one out of every two patients and have not fundamentally changed since their discovery by chance >50 yr ago. This status quo may reflect an exaggerated emphasis on a categorical disease classification that was not intended for biological research and on oversimplified gene-to-disease models for complex illnesses. Indeed, genetic, molecular and cellular findings in major depression suggest shared risk and continuous pathological changes with other brain-related disorders. So, an alternative is that pathological findings in major depression reflect changes in vulnerable brain-related biological modules, each with their own aetiological factors, pathogenic mechanisms and biological/environment moderators. In this model, pathological entities have low specificity for major depression and instead co-occur, combine and interact within individual subjects across disorders, contributing to the expression of biological endophenotypes and potentially clinical symptom dimensions. Here, we discuss current limitations in depression research, review concepts of gene-to-disease biological scales and summarize human post-mortem brain findings related to pyramidal neurons, γ-amino butyric acid neurons, astrocytes and oligodendrocytes, as prototypical brain circuit biological modules. Finally we discuss nested aetiological factors and implications for dimensional pathology. Evidence suggests that a focus on local cell circuits may provide an appropriate integration point and a critical link between underlying molecular mechanisms and neural network dysfunction in major depression.
重度抑郁症的特征是情绪低落、体验愉悦的能力下降以及频繁出现认知、生理和高度焦虑症状。它也是全世界导致女性和男性残疾年数增加的主要原因，反映出反复发作、病情加重和治疗抵抗逐渐增强的终身病程。然而，抗抑郁药最多只能治疗每两个患者中的一个，并且自 50 多年前偶然发现以来并没有从根本上改变。这种现状可能反映出对分类疾病的过分强调，这种分类疾病不是为生物研究设计的，对复杂疾病的简化基因到疾病模型的过度简化。事实上，重度抑郁症的遗传、分子和细胞发现表明，与其他与大脑相关的疾病存在共同的风险和持续的病理变化。因此，另一种观点是，重度抑郁症的病理发现反映了易受影响的大脑相关生物模块的变化，每个模块都有自己的病因因素、发病机制和生物/环境调节剂。在这个模型中，病理性实体对重度抑郁症的特异性低，而是在不同的疾病中在个体患者中共同出现、组合和相互作用，导致生物内表型和潜在的临床症状维度的表达。在这里，我们讨论了抑郁症研究中的当前局限性，回顾了基因到疾病生物尺度的概念，并总结了与锥体神经元、γ-氨基丁酸神经元、星形胶质细胞和少突胶质细胞相关的人类死后大脑发现，作为典型的大脑回路生物模块。最后，我们讨论了嵌套的病因因素及其对维度病理学的影响。有证据表明，关注局部细胞回路可能为重度抑郁症中的潜在分子机制和神经网络功能障碍提供一个适当的整合点和关键联系。
