Maes Michael, Yirmyia Raz, Noraberg Jens, Brene Stefan, Hibbeln Joe, Perini Giulia, Kubera Marta, Bob Petr, Lerer Bernard, Maj Mario
Clinical Research Center for Mental Health, Olmenlaan 9, Antwerp Wilrijk 2610, Belgium.
Metab Brain Dis. 2009 Mar;24(1):27-53. doi: 10.1007/s11011-008-9118-1. Epub 2008 Dec 16.
Despite extensive research, the current theories on serotonergic dysfunctions and cortisol hypersecretion do not provide sufficient explanations for the nature of depression. Rational treatments aimed at causal factors of depression are not available yet. With the currently available antidepressant drugs, which mainly target serotonin, less than two thirds of depressed patients achieve remission. There is now evidence that inflammatory and neurodegenerative (I&ND) processes play an important role in depression and that enhanced neurodegeneration in depression may-at least partly-be caused by inflammatory processes. Multiple inflammatory-cytokines, oxygen radical damage, tryptophan catabolites-and neurodegenerative biomarkers have been established in patients with depression and these findings are corroborated by animal models of depression. A number of vulnerability factors may predispose towards depression by enhancing inflammatory reactions, e.g. lower peptidase activities (dipeptidyl-peptidase IV, DPP IV), lower omega-3 polyunsaturated levels and an increased gut permeability (leaky gut). The cytokine hypothesis considers that external, e.g. psychosocial stressors, and internal stressors, e.g. organic inflammatory disorders or conditions, such as the postpartum period, may trigger depression via inflammatory processes. Most if not all antidepressants have specific anti-inflammatory effects, while restoration of decreased neurogenesis, which may be induced by inflammatory processes, may be related to the therapeutic efficacy of antidepressant treatments. Future research to disentangle the complex etiology of depression calls for a powerful paradigm shift, i.e. by means of a high throughput-high quality screening, including functional genetics and genotyping microarrays; established and novel animal and ex vivo-in vitro models for depression, such as new transgenic mouse models and endophenotype-based animal models, specific cell lines, in vivo and ex vivo electroporation, and organotypic brain slice culture models. This screening will allow to: 1) discover new I&ND biomarkers, both at the level of gene expression and the phenotype; and elucidate the underlying molecular I&ND pathways causing depression; and 2) identify new therapeutic targets in the I&ND pathways; develop new anti-I&ND drugs for these targets; select existing anti-I&ND drugs or substances that could augment the efficacy of antidepressants; and predict therapeutic response by genetic I&ND profiles.
尽管进行了广泛的研究，但目前关于血清素功能障碍和皮质醇分泌过多的理论并不能充分解释抑郁症的本质。针对抑郁症病因的合理治疗方法目前尚未出现。使用目前可用的主要针对血清素的抗抑郁药物，不到三分之二的抑郁症患者能够实现症状缓解。现在有证据表明，炎症和神经退行性（I&ND）过程在抑郁症中起重要作用，并且抑郁症中神经退行性变的加剧可能至少部分是由炎症过程引起的。在抑郁症患者中已经确定了多种炎症细胞因子、氧自由基损伤、色氨酸分解代谢产物以及神经退行性生物标志物，这些发现也得到了抑郁症动物模型的证实。一些易患因素可能通过增强炎症反应而使人易患抑郁症，例如较低的肽酶活性（二肽基肽酶IV，DPP IV）、较低的ω-3多不饱和脂肪酸水平以及肠道通透性增加（肠漏）。细胞因子假说认为，外部因素，如心理社会压力源，以及内部压力源，如器质性炎症性疾病或状况，例如产后时期，可能通过炎症过程引发抑郁症。大多数（如果不是全部的话）抗抑郁药都具有特定的抗炎作用，而恢复可能由炎症过程诱导的神经发生减少可能与抗抑郁治疗的疗效有关。未来旨在解开抑郁症复杂病因的研究需要强大的范式转变，即通过高通量、高质量的筛选，包括功能遗传学和基因分型微阵列；建立新的抑郁症动物模型和离体 - 体外模型，如新的转基因小鼠模型和基于内表型的动物模型、特定细胞系、体内和体外电穿孔以及脑片器官型培养模型。这种筛选将有助于：1）在基因表达和表型水平上发现新的I&ND生物标志物；阐明导致抑郁症的潜在分子I&ND途径；以及2）确定I&ND途径中的新治疗靶点；开发针对这些靶点的新型抗I&ND药物；选择现有的抗I&ND药物或物质以增强抗抑郁药的疗效；并通过遗传I&ND谱预测治疗反应。
