Pariante C M, Miller A H
Section of Clinical Neuropharmacology, Institute of Psychiatry, King's College London, London, United Kingdom.
Biol Psychiatry. 2001 Mar 1;49(5):391-404. doi: 10.1016/s0006-3223(00)01088-x.
Hyperactivity of the hypothalamic--pituitary--adrenal (HPA) axis has been reliably observed in patients with major depression. One of the primary features of this HPA axis hyperactivity is reduced sensitivity to the inhibitory effects of the glucocorticoid dexamethasone on the production of adrenocorticotropic hormone and cortisol during the dexamethasone suppression test and, more recently, the dexamethasone--corticotropin-releasing hormone test. Because the effects of glucocorticoids are mediated by intracellular receptors including, most notably, the glucocorticoid receptor (GR), a number of studies have considered the possibility that the number and/or function of GRs are reduced in depressed patients. Moreover, whether antidepressants act by reversing these putative GR changes has been examined. The extant literature on GR receptors in major depression was reviewed along with studies examining the impact of antidepressants on the GR. The data support the hypothesis that the function of the GR is reduced in major depression in the absence of clear evidence of decreased GR expression. The data also indicate that some antidepressants have direct effects on the GR, leading to enhanced GR function and increased GR expression. Hypotheses regarding the mechanism of these receptor changes involve relevant second messenger pathways that regulate GR function. The findings indicate that the GR is an important molecular target in major depression. Further elucidation of the biochemical and molecular mechanisms involved in GR changes in major depression is an exciting frontier that will no doubt lead to new insights into the pathophysiology and treatment of affective disorders.
在重度抑郁症患者中，下丘脑 - 垂体 - 肾上腺（HPA）轴功能亢进已得到确切证实。这种HPA轴功能亢进的主要特征之一是，在地塞米松抑制试验以及最近的地塞米松 - 促肾上腺皮质激素释放激素试验中，对糖皮质激素地塞米松抑制促肾上腺皮质激素和皮质醇分泌的作用敏感性降低。由于糖皮质激素的作用是通过细胞内受体介导的，其中最主要的是糖皮质激素受体（GR），因此许多研究考虑了抑郁症患者GR数量和/或功能降低的可能性。此外，还研究了抗抑郁药是否通过逆转这些假定的GR变化发挥作用。本文综述了有关重度抑郁症中GR受体的现有文献，以及研究抗抑郁药对GR影响的相关研究。数据支持这样的假设：在没有明确证据表明GR表达降低的情况下，重度抑郁症患者的GR功能降低。数据还表明，一些抗抑郁药对GR有直接作用，导致GR功能增强和表达增加。关于这些受体变化机制的假设涉及调节GR功能的相关第二信使途径。研究结果表明，GR是重度抑郁症中的一个重要分子靶点。进一步阐明重度抑郁症中GR变化所涉及的生化和分子机制是一个令人兴奋的前沿领域，无疑将为情感障碍的病理生理学和治疗带来新的见解。
