Hori Hiroaki, Yoshida Fuyuko, Ishida Ikki, Matsuo Junko, Ogawa Shintaro, Hattori Kotaro, Kim Yoshiharu, Kunugi Hiroshi
Department of Behavioral Medicine, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan; Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
Department of Behavioral Medicine, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo, Japan; Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
J Affect Disord. 2024 Mar 15;349:244-253. doi: 10.1016/j.jad.2024.01.080. Epub 2024 Jan 9.
While depression has been associated with alterations in the hypothalamic-pituitary adrenal (HPA) axis function, there is still controversy regarding the nature and extent of the dysfunction, such as in the debate about hypercortisolism vs. hypocortisolism. It may therefore be necessary to understand whether and how HPA axis function in depression is linked to mRNA expression of key genes regulating this system.
We studied 163 depressed outpatients, most of whom were chronically ill, and 181 healthy controls. Blood mRNA expression levels of NR3C1 (including GRα, GRβ, and GR-P isoforms), FKBP4, and FKBP5 were measured at baseline. HPA axis feedback sensitivity was measured by the dexamethasone (Dex)/corticotropin-releasing hormone (CRH) test. The association between mRNA expression levels and HPA axis feedback sensitivity was examined.
Compared to controls, patients showed significantly higher expression of GRα and lower expression of FKBP5, and higher post-Dex cortisol levels, even after controlling for age and sex. FKBP5 expression was significantly positively correlated with cortisol levels in patients, while GRα expression was significantly negatively correlated with cortisol levels in controls.
Most patients were taking psychotropic medications. The large number of correlation tests may have caused type I errors.
The tripartite relationship between depression, mRNA expression of GR and FKBP5, and HPA axis function suggests that the altered gene expression affects HPA axis dysregulation and, as a result, impacts the development and/or illness course of depressive disorder. The combination of increased GRα expression and decreased FKBP5 expression may serve as a biomarker for chronic depression.
虽然抑郁症与下丘脑 - 垂体 - 肾上腺（HPA）轴功能改变有关，但关于功能障碍的性质和程度仍存在争议，例如在高皮质醇血症与低皮质醇血症的争论中。因此，可能有必要了解抑郁症中HPA轴功能是否以及如何与调节该系统的关键基因的mRNA表达相关联。
我们研究了163名抑郁症门诊患者（其中大多数为慢性病患者）和181名健康对照者。在基线时测量NR3C1（包括GRα、GRβ和GR - P亚型）、FKBP4和FKBP5的血液mRNA表达水平。通过地塞米松（Dex）/促肾上腺皮质激素释放激素（CRH）试验测量HPA轴反馈敏感性。检查mRNA表达水平与HPA轴反馈敏感性之间的关联。
与对照组相比，即使在控制年龄和性别后，患者的GRα表达明显更高，FKBP5表达更低，且地塞米松后皮质醇水平更高。FKBP5表达与患者的皮质醇水平显著正相关，而GRα表达与对照组的皮质醇水平显著负相关。
大多数患者正在服用精神药物。大量的相关性测试可能导致了I型错误。
抑郁症、GR和FKBP5的mRNA表达以及HPA轴功能之间的三方关系表明，基因表达改变会影响HPA轴失调，从而影响抑郁症的发展和/或病程。GRα表达增加和FKBP5表达降低的组合可能作为慢性抑郁症的生物标志物。
