Max Planck Institute of Psychiatry, 80804 Munich, Germany.
kbo-Isar-Amper Clinical Center Munich East, 85540 Munich, Germany.
Int J Mol Sci. 2019 Jan 23;20(3):485. doi: 10.3390/ijms20030485.
Adverse experiences and chronic stress are well-known risk factors for the development of major depression, and an impaired stress response regulation is frequently observed in acute depression. Impaired glucocorticoid receptor (GR) signalling plays an important role in these alterations, and a restoration of GR signalling appears to be a prerequisite of successful antidepressant treatment. Variants in genes of the stress response regulation contribute to the vulnerability to depression in traumatized subjects. Consistent findings point to an important role of FKBP5, the gene expressing FK506-binding protein 51 (FKBP51), which is a strong inhibitor of the GR, and thus, an important regulator of the stress response. We investigated the role of FKBP5 and FKB51 expression with respect to stress response regulation and antidepressant treatment outcome in depressed patients. This study included 297 inpatients, who participated in the Munich Antidepressant Response Signature (MARS) project and were treated for acute depression. In this open-label study, patients received antidepressant treatment according to the attending doctor's choice. In addition to the genotype, changes in blood FKBP51 expression during antidepressant treatment were analyzed using RT-PCR and ZeptoMARK reverse phase protein microarray (RPPM). Stress response regulation was evaluated in a subgroup of patients using the combined dexamethasone (dex)/corticotropin releasing hormone (CRH) test. As expected, increased FKBP51 expression was associated with an impaired stress response regulation at baseline and after six weeks was accompanied by an elevated cortisol response to the combined dex/CRH test. Further, we demonstrated an active involvement of FKBP51 in antidepressant treatment outcome. While patients responding to antidepressant treatment had a pronounced reduction of gene and FKBP51 protein expression, increasing expression levels were observed in nonresponders. This effect was moderated by the genotype of the single nucleotide polymorphism (SNP) rs1360780, with carriers of the minor allele showing the most pronounced association. Our findings demonstrate that and, specifically, its expression product FKBP51 are important modulators of antidepressant treatment outcome, pointing to a new, promising target for future antidepressant drug development.
不良经历和慢性应激是导致重度抑郁症发展的已知危险因素，而急性抑郁症患者常存在应激反应调节受损。糖皮质激素受体 (GR) 信号转导受损在这些改变中起着重要作用，而 GR 信号转导的恢复似乎是成功进行抗抑郁治疗的前提。应激反应调节相关基因的变异与创伤后易患抑郁症有关。一致的研究结果表明 FKBP5 发挥着重要作用，FKBP5 基因表达 FK506 结合蛋白 51 (FKBP51)，FKBP51 是 GR 的强抑制剂，因此是应激反应的重要调节剂。我们研究了 FKBP5 和 FKB51 表达在抑郁患者的应激反应调节和抗抑郁治疗效果中的作用。这项研究纳入了 297 名住院患者，他们参与了慕尼黑抗抑郁反应特征 (MARS) 项目，并接受了急性抑郁症的治疗。在这项开放标签研究中，患者根据主治医生的选择接受抗抑郁治疗。除了 基因型外，还使用 RT-PCR 和 ZeptoMARK 反相蛋白微阵列 (RPPM) 分析了抗抑郁治疗过程中血液 FKBP51 表达的变化。在患者亚组中使用联合地塞米松 (dex)/促肾上腺皮质激素释放激素 (CRH) 测试评估了应激反应调节。正如预期的那样，FKBP51 表达增加与基线时的应激反应调节受损有关，而在六周后，FKBP51 表达增加伴随着联合 dex/CRH 测试中皮质醇反应升高。此外，我们还证明了 FKBP51 积极参与了抗抑郁治疗效果。虽然对抗抑郁治疗有反应的患者的 基因和 FKBP51 蛋白表达明显降低，但在无反应者中观察到表达水平增加。这种效应受 rs1360780 单核苷酸多态性 (SNP) 基因型的调节，携带次要等位基因的个体表现出最显著的关联。我们的研究结果表明， 和特别是其表达产物 FKBP51 是抗抑郁治疗效果的重要调节剂，为未来抗抑郁药物的开发提供了新的有希望的靶点。
