Menke Andreas
Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Wuerzburg, Wuerzburg, Germany.
Front Psychiatry. 2019 Feb 28;10:101. doi: 10.3389/fpsyt.2019.00101. eCollection 2019.
Major depressive disorder (MDD) is a very common stress-related mental disorder that carries a huge burden for affected patients and the society. It is associated with a high mortality that derives from suicidality and the development of serious medical conditions such as heart diseases, diabetes, and stroke. Although a range of effective antidepressants are available, more than 50% of the patients do not respond to the first treatment they are prescribed and around 30% fail to respond even after several treatment attempts. The heterogeneous condition of MDD, the lack of biomarkers matching patients with the right treatments and the situation that almost all available drugs are only targeting the serotonin, norepinephrine, or dopamine signaling, without regulating other potentially dysregulated systems may explain the insufficient treatment status. The hypothalamic-pituitary-adrenal (HPA) axis is one of these other systems, there is numerous and robust evidence that it is implicated in MDD and other stress-related conditions, but up to date there is no specific drug targeting HPA axis components that is approved and no test that is routinely used in the clinical setting identifying patients for such a specific treatment. Is there still hope after these many years for a breakthrough of agents targeting the HPA axis? This review will cover tests detecting altered HPA axis function and the specific treatment options such as glucocorticoid receptor (GR) antagonists, corticotropin-releasing hormone 1 (CRH) receptor antagonists, tryptophan 2,3-dioxygenase (TDO) inhibitors and FK506 binding protein 5 (FKBP5) receptor antagonists.
重度抑郁症（MDD）是一种非常常见的与压力相关的精神障碍，给受影响的患者和社会带来了巨大负担。它与高死亡率相关，死亡率源于自杀行为以及心脏病、糖尿病和中风等严重疾病的发生。尽管有一系列有效的抗抑郁药，但超过50%的患者对首次处方的治疗没有反应，约30%的患者即使经过多次治疗尝试仍无反应。MDD的异质性、缺乏将患者与正确治疗方法相匹配的生物标志物，以及几乎所有现有药物仅针对5-羟色胺、去甲肾上腺素或多巴胺信号传导，而不调节其他可能失调的系统的情况，可能解释了治疗效果不佳的现状。下丘脑-垂体-肾上腺（HPA）轴就是这些其他系统之一，有大量确凿证据表明它与MDD和其他与压力相关的疾病有关，但迄今为止，尚无针对HPA轴成分的获批特效药物，也没有在临床环境中常规使用的检测方法来识别适合这种特定治疗的患者。多年来，针对HPA轴的药物突破还有希望吗？本综述将涵盖检测HPA轴功能改变的检测方法以及糖皮质激素受体（GR）拮抗剂、促肾上腺皮质激素释放激素1（CRH）受体拮抗剂、色氨酸2,3-双加氧酶（TDO）抑制剂和FK506结合蛋白5（FKBP5）受体拮抗剂等特定治疗选择。
