Is the HPA Axis as Target for Depression Outdated, or Is There a New Hope?

Abstract

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 (CRH₁) receptor antagonists, tryptophan 2,3-dioxygenase (TDO) inhibitors and FK506 binding protein 5 (FKBP5) receptor antagonists.

Keywords: CRH1; FKBP5; HPA axis; biomarker; depression; glucocorticoid receptor; personalized medicine; precision medicine.

Figure 1

The hypothalamic-pituitary-adrenal (HPA) axis: Corticotropin-releasing hormone (CRH) is released by neurons in the paraventricular nucleus of the hypothalamus. Subsequently CRH₁ receptors are activated and the secretion of adrenocorticotropic hormone (ACTH) from the pituitary is induced. ACTH induces the release of glucocorticoids (cortisol) by the adrenal glands. After the activation of the HPA axis, negative feedback loops are activated to reinstate homeostasis by cortisol activating glucocorticoid receptors (GR). The unliganded GR complex consists of the co-chaperones FKBP51 or FKBP52 (encoded by their respective genes FKBP5 and FKBP4), p23 (a co-chaperone molecule) and hsp90 dimer. When FKBP51 binds to the GR-complex via hsp90, the GR affinity for cortisol is reduced. When glucocorticoids bind to the GR, FKBP51 is exchanged against FKBP52 and the nuclear translocation of the ligand-bound GR is enabled. The GR directly binds to the DNA via glucocorticoid response elements (GREs) and induces FKBP5 mRNA expression and subsequently FKBP51 production, inducing an ultra-short negative feedback loop on GR sensitivity. Drugs regulating the function of the HPA axis target: (1) the GR, (2) the CRH₁ receptors, and (3) FKBP5/FKBP51 (modified after Leistner and Menke (21); Copyright (2018), with permission from Elsevier).