A closer look at the hypothalamic-pituitary-adrenal axis

Major depressive disorder ( MDD ) is a stress-related mental disorder with a lifetime prevalence of 20%, making it one of the most common mental illnesses worldwide. Many studies with a large number of patients support the assumption that abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis are crucial for the development of MDD.

The Global Burden of Disease studyestimates that MDD is one of the three most debilitating diseases worldwide. According to the World Health Organization, it will also be the leading cause of disease burden worldwide by 2030. Patients with depression have a two-fold increase in mortality and a 7-14 year reduction in life expectancy. This increased mortality is not only due to suicide, but also to the onset or worsening of somatic disorders such as heart disease, metabolic syndrome, diabetes mellitus, cancer or stroke. Although there are numerous effective antidepressants, more than 50% of patients do not respond to the first antidepressant prescribed and about 30% do not respond to several treatment attempts. These cases are often grouped under the term treatment-resistant depression (TRD), which is usually defined as MDD that persists after two adequate attempts with antidepressants. In addition to high rates of partial or no response, commonly used antidepressants have a delayed onset of action and unpleasant or even threatening side effects.

These inadequate treatment options lead to high rates of early retirement and sick leave. Several factors are responsible for this situation, such as the fact that MDD is a heterogeneous disorder with poorly defined subgroups or endophenotypes and most of the currently available antidepressants have similar mechanisms that target components of serotonin, norepinephrine and dopamine signaling. Furthermore, there are no genetic markers or biomarkers that reliably link patients to effective treatment options. Thus, there is a need for objective, measurable biomarkers to enable a precision medicine approach.

Addressing individual goals

Changes in the hypothalamic-pituitary-adrenal (HPA) axis in MDD are well documented. However, not all patients with MDD exhibit HPA axis dysfunction. Even if they have impaired function, however, the dysfunction may occur at different levels of the HPA axis signaling cascade. This could be the reason why certain compounds that target the HPA axis at very specific sites, such as vasopressin V1B receptor antagonists, corticotropin-releasing hormone (CRH)1 receptor antagonists or glucocorticoid receptor (GR) antagonists, only improve depressive symptoms in a certain proportion of patients. In order to find the right treatment method for each patient in terms of individualized treatment, tests that assess the function of the HPA axis, such as the dexamethasone-corticotropin-releasing hormone test (Dex-CRH) or the molecular dexamethasone suppression test (mDST), must be performed. This approach could be used to identify suitable patients for specific drugs targeting the HPA axis. In the meantime, several drugs with different treatment strategies have achieved positive effects in the treatment of depression. These drugs improved not only depressive symptoms but also HPA axis impairments and were generally well tolerated. In particular, the V1B receptor antagonists, such as SSR149415/nelivaptan, and the GR antagonist mifepristone delivered promising results. However, FKBP51 antagonists, which have not yet been tested in clinical samples, also achieved very interesting results in preclinical models of depression and anxiety. In addition, FKBP51 appears to be necessary for some of the effects of ketamine.