Discovery of Personalized Treatment for Immune-Metabolic Depression—Focus on 11beta Hydroxysteroid Dehydrogenase Type 2 (11betaHSD2) and Toll Like Receptor 4 (TLR4) Inhibition with Enoxolone

Treatment options for major depression are limited: only about 1/3 of patients achieve remission with first line treatments. More importantly, there are no established predictive markers to identify patients who may be treatment refractory. Research from us and others have established markers related to metabolic disturbances (increased BMI, increased triglyceride levels), inflammatory markers (C-reactive protein, CRP), autonomic disturbances (reduced blood pressure, reduced heart rate variability), brain morphology changes (increased volume of the choroid plexus and brain ventricle volumes). Approximately 1/3 of patients with depression may express these characteristics. These features can mechanistically be linked to a reduced sensitivity of peripheral mineralocorticoid receptors and as a consequence increased release of renin from the kidney, increased production of angiotensin and increased adrenal release of aldosterone. The primary CNS target of aldosterone is a key center of autonomic and affect regulation, i.e. the nucleus of the solitary tract (NTS), which is also the entry point of the vagus nerve, which provides signals from baroreceptors and chemoreceptors. In search of a mechanism to overcome this pathology we identified a molecule, which is derived from the licorice plant glycyrrhiza glabra, namely glycyrrhizin and it biologically active metabolite enoxolone. These molecules have been demonstrated to reverse some of these markers by a well understood dual mechanism: It inhibits the enzyme 11beta hydroxysteroid- dehydrogenase type 2 (11betaHSD2) and inhibits the toll like receptor 4 (TLR4), i.e. the ligand for lipopolysaccharide (LPS) and trigger of innate immunity. As a consequence, patients which show an increase in inflammation markers, an increase in aldosterone or a low blood pressure, are a preferential target population for this compound. Importantly, these patients can be identified as likely treatment refractory BEFORE a treatment is initiated. Clinically, these patients are primarily young females or patients with a history of childhood trauma. A combination of enoxolone with standard antidepressants may therefore avoid a trial and error approach in these subjects and will benefit them by achieving recovery faster.