Augmented Cortisol and Antiglucocorticoid Therapy in Mood Disorders: the Hippocampus as a Potential Drug Target

The pathophysiology of many mood disorders is closely relatedto abnormal stress response associated with the dysfunction of thehypothalamic–pituitary–adrenal (HPA) axis and cortisol overproduction. Thehippocampus, a key structure of the limbic system responsible forboth cognitive and emotional spheres, is selectively vulnerableto excess of glucocorticoids (GCs) inducing neuroinflammation and neurodegeneration.The antiGC therapy of psychiatric diseases, in particular depressivedisorders, may be a useful additional treatment. Among other approaches,targeting glucocorticoid receptors, abounded in the hippocampus,is regarded as highly promising. However, though the preclinicaldata provide fairly firm evidence to the concept of antiGC therapyfor stress-related diseases, clinical studies still are at the proof-of-conceptstage. Noteworthy, chronic GC excess is associated not only withmood diseases, but also with cognitive decline, metabolic disorders,diabetes. Potentially, antiGC (HPA axis modifying) therapy may alleviateaffective symptoms, cognitive disturbances, GC and insulin resistanceand adverse side effects of conventional drugs through beneficialeffects on the hippocampus mitigating its dysfunction and neurodegeneration,neuroinflammation, and impairment of neurogenesis. Since stress/GC-associatedneuroinflammation-mediated pathology of the limbic system and, specifically,the hippocampus, is a general feature typical for many brain diseases,the concept of antiGC therapy may be extended, tested and validatedin a wider spectrum of cerebral pathologies.