The potential role of excessive cortisol induced by HPA hyperfunction in the pathogenesis of depression

Prolonged hypothalamic-pituitary-adrenocortical (HPA) axis overactivity occurs at all levels of this axis during stress in normals and some depressed patients. This can induce enlargement of the pituitary and adrenals. Various reports showed that cortisol can affect mood and behavior, and disrupt memory and recall. The integrity of the hippocampus is essential for memory function and, via the high density of its cortisol receptors, cortisol induced inhibitory feedback to the HPA axis. Animal data suggest that over time aging and stress can permanently downregulate hippocampal cell receptors, produce chronic hippocampal inflammation (astroglial), and kill cells. Cushing's syndrome patients (high cortisol) show diminished hippocampal size and verbal recall inversely related to cortisol levels. All the above is consistent with the 'cascade hypothesis' of cortisol induced hippocampal damage with resultant diminished inhibition to HPA hyperactivity in a circular manner. High cortisol is associated with altered neurotransmitter function, e.g., diminished brain serotonin synthesis, low CSF 5HIAA, and increased noradrenergic activity.