Objectives: This Anna Monika Award Lecture updates the role of the hypothalamic-pituitary-adrenal (HPA) axis in the pathogenesis and treatment of psychotic major depression (PMD).
Methods: Published reports from our group and others on the clinical phenomenology (including cognition), HPA axis activity, and genetics of PMD are reviewed as are published trials of the GR antagonist, mifepristone.
Results: Current prevalence of PMD is 0.4%. PMD patients demonstrate significant elevations in HPA activity (e.g., particularly high rates of dexamethasone non-suppression, high post-dexamethasone cortisol, etc.) as well as significant impairment in cognition (attention, executive function/response inhibition and verbal and visual memory). High cortisol levels correlate with a number of cognitive deficits (e.g., verbal memory). Allelic variants of the glucocorticoid receptor (GR) gene contribute significantly to both cortisol levels and to measures of psychosis; corticotropin-releasing hormone receptor 1 variants contribute to measures of depression and psychosis. GR antagonists have produced rapid improvement in psychotic symptoms, although failed trials indicate a therapeutic blood level that may require a dose of 1,200 mg/day that is much higher than the commonly tested 600 mg/day.
Conclusions: HPA axis over-activity appears to play a major role in the pathogenesis of PMD and is a target of drug development.
Keywords: cognition; cortisol; major depression; mifepristone; psychosis.