There are times when observations made over the span of a career seem to come together. This excellent series of articles that makes up this month's issue of Psychiatric Annals on hypothalamic-pituitary-adrenal axis (HPA) dysfunction, guest edited by Anthony J. Rothschild, MD, and Owen M. Wolkowitz, MD, resulted in this experience for this editor. HPA hyperfunction has been studied in psychiatry for 30 years. The research has been mainly correlational, but only recently have we learned enough to start making sense of possible mechanisms tying HPA hyperfunction to brain function. Sure, the DST raised our hopes that we had our first "biochemical" test in psychiatry and then disappointed us because of lack of specificity - but we haven't heard the end of the significance of HPA hyperfunction in psychiatry.
Important facts about the role of HPA function in severe psychiatric illness, notably affective disorders, are made clear in this series of articles. They all point to a major possibility, which is not yet completely proven but for which evidence is accumulating; namely, that HPA alterations represent a severity dimension in psychiatric illness that is associated with cognitive dysfunction and severity of chronic social impairment. This, plus results from animal research, suggests the possibility of lasting CNS damage induced by the HPA hyperfunction associated with severe affective disorder, psychotic states, and chronic severe stress situations related to these disorders or sustained periods of overwhelming external stressors, which may lead to posttraumatic stress disorder.
Dr. Rothschild, in his contribution on the dexamethasone suppression test, refers to evidence that psychiatric patients with sustained HPA hyperfunction, depressive features, and, often, psychosis show cognitive deficit changes in ventricle-to-brain ratios and chronic social impairment. K. Ranga Rama Krishnan, MD, points out evidence of both adrenal and pituitary hypertrophy in depressed patients with evidence of HPA hyperfunction. Dominique L. Musselman, MD, and Charles B. Nemeroff, MD, PhD, have traced HPA hyperfunction, adrenal and pituitary hypertrophy, and blunted ACTH response to corticotropinreleasing factor to CRF hypersecretion and down-regulation of CRF receptors.
In their article on the pathophysiologic significance of HPA hyperfunction, Beverley E. Pearson Murphy, MD, and Dr. Wolkowitz point out the genomic and immediate direct effects exerted on the CNS by glucocorticoids. They discuss the numerous related metabolites that appear also to be increased in states of HPA hyperactivity. Additionally, they present some early evidence for the possible therapeutic effects of antiglucocorticoid substances in the treatment-refractory patient with HPA activation.
In her article on HPA axis and psychopathology in Cushing's syndrome, Monica N. Starkman, MD, MS, enumerates symptoms in patients with Cushing's disease similar to those seen in severely depressed patients with HPA hyperfunction, including fatigue, low energy, immobility, impaired memory, middle insomnia, depressed mood, and significant anxiety in the majority of patients studied. To add to this argument, Victor I. Reus, MD, and Dr. Wolkowitz, in their review of the behavioral side effects of corticosteroid therapy, mentioned mood disturbances associated with anxiety; obsessive-compulsive disorder; disturbance in consciousness; insomnia; immobility; changes in sensory perception, attention, concentration, and memory; as well as emotional lability and sensory flooding in patients receiving high doses of glucocorticoids. An increased likelihood of suicide in states of adrenal hyperfunction such as exogenous corticoid administration, Cushing's disease, and HPA hyperfunction in depression is another severity measure that was touched upon by several of the authors. Interestingly, similar adverse behavioral effects of rapid withdrawal of corticoids as well as Addison's disease with its adrenal hypofunction are also associated with increased behavioral disturbances.
These articles, which document the behavioral effects of HPA hyperfunction, just begin to refer to the biologic effects of steroids on brain function. More can be found in the literature, but this issue certainly makes the case for HPA hyperfunction both as a marker for severity and a mechanism for negative outcomes, including cognitive impairment, severe social impairment, and perhaps even suicide in severe psychiatric illness through direct effects on brain both functionally and perhaps even anatomically.
Maybe the DST and other measures of HPA hyperfunction are not so passé because of their diagnostic nonspecificity for depression, but rather might be of value in documenting both severity or improvement in our patients. This continues to be exciting work and the issue of HPA hyperfunction is not going to go away. In fact, the research opportunities to understand and curtail severity factors in outpatients are enormous. After all, we don't want to miss the opportunity to prevent the suicides, chronic impairment, or even possibly brain damage caused by this "functional disorder" or "psychosocial condition" called depression.