|Glucocorticoids and Mood|
|By Dr. Jennifer Kirkland, Ph.D|
On June 20- 21, 2008, I had the rare opportunity to attend the conference Glucocorticoids and Mood: Clinical Manifestations, Risk Factors and Molecular Mechanisms. Sponsored jointly by UC San Diego Department of Psychiatry and The Diana Foundation, this conference came about in part, in response to the death of Diana Padelford Binkley. In 2003, after getting high dose steroids for a herniated disc, Diana suffered the side effect of steroid psychosis and subsequently committed suicide. Since glucocorticoids are used in managing many diseases, the 20% rate of psychiatric impairment found in those getting high dose treatment shows the need for better understanding of the risks and impact on patients. A call for the most recent findings brought researchers from around the world together to unravel the mysteries underlying this phenomenon and to come up with answers to lessen risks on patients.
Given that cortisol and its synthetic partner cortisone are used so widely, the impact of high cortisol on mood and memory was highlighted. Since excess cortisol is the cause of Cushing's related symptoms, patients with Cushing's were studied. As many who have had Cushing's already guessed, high rates of mood and memory problems were found. Two-thirds (66%) to 100% of those studied had symptoms ranging from anxiety (66%), impaired concentration (66%), night awakenings (69%), decreased sex drive (74%), impaired memory 83%, irritability (86%), decreased energy (97%), fatigue (100%). High cortisol was found to actually shrink the hippocampus brain region, which related directly to verbal memory problems in Cushing's patients. Luckily, when the high cortisol state is reversed, the brain region goes back to normal size, and memory problems are largely reversed. And with treatment, over time, mood and psychiatric symptoms returned to levels found in those without Cushing's. What a relief to hear in a scientific conference that we aren't crazy, but having Cushing's can make us that way temporarily!
The implications of such difficulties have raised awareness of the risks of giving high dose steroids. The types of treatments that tend to trigger mood problems and steroid psychosis were presented. They found that single high dose administrations of corticosteroids can cause temporary irritability, restlessness or memory problems. However, when the treatment is prolonged, steroid psychosis can happen. Studies vary on the rate this happens, but the range is 1.3% to a whopping 57%, making the average across studies 6%. The disturbing part to this finding is that no one knows why one person may have no symptoms and another may commit suicide. Thus, researchers urged that the risk be communicated with a "black box" warning by pharmaceutical companies.
The one upside to this problem is that a whole new area of treating psychiatric disorders with cortisol lowering drugs has evolved. Although largely experimental, in some cases, lowering cortisol with mifepristone had a therapeutic effect similar to standard antidepressants making it a potentially good alternative when standard treatment can not be given.
The second half of the conference was basic research that studied glucocorticoids on the molecular level. Glucocorticoids (cortisol) exert their effects on individual cells in the body by binding to a protein called a glucocorticoid receptor. Although still in the experimental stages, such research is paving the way for exciting developments. The first of such was the finding that glucocorticoid receptors (GR) can behave differently not just among people but even within a person. Thus, depending on the tissue type, the GR can respond in a highly sensitive or even an immune way. This variability in the action of GR may explain why Cushing's can appear so different in the way it presents clinically. Some people may or may not get the same symptoms in part due to how the GRs respond at the cellular level. Once again, we are finding that Cushing's has many faces, and can not be diagnosed on the basis of having a specific set of symptoms.
Researchers have also expanded on the finding that glucocorticoids are the "first-responders" when the body is stressed. The body sends out a red flag that there is a problem by showing markers of inflammation. Glucocorticoids respond by moving in to reduce the inflammation. When studying mood disorders such as depression, a link between having an exaggerated inflammatory response to stress was linked with both depression and illness. Thus, when an individual has a GR that is resistant to this red flag of inflammation, more inflammation occurs. This lack of response is implicated in both cancer risk and depression.
Perhaps the most exciting part of this half of the conference was how researchers are working to improve treatments based on basic research findings. Because different GRs behave differently, finding drugs that change behavior at the receptor level could increase the quality of many people's lives. Right now, pharmaceutical researchers are working on this issue in developing a glucocorticoid that does not cause
osteoporosis. Thus, for those thousands of people who are on long term, higher dose corticosteroid treatment, within a few years, the new drug could greatly reduce the risk of osteoporosis!
Another promising finding will help the many people who suffer with chronically high cortisol levels because of anxiety or depression. The challenge in treating it has been to lower cortisol without completely shutting it down. Even though chronically high cortisol has unpleasant effects, losing the body's ability to respond to stress can be life threatening. Trials of the drug mifepristone have demonstrated that the drug can lower cortisol effects without shutting it down. Thus, those who have chronically high cortisol can get relief without the danger of losing this response that is necessary during stress completely.
The final panel discussion revealed that, despite having the best and the brightest researchers in the world present, we were left with more questions than answers. Obviously, the research presented is scratching the surface in finding solutions to complex problems such as Cushing's. But the best part for me though, was to see how the awareness of Cushing's as both a clinical syndrome and model for study has spread worldwide. I was able to look around at the treatment providers in the audience, and say "yeah, I think they get it" when it comes to a compassionate understanding of how devastating Cushing's can be. That was the best realization of all.
Editor's Note: Jennifer Kirkland is a clinical neuropsychologist in private practice in the San Francisco Bay Area, California. Dr. Kirkland has the unique combination of years of psychological experience as well as personal experience with Cushing's, which makes her extremely qualified to report on the psychological impact of glucocorticoids.. She counts her two greatest accomplishments as completing her Ph.D. while being diagnosed and treated for adrenal Cushing's and having a baby on 11/30/07.