A new class of antidepressant drugs may be on the horizon as scientists develop a better understanding of the hormonal link between stress and depression.
Studies have found that approximately half of patients with major depression have high levels of cortisol, a steroid hormone triggered by stress. Now, recent research suggests that high cortisol levels might be a cause of depression, rather than a symptom, as previously thought. If so, scientists believe that drugs aimed at reducing cortisol levels may be effective ways to manage depression.
"The idea that stress hormones may actually affect the brain's biochemistry and cause depression is an evolving concept," said Owen Wolkowitz, MD, UCSF professor of psychiatry, director of the UCSF Psychopharmacology Assessment Clinic, and co-author of the paper. "Recent studies have amassed enough evidence to suggest that at least some cases of depression may be a disease or disorder of the endocrine system which manifests itself in the brain rather than in the body."
UCSF researchers reviewed the findings of recent cortisol-lowering drug studies in the September/October issue of Psychosomatic Medicine.
Scientists first noticed the link between cortisol and depression in patients with Cushing's syndrome, a disease caused by an excess production of cortisol. The normal function of cortisol, which is produced in the adrenal glands, is to help the body respond to stress and change. Too much cortisol results in changes in many of the body's tissues and organs and may cause symptoms commonly seen in severe depression.
Patients with Cushing's syndrome who received treatment that lowered cortisol levels experienced decreased depression in 28 separate studies. In the largest study of 176 patients, researchers reported in Clinical Endocrinology that 73 percent of their depressed patients improved.
Until recently, surprisingly few studies assessed the effects of lowering cortisol levels in psychiatric patients with major depression, said Wolkowitz. To date, 11 studies have done so. Across all the studies, some lessening of depression was noted in 67 to 77 percent of patients. Although many were small and not placebo-controlled, the fact that all of them showed some effect is worth noting, said Wolkowitz.
The only double-blind, placebo-controlled study tested the effectiveness of ketoconazole, one of three cortisol-lowering drugs that are currently being investigated. UCSF researchers found a significant effect in depressed patients with high cortisol levels, but not in patients with normal cortisol levels.
Cortisol is probably not the only steroid hormone related to depression, said Wolkowitz. Scientists are also beginning to look at DHEA (dehydroepiandrosterone), the most plentiful steroid hormone in the body. In another UCSF study, 22 patients suffering from major depression were given either DHEA or a placebo. While none of the 11 placebo recipients experienced a significant improvement, half of the DHEA recipients showed a 50 percent or greater decrease in depressive symptoms.
"These findings raise the possibility of biologically distinct subgroups of patients with major depression, although the results are tentative due to the small number of patients studied," said Victor Reus, MD, UCSF professor of psychiatry and co-author of the review paper. "We might not be able to treat all people with depression in the same way. Different drugs and drug combinations might be more effective in some people than on others."
In addition to hormones, neurotransmitters also play a role in depression. Whereas hormones are chemical messengers that travel through the blood stream to target tissues, neurotransmitters are chemicals that relay information between cells in the nervous system. Low levels of neurotransmitters like serotonin and dopamine have been linked to depression, said Wolkowitz, and most anti-depressant drugs on the market effectively raise those levels. Hormones and neurotransmitters could each affect the other, so disturbances in both may be important in depression, he said.
Another important factor to consider is that everybody handles stress differently, said Wolkowitz. For example, not all people who have high cortisol levels develop depression, and not all depressed patients have high cortisol levels, so genetic and environmental factors are undoubtedly important, said Wolkowitz. People who suffer from depression may have a genetic predisposition for high cortisol levels, poor coping skills, or may have an inadequate social support network, he said. In any of these cases, stressful situations can change cortisol and other hormone levels, possibly resulting in depression.
Although the cortisol-lowering drugs currently being tested have a number of potential side-effects ranging from nausea to liver damage, anticipated confirmation of their effectiveness will likely spur the development of safer compounds, said Wolkowitz. However, using drugs is not the only way to treat depression, he said. Cognitive behavioral therapy (CBT) seems to reduce cortisol levels and increase DHEA. Researchers are now investigating whether CBT and various "alternative" treatments, such as yoga and meditation, yield some of their beneficial effects through changes in stress hormone levels.
In addition to prompting the development of new antidepressant drugs, a better understanding of the link between hormones and depression could help scientists understand the mechanisms by which hormones and stress affect mental well-being, said Wolkowitz.
Funding sources for the study include the National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD); the National Alliance for the Mentally Ill (NAMI), and the Scottish Rite Foundation.
Journal
Psychosomatic Medicine