Published by Lexi Nutkiewicz
Center for Neuroscience in Women’s Health, Stanford University School of Medicine
These findings are described in the article entitled Cognitive effects of mifepristone in overweight, euthymic adults with depressive disorders, recently published in the Journal of Affective Disorders (Journal of Affective Disorders 239 (2018) 242-246). This work was conducted by S. Roat-Shumway, T.E. Wroolie, K. Watson, A.F. Schatzberg, and N.L.Rasgon from the Stanford University School of Medicine.
The body’s “stress hormone” is cortisol, a glucocorticoid that is made in the cortex of the adrenal glands and released into the blood in response to stress. Cortisol helps regulate metabolism and influences memory formation. In fight-or-flight scenarios, cortisol levels rise in order to respond to stressful situations appropriately. However, the body cannot handle long-term stress without consequences.
Cortisol works by shutting down various bodily functions that might interfere with survival mechanisms, so consistently high cortisol levels cause the body to malfunction. For example, this can cause weakened immunity, increased blood pressure, fertility problems, type 2 diabetes, and Cushing’s syndrome. Cushing’s occurs when there is too much cortisol in the blood for an extended period of time and has been consistently associated with significant cognitive impairment and depression.
Approximately 10% of U.S. adults were diagnosed with a mood disorder, such as depression and bipolar disorder, in the past year. Mood disorders can lead to high cortisol levels which cause dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. In individuals with mood disorders, a dysregulated HPA axis can contribute to depressive symptoms and cognitive impairment. Along with high cortisol levels, individuals with mood disorders have a higher prevalence of insulin resistance (IR), or prediabetes. Based on past studies, IR is thought to affect memory and attention and contribute to cognitive deficits experienced by individuals with depression. Even when depression has been treated, the cognitive deficits in verbal memory and attention remain.
A potential solution is to use medication that reduces cortisol levels. Mifepristone, a peripheral progesterone receptor antagonist that prevents cortisol from binding to the glucocorticoid receptor, has been shown to improve depressive symptoms and neurocognitive functioning in individuals with bipolar disorder by lowering cortisol levels. Mifepristone has also been shown to improve cognitive flexibility in a sample of patients with Cushing’s Syndrome as well as treat Cushing’s by rapidly reversing acute psychosis. Given previous research on mifepristone, we studied the effects of this medication on a population of overweight, euthymic adults with depressive disorders.
Over a 28-day period, we administered a 600 mg/day dose of open-label mifepristone to men and women between the ages of 45 and 70 years old with a BMI greater than 25 kg/m2. We collected metabolic and cognitive data at baseline (time 1) and after 28 days of medication treatment (time 2). Metabolic function was measured using an Oral Glucose Tolerance Test (OGTT), which is designed to measure how effectively cells respond to and remove glucose from the blood. Participants underwent a cognitive assessment that used validated measures of verbal memory and executive functioning.
In response to treatment with mifepristone, we found improvements in attention and verbal learning associated with a reduction of fasting plasma glucose (FPG). However, we found no effects due to mifepristone on either verbal immediate or delayed memory, nor any improvement in cognitive flexibility. Nevertheless, with further research, mifepristone has the potential to become a treatment option for insulin-resistant individuals with mood disorders.