Glucocorticoid receptor antagonism and cognition in alcoholics

Alcohol dependence is a chronic relapsing disease, the incidence of which was recently estimated by the Department of Health to be 7% of the adult population. Currently, up to 90% of alcoholics who manage to stop drinking relapse back to the alcohol within a year. Alcohol dependence is a major health problem, and the alcohol consumption causes many other medical disorders and extensive social problems. Between 50 and 80% of alcoholics suffer from memory problems caused by the alcohol consumption and many also have other medical problems, particularly depression. The former symptoms are very difficult to treat, largely because the changes in the brain that cause the memory problems are not yet understood, and also because there are different patterns of excess alcohol drinking. If the mechanisms involved in the memory problems are understood, this will enable effective treatments to be developed that will improve quality of life and reduce health costs. Recent laboratory and clinical studies have suggested that changes in the brain when someone stops drinking excessively are responsible for memory deficits. Excess of the stress hormones known as glucocorticoids is known to result in damage to nerves in the brain and to result in memory loss, and these are released in high concentrations during alcohol detoxification. Work has also shown that a drug, mifepristone, that prevents actions of the important stress hormone cortisol on a particular brain protein, known as the Type II glucocorticoid receptor, has beneficial effects in those who suffer from memory problems and also in people who are clinically depressed, but this has not yet been studied in alcoholics. Laboratory studies, however, demonstrated that prevention of actions of cortisol at this receptor protein decreases the nerve damage caused by cessation of long term alcohol consumption. This project will measure the effects of the drug mifepristone in a group of alcoholics who enter the treatment unit to undergo alcohol detoxification. Measures will be made of performance in tests of cognitive ability, and also depressive symptoms, since the latter can contribute to memory loss. If the results of this project are positive it will suggest that the receptor protein is involved in the genesis of the memory deficits and/or the depressive symptoms. Such knowledge will aid the development of new treatments that would provide effective therapy for these problems that are suffered by large numbers of alcoholics.

Alcoholism is a chronic disorder with high personal and NHS costs. Alcohol dependence includes a range of drinking behaviours and comorbidity with other mental disorders is common. There is little effective treatment, and the majority of abstinent alcoholics relapse within 12 months. A large proportion of alcoholics have cognitive deficits and many are clinically depressed. The causal mechanisms of the latter problems are little understood, but clinical and preclinical studies have suggested the hypothalamo-pituitary-adrenal axis could be important. There is considerable clinical and experimental evidence that alcohol withdrawal plays a major role in causing the memory deficits and this offers a window of opportunity for intervention. Recent laboratory investigations have indicated that the glucocorticoid Type II glucocorticoid receptor is involved in the neurotoxicity caused by withdrawal from chronic alcohol treatment. In addition, clinical studies in other mental disorders showed that antagonism of this receptor can alleviate both cognitive deficits and depressive symptomatology. This Proof of Concept study will demonstrate whether antagonism of this receptor by the drug mifepristone could have beneficial effects in alcoholics entering our Alcohol Assessment and Treatment Unit for detoxification. Exclusion criteria will be limited to physical health and ability to give informed consent, in order that the study will include a representative alcoholic population. Two treatment groups of equal size, stratified for alcohol dependence severity, age, depression/no depression and smoking/nonsmoking, will receive either mifepristone or placebo. In the third and fourth weeks after cessation of drinking, cognitive function will be examined using the CANTAB test battery; the Beck Depression scale will examine depressive symptoms once per week for four weeks after drinking cessation. Data analysis will examine potential influences of comorbid mental disorders, severity of dependence, withdrawal symptoms, number of prior detoxifications, withdrawal medication and other medication. The study will recruit males only, owing to the progesterone antagonist actions of mifepristone, but will demonstrate whether or not antagonism of this receptor has beneficial actions, the effect sizes, and whether specific symptoms are affected or changes seen in clients with particular comorbidity or level of alcohol withdrawal severity. Specific Type II glucocorticoid receptor antagonists are currently under development and could be used in future studies on a wider population. The results, whether positive or negative, will provide valuable information about the role of the Type II glucocorticoid receptor in cognitive function and depression in alcoholics that will be of great value in understanding the underlying mechanisms.