M. Khaled El-Yousef

A CHOLINERGIC-ADRENERGIC HYPOTHESIS OF MANIA AND DEPRESSION

Abstract Central cholinergic factors may play a role in the aetiology of affective disorders. Specifically, a given affective state may represent a balance between central cholinergic and adrenergic neurotransmitter activity in those areas of the brain which regulate affect, with depression being a disease of cholinergic dominance and mania being the converse. Support for this hypothesis comes from animal experiments demonstrating antagonistic cholinergic and adrenergic central behavioural effects. Furthermore, reserpine, a drug which causes depression, has central cholinomimetic properties. Conversely, tricyclic antidepressants have central anticholinergic properties. In man, physostigmine and other centrally acting cholinomimetic agents which increase central acetylcholine levels counteract mania and may cause depression in some individuals. Considering manic-depressive disorders and related phenomena from the viewpoint of cholinergic-adrenergic balance, or conceptualising behaviour as having both adrenergic and cholinergic components, provides a framework for understanding the affective disorders. Possibly, manic-depressive illness represents compensatory overreaction of certain parts of the central autonomic nervous system. A natural tendency toward hom1/2ostasis, associated with compensatory adrenergic activcation, could explain why most depressions are self-limiting. To balance hypothesis, more direct evidence is needed on the changes which occur in both systems during various affective states. Nevertheless, it seems that biological influences are involved in the aetiology of affective disorders, and possibly they include cholinergic and adrenergic factors.

Interaction of physostigmine and delta-9-tetrahydrocannabinol in man.

To investigate the hypothesis that delta‐9‐tetrahydrocannabinol (THC), the major psychoactive ingredient of marihuana, acts by interfering with cholinergic brain mechanisms, 0.75 to 1.25 mg of physostigmine, a centrally active cholinergic drug, was given intravenously to 5 normal volunteers who had ingested 20 to 40 mg of THC 2 hours earlier. Physostigmine decreased the degree of tachycardia and conjunctival injection produced by THC. The major psychologic effects of physostigmine were amplification of the lethargy and somnolence which occur late in the course of THC intoxication. We interpret the lack of physostigmine counteraction of the peak psychologic effects of THC as evidence against the hypothesis that THC acts predominantly by an anticholinergic mechanism.

Effects of conjugated estrogens on plasma butaperazine levels

A randomly assigned control-experimental grouping with a crossover design, using subjects as their own controls, was utilized to study the effects of conjugated estrogens on plasma butaperazine (Repoise) levels in post-menopausal female subjects. Significantly higher plasma butaperazine levels were measured following both a single loading dose and with maintenance doses of oral butaperazine in subjects when they were taking conjugated estrogens as compared to when they were not taking conjugated estrogens. The underlying mechanisms for these findings and their clinical implications are discussed briefly.

Clinical Problems in Treating the Aged With Psychotropic Drugs

The purpose of this paper is to review the use of psychotropic drugs in the aged. Psychotropic agents can be an effective tool in a physician’s armamentarium in treating mental disorders in the aged. However, these drugs can also be inappropriately used. The aged may be more susceptible to certain drug side effects. In addition, since they are more apt to have medical problems, there is more likelihood of drug-drug interactions occurring. Even physicians who may not be particularly interested in psychotropic drug use may need to be knowledgeable about this aspect of patient care since patients may suffer from toxicity due to psychotropic drugs administered by another physician or by the patients themselves. Psychotropic drugs are commonly taken by a large percentage of the population of the United States (Balter and Levine, 1971). Two hundred twenty million prescriptions are filled by patients for psychotropic drugs; 80 million for antianxiety agents; 40 million for hypnotics; 30 million for stimulants. Patients can often be taking several psychotropic drugs, sometimes administered by one physician, sometimes administered by several different physicians with the patient continuing to take one doctor’s prescription as well as a second psychotropic agent added by another doctor. To this cocktail can be added proprietary medications bought without prescription. Since sedative hypnotics do reduce mental function, it is not unusual to find elderly patients who are over-medicated who may do better when they discontinue the cocktail of sedative hypnotic drugs which they are taking. For that reason, the first problem in treating the aged with psychotropic drugs is for the clinician to consider whether the patient needs the psychotropic drugs he may be on. The discontinuance of current medication to get a drug-free baseline state is a useful strategy for the treatment of many patients. It is important to evaluate the patient’s medical status and use of the wide variety of drugs for treating his medical problems. This information is relevant to drug-drug interactions and side effects of possible psychotropic drugs. Having reviewed the patient’s baseline status and his medical problems, one may move on to consider which psychotropic drugs may be indicated for a given patient.