The effects of psychotropic drugs in different populations

Bulletin of the World Health Organization, 56 (4): 519-523 (1978) The effects of psychotropic drugs in different populations M. O. OLATAWURAl Although psychotropic drugs are known to be effective in all populations, the known differences in terms ofhealth and disease in different parts of the world have not been related to the effectiveness of such drugs. Nutritional/metabolic, genetic, cultural, and ecological/climatic factors that could be important in this respect are discussed. The benefits that could accrue from a knowledge ofproper drug dosage, namely, fewer side effects and reduction in cost, particularlyfor developing countries, are highlighted. The introduction in the early 1950s of the phenothiazines for the management of severe mental disorders, particularly schizophrenic psychoses, significantly improved the prognosis of these disorders all over the world. This discovery was particularly momentous for psychotic patients at mental hospitals in the less technologically developed countries because these poor countries could not afford the treatment procedures, notably insulin- coma, that were then in vogue. As is now well known, research into the pharmacology of promethazine soon led not only to the discovery of a wide range of substituted pheno- thiazines (trifluoperazine, thioridazine, promazine, etc.) but also contributed to the discovery of different kinds of antipsychotic agents such as the butyrophenones and thioxanthenes. Antineurotic and antidepressant agents also enjoyed a similar popularity. Thus, it cannot be denied that science, through research, has provided man over the last 25 years with a considerable number of psychoactive agents to help him cope with his problems. Just as it is true that the effectiveness of psychoactive agents in general has been demonstrated in all populations, so it is true that the effectiveness and adverse effects of the medicaments may not have received adequate attention in all parts of the world. The customary areas of interest have been, inter alia, the range of dosage presenting danger to the respiratory and cardiac centres of experimental animals and teratogenic effects on the offspring of laboratory animals. The therapeutic effectiveness of any drug is known to be related to the body weight of the patient, the rate of absorption of the drug into the system, and the rate of breakdown, transport, and ultimate disposal of the drug from the body. These factors are also known to contribute to the emergence of unwanted side effects. In other words, factors such as body weight and physical health assume greater importance in relation to effective dosage and undesirable side effects when it is realized that these factors are different from population to population. Some of these factors, which are hereditary, sociocultural, nutritional, and climatic, are discussed in greater detail below. HEREDITARY FACTORS AND PSYCHOTROPIC DRUG EFFECTIVENESS It is known that there are different but distinct characteristics relating to body weight for different populations. Some are heavily built or constitutionally tall and others are not 1 Professor of Psychiatry, Department of Psychiatry, University of Ibadan, Ibadan, Nigeria. 3716 - 519 - 520 M. 0. OLATAWURA so naturally endowed. While it could be argued that nutrition may be a factor, there is no doubt that heredity also contributes to the different average weights noted for different populations of the world. What is the importance of this for drug effectiveness? For example, it has been stated that for an Indonesian patient, 25 mg of chlorpromazine three times a day could be expected to produce as good a result as 100 mg of chlorpromazine three times a day in some other cultures. By implication, therefore, if side effects develop in the Indonesian patient, they would probably be more severe if the patient were given the dose conventional in some other cultures. Even if the patient tolerated the side effects, it could be argued that such a level of medication would amount to a waste of expensive drugs, especially if other drugs had to be used to counter the side effects. In terms of the scarce national resources of most developing countries, this point ceases to be of mere academic interest. NUTRITIONAL STATUS AND PSYCHOTROPIC DRUG EFFECTIVENESS The nutritional status of an individual is often the result of many interrelated factors. It is influenced by the adequacy of food intake both in terms of quantity and quality, and also by the physical health of the individual. This is largely because the rate and com- pleteness of digestion and absorption are dependent on the state of health of the gastro- intestinal tract. In many parts of Africa, Asia, and Latin America there is a prevalence of endemic parasitic and intestinal diseases that bring about poor nutritional status in a very large percentage of the population. This is in addition to a poor diet brought about by ignorance of what is actually beneficial to the body; nutritionally important items of food are forbidden to some religious sects and the harsh climate and the method of preparation often reduce the nutritional value of the food. The likely effects of the nutritional status of a patient on the potency of psychotropic drugs are further emphasized when implica- tions for the absorption, transport, storage, and excretion of drugs are more closely examined. At the cellular level, malnutrition alters the biochemistry of the malnourished individual and important body constituents such as electrolyte ions become deficient. Another important and often striking result of malnutrition is vitamin deficiency. In this regard, vitamins of the B group are crucial because of their role as coenzymes in several bio- chemical reactions including the absorption, transport, and excretion of various substances such as drugs.a Thus, apart from the well known diseases precipitated by deficiencies of vitamin B1 (thiamine), vitamin B2 (riboflavin), nicotinic acid, vitamin B6 (pyridoxine), and vitamin B12 (cyanocobalamin and hydroxocobalamin), such deficiencies have important implications not only for the effectiveness of psychotropic drugs but also for the incidence of side effects when these drugs are prescribed for malnourished patients. One other sign of poor nutritional status is protein/energy imbalance. Serum proteins are important not only in the transport systems of the body but also for immune response. Edozien b showed that serum proteins, particularly the albumin fraction, are altered in malnourished subjects in developing countries. One other consequence of malnutrition is disturbed folic acid turnover. Carney & Sheffield c have suggested that psychotropic drugs, especially phenothiazines and tricyclic antidepressants, may also contribute to serum folate deficiency, thus further compromising a BENNETT, T. P. & FRIEDEN, E. Modern topics in biochemistry. New York, Macmillan, 1967, pp. 43-56. b EDOZIEN, J. C. Journal of clinical pathology, 10: 276-279 (1957). C CARNEY, M. W. P. & SHEFFIELD, B. F. Journal ofnervous and mental disease, 150: 404-412 (1970). PSYCHOTROPIC DRUGS IN DIFFERENT POPULATIONS 521 the nutritional status of malnourished patients. A recent review a of oral contraceptives (widely recommended in family planning programmes, often in malnourished populations) and vitamins showed that there appeared to be a clear link between disturbances in some pyridoxine-dependent enzyme systems and symptoms of mental depression. Low availability of pyridoxine induces deficiency of pyridoxine phosphate, which is a constituent of several coenzymes active in the tryptophan-nicotinic acid cycle. As some of the tricyclic anti- depressant drugs have similar biochemical pathways, the influence of malnutrition on the effectiveness of these drugs becomes important. Carney & Sheffield also showed that the plasma concentration of vitamin B12 and/or folic acid may be reduced during the ingestion of estrogen-containing oral contraceptives. All these points serve to highlight the importance of vitamins and the general state of nutrition on the effectiveness and side effects of psycho- tropic drugs. The importance of nutrition in relation to psychotropic drugs is not limited to the role of vitamins as coenzymes in the body. Malnutrition combined with inclement weather, particularly a hot climate, can also affect serum ion levels. Kelly et al. b have reported deaths from ventricular tachycardia and fibrillation due to hypokalaemia, which may be pre- cipitated not only by gastrointestinal diseases known to be common in developing countries but also by an inadequate diet. Finally, the pH of the urine is known to have pronounced effects on the excretion of partially ionized drugs.c Hadzija d has suggested that the pH of the urine of malnourished Africans may be different from that of Europeans and that this may alter the ratio of metabolites to parent drugs in the bodies of Africans. He warned that it may be unwise to use the effects and side effects observed in clinical trials in developed countries to predict the effect of the same drugs in communities with different dietary customs. In summary, psychotropic drug effectiveness and poor nutritional status can be related in a number of ways. First, the mechanism of the sensitivity of patients to particular drugs is not fully known; what are the implications of this in terms of the immune potential of malnourished patients? Second, the presence of a concurrent disease may alter the thera- peutic action of a drug to produce unexpected results. For example, agranulocytosis is thought to be partly the result of a direct toxic effect on the myeloid elements of bone marrow by chlorpromazine as well as other phenothiazines and tricyclic antidepressants. Although these adverse effects are rare, what are the implications of such side effects in patients with impaired natural defences? The issues raised above are important and should encourage drug houses, clinicians, health planners, and administrators in both developed and developing countries to take into account the different effects of psychotropic drugs in different populations. Apart from the importance of ensuring the reduction (through research) of the unwanted side effects of drugs, the cost-benefit ratio of the huge investment on drugs vis-ac-vis other national priorities in developing countries in particular ought to be kept under constant surveillance. This is why the present World Health Organization Project on the Effects of Psychotropic Drugs in Different Populations is particularly timely. It is hoped that at the end of the study WHO will be in a position to advise Member States on the effectiveness and limitations of the psychotropic drugs most commonly prescribed. a LARSSON-COHN, U. American journal of obstetrics and gynecology, 121: 84-90 (1975). b KELLY, H. G. ET AL. Canadian Medical Association journal, 89: 546-554 (1963). C BECKErr, A. H. & TUCKER, G. T. Journal ofpharmacy and pharmacology, 18: 72-75 (1966). d HADZIJA, B. W. Journal ofpharmacy and pharmacology, 21: 196-197 (1969). M. 0. OLATAWURA RjSUME Les effets des m6dicaments psychotropes dans differentes populations Dans la lutte contre les troubles mentaux graves, l'application des les annees cinquante d'une chimiotherapie axee notamment sur I'administration de phenothiazines a constitue un grand progres pour les pays en developpement particulierement demunis de ressources. Les recherches sur la promethazine ont permis de decouvrir, outre toute une variete de phenothiazines de remplacement (trifluoperazine, thioridazine, promazine, etc.), des agents antipsychotiques comme les butyroph6nones et les thioxanthenes, auxquels se sont encore ajout6s depuis de nombreux neuroleptiques et antidepresseurs. Si l'efficacite de ces agents a e partout demontr6e, on ne s'est pas suffisamment preoccupe des variations dans leur action et leurs effets secondaires qui peuvent etre liees a l'etat sanitaire des populations consider6 au sens large, c'est-'a-dire incluant l'etat nutritionnel aussi bien que l'ensemrble des facteurs psycho-sociaux et ecologiques. Parmi les risques le plus generalement etudies chez des animaux de laboratoire figurent ceux qui menacent l'appareil respiratoire et l'appareil circulatoire, ainsi que les effets teratogenes possibles. On sait que la posologie doit tenir compte du poids du malade et de la biodisponibilite du medicament. Or les facteurs hereditaires influent notamment sur le poids, a tel point qu'on a pu dire que la dose de chlorpromazine efficace pour le traite- ment d'un malade indonesien etait le quart de celle a administrer dans d'autres populations. I1 convient de noter que les effets secondaires d'un medicament - et la depense que celui-ci represente - varient eux aussi dans les memes proportions. L'etat nutritionnel est egalement important. Or il depend naturellement des aliments absorbes et de leur preparation, mais aussi du bon fonctionnement de l'appareil digestif, qui peut lui-meme etre affect6 par des maladies parasitaires et intestinales largement repandues. Sur le plan biochimique, certaines reactions importantes pour l'assimilation, le stockage et l'Flimination des medicaments peuvent etre compromises par une carence en vitamines B ou en ions electrolytiques. La malnutrition proteino-energetique, en agissant sur I'albumine serique, affecte les mecanismes d'assimilation et la defense immunitaire. Le serum peut egalement presenter une carence en folates sous 1'effet combine des medica- ments psychotropes et de la malnutrition. Lors d'etudes concernant 1'effet des contra- ceptifs oraux sur la concentration plasmatique des vitamines B, on a constat6 une carence en pyridoxal-phosphate - forme co-enzymatique importante dans le metabolisme de plusieurs acides amines. Or certains des medicaments antidepresseurs agissent par les memes voies biochimiques. La malnutrition, combin6e 'a des conditions climatiques defa- vorables, notamment la chaleur, peut aussi provoquer une grave hypokaliemie. Enfin, elle agit sur le pH de l'urine, lequel est determinant dans 1'elimination des medicaments partiellement ionises. L'importance du role joue par l'etat nutritionnel dans I'action d'un medicament rend donc douteuse la valeur des essais cliniques effectu6s dans les pays developp6s pour pre- juger son efficacite dans des populations aux habitudes alimentaires diff6rentes. I1 faut particulierement veiller 'a ce que des malades dont les m6canismes de defense immunitaire sont alt6r6s par un mauvais etat nutritionnel ne soient pas exposes aux effets toxiques possibles de certains medicaments psychotropes (par exemple une agranulocytose provo- quee par la chlorpromazine). 522 PSYCHOTROPIC DRUGS IN DIFERENT POPULATIONS 523 Le projet lanc6 par l'Organisation mondiale de la Sante pour 6tudier les effets des m6dicaments psychotropes dans differentes populations est donc venu 'a son heure. II devrait permettre, grace a de nouvelles recherches sur les plus couramment utilis6s de ces m6dicaments, de r6duire les effets secondaires de ceux-ci et d'etablir de maniere plus pr6cise la relation colit/avantages a prendre en consideration pour toute decision quant a l'oppor- tunit6 de leur emploi dans des pays en developpement.