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Ethical aspects of psychopharmacology
Prog.
Vo1.3,
Nemo-Psychopharmacol.
IR’HICAL
pp.297-301,1979.
ASPECTS
Pergamon
OF C.
Unidad
de
Salud
Ltd.
Printed
in
Great
Britain
PSYCHOPHARMACOLOGY
A.
Mental, Cali,
Press
LEON Hospital Columbia
Universitario
Contents 297
Abstract 1. 2. 3. 4.
Introduction The use of placebo The experimental The prescription
in clinical design of psychotropic
5.
Informed
consent
for
6.
The cost References
of
psychiatric
psychotropic
297 298 298
trials drugs
295
treatment
299 300
drugs
301
Abstract 1.
2.
A series of topics are presented for the purpose of These include parameters on the ethical of issues. a. Psychopharmacological research in human subjects placebo for drug trials and problems related to b. Prescription of psychotropic drugs, the role of legation of functions to pars-medical personnel. c. The administration of psychotropic drugs: Issues patient, side effects, and groups at special risk. d. Availability and cost of drugs, generic and trade tive use of drugs for different populations. Special reference is made to points contained in the
Key
words:
medical ethics, human risk ratio, groups at
subjects, special
1. Following the notion that a “primary role sues” (Clouser, 1975), an effort is made in to be analyzed in relation to relevant facts.
clinical
eliciting discussion and clarification implications of: with special emphasis on the use of the choice of research methods. and the problem of the dephysicians, related
to
name
preparations,
“Declaration
trials,
informed
as of
placebo,
consent
Hawaii”
informed
of
well
as
the selec-
(1978). consent,
benefit/
risk
Introduction of medical this paper
297
ethics is to present
to ‘structure’ some principles
the and
disputed concepts
is-
C.
298
A.
Leon
When one wonders if a particular action is moral, then as Clouser occurs in a context laden with many variables, pressures and causal and the strands of the argument and all the contingent conditions... lance all this out to determine the best action or the least isunoral does circumstances” (Clouser, 1975). This process of “structuring” but rather searching a decision on how to act in a given situation, so that deliberation can take place. problem and making them explicit,
elucidates “if the action chains, you sort out all ultimately you try to baaction you can do in the not necessarily mean taking for the elements of the
Out of the various ethical issues in the area of psychopharmacotherapy I have selected those I am not necessarily claiming that with which I am most familiar because of personal exposure. For purposes of this presentation, a they are or should be regarded as the most important. set of principles contained in the ethical guidelines of the “Declaration of Hawaii” (World (Although this document Psychiatric Association, 1977), are used as directions for judgement. is still in its draft-form it is the product of an active process of consultation and will be submitted for approval at the General Assembly of the World Psychiatric Association in Honolulu, next September.)
2. There seems to fact that several may be reinforced unquestioningly. through controlled be tallied against
The
Use
of
Placebo
in
Clinical
Trials
be enough justification for the use of placebo in controlled drug trials in the studies have demonstrated its eventual therapeutic effectiveness. This notion with the argument that various well established treatment methods are accepted The prior use of a treatment rather than a demonstration of its efficacy However, the worth of such a practice should trials produced acceptability. guiding principles such as the following:
Guide-line 1 (g-l) of the declaration stipulates clearly that “In clinical research, as in therapy, every subject must be offered the best available treatment.” This is supported by other statements such as: “The Psychiatrist shall serve the best interests of the patient” “every patient must be offered the best therapy available” (g-2). “the patient (must) k-l), be given the opportunity to choose between appropriate and available methods” (g-4). Whereas it is a well demonstrated fact that sometimes placebos may turn out to be therapeutically active, by definition they are (or should be) phurmcologicully inert substances. How is then the use of such substances to be reconciled with the “best interest of the patient”? If we are to be directed by the guidelines quoted above, the new drug to be tested in a clinical trial should have demonstrated its safety and therapeutic properties through animal experimentation. The latter should be potentially higher than those of existing similar drugs, and clinical trials shouldn’t be conducted using as controls a pharmacologically inert substance, but a standard or reference product considered to be the best available treatment for the pathological condition in question from the perspectives of therapeutic efficacy and tolerance. Such a procedure would indeed serve the “best interest” of the patients since they would have the chance of receiving either the best therapy available at the time of the trial (the reference drug) or eventually something better (the new drug). The implementation of measures of this kind also protect the best interest of the “consumers” (physicians, patients) by decreasing the present bombardment of competitive advertising of products introduced to the market because they did better than placebos at a trial. As mentioned this does not necessarily mean that they are better than (or even as good as) a standard product. On the other hand, an appropriately conducted trial may show that a new drug is not significantly better, in the therapeutic sense, than the standard drug, but that its side effects are less frequent or severe, and this may be regarded as a clear advantage of the former. raing from the general bo in severely depressed homicidal, and accutely
Another
issue
related
to the patients anxious
to
the
specific, (with patients?
the
3.
Experimental
“best
The
interest
how can implicit
of
a clinical risk
of
researcher suicide)
or
justify the in agitated,
use
of placeassaultive,
Design the
patient”
may
be
the
&oice
of
methodology
Ethical
aspects
299
of psychopharmacology
Rere scientific purism may enter for conducting the experiment. interest of the patient as the case of using a randomized control designs may serve a better purpose.
in conflict with the best trial, when alternative
As pointed out by Weinstein (1974). the use of matched or blocked groups may bring out associations that a randomized design may not, particularly if the matched groups are randomized for Adaptive designs such as the pair-wise sequential design treatment as in a double blind trial. will protect the interest of patients allocated to the less favorable treatment, by allowing optional stopping of the experiment or changes in the proportion of subjects in each group, Scientific purists may feel unhappy about, and according to interim results of the trial. find objections to, these methods, but the fact remains that they certainly reduce the chances of exposing patients to a treatment of inferior quality, when something better is available. As pointed out by Riis (1975), "A methodologically bad trial is always unethical but a methodologically good one, is not in itself ethical." 4.
The Prescription
of Psychotropic
Drugs
The changes and innovations in the system for health care and the delivery of health services have posed a number of interrogants as to the roles of the different types of health professionals. Particularly relevant to our interest is the question of who should prescribe peychotropic drugs. A broad area of conflict is generated when some people assert that prescribing is the exclusive right and privilege of the doctor , who is the only professional with sufficient qualifications for the task, and that this function can not be delegated to other health workers. several existing models for health delivery include In flagrant contradiction to this dictum, a whole gamut of "primary health workers", "health promoters", "bare-foot doctor", who prescribe and dispense drugs as part of their routine tasks; some of them after having had a minimum of training and in most cases, with the help of makeshift manuals. The only reference in the Declaration of Hawaii to the problem of professional responsibility is the well intentioned statement that "the psychiatrists are responsible for treatment given by team members and owes them qualified supervision and education". Row can this statement and the view that th9 physician is the only professional qualified for the task of prescribing be reconciled with the fact that in many countries of the world the proportion of psychiatrists is 1 per 100,ooO inhabitants or less . ..with the added problem of a concentration of service facilities and personnel in the urban areas, to the complete neglect of the rural areas. Indeed, who should prescribe? Under what circumstances? To whom . ..? are questions to be carefully pondered not only because of their ethical implications but also because of their great practical importance. Should perhaps a systematic delegation of the doctor's functions be made to other types of health workers when no other strategy is feasible, for conditions that are easily identifiable and which usually respond to appropriate medication (such as epileptic seizures or psychotic agitation?). 5.
Informed
Consent
for
Psychiatric
Treabnent
Apparently related to the pressure brought about by the current universal concern with the "rights of minorities" and in parallel with the "decrease of political and social authority in western democracies" (Redlich, 1976) there is at present a very forceful current of opinion in favor of the informed consent of the patient as a prerequisite basis of all psychiatric intervention and without it no psychiatric intervention can be justified. As to the type and extent of the information to be given to the patient guideline 4 of the Declaration of Hawaii, states: "the psychiatrist should inform the patient of the nature of the condition, of the proposed diagnostic; and therapeutic procedures, including possible alternatives, and of the prognosis. This information must be offered in a considerate way and the patient be given the opportunity to choose between appropriate and available methods." A number of questions arise as to the practical problems related to the application of these principles. (a) If the choice of treatment is ultimately left to the best judgement of the patient his or her choice may not fall on the "best therapy available" and may not therefore "serve the best interest of the patient", generating a dilemma. (b) What is the role of exposure to advertisement of selective previous information in the choice of method favored by the patient? (c) What is the
C.
300
responsibility of treatment description suggestion?
of doctors for patients offered? (d) What about of all of these conditions
A.
Leon
who, upon being informed, refuse any alternative informing the patient about side effects...? be a possible way of inducing their occurrence,
form Could a through
Severe criticisms have been formulated about the fallacy of “informed consent”, when it is evident that the highest proportion of subjects for medical experiments comes from the poor, It has even been the neglected, ward patients, inmates of public institutions and prisoners. suggested that in order to discourage these practices, granting agencies might “require that subjects for experiments come from several socio-economic groups, not one” (Stephens, 1975). An essential element of the process of informed consent is the weighing of benefits and risks and this exercise is particularly difficult when dealing with certain types of specially vulIn these cases clinical nerable patients such as children, pregnant women and elderly people. testing by itself may not be sufficient to guarantee the safety of a product and careful monito. ing may be required for detection of undesirable effects which may have escaped the vigilance of the clinical trials.
6.
The
Cost
of
Psychotropic
Drugs
Because of its crucial importance for the implementation and success of health care programs, but essentially because of its relevance to ethics, something should be said about the need for a just and equitable distribution of resources for health. A basic prerequisite for the is the existence of adequate means and resources to implement this right. “right to health” The Declaration of Hawaii makes only one marginal remark about this problem: “(The psychiatrist shall) also be concerned for the common good and just allocation of health resources” But the fact is that the costs of health services increase, in all countries, faster (g-1). than the gross national product; in mDst cases from 3 to 5 times faster; and the budgets for health and education combined are substantially inferior to those for weapons and military expenses. And what about the cost of drugs? What is one to do when in several countries the cost of one daily dose of a neuroleptic is equal to the daily average per capita income of a manual laborer? There are enormous differences in the cost of patent drugs and their generic counterparts, without demonstrable difference in their therapeutic efficacy. The same is true for drugs within the same pharmacological category and with similar therapeutic effects but produced at different periods: the new drug invariably costs more. The problem is additionally complicated for developing countries which lack the means to produce pharmaceuticals and are forced to import them. Many such countries complain that the drugs they import are inferior in quality to those of the same kind used in developed countries (WHO 1971). On the other hand where there is a local pharmaceutical industry the measures and procedures used for quality control of the product are often only nominal and in any case below the standards enforced in highly developed countries. It has been argued that the promotional costs connected with marketing and advertising of drugs (which in some cases exceed by far the costs of research and production) are ultimately passed on to the consumer and that many people are deprived of the potential benefit of drugs because they or their health systems can not afford them. Bulk-buying and controlled distribution of health products by state agencies is advocated as a possible means for a more equitable allocation of resources, but of course such measures call for the existence of corresponding political and socio-economic systems and mechanisms which, however, may not be regarded as feasible or even desirable by some countries. Another alternative, of course, would be to stimulate the development of the local pharmaceutical industry together with the means for quality control. As a final conmmnt it must be said that in parallel to what occurs in other aspects of moden progress, the impressive growth of knowledge in psychopharmacology and the ever increasing expansion of the pharmaceutical industry are not matched as yet by a corresponding development of the ethical means to guarantee a full protection of the public and an equitable distribution of health means. Becoming conscious of these problems and exploring their structural elements may be a basic step towards their eventual solution.
Ethical
aspects
of psychopharmacology
301
References CLOUSER, K. D. (1975). Medical ethics, some abuses and limitations. New Engl. J. Med. -293: 304-387. DECLARATION OF HAWAII (1978). J. Med. Ethics 4: 71-73. REDLICH, F. (1976). Overview: Ethical issues-in contemporary psychiatry. Am. J. Psychiat. 133: 125-135. RIIS, P. (1975). Ethical aspects of biomedical research. Acta Neurol. Stand. Suppl. 60: 90-92. STEPHENS, J. (1975). Medical experiments on humans and the need for a public policy. In: What Government Does, Vol. 1, M. Holden and D. L. Dressang (eds.). Sage Publications, Beverly Hills. WEINSTEIN, M. C. (1974). Allocation of subjects in medical experiments. New Engl. J. Med. 291: 1278-278s. WOS HEALTH ORGANIZATION (1971). Pharmacology; Safety and Efficacy, 27 pp. World Health Organization, Geneva. .ln+iries
and
reprint
Dr. Carlos A. Leon Unidad de Salud Mental, Cali, Columbia.
requests Hospital
should
be addressed
Universitario
to:
Vo1.3,
Nemo-Psychopharmacol.
IR’HICAL
pp.297-301,1979.
ASPECTS
Pergamon
OF C.
Unidad
de
Salud
Ltd.
Printed
in
Great
Britain
PSYCHOPHARMACOLOGY
A.
Mental, Cali,
Press
LEON Hospital Columbia
Universitario
Contents 297
Abstract 1. 2. 3. 4.
Introduction The use of placebo The experimental The prescription
in clinical design of psychotropic
5.
Informed
consent
for
6.
The cost References
of
psychiatric
psychotropic
297 298 298
trials drugs
295
treatment
299 300
drugs
301
Abstract 1.
2.
A series of topics are presented for the purpose of These include parameters on the ethical of issues. a. Psychopharmacological research in human subjects placebo for drug trials and problems related to b. Prescription of psychotropic drugs, the role of legation of functions to pars-medical personnel. c. The administration of psychotropic drugs: Issues patient, side effects, and groups at special risk. d. Availability and cost of drugs, generic and trade tive use of drugs for different populations. Special reference is made to points contained in the
Key
words:
medical ethics, human risk ratio, groups at
subjects, special
1. Following the notion that a “primary role sues” (Clouser, 1975), an effort is made in to be analyzed in relation to relevant facts.
clinical
eliciting discussion and clarification implications of: with special emphasis on the use of the choice of research methods. and the problem of the dephysicians, related
to
name
preparations,
“Declaration
trials,
informed
as of
placebo,
consent
Hawaii”
informed
of
well
as
the selec-
(1978). consent,
benefit/
risk
Introduction of medical this paper
297
ethics is to present
to ‘structure’ some principles
the and
disputed concepts
is-
C.
298
A.
Leon
When one wonders if a particular action is moral, then as Clouser occurs in a context laden with many variables, pressures and causal and the strands of the argument and all the contingent conditions... lance all this out to determine the best action or the least isunoral does circumstances” (Clouser, 1975). This process of “structuring” but rather searching a decision on how to act in a given situation, so that deliberation can take place. problem and making them explicit,
elucidates “if the action chains, you sort out all ultimately you try to baaction you can do in the not necessarily mean taking for the elements of the
Out of the various ethical issues in the area of psychopharmacotherapy I have selected those I am not necessarily claiming that with which I am most familiar because of personal exposure. For purposes of this presentation, a they are or should be regarded as the most important. set of principles contained in the ethical guidelines of the “Declaration of Hawaii” (World (Although this document Psychiatric Association, 1977), are used as directions for judgement. is still in its draft-form it is the product of an active process of consultation and will be submitted for approval at the General Assembly of the World Psychiatric Association in Honolulu, next September.)
2. There seems to fact that several may be reinforced unquestioningly. through controlled be tallied against
The
Use
of
Placebo
in
Clinical
Trials
be enough justification for the use of placebo in controlled drug trials in the studies have demonstrated its eventual therapeutic effectiveness. This notion with the argument that various well established treatment methods are accepted The prior use of a treatment rather than a demonstration of its efficacy However, the worth of such a practice should trials produced acceptability. guiding principles such as the following:
Guide-line 1 (g-l) of the declaration stipulates clearly that “In clinical research, as in therapy, every subject must be offered the best available treatment.” This is supported by other statements such as: “The Psychiatrist shall serve the best interests of the patient” “every patient must be offered the best therapy available” (g-2). “the patient (must) k-l), be given the opportunity to choose between appropriate and available methods” (g-4). Whereas it is a well demonstrated fact that sometimes placebos may turn out to be therapeutically active, by definition they are (or should be) phurmcologicully inert substances. How is then the use of such substances to be reconciled with the “best interest of the patient”? If we are to be directed by the guidelines quoted above, the new drug to be tested in a clinical trial should have demonstrated its safety and therapeutic properties through animal experimentation. The latter should be potentially higher than those of existing similar drugs, and clinical trials shouldn’t be conducted using as controls a pharmacologically inert substance, but a standard or reference product considered to be the best available treatment for the pathological condition in question from the perspectives of therapeutic efficacy and tolerance. Such a procedure would indeed serve the “best interest” of the patients since they would have the chance of receiving either the best therapy available at the time of the trial (the reference drug) or eventually something better (the new drug). The implementation of measures of this kind also protect the best interest of the “consumers” (physicians, patients) by decreasing the present bombardment of competitive advertising of products introduced to the market because they did better than placebos at a trial. As mentioned this does not necessarily mean that they are better than (or even as good as) a standard product. On the other hand, an appropriately conducted trial may show that a new drug is not significantly better, in the therapeutic sense, than the standard drug, but that its side effects are less frequent or severe, and this may be regarded as a clear advantage of the former. raing from the general bo in severely depressed homicidal, and accutely
Another
issue
related
to the patients anxious
to
the
specific, (with patients?
the
3.
Experimental
“best
The
interest
how can implicit
of
a clinical risk
of
researcher suicide)
or
justify the in agitated,
use
of placeassaultive,
Design the
patient”
may
be
the
&oice
of
methodology
Ethical
aspects
299
of psychopharmacology
Rere scientific purism may enter for conducting the experiment. interest of the patient as the case of using a randomized control designs may serve a better purpose.
in conflict with the best trial, when alternative
As pointed out by Weinstein (1974). the use of matched or blocked groups may bring out associations that a randomized design may not, particularly if the matched groups are randomized for Adaptive designs such as the pair-wise sequential design treatment as in a double blind trial. will protect the interest of patients allocated to the less favorable treatment, by allowing optional stopping of the experiment or changes in the proportion of subjects in each group, Scientific purists may feel unhappy about, and according to interim results of the trial. find objections to, these methods, but the fact remains that they certainly reduce the chances of exposing patients to a treatment of inferior quality, when something better is available. As pointed out by Riis (1975), "A methodologically bad trial is always unethical but a methodologically good one, is not in itself ethical." 4.
The Prescription
of Psychotropic
Drugs
The changes and innovations in the system for health care and the delivery of health services have posed a number of interrogants as to the roles of the different types of health professionals. Particularly relevant to our interest is the question of who should prescribe peychotropic drugs. A broad area of conflict is generated when some people assert that prescribing is the exclusive right and privilege of the doctor , who is the only professional with sufficient qualifications for the task, and that this function can not be delegated to other health workers. several existing models for health delivery include In flagrant contradiction to this dictum, a whole gamut of "primary health workers", "health promoters", "bare-foot doctor", who prescribe and dispense drugs as part of their routine tasks; some of them after having had a minimum of training and in most cases, with the help of makeshift manuals. The only reference in the Declaration of Hawaii to the problem of professional responsibility is the well intentioned statement that "the psychiatrists are responsible for treatment given by team members and owes them qualified supervision and education". Row can this statement and the view that th9 physician is the only professional qualified for the task of prescribing be reconciled with the fact that in many countries of the world the proportion of psychiatrists is 1 per 100,ooO inhabitants or less . ..with the added problem of a concentration of service facilities and personnel in the urban areas, to the complete neglect of the rural areas. Indeed, who should prescribe? Under what circumstances? To whom . ..? are questions to be carefully pondered not only because of their ethical implications but also because of their great practical importance. Should perhaps a systematic delegation of the doctor's functions be made to other types of health workers when no other strategy is feasible, for conditions that are easily identifiable and which usually respond to appropriate medication (such as epileptic seizures or psychotic agitation?). 5.
Informed
Consent
for
Psychiatric
Treabnent
Apparently related to the pressure brought about by the current universal concern with the "rights of minorities" and in parallel with the "decrease of political and social authority in western democracies" (Redlich, 1976) there is at present a very forceful current of opinion in favor of the informed consent of the patient as a prerequisite basis of all psychiatric intervention and without it no psychiatric intervention can be justified. As to the type and extent of the information to be given to the patient guideline 4 of the Declaration of Hawaii, states: "the psychiatrist should inform the patient of the nature of the condition, of the proposed diagnostic; and therapeutic procedures, including possible alternatives, and of the prognosis. This information must be offered in a considerate way and the patient be given the opportunity to choose between appropriate and available methods." A number of questions arise as to the practical problems related to the application of these principles. (a) If the choice of treatment is ultimately left to the best judgement of the patient his or her choice may not fall on the "best therapy available" and may not therefore "serve the best interest of the patient", generating a dilemma. (b) What is the role of exposure to advertisement of selective previous information in the choice of method favored by the patient? (c) What is the
C.
300
responsibility of treatment description suggestion?
of doctors for patients offered? (d) What about of all of these conditions
A.
Leon
who, upon being informed, refuse any alternative informing the patient about side effects...? be a possible way of inducing their occurrence,
form Could a through
Severe criticisms have been formulated about the fallacy of “informed consent”, when it is evident that the highest proportion of subjects for medical experiments comes from the poor, It has even been the neglected, ward patients, inmates of public institutions and prisoners. suggested that in order to discourage these practices, granting agencies might “require that subjects for experiments come from several socio-economic groups, not one” (Stephens, 1975). An essential element of the process of informed consent is the weighing of benefits and risks and this exercise is particularly difficult when dealing with certain types of specially vulIn these cases clinical nerable patients such as children, pregnant women and elderly people. testing by itself may not be sufficient to guarantee the safety of a product and careful monito. ing may be required for detection of undesirable effects which may have escaped the vigilance of the clinical trials.
6.
The
Cost
of
Psychotropic
Drugs
Because of its crucial importance for the implementation and success of health care programs, but essentially because of its relevance to ethics, something should be said about the need for a just and equitable distribution of resources for health. A basic prerequisite for the is the existence of adequate means and resources to implement this right. “right to health” The Declaration of Hawaii makes only one marginal remark about this problem: “(The psychiatrist shall) also be concerned for the common good and just allocation of health resources” But the fact is that the costs of health services increase, in all countries, faster (g-1). than the gross national product; in mDst cases from 3 to 5 times faster; and the budgets for health and education combined are substantially inferior to those for weapons and military expenses. And what about the cost of drugs? What is one to do when in several countries the cost of one daily dose of a neuroleptic is equal to the daily average per capita income of a manual laborer? There are enormous differences in the cost of patent drugs and their generic counterparts, without demonstrable difference in their therapeutic efficacy. The same is true for drugs within the same pharmacological category and with similar therapeutic effects but produced at different periods: the new drug invariably costs more. The problem is additionally complicated for developing countries which lack the means to produce pharmaceuticals and are forced to import them. Many such countries complain that the drugs they import are inferior in quality to those of the same kind used in developed countries (WHO 1971). On the other hand where there is a local pharmaceutical industry the measures and procedures used for quality control of the product are often only nominal and in any case below the standards enforced in highly developed countries. It has been argued that the promotional costs connected with marketing and advertising of drugs (which in some cases exceed by far the costs of research and production) are ultimately passed on to the consumer and that many people are deprived of the potential benefit of drugs because they or their health systems can not afford them. Bulk-buying and controlled distribution of health products by state agencies is advocated as a possible means for a more equitable allocation of resources, but of course such measures call for the existence of corresponding political and socio-economic systems and mechanisms which, however, may not be regarded as feasible or even desirable by some countries. Another alternative, of course, would be to stimulate the development of the local pharmaceutical industry together with the means for quality control. As a final conmmnt it must be said that in parallel to what occurs in other aspects of moden progress, the impressive growth of knowledge in psychopharmacology and the ever increasing expansion of the pharmaceutical industry are not matched as yet by a corresponding development of the ethical means to guarantee a full protection of the public and an equitable distribution of health means. Becoming conscious of these problems and exploring their structural elements may be a basic step towards their eventual solution.
Ethical
aspects
of psychopharmacology
301
References CLOUSER, K. D. (1975). Medical ethics, some abuses and limitations. New Engl. J. Med. -293: 304-387. DECLARATION OF HAWAII (1978). J. Med. Ethics 4: 71-73. REDLICH, F. (1976). Overview: Ethical issues-in contemporary psychiatry. Am. J. Psychiat. 133: 125-135. RIIS, P. (1975). Ethical aspects of biomedical research. Acta Neurol. Stand. Suppl. 60: 90-92. STEPHENS, J. (1975). Medical experiments on humans and the need for a public policy. In: What Government Does, Vol. 1, M. Holden and D. L. Dressang (eds.). Sage Publications, Beverly Hills. WEINSTEIN, M. C. (1974). Allocation of subjects in medical experiments. New Engl. J. Med. 291: 1278-278s. WOS HEALTH ORGANIZATION (1971). Pharmacology; Safety and Efficacy, 27 pp. World Health Organization, Geneva. .ln+iries
and
reprint
Dr. Carlos A. Leon Unidad de Salud Mental, Cali, Columbia.
requests Hospital
should
be addressed
Universitario
to: