- Email: [email protected]
Neuroleptics
M.N.G. Dukes
6 As Prof. Babayan and his colleagues pointed out in SEDA-9, the number of new antipsychotic drugs coming into use has sharply declined in recent years, as has the flow of reports on new and unexpected adverse reactions to these now very-well-known therapeutic agents. It therefore seems appropriate, in this tenth Annual, to set aside for a year the relatively minor reports which have continued to appear and to concentrate our attention on two matters of principle which have recently come to the fore and seem likely to provide important topics for debate within the coming year.
Should neuroleptic drugs be banned? The title o f this special review is not that o f the present writer. It is taken literally from a remarkable document by the Swedish physician, Lars M(trtensson, which was distributed at the Congress o f the World Federdtion for Mental Health, held at Brighton in July, 1985 (1). It raises a plea, among other things, for a legal prohibition on neuroleptic drugs, on the grounds that the harm which they do far outweighs any benefits which they can offer, and that the situation cannot be corrected rapidly by any means other than legal action. It is an extreme point o f view; but, like many documents which express an extreme view, it offers a great deal o f food for thought. It is some 40 years since chlorpromazine, first o f the neuroleptic drugs, first came into use in medicine (2). Since that time this group o f compounds has been largely held responsible for reducing the population o f mental institutions by providing means o f controlling, and perhaps alleviating, psychotic conditions which until that time had rendered their victims unable to maintain themselves in normal society, at least without incurring the risk o f grave harm to themselves and to others. For such reasons the
Side Effects of Drugs Annual 10 M.N.G, Dukes, editor 9 Elsevier Science Publishers B.V., 1986
Neuroleptics neuroleptics came into widespread use: it has been estimated that in Sweden, with a population o f 8.5 million, about 100,000 persons receive these drugs every day; about one-third of these patients have been diagnosed as schizophrenic, while others are retarded or suffering from confusion or negativism in old age (1). The challenge to the use o f neuroleptic drugs, as to many other practices in clinical psychiatry, has come very largely from patients themselves who have experienced the effects o f these substances. They have argued, on the one hand, that the neuroleptics have caused direct damage to the brain and to mental functions, and, on the other, that their use reflects a reprehensible approach to human problems and human suffering. The most concretely demonstrable harm done by the neuroleptic drugs - the induction o f both acute and tardive dyskinesias - has been repeatedly discussed in these volumes since 1977. Perhaps a third o f all patients treated with neuroleptics in adequate doses will suffer from these symptoms, which will sometimes persist after treatment has been withdrawn and may even appear at that time. One neuroleptic may be a little better than another in this respect, but the extent o f the problem should be a grave source o f concern and there is no adequate therapeutic approach to it. The patient who is released from confinement in a mental institution may find himself an outcast in the world which he reenters because o f his odd and unpredictable disorders of movement, which an unsympathetic environment may regard as clearer proof that he is 'odd' or 'mad' than the sometimes more subtle changes in his mental state. Much more difficult to define and understand, for those who have never themselves taken neuroleptic drugs, are the effects on the mind. As M6rtensson puts it: 'The main and the intended target o f neuroleptic drugs is the limbic system, which is a center for emotions, for control and appreciation o f the inner environment o f the body, for sexuality.., The damage to the limbic system...means a direct disturbance o f emotional life and o f the highest mental functions...' It is hard to put the consequences o f these changes into words. Reading the papers which
50
emerge from the protest movements organized by present or former patients o f mental institutions, one finds references to a deprivation o f free will and o f the ability to work consciously to overcome one's mental ailment. The person loses his ability to identify with himself, with others and with the rest o f the perceived and remembered world. It is this drug effect that people on the drugs try to explain when they say: "lama living dead. l a m a zombie. I am an automaton. I have lost my taste, my reflexes...! cannot read a book, not even watch TV. I have no memory...' (1) Viewed in this light, the usual clinical explanations as to the usefulness o f the neuroleptic drugs in psychotic states take on an almost ominous significance. Traditionally the interpretation is that the patients become "less active and more or less indifferent to experiences and situations which had previously made them very emotional...' From the point o f view o f the patient, he may find that as he loses his passions, his inspiration and his ability to care, he does not merely become less troublesome for his environment; he also loses his selfassertiveness and his spontaneity. No-one who has, either as a physician or a layman, had contact with patients who are heavily dosed with neuroleptic drugs can really doubt that this description is in large measure true. The price paid for ease o f control o f the patient may indeed be that he becomes an automaton, unable to have pleasure in life or to work actively towards his own recovery. There would be little point in criticism o f this type if the neuroleptic drugs did indeed offer a unique hope o f recovery. Whether they do so seems very dubious; they have never been claimed to have more than symptomatic effects, and while the simple view is that a patient who has been calmed may be more amenable to treatment, one can also have sympathy with the view that a patient whose mental processes have been further deranged and whose ability to react has been undermined will in fact be rendered incurable or at least more resistant to therapy. There are alternatives to neuroleptic drugs and they produce results which are apparently no less satisfactory and perhaps more so. The Soteria project in San Francisco (3) seems to show that if intensive personal care can be provided to the schizophrenic patient for a period of some months, his prognosis will be rather better than that o f a patient receiving neuroleptic drugs. The difficulty, as always, is that mass-production medicine can provide pills considerably more cheaply than one can provide personalized and devoted care.
Chapter 6 M.N.G. Dukes The patient protest movement may not have all the right on its side, but it deserves to be taken very seriously, and various psychiatrists are coming to share some o f its views as to the risk~benefit imbalance o f the neuroleptic drugs (4, 5). Perhaps there is some place for the neuroleptic drugs in the short-term control o f an acute psychosis, but their prolonged use, with all their mental and physical drawbacks, in large populations, is something which, after 40 years surely deserves to be looked at again, and much more critically than before.
Neuroleptics and behavioral teratogenicity Familiarity with a class o f drugs can breed contempt; more commonly it can breed recklessness. During the long career o f the neuroleptics a certain degree o f incautious optimism has more than once been shown as to their safety in situations in which they had not been positively proven to be safe. In the early 1970s, with concern being expressed as to the sedative effects o f the benzodiazepines, one school of opinion began to press the case for using low doses o f neuroleptics in their place. For a much longer period they have been recommended by manufacturers for use in pregnancy, either for their primary (psychiatric) purpose or to treat hyperemesis or chorea gravidarum. How sure can we be that they are safe when used under these conditions? The tenth edition o f "Meyler's Side Effects o f Drugs' expressed some reserves as to the use of haloperidol in pregnancy, but cited only a single paper which provided some doubtful evidence that the drug might on occasion be physically teratogenic. Nowhere in the literature is there very much evidence to be found that such an effect actually occurs; the reports from Dieulangard in 1966 (6) and Koppelman in 1975 (7) o f suspected physical teratogenicity induced by haloperidol both relate to cases where other drugs had been taken as well. For this class o f drugs as a whole, however, one might reasonably be more concerned that, having regard to their drastic effects on the functioning o f the brain, they might have some effect upon the mental or neurological development o f the fetus, rather than on physical normality. The concept o f 'behavioral teratogenicity' was first raised in the 1960s (8), largely in the light o f evidence that estrogens might have this effect. More recently, other drugs have come under
Neuroleptics Chapter 6 suspicion, notably the corticosteroids (9), used for the prophylaxis o f hyaline membrane disease where premature delivery appears inevitable. The benzodiazepine tranquilizers have been looked at very carefully; there is so far very little evidence to incriminate them. With the neuroleptic drugs things may be rather different. Within the last f e w years, various animal experiments have been reported, particularly from Japan, which throw a particular shadow on haloperidol in this respect, and which might also be considered as incriminating the neuroleptics belonging to other chemical classes. The results from some o f these papers deserve to be briefly summarized here. Watanabe and colleagues in 1985 (10) studied postnatal neurobehavioral development in rats treated prenatally with various drugs acting on the autonomic nervous system. Both haloperidol and chlorpromazine, administered from day 7 to day 19 o f gestation, inhibited behavioral development o f the righting reflex, cliff-drop avoidance and negative geotaxis as compared with controls. Moon (11) found that when haloperidol was given prenatally to block dopamine receptors, an elevation o f dopamine receptor binding was still in evidence 16 days after birth, as was a reduction in opiate receptor binding. Hill and Engblom (12) reported in 1984 that when pregnant rats were given haloperidol orally in 3 different doses from the 14th gestational day to postnatal day 12, the offspring showed drug-induced decreases in cortical and spinal noradrenaline levels and in striatal dopamine content which persisted into adulthood. Hull and co-workers reported in that same
51
year (13) that giving haloperidol to pregnant or lactating rats impaired the masculine sex behavior o f their male offspring; some reason was advanced for the belief that it might act directly on neurons controlling masculine behavior without lowering testosterone either prenatally or in adulthood. Bhanot and Wilkinson (14) similarly showed in a paper published in 1982 that treatment o f pregnant rats with haloperidol delayed the onset o f sexual maturation in the female offspring. No-one will be very anxious to accept animal data as to behavioral teratogenicity data at their face value, but reports such as these represent a warning which simply cannot be ignored. It is all too easy to dismiss inconvenient animal studies o f psychotropic drugs as irrelevant, forgetting that drugs of this type have generally first been identiffed as active in the light o f animal experiments. On the possible behavioral teratogenicity of one or more neuroleptics, the animal studies seem to be all we have. Little or no attempt appears to have been made by independent investigators, health authorities, the pharmaceutical industry or any other party to determine whether it is indeed proper to continue using neuroleptics for any purpose or in any dose in pregnancy. It is not at all easy to study the issue in man, where long-term follow up in the second generation provides the only sound source o f evidence; the question must also arise as to whether, in the light o f such suspicions, it wouM not be wiser to abandon the neuroleptics altogether in pregnancy, at least so long as no follow-up studies have been undertaken o f the many children who in recent decades must have been exposed to them in fetal life.
REFERENCES 1. Mfi.rtensson L (1985) Should Neuroleptic Drugs be Banned?. Brochure published by RSMH-Malm6 (Malm6 branch of the Swedish Association for Social and Mental Health), Bergsgatan 12B, 21154 Malm6, Sweden. 2. World Health Organisation (1985) Guidelinesfor
the Clinical Investigation of Neuroleptic Drugs. WHO Regional Office for Europe, Copenhagen. 3. Matthews SM, Roper MT, Mosher LR, Menn AZ (1979) A non-neuroleptic treatment for schizophrenia: analysis of two-year postdischarge risk of relapse. Schizophr. Bull., 5, 322. 4. Bierer J (1983) Medicine or manslaughter? Int. J. Soc. Psychiatry, 29, 247. 5. Breggin PR (1983) Psychiatric Drugs: Hazards to the Brain. Springer, New York. 6. Dieulangard P e t al (1966) Sur un cas d'ectro-
phocom61ie: peut-~tre d'origine m6dicamenteuse. Bull. F~d. Soc. Gynbcol. Obst~t., 18, 85. 7. Koppelman AE et al (1975) Limb malformations following maternal use of haloperidol. J. Am. Med. Assoc., 231, 62. 8. Meyer-Bahlburg HFL, Ehrhardt AA (1980) Neurobehavioural effects of prenatal origin: sex hormones. Id: Schwarz RH, Yaffe SJ (Eds), Drug and Chemical Risks to the Fetus and Newborn. Alan R Liss, Inc., New York. 9. Besenova O, Pavlik A (1985) Perinatal pharmacotherapy and the risk of the late psychobehavioural complications. In: The Proper Use of Drugs in Infancy. World Health Organization, Regional Office for Europe, Copenhagen. 10. Watanabe T, Matsuhashi K, Takayama S (1985) Study on the postnatal neuro-behavioural
52 development in rats treated prenatally with drugs acting on the autonomic nervous system. Nippon Yakurigaku Zasshi, 85(2), 79. 11. Moon SL (1984) Prenatal haloperidol alters striatal dopamine and opiate receptors. Brain Res.,
323, 109. 12. Hill HF, Engblom J (1984) Effects of pre- and postnatal haloperidol administrations to pregnant
Chapter 6 M.N.G. Dukes and nursing rats on brain catecholamine levels in their offspring. Dev. Pharmacol. Ther., 7, 188. 13. Hull EM, Nishita JK, Bitran D, Dalterio S (1984) Perinatal dopamine-related drugs demasculinize rats. Science, 224, I011. 14. Bhanot R, Wilkinson M (1982) Treatment of pregnant rats with haloperidol delays the onset of sexual maturation in female offspring. Experientia, 38, 137.
6 As Prof. Babayan and his colleagues pointed out in SEDA-9, the number of new antipsychotic drugs coming into use has sharply declined in recent years, as has the flow of reports on new and unexpected adverse reactions to these now very-well-known therapeutic agents. It therefore seems appropriate, in this tenth Annual, to set aside for a year the relatively minor reports which have continued to appear and to concentrate our attention on two matters of principle which have recently come to the fore and seem likely to provide important topics for debate within the coming year.
Should neuroleptic drugs be banned? The title o f this special review is not that o f the present writer. It is taken literally from a remarkable document by the Swedish physician, Lars M(trtensson, which was distributed at the Congress o f the World Federdtion for Mental Health, held at Brighton in July, 1985 (1). It raises a plea, among other things, for a legal prohibition on neuroleptic drugs, on the grounds that the harm which they do far outweighs any benefits which they can offer, and that the situation cannot be corrected rapidly by any means other than legal action. It is an extreme point o f view; but, like many documents which express an extreme view, it offers a great deal o f food for thought. It is some 40 years since chlorpromazine, first o f the neuroleptic drugs, first came into use in medicine (2). Since that time this group o f compounds has been largely held responsible for reducing the population o f mental institutions by providing means o f controlling, and perhaps alleviating, psychotic conditions which until that time had rendered their victims unable to maintain themselves in normal society, at least without incurring the risk o f grave harm to themselves and to others. For such reasons the
Side Effects of Drugs Annual 10 M.N.G, Dukes, editor 9 Elsevier Science Publishers B.V., 1986
Neuroleptics neuroleptics came into widespread use: it has been estimated that in Sweden, with a population o f 8.5 million, about 100,000 persons receive these drugs every day; about one-third of these patients have been diagnosed as schizophrenic, while others are retarded or suffering from confusion or negativism in old age (1). The challenge to the use o f neuroleptic drugs, as to many other practices in clinical psychiatry, has come very largely from patients themselves who have experienced the effects o f these substances. They have argued, on the one hand, that the neuroleptics have caused direct damage to the brain and to mental functions, and, on the other, that their use reflects a reprehensible approach to human problems and human suffering. The most concretely demonstrable harm done by the neuroleptic drugs - the induction o f both acute and tardive dyskinesias - has been repeatedly discussed in these volumes since 1977. Perhaps a third o f all patients treated with neuroleptics in adequate doses will suffer from these symptoms, which will sometimes persist after treatment has been withdrawn and may even appear at that time. One neuroleptic may be a little better than another in this respect, but the extent o f the problem should be a grave source o f concern and there is no adequate therapeutic approach to it. The patient who is released from confinement in a mental institution may find himself an outcast in the world which he reenters because o f his odd and unpredictable disorders of movement, which an unsympathetic environment may regard as clearer proof that he is 'odd' or 'mad' than the sometimes more subtle changes in his mental state. Much more difficult to define and understand, for those who have never themselves taken neuroleptic drugs, are the effects on the mind. As M6rtensson puts it: 'The main and the intended target o f neuroleptic drugs is the limbic system, which is a center for emotions, for control and appreciation o f the inner environment o f the body, for sexuality.., The damage to the limbic system...means a direct disturbance o f emotional life and o f the highest mental functions...' It is hard to put the consequences o f these changes into words. Reading the papers which
50
emerge from the protest movements organized by present or former patients o f mental institutions, one finds references to a deprivation o f free will and o f the ability to work consciously to overcome one's mental ailment. The person loses his ability to identify with himself, with others and with the rest o f the perceived and remembered world. It is this drug effect that people on the drugs try to explain when they say: "lama living dead. l a m a zombie. I am an automaton. I have lost my taste, my reflexes...! cannot read a book, not even watch TV. I have no memory...' (1) Viewed in this light, the usual clinical explanations as to the usefulness o f the neuroleptic drugs in psychotic states take on an almost ominous significance. Traditionally the interpretation is that the patients become "less active and more or less indifferent to experiences and situations which had previously made them very emotional...' From the point o f view o f the patient, he may find that as he loses his passions, his inspiration and his ability to care, he does not merely become less troublesome for his environment; he also loses his selfassertiveness and his spontaneity. No-one who has, either as a physician or a layman, had contact with patients who are heavily dosed with neuroleptic drugs can really doubt that this description is in large measure true. The price paid for ease o f control o f the patient may indeed be that he becomes an automaton, unable to have pleasure in life or to work actively towards his own recovery. There would be little point in criticism o f this type if the neuroleptic drugs did indeed offer a unique hope o f recovery. Whether they do so seems very dubious; they have never been claimed to have more than symptomatic effects, and while the simple view is that a patient who has been calmed may be more amenable to treatment, one can also have sympathy with the view that a patient whose mental processes have been further deranged and whose ability to react has been undermined will in fact be rendered incurable or at least more resistant to therapy. There are alternatives to neuroleptic drugs and they produce results which are apparently no less satisfactory and perhaps more so. The Soteria project in San Francisco (3) seems to show that if intensive personal care can be provided to the schizophrenic patient for a period of some months, his prognosis will be rather better than that o f a patient receiving neuroleptic drugs. The difficulty, as always, is that mass-production medicine can provide pills considerably more cheaply than one can provide personalized and devoted care.
Chapter 6 M.N.G. Dukes The patient protest movement may not have all the right on its side, but it deserves to be taken very seriously, and various psychiatrists are coming to share some o f its views as to the risk~benefit imbalance o f the neuroleptic drugs (4, 5). Perhaps there is some place for the neuroleptic drugs in the short-term control o f an acute psychosis, but their prolonged use, with all their mental and physical drawbacks, in large populations, is something which, after 40 years surely deserves to be looked at again, and much more critically than before.
Neuroleptics and behavioral teratogenicity Familiarity with a class o f drugs can breed contempt; more commonly it can breed recklessness. During the long career o f the neuroleptics a certain degree o f incautious optimism has more than once been shown as to their safety in situations in which they had not been positively proven to be safe. In the early 1970s, with concern being expressed as to the sedative effects o f the benzodiazepines, one school of opinion began to press the case for using low doses o f neuroleptics in their place. For a much longer period they have been recommended by manufacturers for use in pregnancy, either for their primary (psychiatric) purpose or to treat hyperemesis or chorea gravidarum. How sure can we be that they are safe when used under these conditions? The tenth edition o f "Meyler's Side Effects o f Drugs' expressed some reserves as to the use of haloperidol in pregnancy, but cited only a single paper which provided some doubtful evidence that the drug might on occasion be physically teratogenic. Nowhere in the literature is there very much evidence to be found that such an effect actually occurs; the reports from Dieulangard in 1966 (6) and Koppelman in 1975 (7) o f suspected physical teratogenicity induced by haloperidol both relate to cases where other drugs had been taken as well. For this class o f drugs as a whole, however, one might reasonably be more concerned that, having regard to their drastic effects on the functioning o f the brain, they might have some effect upon the mental or neurological development o f the fetus, rather than on physical normality. The concept o f 'behavioral teratogenicity' was first raised in the 1960s (8), largely in the light o f evidence that estrogens might have this effect. More recently, other drugs have come under
Neuroleptics Chapter 6 suspicion, notably the corticosteroids (9), used for the prophylaxis o f hyaline membrane disease where premature delivery appears inevitable. The benzodiazepine tranquilizers have been looked at very carefully; there is so far very little evidence to incriminate them. With the neuroleptic drugs things may be rather different. Within the last f e w years, various animal experiments have been reported, particularly from Japan, which throw a particular shadow on haloperidol in this respect, and which might also be considered as incriminating the neuroleptics belonging to other chemical classes. The results from some o f these papers deserve to be briefly summarized here. Watanabe and colleagues in 1985 (10) studied postnatal neurobehavioral development in rats treated prenatally with various drugs acting on the autonomic nervous system. Both haloperidol and chlorpromazine, administered from day 7 to day 19 o f gestation, inhibited behavioral development o f the righting reflex, cliff-drop avoidance and negative geotaxis as compared with controls. Moon (11) found that when haloperidol was given prenatally to block dopamine receptors, an elevation o f dopamine receptor binding was still in evidence 16 days after birth, as was a reduction in opiate receptor binding. Hill and Engblom (12) reported in 1984 that when pregnant rats were given haloperidol orally in 3 different doses from the 14th gestational day to postnatal day 12, the offspring showed drug-induced decreases in cortical and spinal noradrenaline levels and in striatal dopamine content which persisted into adulthood. Hull and co-workers reported in that same
51
year (13) that giving haloperidol to pregnant or lactating rats impaired the masculine sex behavior o f their male offspring; some reason was advanced for the belief that it might act directly on neurons controlling masculine behavior without lowering testosterone either prenatally or in adulthood. Bhanot and Wilkinson (14) similarly showed in a paper published in 1982 that treatment o f pregnant rats with haloperidol delayed the onset o f sexual maturation in the female offspring. No-one will be very anxious to accept animal data as to behavioral teratogenicity data at their face value, but reports such as these represent a warning which simply cannot be ignored. It is all too easy to dismiss inconvenient animal studies o f psychotropic drugs as irrelevant, forgetting that drugs of this type have generally first been identiffed as active in the light o f animal experiments. On the possible behavioral teratogenicity of one or more neuroleptics, the animal studies seem to be all we have. Little or no attempt appears to have been made by independent investigators, health authorities, the pharmaceutical industry or any other party to determine whether it is indeed proper to continue using neuroleptics for any purpose or in any dose in pregnancy. It is not at all easy to study the issue in man, where long-term follow up in the second generation provides the only sound source o f evidence; the question must also arise as to whether, in the light o f such suspicions, it wouM not be wiser to abandon the neuroleptics altogether in pregnancy, at least so long as no follow-up studies have been undertaken o f the many children who in recent decades must have been exposed to them in fetal life.
REFERENCES 1. Mfi.rtensson L (1985) Should Neuroleptic Drugs be Banned?. Brochure published by RSMH-Malm6 (Malm6 branch of the Swedish Association for Social and Mental Health), Bergsgatan 12B, 21154 Malm6, Sweden. 2. World Health Organisation (1985) Guidelinesfor
the Clinical Investigation of Neuroleptic Drugs. WHO Regional Office for Europe, Copenhagen. 3. Matthews SM, Roper MT, Mosher LR, Menn AZ (1979) A non-neuroleptic treatment for schizophrenia: analysis of two-year postdischarge risk of relapse. Schizophr. Bull., 5, 322. 4. Bierer J (1983) Medicine or manslaughter? Int. J. Soc. Psychiatry, 29, 247. 5. Breggin PR (1983) Psychiatric Drugs: Hazards to the Brain. Springer, New York. 6. Dieulangard P e t al (1966) Sur un cas d'ectro-
phocom61ie: peut-~tre d'origine m6dicamenteuse. Bull. F~d. Soc. Gynbcol. Obst~t., 18, 85. 7. Koppelman AE et al (1975) Limb malformations following maternal use of haloperidol. J. Am. Med. Assoc., 231, 62. 8. Meyer-Bahlburg HFL, Ehrhardt AA (1980) Neurobehavioural effects of prenatal origin: sex hormones. Id: Schwarz RH, Yaffe SJ (Eds), Drug and Chemical Risks to the Fetus and Newborn. Alan R Liss, Inc., New York. 9. Besenova O, Pavlik A (1985) Perinatal pharmacotherapy and the risk of the late psychobehavioural complications. In: The Proper Use of Drugs in Infancy. World Health Organization, Regional Office for Europe, Copenhagen. 10. Watanabe T, Matsuhashi K, Takayama S (1985) Study on the postnatal neuro-behavioural
52 development in rats treated prenatally with drugs acting on the autonomic nervous system. Nippon Yakurigaku Zasshi, 85(2), 79. 11. Moon SL (1984) Prenatal haloperidol alters striatal dopamine and opiate receptors. Brain Res.,
323, 109. 12. Hill HF, Engblom J (1984) Effects of pre- and postnatal haloperidol administrations to pregnant
Chapter 6 M.N.G. Dukes and nursing rats on brain catecholamine levels in their offspring. Dev. Pharmacol. Ther., 7, 188. 13. Hull EM, Nishita JK, Bitran D, Dalterio S (1984) Perinatal dopamine-related drugs demasculinize rats. Science, 224, I011. 14. Bhanot R, Wilkinson M (1982) Treatment of pregnant rats with haloperidol delays the onset of sexual maturation in female offspring. Experientia, 38, 137.