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LITHIUM AS ACUTE TREATMENT OF MANIC-DEPRESSIVE ILLNESS
92 SERVICE FOR THE MENTALLY HANDICAPPED
SiR,-About 150,000 mentally handicapped people have given a white-paper which promises new policies, though too timid; and more money, though not enough. But it is a triumph to get a white-paper at all. It is a document which ought to encourage a considerable number of people in all professions whose voice has so far been little heard. These are the people who are not satisfied with our hospitals as they are, nor with our service as it is, and who believe that a hospital should only exist if it can offer some special service which cannot be given equally well in the open community. In other words, a hospital must justify its existence by its ability to produce unique results. These hospital reformists, as they might be termed, will been
welcome many features in the document-the attack on large old hospitals, the insistence on the common basic rights of the mentally handicapped, the small-group approach, the setting of targets for local authorities, the insistence on a multidisciplinary approach to the management of the service. The paper sounds off some stirring trumpet calls for action, but it is weak on the battle orders. The troops are ready to charge-but where ? " The government considers it premature to form a final view on these questions." Time and again, this hesitation weakens the proposals for action. Joy at the headline " No new large hospitals " fades on reading in small print that this veto applies only " for the time being ". Why ? If we are to see localauthority homes, plus hospital home units of a domestic character, plus new area hospitals, why not ban new large hospitals for all time; scrap the large old hospitals on isolated sites; and give the remaining hospitals the chance and the challenge to show what it is which they uniquely
do ? Area hospitals of up to 200 beds are being proposed, but what precisely is meant ? Are these just hospitals in traditional terms for those who need medical supervision or are they to be considered as key places where training and socialisation may be centred, where severely handicapped people may be helped towards a trial run in the community, and where staff training may be concentrated ? If so, units of this kind could provide a splendid focus for all branches of the mental handicap service and would encourage those who believe that people of other disciplines than medicine-for example, social workers, psychologists, teachers, and nurses-sometimes need to take the lead in what in many ways is a social and educational venture. Lubricative words like coordination, collaboration, partnership, liaison, appear in this paper every time a creaking hinge is encountered. Why not more attention to the construction of the hinge itself ? Recent legislation has split the mental handicap service into three separately financed parts, but could not this be overcome by setting up for each area a board or directorate for the whole mentalhandicap service, even though constituted by workers from the legally separated services of health, education, and social work ? Why not combine efforts for the training of staff instead of having two separate streams ? Nothing would be more likely to develop the common pattern of care and training which is so desirable. There are some ominous Treasury undertones: the Government will try to help authorities to complete their programmes " so far as the resources available for capital projects allow "; or " further progress will depend on what rate of development can reasonably be expected, taking into account the priority which these services deserve and the many other calls on resources ". To make a programme to provide 20,000 places in residential homes over a period of fifteen years is the equivalent of making a programme to build 5000 council houses over fifteen years
for people who have in any case been queuing for most of their lives. This white-paper holds the balance between the extremists, and it may give hospital reformists the chance to show whether a re-formed hospital has something to contribute, uniquely, within the general range of services for the handicapped. As its title promises, it should produce a number of separate better services for the mentally handicapped, but it will never, in its present form, produce one united and comprehensive service. A great chance of fundamental reform has been missed, or, dare we hope, only postponed. There has to date been no attempt to undertake a critical examination of the available options in the light of international experience and research: the great issues have been avoided: no brave choice has been made. In spite of this, those who work with and for the mentally handicapped are bound to be glad that what they have been doing today they will be able to do a little better tomorrow and that there is a chance for hospitals and local authorities to work together in providing one good system of community-based care, using hospitals only when that is the best thing for the mentally handicapped person. As an interim white-paper, as a first step to righting the wrongs of years, it can unconditionally be given two rousing cheers. But that is simply not good enough. Those workers who care deeply about the future of the mentally handicapped must try to exploit the white-paper to its maximum. At the same time, whatever their professional differences, they need to unite for one more dogged push towards a truly civilised service for the mentally handicapped. The Hospital Centre, London W.1.
JAMES ELLIOTT, Associate Director.
can
LITHIUM AS ACUTE TREATMENT OF MANIC-DEPRESSIVE ILLNESS
SIR,-Iwould like to comment on the excellent paper by Dr. Stokes and his co-workersdemonstrating the efficacy of lithium in mania. They point out that most of their patients " did not show a predictable rapid (24-hour) change in behaviour upon withdrawal from lithium as observed in three patients reported by Goodwin et al.". This seemingly small discrepancy between the findings of two eminently scrupulous studies does, I feel, point a wider moral. In the study by Goodwin et al.,2 rating was by a 25-item, 15-point scale previously developed by these workers 3 in collaboration with medical and nursing staff who were to use it. It is not surprising, therefore, that sharper definition of small changes in mood and behaviour were recorded in this study than in that of Stokes et al., where a global 7-point scale (plus and minus) was used. The scale used by Stokes et al. assumes implicitly that all symptoms in mania change pari passu, which is very doubtful. Unfortunately, Bunney and Hamburg3 do not give any data regarding test reliability for their scale nor a factor analysis of the items, which could have proved of great value. In another study by Bunney et al.,4 where there are also sharp measures of change in degree of mania on and off lithium, another scale is used, described as global ", attributed to F. K. Goodwin (" A Multi-Item Rating Scale for Mania "), but sadly referred to as unpublished. Crucial to the results and reliability of any study in mania will be the measuring tool employed. Moreover, "
Stokes, P. E., Stoll, P. M., Shamoian, C. A., Patton, C. A. Lancet, 1971, i, 1319. 2. Goodwin, F. K., Murphy, D. L., Bunney, W. E. Archs gen. Psychiat. 1969, 21, 486. 3. Bunney, W. E., Hamburg, D. A. ibid. 1963, 9, 280. 4. Bunney, W. E., Goodwin, F. K., Davis, J. M., Fawcett, J. A. Am. J. Psychiat. 1968, 125, 499. 1.
93 item and factor analysis would allow far more information be extracted from the experiment, perhaps shedding light on the problem of the lithium non-responder. Also such a scale, so refined, might answer the question half posed by Stokes et al. about another study-namely, whether chlorpromazine had a placebo effect (as they or whether, as seems more likely, it also had a suggest) " true ", though symptomatic, effect as well.
to
University Department of Psychiatry, Sheffield 10.
MITOTIC INDEX AND LYMPHOCYTE-TRANSFORMATION RATE IN CULTURES EXPOSED TO LITHIUM CARBONATE (AVERAGE OF THREE
EXPERIMENTS)
GERALD SILVERMAN.
LITHIUM AND MITOSIS
SIR,-Lithium is being increasingly used in the treatment manic-depressive psychosis and, since Szabo 1,2 and Wright et awl. have shown that it may be teratogenic in mice and rats, it is important to determine the effect of
of
lithium in man. Goldfield and Weinstein4 reviewed the effects of lithium in human pregnancies and in animal experiments and concluded that the evidence for a teratogenic effect of lithium salts is conflicting, but that no clear relationship between the use of lithium and birth defects has been established. The data on chromosome damage due to lithium are also confusing. Friedrich and Nielsen5 examined the chromosomes of 3 patients treated with lithium and found a significant increase in the incidence of chromosome breaks and hypodiploid cells compared with controls. Jarvik et al. studied 16 patients who had taken lithium carbonate for between two weeks and two years and found no statistical difference in the frequency of chromosome breaks between these patients and controls. Genest and Villeneuveexamined the chromosomes of 19 patients on lithium therapy and also found no difference in the frequency of chromosome breaks between them and controls. They also found, however, a highly significant decrease in the mitotic index in the lithium-treated patients compared with the controls. We report here the results of some in-vitro experiments using blood samples obtained from healthy adult volunteers. Using the technique previously described,8 we added lithium carbonate to peripheral blood-lymphocyte cultures at the beginning of the 72-hour incubation period in concentrations equivalent to 10, 1-0, and 0-1 g. of lithium carbonate being distributed throughout the total bodywater of a 70 kg. (154 lb.) man. Control cultures without lithium carbonate were also set up. Examination of the chromosomes showed a slight, not statistically significant, increase in the number of cells showing chromosome damage in the cultures with the highest lithium-carbonate concentration (3%) when compared with controls (1%). The effect of lithium carbonate at these concentrations on the mitotic index and on the lymphocyte-transformation rate in response to phytohaemagglutinin stimulation is shown in the table. Our results with regard to chromosome damage are, therefore, consistent with those of Jarvik et al. and Genest and Villeneuvebut not with those of Friedrich and Nielsen.5 In our cultures lithium did not significantly lower the mitotic rate and had no effect on the lymphocyte-transformation rate, suggesting that it has no action on either D.N.A. synthesis or the mechanism of induction of mitosis. These results are not in agreement with those of Genest and Villeneuve. This may be due to the relatively short time that the cells in our experiments were exposed 1. 2. 3. 4. 5. 6.
Szabo, K. T. Lancet, 1969, ii, 849. Szabo, K. T. Nature, 1970, 225, 73. Wright, T. L., Hoffman, L. H., Davies, J. Lancet, 1970, ii, 876. Goldfield, M., Weinstein, M. R. Am. J. Psychiat. 1971, 127, 888. Friedrich, U., Nielsen, J. Lancet, 1969, ii, 435. Jarvik, L. F., Bishun, N. P., Bleiweiss, H., Kato, T., Moralishvili, E. Archs gen. Psychiat. 1971, 24, 166. 7. Genest, P., Villeneuve, A. Lancet, 1971, i, 1132. 8. Timson, J. ibid. 1968, ii, 1084.
lithium, although the highest concentration used is equivalent to about ten times the normal therapeutic dose. Alternatively, the difference may be due to the fact that we
to
used the donor’s own cells as controls rather than the mitotic index of control subjects. This seems a more probable explanation to us, since we have recently shown that there is considerable variation in the mitotic index of a particular individual over a period of time.9 This suggests that comparisons of mitotic index between groups of patients and controls are not valid. We thank the Smith Kline and French Foundation for financial support.
University Department of Medical Genetics, St. Mary’s Hospital, Manchester.
J. TIMSON D. J. PRICE.
ISONIAZID-INDUCED CHROMOSOME ABERRATIONS SiR,—The antituberculous drug isonicotinic-acid hydrazide (isoniazid, I.N.H.) is a pyridoxal-phosphate inhibitor,lO and may thus be involved in D.N.A. synthesis. An action on chromosomes might be expected. We studied the effect of an intravenous dose of 65 -g. per g. body-weight for one week to 5 Wistar rats. Chromosome analysis of bone-marrow cells by the modified method of Ford and Hamerton 11 revealed a high percentage of cells with structural chromosome anomalies: of 140 cells examined, 57 were abnormal (40-71-4-15%). The percentage with abnormalities was significantly greater than in 5 rats which did not receive I.N.H. In the livers of the embryos of 2 female rats given I.N.H., only 1-4% of the cells were abnormal. This may be due to the rapid inactivation of the drug in the body.12 The chromosome changes observed after I.N.H. were gaps, breaks, deletions, and fragments; a small number The showed translocations and increased stickiness. chromosome pairs most affected were the first and second, perhaps because their large size, the secondary constrictions, or the heterochromatin content make them especially
liable
to
aberrations.13
Institute of Pathology and Medical Genetics Dr. V. Babes " and Institute of Forensic Medicine " Dr. Mina Minovici ", "
Bucharest, Rumania.
LILIANA CIRNU-GEORGIAN
VIORICA LENGHEL.
RUBELLA VACCINATION
SIR,-With reference to Lieutenant-Colonel Wally on general epidemiological grounds it would appear better to first offer immunisation against rubella to children of both sexes aged 5-10 years. This would, besides
Vella’s letter,14
9. Price, D. J., Timson, J. Unpublished. 10. Pope, H. Am. Rev. Tuberc. pulm. Dis. 1953, 68, 938. 11. Ford, C. E., Hamerton, J. L. Stain Technol. 1956, 31, 247. 12. Hughes, H. B., Biehl, J. P., Jones, A. P., Schmidt, L. H. Am. Rev. Tuberc. pulm. Dis. 1954, 70, 266. 13. Natarajan, A. T., Ahnström, G. Chromosoma, 1969, 29, 48. 14. Vella, E. E. Lancet, 1971, i, 1188.
SiR,-About 150,000 mentally handicapped people have given a white-paper which promises new policies, though too timid; and more money, though not enough. But it is a triumph to get a white-paper at all. It is a document which ought to encourage a considerable number of people in all professions whose voice has so far been little heard. These are the people who are not satisfied with our hospitals as they are, nor with our service as it is, and who believe that a hospital should only exist if it can offer some special service which cannot be given equally well in the open community. In other words, a hospital must justify its existence by its ability to produce unique results. These hospital reformists, as they might be termed, will been
welcome many features in the document-the attack on large old hospitals, the insistence on the common basic rights of the mentally handicapped, the small-group approach, the setting of targets for local authorities, the insistence on a multidisciplinary approach to the management of the service. The paper sounds off some stirring trumpet calls for action, but it is weak on the battle orders. The troops are ready to charge-but where ? " The government considers it premature to form a final view on these questions." Time and again, this hesitation weakens the proposals for action. Joy at the headline " No new large hospitals " fades on reading in small print that this veto applies only " for the time being ". Why ? If we are to see localauthority homes, plus hospital home units of a domestic character, plus new area hospitals, why not ban new large hospitals for all time; scrap the large old hospitals on isolated sites; and give the remaining hospitals the chance and the challenge to show what it is which they uniquely
do ? Area hospitals of up to 200 beds are being proposed, but what precisely is meant ? Are these just hospitals in traditional terms for those who need medical supervision or are they to be considered as key places where training and socialisation may be centred, where severely handicapped people may be helped towards a trial run in the community, and where staff training may be concentrated ? If so, units of this kind could provide a splendid focus for all branches of the mental handicap service and would encourage those who believe that people of other disciplines than medicine-for example, social workers, psychologists, teachers, and nurses-sometimes need to take the lead in what in many ways is a social and educational venture. Lubricative words like coordination, collaboration, partnership, liaison, appear in this paper every time a creaking hinge is encountered. Why not more attention to the construction of the hinge itself ? Recent legislation has split the mental handicap service into three separately financed parts, but could not this be overcome by setting up for each area a board or directorate for the whole mentalhandicap service, even though constituted by workers from the legally separated services of health, education, and social work ? Why not combine efforts for the training of staff instead of having two separate streams ? Nothing would be more likely to develop the common pattern of care and training which is so desirable. There are some ominous Treasury undertones: the Government will try to help authorities to complete their programmes " so far as the resources available for capital projects allow "; or " further progress will depend on what rate of development can reasonably be expected, taking into account the priority which these services deserve and the many other calls on resources ". To make a programme to provide 20,000 places in residential homes over a period of fifteen years is the equivalent of making a programme to build 5000 council houses over fifteen years
for people who have in any case been queuing for most of their lives. This white-paper holds the balance between the extremists, and it may give hospital reformists the chance to show whether a re-formed hospital has something to contribute, uniquely, within the general range of services for the handicapped. As its title promises, it should produce a number of separate better services for the mentally handicapped, but it will never, in its present form, produce one united and comprehensive service. A great chance of fundamental reform has been missed, or, dare we hope, only postponed. There has to date been no attempt to undertake a critical examination of the available options in the light of international experience and research: the great issues have been avoided: no brave choice has been made. In spite of this, those who work with and for the mentally handicapped are bound to be glad that what they have been doing today they will be able to do a little better tomorrow and that there is a chance for hospitals and local authorities to work together in providing one good system of community-based care, using hospitals only when that is the best thing for the mentally handicapped person. As an interim white-paper, as a first step to righting the wrongs of years, it can unconditionally be given two rousing cheers. But that is simply not good enough. Those workers who care deeply about the future of the mentally handicapped must try to exploit the white-paper to its maximum. At the same time, whatever their professional differences, they need to unite for one more dogged push towards a truly civilised service for the mentally handicapped. The Hospital Centre, London W.1.
JAMES ELLIOTT, Associate Director.
can
LITHIUM AS ACUTE TREATMENT OF MANIC-DEPRESSIVE ILLNESS
SIR,-Iwould like to comment on the excellent paper by Dr. Stokes and his co-workersdemonstrating the efficacy of lithium in mania. They point out that most of their patients " did not show a predictable rapid (24-hour) change in behaviour upon withdrawal from lithium as observed in three patients reported by Goodwin et al.". This seemingly small discrepancy between the findings of two eminently scrupulous studies does, I feel, point a wider moral. In the study by Goodwin et al.,2 rating was by a 25-item, 15-point scale previously developed by these workers 3 in collaboration with medical and nursing staff who were to use it. It is not surprising, therefore, that sharper definition of small changes in mood and behaviour were recorded in this study than in that of Stokes et al., where a global 7-point scale (plus and minus) was used. The scale used by Stokes et al. assumes implicitly that all symptoms in mania change pari passu, which is very doubtful. Unfortunately, Bunney and Hamburg3 do not give any data regarding test reliability for their scale nor a factor analysis of the items, which could have proved of great value. In another study by Bunney et al.,4 where there are also sharp measures of change in degree of mania on and off lithium, another scale is used, described as global ", attributed to F. K. Goodwin (" A Multi-Item Rating Scale for Mania "), but sadly referred to as unpublished. Crucial to the results and reliability of any study in mania will be the measuring tool employed. Moreover, "
Stokes, P. E., Stoll, P. M., Shamoian, C. A., Patton, C. A. Lancet, 1971, i, 1319. 2. Goodwin, F. K., Murphy, D. L., Bunney, W. E. Archs gen. Psychiat. 1969, 21, 486. 3. Bunney, W. E., Hamburg, D. A. ibid. 1963, 9, 280. 4. Bunney, W. E., Goodwin, F. K., Davis, J. M., Fawcett, J. A. Am. J. Psychiat. 1968, 125, 499. 1.
93 item and factor analysis would allow far more information be extracted from the experiment, perhaps shedding light on the problem of the lithium non-responder. Also such a scale, so refined, might answer the question half posed by Stokes et al. about another study-namely, whether chlorpromazine had a placebo effect (as they or whether, as seems more likely, it also had a suggest) " true ", though symptomatic, effect as well.
to
University Department of Psychiatry, Sheffield 10.
MITOTIC INDEX AND LYMPHOCYTE-TRANSFORMATION RATE IN CULTURES EXPOSED TO LITHIUM CARBONATE (AVERAGE OF THREE
EXPERIMENTS)
GERALD SILVERMAN.
LITHIUM AND MITOSIS
SIR,-Lithium is being increasingly used in the treatment manic-depressive psychosis and, since Szabo 1,2 and Wright et awl. have shown that it may be teratogenic in mice and rats, it is important to determine the effect of
of
lithium in man. Goldfield and Weinstein4 reviewed the effects of lithium in human pregnancies and in animal experiments and concluded that the evidence for a teratogenic effect of lithium salts is conflicting, but that no clear relationship between the use of lithium and birth defects has been established. The data on chromosome damage due to lithium are also confusing. Friedrich and Nielsen5 examined the chromosomes of 3 patients treated with lithium and found a significant increase in the incidence of chromosome breaks and hypodiploid cells compared with controls. Jarvik et al. studied 16 patients who had taken lithium carbonate for between two weeks and two years and found no statistical difference in the frequency of chromosome breaks between these patients and controls. Genest and Villeneuveexamined the chromosomes of 19 patients on lithium therapy and also found no difference in the frequency of chromosome breaks between them and controls. They also found, however, a highly significant decrease in the mitotic index in the lithium-treated patients compared with the controls. We report here the results of some in-vitro experiments using blood samples obtained from healthy adult volunteers. Using the technique previously described,8 we added lithium carbonate to peripheral blood-lymphocyte cultures at the beginning of the 72-hour incubation period in concentrations equivalent to 10, 1-0, and 0-1 g. of lithium carbonate being distributed throughout the total bodywater of a 70 kg. (154 lb.) man. Control cultures without lithium carbonate were also set up. Examination of the chromosomes showed a slight, not statistically significant, increase in the number of cells showing chromosome damage in the cultures with the highest lithium-carbonate concentration (3%) when compared with controls (1%). The effect of lithium carbonate at these concentrations on the mitotic index and on the lymphocyte-transformation rate in response to phytohaemagglutinin stimulation is shown in the table. Our results with regard to chromosome damage are, therefore, consistent with those of Jarvik et al. and Genest and Villeneuvebut not with those of Friedrich and Nielsen.5 In our cultures lithium did not significantly lower the mitotic rate and had no effect on the lymphocyte-transformation rate, suggesting that it has no action on either D.N.A. synthesis or the mechanism of induction of mitosis. These results are not in agreement with those of Genest and Villeneuve. This may be due to the relatively short time that the cells in our experiments were exposed 1. 2. 3. 4. 5. 6.
Szabo, K. T. Lancet, 1969, ii, 849. Szabo, K. T. Nature, 1970, 225, 73. Wright, T. L., Hoffman, L. H., Davies, J. Lancet, 1970, ii, 876. Goldfield, M., Weinstein, M. R. Am. J. Psychiat. 1971, 127, 888. Friedrich, U., Nielsen, J. Lancet, 1969, ii, 435. Jarvik, L. F., Bishun, N. P., Bleiweiss, H., Kato, T., Moralishvili, E. Archs gen. Psychiat. 1971, 24, 166. 7. Genest, P., Villeneuve, A. Lancet, 1971, i, 1132. 8. Timson, J. ibid. 1968, ii, 1084.
lithium, although the highest concentration used is equivalent to about ten times the normal therapeutic dose. Alternatively, the difference may be due to the fact that we
to
used the donor’s own cells as controls rather than the mitotic index of control subjects. This seems a more probable explanation to us, since we have recently shown that there is considerable variation in the mitotic index of a particular individual over a period of time.9 This suggests that comparisons of mitotic index between groups of patients and controls are not valid. We thank the Smith Kline and French Foundation for financial support.
University Department of Medical Genetics, St. Mary’s Hospital, Manchester.
J. TIMSON D. J. PRICE.
ISONIAZID-INDUCED CHROMOSOME ABERRATIONS SiR,—The antituberculous drug isonicotinic-acid hydrazide (isoniazid, I.N.H.) is a pyridoxal-phosphate inhibitor,lO and may thus be involved in D.N.A. synthesis. An action on chromosomes might be expected. We studied the effect of an intravenous dose of 65 -g. per g. body-weight for one week to 5 Wistar rats. Chromosome analysis of bone-marrow cells by the modified method of Ford and Hamerton 11 revealed a high percentage of cells with structural chromosome anomalies: of 140 cells examined, 57 were abnormal (40-71-4-15%). The percentage with abnormalities was significantly greater than in 5 rats which did not receive I.N.H. In the livers of the embryos of 2 female rats given I.N.H., only 1-4% of the cells were abnormal. This may be due to the rapid inactivation of the drug in the body.12 The chromosome changes observed after I.N.H. were gaps, breaks, deletions, and fragments; a small number The showed translocations and increased stickiness. chromosome pairs most affected were the first and second, perhaps because their large size, the secondary constrictions, or the heterochromatin content make them especially
liable
to
aberrations.13
Institute of Pathology and Medical Genetics Dr. V. Babes " and Institute of Forensic Medicine " Dr. Mina Minovici ", "
Bucharest, Rumania.
LILIANA CIRNU-GEORGIAN
VIORICA LENGHEL.
RUBELLA VACCINATION
SIR,-With reference to Lieutenant-Colonel Wally on general epidemiological grounds it would appear better to first offer immunisation against rubella to children of both sexes aged 5-10 years. This would, besides
Vella’s letter,14
9. Price, D. J., Timson, J. Unpublished. 10. Pope, H. Am. Rev. Tuberc. pulm. Dis. 1953, 68, 938. 11. Ford, C. E., Hamerton, J. L. Stain Technol. 1956, 31, 247. 12. Hughes, H. B., Biehl, J. P., Jones, A. P., Schmidt, L. H. Am. Rev. Tuberc. pulm. Dis. 1954, 70, 266. 13. Natarajan, A. T., Ahnström, G. Chromosoma, 1969, 29, 48. 14. Vella, E. E. Lancet, 1971, i, 1188.