PROPHYLACTIC LITHIUM IN RECURRENT AFFECTIVE DISORDERS

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PROPHYLACTIC LITHIUM IN RECURRENT AFFECTIVE DISORDERS R. MCDONALD R. P. HULLIN M. N. E. ALLSOPP

Regional Metabolic Research Unit, High Royds Hospital, Menston, Yorkshire, and Departments of Biochemistry and Psychiatry, University of Leeds The effect of lithium given prophylactically to a group of sixty-nine patients with recurrent affective disorders was studied for an average period of 40 months (range 18-75 months). The patients were selected on the basis of a previous history of an average of at least one admission to a psychiatric hospital per year over the 5 years before treatment. Plasma-lithium levels were regularly monitored during treatment. The mean number of admissions to hospital for episodes of depression and/or mania during the period of lithium treatment (average 40 months) was 0·55, compared with 3·36 during a period of similar duration before lithium. Time spent in hospital dropped from a group average of 26·9 weeks to 3·5 weeks. Forty-eight patients required no hospital admissions while receiving lithium. Only two patients had higher admission-rates and longer time in hospital than during the equivalent

Sum ary

period before treatment. Fifteen of the twenty-one relapses occurred in the manic phases of bipolar manic-depressive psychosis, and there was biochemical evidence for low or zero lithium levels in ten of these fifteen cases. In a double-blind trial in thirty-six patients who had not required hospital admission for at least 2 years on prophylactic lithium, six out of the eighteen patients on placebo relapsed within 6 months, compared with only one of the eighteen patients continuing to receive lithium. Introduction

IN 1967 Baastrup and Schou1 claimed that lithium of value as a prophylactic agent against the depressive and manic phases of manic-depressive psychosis; their methods were criticised2 although later work3 met much of this criticism. Coppen et al.,4 using a different approach, also reported the value of prophylactic lithium, whilst Platman,5 in a very short study, recorded disappointing results. We describe here the results of a trial in one centre which began in 1965. The method was similar to that of Baastrup and Schou,1 but with modifications, including a double-blind study of a subgroup. was

Patients and Methods Patients who had been admitted, with

definite manic depressive illness, psychiatric hospital at least once a year, during the previous 5 years, were selected for the trial. Usually lithium treatment was started in hospital during an admission for an affective illness. The presenting illness was treated by electroconvulsive therapy or antidepressive drugs (depression) or by haloperidol or chlorpromazine (mania). Patients were screened to exclude urinary infections, cardiovascular disease, or renal disease, and a lithium-clearance test was performed. Lithium carbonate (‘ Priadel *) was given at a dosage indicated by clearance test to produce a plasma-lithium level between 0-6 and 1’4 meq. per litre. Lithium blood-levels were checked each week, and, when the blood-level was stable, the patient was discharged. He then attended a lithium clinic every 4 weeks at first, and later, when stability had been maintained for at least 6 months, every 6 weeks. After 18 months of treatment with stable plasma levels and no side-effects, appointments were extended to every 8 weeks. If the dosage had to be adjusted to keep the lithium concentration in the required range, more frequent appointments were made until stability was again attained. At each visit plasma-lithium, blood-urea, electrolytes, hmmoglobin, and protein-bound iodine (P.B.I.) were determined, the psychiatric state of the patient was briefly assessed, and the patient was given enough tablets to cover treatment until the next appointment. Each patient was seen concurrently by the referring consultant psychiatrist in psychiatric outpatient clinics after discharge from hospital; when prophylactic lithium was started some time after a phase of affective disorder and when the patient was well, similar arrangements were made. The frequency of the outpatient appointment schedule was determined by each consultant psychiatrist according to his usual practice; the interval between appointments was longer when the patient had been well for some time. Appointments for attendance at the lithium clinic were made independently of outpatient or

6. Colwell, J. A., Lein, A. Diabetes, 1967, 16, 560. 7. Pyke, D. A., Cassar, J., Todd, J., Taylor, K. W. Br. med.J. 1970,

iv, 649. 8. Hales, C. N., Greenwood, F. C., Mitchell, F. L., Strauss, W. T. Diabetologia, 1968, 4, 73. 9. Goto, Y., Toyota, T., Takaku, I., Sato, Y., Irie, M. in Early Diabetes (edited by R. Camerini-Davalos and H. S. Cole); p. 305. New York, 1970. 10. Ricketts, H. T., Cherry, R. A., Kirsteins, L. Diabetes, 1966, 15, 880. 11. Kipnis, D. M. Ann. intern. Med. 1968, 69, 891. 12. Khurana, R. C., Robin, J. A., Jung, Y., Corredor, D. G., Gonzalez, A., Sunder, J. H., Danowski, T. S. Horm. Metab. Res. 1971, 3, 71. 13. Paulsen, E. P., Richenderfer, L., Ginsberg-Fellner, F. Diabetes, 1968, 17, 265. 14. Bigelow-Sherman, J. D., Shima, K., Borden, E. K., Penhallegon, R., Foa, P. P. Acta diabet. lat. 1966, 7, 68. 15. Chlouverakis, C., Jarrett, R. J., Keen, H. Lancet, 1967, i, 806. 16. Grodsky, G. M., Karam, J. H., Pavlatos, F. C., Forsham, P. H. ibid. 1965, i, 290. 17. Danowski, T. S., Lombardo, Y. B., Mendelsohn, L. V., Corredor, D. G., Morgan, C. R., Sabeh, G. Metabolism, 1969, 18, 731. 18. Hales, C. N. Lancet, 1967, ii, 389. 19. Rosenbloom, A. L. New Engl.J. Med. 1970, 282, 1228. 20. Johansen, K. Acta med. scand. 1971, 189, 337. 21. Reaven, G. M., Silvers, A., Farquhar, J. Diabetes, 1970, 19, 571. 22. Reaven, G. M., Shen, S. W., Silvers, A., Farquhar, J. W. ibid. 1971, 20, 416. 23. Jackson, W. P. U., Goldberg, M. D., Marine, N., Keller, P., Campbell, G. D., Vinik, A., Saxe, N. Proc. 6th Congr. int. Diabetes Fedn (1967): Excerpta med. int. Congr. Ser. 1961, no. 172, p. 486. 24. Jackson, W. P. U. in Early Diabetes (edited by R. Camerini-Davalos and H. S. Cole); p. 331. New York, 1970. 25. Marine, N., Jackson, W. P. U. Proc. Wld Congr. Diabetes Trop. 1966, p. 101. 26. Michael, C., Edelstein, I., Whisson, A., MacCullum, M., O’Reilly, I., Hardcastle, A., Toyer, M. G., Jackson, W. P. U. S. Afr. med.J. 27. 28.

1971, 45, 895. Hales, C. N., Randle, P. J. Biochem. J. 1963, 88, 137. Bagdade, J. D., Bierman, E. L., Porte, D. Metabolism, 1971, 20, 1000.

Birmingham Diabetes Survey Working Party. Br. med. J. 1970, iii, 301. 30. McKiddie, M. T., Scott, R. T. A., Cole, R. Postgrad. med. J. 1971, 47, 605. 31. O’Sullivan, J. B. Diabetologia, 1969, 4, 207. 32. Selzer, H., Allen, E. W., Herron, A., Brennan, M. J. clin. Invest. 29.

1967, 46, 323. 33. Proc. 6th Congr. int. Diabetes Fedn (1967): Ser. 1969, no. 172, p. 239. 34. Lancet, 1970, i, 1211.

Excerpta med. int. Congr.

a

to a

appointments. Most readmissions to psychiatric hospitals in the lithiumtreated group were a result of referrals by the general

practitioner. The patient was usually referred to the original consultant, but beds in the research unit were available if the consultant wanted

to use

them; the practice

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psychiatrist tended to vary in this respect also Occasionally, when a patient attending a routine appoint

of each

TABLE III-EFFECT OF PROPHYLACTIC LITHIUM ON TIME IN HOSPITAL

the lithium clinic showed evidence of affective was referred to the original psychiatrist fo the decision as to whether inpatient treatment was necessary Patients were referred if there was information from th, patient, relatives, or friends which indicated that th patient was already unable to carry out satisfactoril normal work or household duties. The double-blind trial was controlled by randomly allotting each patient to one of two numbered regimens the name of each patient in this trial was given to th laboratory staff with instructions not to divulge any infor mation obtained from the blood tests unless the blood lithium level of any patient on active tablets exceede< 1-6 meq. per litre. This did not happen during the< months of the trial. Blood values below 0-6 meq. per litr were recorded but not reported until the trial had ended. Plasma-lithium was determined initially with an E.E.L flame photometer using a filter and latterly with Unicarr SP 90 atomic-absorption spectrophotometer at wavelengtl of 670-8 nm. ment at

disturbance, he

*p

<

TABLE IV-LITHIUM RESPONSE RELATED TO AGE

*

Results

The age, sex, and diagnostic category of the groin are shown in table 1. Bipolar manic-depression wa: diagnosed if the patient had been admitted at leas once for inpatient treatment of mania with a history o: one or more episodes of depression, or if a patien who had had several episodes of mania was admittec for treatment of depression. We have used as criteria for assessing the effect o: prophylactic lithium the number of readmissions anc time spent in psychiatric hospitals. Both criteria arc influenced by factors such as family support and atti tude, intensity and duration of episode, treatment and policy of the consultant psychiatrist, but the3 can be independently and accurately determined Since more than eight psychiatrists determinec treatment and admission policy both in the preTABLE I-CHARACTERISTICS OF PATIENT

*

Age

range

28-81;

mean

age 56.

TABLE II-EFFECT OF PROPHYLACTIC LITHIUM ON EPISODE

FREQUENCY

Values given The

as

means.B.M.

episode frequency was calculated in each patient from the number of inpatient admissions to a psychiatric hospital during the period on lithium compared with those during an equivalent period immediately before lithium treatment. No patient is included with less than 18 months of treatment.

*

P<

0-002

(rank-sum test).

0-002.

P <

0-02.

lithium

period and during the period on prophylactic lithium, a consistent bias in any one direction seems unlikely. The effect of lithium on episode frequency for the group is shown in table II and on time spent in hospital in table ill. The data for each patient were calculated for the time the patient had been treated with lithium and for the equivalent period immediately before the start of lithium treatment; this procedure was adopted to avoid the bias of comparing a short period on treatment with a much longer period in the previous history. Statistical analysis of the data by the rank-sum test indicated that there was a highly significant difference between the pre-lithium and treatment periods with respect to both variables. The proposition that the improvement in the psychiatric condition of the group was due to the prophylactic effect of lithium is supported by the results of a TABLE V-LITHIUM RESPONSE RELATED TO DIAGNOSTIC CATEGORY

double-blind trial which showed that six out of eighteen patients who had not required admission during at least 2 years on lithium relapsed during 6 months of placebo treatment. The corresponding figure for the eighteen patients continuing to receive lithium was one admission only. More detailed examination of the results (table iv) indicated that the improvement in patients over the age of 46 was significantly greater than that in the younger age-group, although both groups were better than they had been before lithium treatment. Table v shows efficacy related to diagnostic categories for the forty-eight patients who have required no readmission to hospital since being treated with prophylactic lithium. The numbers in each category

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small, but it does seem that unipolar manic patients and unipolar depressives do better than bipolar manic-depressives. Of the twenty-one patients who have required at least one admission to a psychiatric hospital during lithium treatment, fifteen were bipolar, one unipolar manic, one schizoaffective, and four unipolar depressives. Each of the bipolar patients was admitted for a manic episode, and in ten of the fifteen, blood-samples taken immediately after admission contained less than 0-6 meq. per litre of lithium; indeed, in six samples no lithium was detectable. Ten of fifteen were single or widowed. It is likely, therefore, that are

the results would have shown an even greater improvement in the absence of factors such as failure to take lithium regularly in the early stages of a manic phase, especially when family support was not available. Bipolar manic-depressives are notoriously prone to lose insight at this stage of the illness, which for them, but not for their relatives, friends, and employers, is the time when they feel on top of the world and full of plans and projects, many of which The importance of taking tablets are unrealisable. regularly at this vulnerable stage does not loom high on their list of priorities unless there is close family or social support.

Side-effects and Acute Toxicity Very few patients have shown

even

fine

tremors

after the first few weeks.

In the double-blind trial, no patient was complaining of any physical symptom at the time of selection.

One female patient was readmitted in a depressed state, and she had a plasma-lithium of2’3meq. per litre; this was associated with an infection of the urinary tract. Discontinuance of lithium, and high fluid and salt intake, reduced the level to below 1 meq. per litre within 4 days. In view of the evidence of a thyroid-depressing effect of lithium,6,? P.B.I. levels were measured routinely. P.B.I. values for the lithium-treated group show a normal distribution curve but with a mean value 1-0 jjLg. per 100 ml. less than a normal euthyroid group; seven of the sixty-nine patients in the group have had P.B.I. values less than 3-5 (g. per 100 ml. at some time during lithium treatment, but only three of these showed consistently low values. In the early stages of the trial, persistently low P.B.I. values, even in the absence of other evidence of thyroid hypofunction, were considered a contraindication to continuing treatment; euthyroid values were restored after 6-8 weeks off lithium, but the psychiatric state of the patients usually deteriorated. Lately, lithium has been continued in such cases together with a daily dose of thyroxine; P.B.i. levels have been kept in the euthyroid range without the psychiatric disadvantages of withdrawing lithium. Discussion

The natural history of recurrent affective illness does not seem to be characterised by decreasing episode frequency with increasing age-indeed Angst et al.11 have suggested an opposite trend. Assuming that epi-

frequency would not have decreased in our patients, then the probability that the recorded decreases in episode frequency and time spent in hospital during prophylactic lithium treatment were sode

due

to

chance is less than 1 in 500.

The statistical effect of starting treatment during an affective episode, which was usually the case, can be considered by reference to the notional average patient indicated by the statistical data. This patient, with 3-36 admissions to hospital during 40 months before lithium treatment, would be expected, after successful treatment of an episode, to have a remission of approximately 12 months if the pattern of illness remained unchanged: and so the episode frequency would decrease by about 25% because of this factor. The actual reduction observed was about 84%.

against a lithium effect has been introduced by not excluding from the data patients who relapsed and required admission during the first few months on lithium which, it could be argued, was an inadequate period to produce an effect. More important, however, is the bias against lithium introduced by not excluding admissions where there was eviA bias

dence of low or non-existent levels of lithium at the time of admission. It is possible to suggest that the results may be due to observer bias or the support offered involuntarily to patients by the appointments required for plasma monitoring. The results of the double-blind trial do not support this objection nor the objection that starting lithium therapy during a phase of affective abnormality might distort the results. This trial, together with the reports of Baastrup and Schou and Coppen et al., demonstrates very strong evidence for a prophylactic effect of lithium against recurrent affective disorders. Only two of the sixty-nine patients have a greater episode frequency or spent more time in hospital during lithium treatment than during a similar period of time before treatment

began. We thank the following consultant psychiatrists who referred patients for this trial, Prof. M. Hamilton, Dr. R. W. Carty, Dr. G. A. Dransfield, Dr. A. K. Gillie, Dr. C. P. Gore, Dr. R. Maxwell, Dr. H. B. Milne, Dr. P. H. Rack, Dr. J. Todd, and Dr. J. Valentine; the laboratory staff at High Royds Hospital and the nursing staff of the Regional Metabolic Research Unit, especially Mr. R. Stead, Mr. R. Sanctuary, Mr. T. P. Booth, and Mr. M. Tonkin; to Delandale Laboratories for the supply of lithium-carbonate tablets and identical placebos; and Dr. R. L. Noble and his staff, of the department of chemical pathology, Huddersfield Royal Infirmary, for the P.B.I. determinations.

Requests for reprints should be addressed to R. P. H., High Royds Hospital, Menston, Ilkley, Yorkshire LS29 6AQ. REFERENCES 1. 2. 3.

Baastrup, P. C., Schou, M. Archs gen. Psychiat. 1967, 16, 162. Blackwell, B., Shepherd, M. Lancet, 1968, i, 968. Baastrup, P. C., Poulsen, J. C., Schou, M., Thomsen, K., Amdisen, A. ibid. 1970, ii, 326. 4. Coppen, A., Noguera, R., Bailey, J., Burns, B. H., Swani, M. S., Hare, E. H., Gardner, R., Maggs, R. ibid. 1971, ii, 275. 5. Platman, S. R. Int. J. Pharmacopsyshiat. 1970, 5, 132. 6. Fieve, R. R., Platman, S. Am. J. Psychiat. 1968, 125, 527. 7. Shopsin, B., Blum, M., Gershon, S. Compreh. Psychiat. 1969, 10, 215. 8.

Angst, J., Graf, P., Hippins, H., Pöldinger, W., Weis, P. Cycles biologiques et psychiatrie; p. 339. Paris, 1968.