Reprinted from American Journal of Psychiatry (1968) 125 558-560

NATHAN S KLINE, MD

Lithium, the 20-year old Cinderella of psychopharmacology, is at last receiving her sovereign due. Just plain old lithium - widely discredited by early abuse in the treatment of gout, rheumatism, kidney stone, uraemia; briefly but dramatically misused as a salt substitute for precisely the type of patient in cardiac or renal failure for whom it should not ordinarily be used - the modest proclamation of its use for manic and other excitement states in a journal of limited circulation in a remote country was to pass almost unnoticed. Only 9 papers or letters were published in the first 5 years reporting new cases and very few more in each of the next two 5-year periods (3), in contrast to some 10,000 papers on chlorpromazine in its first 15 years and more than 2,000 on LSD. This year, however, will probably witness the publication of more papers on the subject than in all the previous 19 years (4).

What major claims are made in the roughly 3,000 treated cases (4) thus far described? Cade (Australia) was the first to report on its use for acute manic states; he also noted that continuing use prevented recurrence of periodic attacks. Margulies (Australia) and Vojtechovsky (Czechoslovakia) first reported favourably on depressed patients, although most investigators have not been too encouraging on this score. Andreani (Italy) prevented manic-depressive cycles by continued administration, while Hartigan (England) and Baastrup (Denmark) were the pioneers in its specific prophylactic use to prevent recurrent depressions. A number of French psychiatrists reported on its use in excitement states regardless of origin. In a brilliant statistical analysis of periodicity in affective disorders, Angst (1) (Switzerland) recently confirmed the effectiveness of lithium in recurrent depressions and also confirmed the earlier demonstration by Mosketi (USSR) of its effectiveness in schizo-affective disorders. More recently Gershon (USA) has described its use in premenstrual tension. Schou (Denmark), who has been the most enthusiastic, consistent, and effective of advocates, reported at a round table on lithium at the recent APA annual meeting in Boston concerning its use to relieve rigid, overly conscientious obsessives. He also described its use in Sweden for treating childhood (and adult) behavioural disorders characterised by an undulating course, regardless of diagnosis.

The only sour note is a recent exchange in the Lancet instituted by Blackwell and Shepherd, who claimed that Baastrup and Schou in their paper in the Archives of General Psychiatry had not conclusively proved the case for prophylaxis. Following Baastrup and Schou's reply, all of the principals plus a few other interested persons were scheduled to appear at a symposium at the Royal Medico-Psychological Association meeting in Plymouth, England, in July. Shepherd missed out because of a prior engagement plus a misunderstanding about the date, and Schou was ill. Blackwell led off his own presentation with the clear statement that he had never treated a single patient with lithium and that his argument was not against the fact that lithium was effective but that the case for it effectiveness had not been proved. The symposium was too brief to permit the report of a double-blind study done by Melia (5) at St Patrick's Hospital, Dublin, Ireland.

Lithium is remarkably free of serious side-effects. Initially there may be some nausea and "lithargy" (courtesy Reginald Lourie) as well as occasional loose stools. Sometimes patients (the elderly?) exhibit a fine tremor or unsteady gait, which is usually relieved by a reduction in dosage. Nontoxic thyroid goiters have been reported in a limited number of patients (6). Our own work (2) studying patients before and after they were placed on lithium has thus far revealed no systematic thyroid changes (See footnote). In any case, the goiter is controlled by thyroxine or desiccated thyroid extract.

At the Plymouth RMPA meeting it became evident that practitioners of skill and experience did not uniformly test for serum lithium but depended on clinical reactions. In Denmark, where hospitals are used much more freely than here, Schou has advocated taking serum lithium levels for a few weeks until stability is assured. In our own experience with 200 ambulatory patients, we have done regular serum levels but found their greatest use was in identifying patients who were not taking medication rather than in detecting impending toxicity. For clinical use it is our considered judgement that such serum levels are not essential. For practical purposes it would be well to have a level at the end of 1 or 2 weeks to rule out a rare idiosyncrasy; another determination after a month would provide some measure of serum level if done the appropriate time of day a fixed number of hours after the last dose. Simply because serum levels can be obtained does not mean they should be; they are not even seriously thought of in respect to much more complex antidepressant medications.

Despite apprehensions that no American pharmaceutical house would market the drug because of the considerable expense and the absence of patent protection, at least 2 companies, Rowell Laboratories and Chas Pfizer & Co expect to have lithium on the market by the end of the year.

The research possibilities are most exciting, for at last we are dealing with an active known agent rather than a hypothesised metabolite. The amount of lithium is too small to produce any immediate effect on the sodium and potassium levels. In theory it might alter the steady-state relationship after months of administration. Perhaps this accounts for the crucial clinical fact that the longer lithium is given, the shorter and milder the attacks. A full year of usage is often required before the swings become so damped that they virtually disappear. As far as we know there is complete compatibility with other psychopharmaceuticals; so that unless it cannot be tolerated lithium should be continued in any case.

Lithium is a new and different key for dealing with affective and possibly other psychiatric disorders. How many locks it will fit - clinical and research - remains to be seen, but even the few doors thus far opened have given us glimpses into vast new potentials.

1. Angst, J., Dittrich, A., & Grof, P. The course of endogenous affective psychoses and modification by prophylactic treatment, read at the annual meeting of the Royal Medico-Psychological Association, Plymouth, England, July 12, 1968.

2. Cooper, T., & Kline, N.S. Lithium and thyroid, in preparation.

3. Kline, N.S. "The history of lithium usage in psychiatry," in Modern Problems of Pharmacopsychiatry. New York: S. Karger, in press.

4. Kline, N.S. & Kistner, G.A. "Bibliography of the clinical uses of lithium in psychiatry," in Modern Problems of Pharmacopsychiatry. New York: S. Karger, in press.

5. Melia, P.I. personal communication.

6. Schou, M., Amdisen, A., Eskjaer-Jensen, S., & Olsen, T. The occurrence of goitre during lithium treatment, in press.

Footnote. Drs David Becker, James R Hurley and associates of New York Hospital report that in the first phase of a clinical study, 7 of 30 patients showed some thyroid irregularities or abnormalities. There was no apparent difference between those on lithium for an average of 8 months (with range up to 2 years) and those not on lithium.