Millennial articleLithium treatment at 52
Introduction
It is difficult to tell the exact age of lithium treatment of mood disorders. In the 1880s lithium was used for the treatment and prevention of recurrent depressions (Lange, 1886), but statistics and controlled trials were not known at that time, and the observations remained clinical impressions. In 1954 lithium treatment of mania became evidence-based (Schou et al., 1954), and in 1967–1970 prophylactic lithium treatment did the same (Baastrup and Schou, 1967, Baastrup et al., 1970). There is nevertheless good reason to count the age of lithium treatment from 1949, when John Cade published his paper about ‘Lithium salts in the treatment of psychotic excitement’ (Cade, 1949), for lithium has remained in psychiatric use since then.
Why is lithium treatment still being used after half a century? The present paper does not aim at giving a systematic chronological exposition of the history of lithium treatment in psychiatry. This has been done in other publications to which the reader is referred, e.g. Johnson (1984) and Schou (1992). An attempt will be made to answer the question by recounting briefly and commenting in detail on selected events. Methodological problems are given more attention than presentation of data. There have been many misunderstandings about lithium. Some of them will be corrected in this paper, but it has not been possible to deal with them all.
Since lithium is used primarily for the prevention of recurrences, this review deals with prophylactic treatment and disregards treatment of single episodes.
Section snippets
Cade’s pioneering study
It has often been claimed that the so-called psychopharmacological era started with the introduction of chlorpromazine in 1952. That is not correct. The era started when Cade (1949) introduced lithium as an antimanic drug.
When the word serendipity was used about Cade’s discovery, he became annoyed and pointed out that it was based on a specific hypothesis and experimental observations. The hypothesis was that mental illnesses are caused by intoxication with an unknown compound, and that this
Non-blind mirror trial
A non-blind trial lasting 6 years and involving 88 patients who had suffered at least two episodes within 2 years provided the first systematically collected evidence of a prophylactic action of lithium (Baastrup and Schou, 1967). The average number of episodes per year fell 87% from the time before lithium treatment to the time during lithium treatment (P<0.001). Blackwell and Shepherd (1968) contested the validity of the evidence. They felt that bias and the suggestive power of the
Debate
There are few psychiatric treatments that have been debated so hotly as has prophylactic treatment with lithium. It is difficult to understand why. One could expect that psychiatrists would welcome the advent of a new and effective treatment for their seriously ill patients, and many in fact did so. But some skepticism remained. Perhaps the treatment was so effective that psychiatrists who had not themselves used it for their patients found the observations utterly unlikely and refused to
Effect of the serum lithium concentration
Lithium has many side effects, and sometimes they are so troublesome that the treatment has to be discontinued. However, the frequency and severity of the side effects are different at different serum lithium concentration. In 1979 at the psychiatric hospital in Risskov, Denmark, the range of serum lithium concentrations was lowered from 0.8–1.0 mmol/l to 0.5–0.8 mmol/l. The average serum lithium concentration fell by about 30%, and the proportion of patients not having any side effects rose
Use during pregnancy and lactation
When manufacturers and official agencies warn against drug treatment during pregnancy, their warnings serve to protect themselves and are of little use to clinically responsible physicians. If a woman’s health and life are endangered by the withholding of treatment, then treatment must be given. A manic-depressive woman who has had severe recurrences before she started on lithium is in such a situation. She must be given prophylactic treatment during the second and third trimester of the
Non-compliance, selection of patients, information and instruction
In recent ‘naturalistic’ or ‘out-patient’ or ‘clinical practice’ trials the prophylactic effectiveness of lithium has often been found lower than it was in the early trials. The explanation of this discrepancy is hardly that lithium has changed its properties. In the new trials the patients were supervised insufficiently to keep non-compliance under control, and lithium was given to patients who differed markedly from those treated in the earlier trials (Schou, 1993a).
Poor compliance is the
Are new and better prophylactic agents about to oust lithium?
Lithium has side effects and lithium treatment shortcomings, and it would be welcome if something better were forthcoming and its advantages convincingly demonstrated. However, the search for other prophylactic drugs has faced substantial obstacles. Since lithium prophylaxis is so effective (Goodwin and Jamison, 1990), there have been difficulties about obtaining permission from ethical committees and informed consent from patients to compare new drugs of unproved prophylactic efficacy with
Combination treatment
There is mounting clinical evidence that combinations of lithium with an anticonvulsant drug can be of prophylactic value in atypical or difficult cases and that in patients refractory to lithium the addition of an anticonvulsant may be of use. This procedure is reasonable and clinically responsible practice, even if until now there have been no controlled trials demonstrating superiority of the combination over either drug given alone. One can hope that such studies will be carried out, but
The effect of lithium on the patients’ suicidal behavior
Two recent reviews (Tondo et al., 1997, Schou, 1998c), both based on studies with large numbers of patients and long observation periods, dealt with mortality and suicidal behavior during lithium treatment. Tondo and Baldessarini’s group in Cagliari, Coppen’s group in Epsom, and the international IGSLI group coordinated by Müller-Oerlinghausen in Berlin were major contributors of data.
Most of the studies showed that there is a close association between long-term lithium treatment, on the one
Benefits of prophylactic lithium treatment
The discovery and implementation of prophylactic lithium treatment have had far-reaching results. For the persons having been directly involved in the development, it is not always easy to assess the benefits, but researchers, clinical psychiatrists, and patients often stress their significance.
The efficacy of lithium therapy and prophylaxis has established recurrent manic-depressive illness as a treatable condition and psychiatry as a medical discipline.
Lithium was the first psychotropic drug
Future comparative trials
Everybody must wish that a drug distinctly better than lithium will eventually replace it. But when this drug comes, how can it then be recognized? Prophylactic trials take a long time, and in order to justify the consumption of resources and manpower and the prolonged exposure of patients to drugs of unproved prophylactic efficacy, their design must ensure that they provide valid information. Anything else would be unethical.
Since experience has shown that it is difficult for trials with a
Conclusion
When prophylactic lithium treatment is still in use after half a century, a number of factors have played a role. Prophylactic lithium treatment is highly efficacious in typical bipolar manic-depressive illness; no other mood stabilizers have been proved more efficacious. There is a close association between long-term lithium treatment, on the one hand, and lowered mortality and reduced suicidal behavior, on the other; for no other mood stabilizers has such an association been demonstrated.
Acknowledgements
Jette Kraft and Paul Grof commented on the manuscript.
References (75)
- et al.
Prophylactic lithium
Lancet
(1968) - et al.
Prophylactic lithium: double-blind discontinuation in manic-depressive disorders
Lancet
(1970) - et al.
Prophylactic lithium: another therapeutic myth? An examination of the evidence to date
Lancet
(1968) - et al.
Prophylactic lithium in affective disorders: controlled trial
Lancet
(1971) Designing long-term clinical trials in affective disorders
J. Affect. Disord.
(1994)Has the effectiveness of lithium changed? Impact of the variety of lithium’s effects
Neuropsychopharmacology
(1998)- et al.
Prophylactic lithium in recurrent affective disorders
Lancet
(1972) Bipolar disorders
Affective disorders
- et al.
Zum Verlauf depressiver Psychosen
Lithium prophylaxis in recurrent affective disorders
Br. J. Psychiatry
Lithium as a prophylactic agent: its effect against recurrent depressions and manic-depressive psychosis
Arch. Gen. Psychiatry
Does lithium treatment still work? Evidence of stable responses over three decades
Arch. Gen. Psychiatry
Renal function on and off lithium in patients treated with lithium for 15 years or more: a controlled, prospective lithium withdrawal study
Nephrol. Dial. Transplant.
Is there a loss of efficacy of lithium in patients treated over 20 years?
Neuropsychobiology
Lithium prophylaxis: proposed guidelines for good clinical practice
Lithium
Efficacy of divalproex vs. lithium and placebo in the treatment of mania
J. Am. Med. Assoc.
Maintenance clinical trials in bipolar disorder: design implications of the divalproex-lithium-placebo study
Psychopharmacol. Bull.
A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of out-patients with bipolar I disorder
Arch. Gen. Psychiatry
Sixteen-year mortality in patients with affective disorder commenced on lithium
Br. J. Psychiatry
Lithium salts in the treatment of psychotic excitement
Med. J. Aust.
A controlled evaluation of lithium prophylaxis in affective disorders
Psychol. Med.
Does maintenance lithium therapy prevent recurrences of mania under ordinary clinical conditions?
Psychol. Med.
Information des patients sous lithium
Concours Médical
Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder
N. Engl. J. Med.
Current therapeutic profile of lithium
Arch. Gen. Psychiatry
Lithium-induced renal insufficiency
J. Clin. Psychopharmacol.
Unanswered questions, unknown future for one of our oldest medications
Arch. Gen. Psychiatry
Manic-Depressive Illness
Lithium vs. carbamazepine in the maintenance treatment of schizoaffective disorder: a randomised study
Eur. Arch. Psychiatry Clin. Neurosci.
Differential response to lithium and carbamazepine in the prophylaxis of bipolar disorder
J. Clin. Psychopharmacol.
Lithium versus carbamazepine in the maintenance treatment of bipolar II disorder and bipolar disorder not otherwise specified
Int. Clin. Psychopharmacol.
Methodological problems of prophylactic trials in recurrent affective disorders
Br. J. Psychiatry
Lithium drop-outs: a follow-up study of patients who discontinued prophylactic treatment
Int. Pharmacopsychiatr.
Admission rates and lithium therapy
Br. J. Psychiatry
Lithium prophylaxis in recurrent affective illness: efficacy, effectiveness and efficiency
Br. J. Psychiatry
The therapeutic effect of lithium carbonate on a patient with a forty-eight hour periodic psychosis
Br. J. Psychiatry
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