Senior Medical Officer, Victorian Department of Mental Hygiene.
Vol. II - 36th Year
Sydney, Saturday, September 3, 1949
No. 10
By John F. J. Cade, M.D.
Senior Medical Officer, Victorian Department of Mental Hygiene.
Lithium salts enjoyed their hey-day in the latter half of last century when, commencing with their introduction by Garrod, they were vaunted as curative in gout, and so doubtless in a multitude of other so-called gouty manifestations. This followed the demonstration that lithium urate was the most soluble of the urates. It was shown that if pieces of cartilage with urate deposit were immersed in solutions of sodium, potassium and lithium carbonate, the urate was dissolved first from that piece immersed in the lithium carbonate solution.
As time went on and lithia tablets were consumed on an ever-increasing scale for an ever-increasing range of ailments, the toxic and depressant effects were more and more commonly seen.
Garrod (1859) wrote of lithium carbonate: “When given internally in doses of from one to four grains dissolved in water, two to three times a day, it produces no direct physiological symptom … their use does not appear to be attended with any injurious consequences.” And certainly, in that dosage, there should never be any toxic symptoms.
But about fifty years later cases are reported “of cardiac depression and even dilatation, as a result of excessive and continued consumption of lithia tablets” (The Practitioner, 1907).
“Cardiac depression and even dilatation” was perhaps very vaguely a physiology, but the note of warning was clear also the statement in Squires’s “Companion to the British Pharmacopoeia” that “lithia salts upset the stomach very easily” (The Practitioner, 1909).
What with the hypothetical cardiac depression and the actual mental depression, nausea and giddiness, the uselessness of lithium in most of the conditions for which it was prescribed, and the fact that there was other, more efficacious treatment in the only disease in which it had been shown to be of some value, it is not surprising that lithium salts have fallen into desuetude.
Culbreth (1927) says of lithium bromide that it is the most hypnotic of all bromides. The dosage stated there is the relatively enormous one of 10 to 30 grains. It is not stated how often this huge dose might be repeated each day, but one presumes the traditional two to three times. Squires, too, states that “in epilepsy it is the best of all bromides” and gives the dose more conservatively as five to 15 grains.
It is worth noting that the hypnotic action of lithium bromide was thought to be due to the fact that, the atomic weight of lithium being so small, weight for weight, lithium bromide must contain more bromide ion than any other bromide. There is no evidence that the lithium ion was recognized as having a marked sedative action superior in some respects to that of the bromide.
But 15 grains of lithium bromide repeated three times a day would soon lead, not to bromide, but to far more dangerous lithium, intoxication, and it is little wonder that it has never found favour in the treatment of epilepsy. It is a pity, because properly used, lithium salts might well be an important addition to the anti-convulsant armamentarium.
In the course of some investigations by the writer into the toxicity of urea when injected intraperitoneally into guinea-pigs, it appeared desirable to ascertain whether uric acid enhanced this toxicity. The great difficulty was the insolubility of uric acid in water, so the most soluble urate was chosen - the lithium salt. When an aqueous solution of 8% urea, saturated with lithium urate, was injected, the toxicity was far less than was expected. It looked as if the lithium ion might have been exerting a protective effect. To determine this, more observations were made, lithium carbonate being used instead of lithium urate. An 8% aqueous solution of urea kills five out of ten guinea-pigs when injected intraperitoneally in doses of 1.25 millilitres per ounce of body weight. When 0.5% lithium carbonate in an 8% urea solution was injected in the same dose, all ten animals survived; and this argued a strong protective function for the lithium ion against the convulsant mode of death caused by toxic doses of urea.
To determine whether lithium salts per se had any discernible effects on guinea-pigs, animals were injected intraperitoneally with large doses of 0.5% aqueous solution of lithium carbonate. At noteworthy result was, that after a latent period of about two hours the animals, although fully conscious because extremely lethargic and unresponsive to stimuli for one to two hours before once again becoming normally active and timid.
It may seem a long distance from lethargy in guinea-pigs to the excitement of psychotics, but as these investigations had commenced in an attempt to demonstrate some possibly excreted toxin in the urine of manic patients, the association of ideas is explicable.
It appeared worth while in view of these results to try lithium salts in the treatment of two distinct disorders - firstly, mania, in view of their sedative effect; secondly epilepsy, in view of their anti-convulsant action. With the latter, this paper is not concerned.
Henderson and Gillespie (1944) remark, in their historical survey of psychiatry, that the writers of certain wells were considered to have special virtue in the treatment of mental illness, and mention some of the more famous in the British Isles. It is very likely that their supposed efficacy was a real efficacy and directly proportional to the lithium content of the waters.
In the treatment of such a self-limiting disorder as mania, the therapeutic innovator must be more than ordinarily on his guard. Whether this or that treatment is of any value must be carefully assessed from as many angles as possible. With an episodic disorder of this type, the efficacy of a particular treatment may be judged by one or more of the following criteria. The more criteria that are satisfied, the more sure are we that it is a treatment of real and not dubious value.
So far ten manic patients have been treated, of whom three suffered from chronic and the remainder from recurrent mania. In addition, similar treatment was given to six patients with dementia praecox and three melancholics.
A male, aged fifty-one years, who had been in a state of chronic manic excitement for five years; restless, dirty, destructive, mischievous and interfering, had long been regarded as the most troublesome patient in the ward. His response was highly gratifying. From the start of treatment on March 29, 1948, with lithium citrate he steadily settled down and in three weeks was enjoying the unaccustomed surroundings of the convalescent ward. As he had been ill so long and confined to a “chronic ward”, the found normal surroundings and liberty to move about strange at first. Quite to this and as though disinclined to the necessity of determining a satisfactory maintenance dose, he was kept under observation for two months. He remained perfectly well and left hospital on July 9, 1948, indefinite leave with instructions to take a maintenance dose of lithium carbonate, five grains twice a day. The carbonate had been substituted for the citrate as he had become intolerant of lithium citrate, of severe nausea. He was soon back working happily at his old job. However, he became more lackadaisical about his medicine. The finally ceased taking it. His relatives reported that he had not had any for at least six weeks prior to readmission on January 30, 1949, and was becoming steadily more irritable and erratic. He seemed work just before Christmas. On readmission, to hospital he was at once started on lithium carbonate, ten grains three times a day, and in a fortnight had again settled down to normal. The dose of carbonate was then reduced to five grains three times a day, and in a further two weeks to five grains twice a day. He is now (February 28, 1949) ready to return to home care.
A male, aged forty-six years, had been in a chronic manic state for five years. He commenced taking lithium citrate, 20 grains three times a day, on May 5, 1948. In a fortnight he had settled down, was transferred to the convalescent ward in another week, and a month later, having continued well, was permitted to go on indefinite trial leave whilst taking lithium citrate 10 grains three times a day. This was reduced in one month to 10 grains twice a day, and two months later to 10 grains once a day. Seen on February 13, 1949, he remains well and had been in full employment for three months.
A male, aged forty years, was suffering from a second attack of mania which had already lasted five months and showed no signs of clearing up. He commenced lithium citrate, 20 grains three times a day, on April 5, 1948, and in a week was sufficiently settled down to go to the convalescent ward. He continued to improve over several weeks and remained well. On January 31, 1949, he reported for follow-up. He continued well and had been in full employment for over three months. He had been on a maintenance dose of five grains of lithium carbonate twice daily. He was advised to continue with five grains once a day.
A male, aged sixty-three years, was suffering from chronic mania of two and a quarter years’ duration. There was a strong history of alcoholism with some evidence of senile enfeeblement. He was continuously garrulous, restless, irritable and euphoric. He commenced taking lithium citrate, 20 grains three times a day, on June 15, 1948. He forthwith began to quieten down, and, although citrate had to be discontinued on June 28, 1948, because of nausea and malaise, by June 30, 1948, he was quiet and capable of rational conversation. His euphoria and excitement had quite disappeared only to leave a rather irritable attitude of his mind. He recommenced taking lithium citrate, 10 grains three times a day, but in view of constant abdominal discomfort the carbonate, five grains three times a day, was substituted on July 8, 1948. As his discomfort persisted and even when no longer manic he was still a mildly enfeebled, irritable old man, it hardly seemed worth while to persist and treatment was discontinued on August 10, 1948. In a fortnight he had drifted back to his previous manic state.
A male, aged forty-four years, was suffering from a recurrent manic episode. The present attack had lasted two and a half months and showed no signs of abating. He was restless, noisy, elated, with marked distractibility and flights of ideas. He commenced taking lithium citrate, 20 grains three times a day, on July 30, 1948. By the end of the first week he had shown some improvement. This continued steadily for a further two weeks, by which time he was quite normal. On August 27, 1948, the dose of citrate was reduced to 10 grains three times a day for one week, with instructions to the patient, an intelligent man, who was then leaving hospital, to take 10 grains twice a day for a further week and then to continue on 10 grains at night indefinitely. He has remained well.
A man of sixty years, suffered from manic depressive insanity associated with alcoholism. His previous attacks had been mainly depressive, but he had had a manic phase lasting five months two years previously. By November 17, 1948, he had been developing a manic phase for a fortnight, steadily worsening until now he was noisy, restless and aggressive. On this date he commenced taking lithium citrate 20 grains three times a day. In a week he was settling down, but at the end of a fortnight the administration of lithium citrate had to be temporarily discontinued as he was showing toxic symptoms - he was asthmatic and tremulous, with slurring speech. The toxic symptoms disappeared in four days and citrate administration was resumed with a dose of 10 grains three times a day. By this time he had settled down completely. On February 14, 1949, after lithium citrate administration had been discontinued for seven weeks, he was again becoming unsettled and noisy enough. Given lithium citrate 20 grains three times a day, he once again settled down promptly in four days, and at the end of a week when he had put on three pounds in weight the dose was reduced to a maintenance dose of 10 grains once daily.
Aged forty years, was suffering from recurrent mania. In this episode he had been excited, restless and violent for over two months and was so interfering that he often had to be confined to a single room during the day. On February 7, 1949, he commenced taking lithium citrate 20 grains three times a day. In four days he was distinctly quieter and by February 13, 1949, appeared practically normal. He continued well and on February 20, 1949, the dose of citrate was reduced to 10 grains three times a day. He left hospital on February 27, 1949, with instructions to take 10 grains three times a day for a further week, 10 grains twice a day for a further two weeks, and then 10 grains at night indefinitely.
A man of fifty years, was suffering from an attack of recurrent mania, the first of which he had had at the age of twenty. The present attack had lasted two months and showed no signs of abating. He was garrulous, euphoric, restless and unkempt when he started taking lithium citrate 20 grains three times a day on February 11, 1949. Two days later he was reported to be quieter. By the ninth day he was definitely settling down and the following day he was allowed to out of the ward. This, and of two weeks he was practically normal, tidy and rational, with insight into his previous condition. This was in marked contrast to his condition a fortnight before when he had to be locked in a single room all night with a regular nocturnal hypnotic and was too restless to eat in the dining room owing to his unsettling effect on the other patients.
A powerful but manic depressive seventeen years, had suffered from recurrent manic phases since the age of twenty-five years. He last left hospital after a stay of seven months on August 31, 1948, whilst still in a hypomanic state and appears to have remained thus until his condition became worse and he was readmitted to hospital on February 11, 1949, in a state of typical manic excitement. Fortunately, in view of his physique, he is not recommended and vehemently becomes violent. On February 11, 1949, he commenced taking lithium citrate three times a day. He was considered ably quieter two days later, was working happily in the kitchen in a few days, and by the ninth day was practically normal. On February 27, 1949, as he was remaining well, the dose of citrate was reduced to 10 grains three times a day. On March 1, 1949, he was complaining of mild malaise and abdominal discomfort and administration of the drug was discontinued for a few days. He recommenced taking lithium citrate 10 grains twice a day on March 4, 1949. An acquaintance who has known the patient for years reports that he has never seen him as normal as at present.
A man of sixty-one years, presents several points of interest. He has had manic episodes for twenty-eight years, the attacks lasting from three to ten months. He was readmitted to hospital on January 5, 1949, in his usual silly, elated, restless state with probable flights of ideas and speech that was almost impossible to determine whether or not he is hallucinated or delusional. He commenced taking lithium citrate 20 grains three times a day on January 28, 1949. On February 3, 1949, he was quieter, but mildly toxic - dizzy, unsteady and nauseated. Lithium citrate administration was discontinued, and on February 7, 1949, when the toxic symptoms had disappeared and the patient was becoming grandiose and truculent again, he was started on lithium carbonate 10 grains three times a day. By February 9, 1949, it was evident that his excitement was abating steadily, but it was becoming obvious that he was also constantly hallucinated and delusional, muttering to himself as he communicated “by telepathy” with various people. This state continued, that is, an excited delusional state in which the excitement was well controlled by lithium, but the delusional state was quite unaffected. Whether such a case can be regarded as one of true mania is a matter upon which there may well be considerable difference of opinion.
In addition to these ten patients, six patients suffering from dementia praecox were treated with lithium citrate, 20 grains three times a day, for from three to four weeks. An important feature was that, although there was no fundamental improvement in any of them, three who were usually restless, noisy and shouting nonsensical abuse, paralleling the patient in Case X, lost their excitement and restlessness and became quiet and amenable for the first time for years. The taking of a nocturnal hypnotic had been a routine and could be discontinued during treatment. They reverted to their previous state upon cessation of lithium medication.
It would be natural to suppose that as lithium salts cause the symptoms of mania to subside, they might predispose a depressive episode in predisposed persons. So far there is no evidence of this. Three patients suffering from chronic depressive psychoses were given, for several weeks, lithium citrate in the same dosage as that prescribed for mania patients. There was no improvement, but neither was there any aggravation of the depression.
The British Pharmacopoeia gives the dose of lithium carbonate as two to five grains and that of lithium citrate as five to ten grains, but such figures convey little information of value in therapeutics in the absence of any information as to how often such a dose may be given in each twenty-four hours, or of the rate of elimination.
Culbreth (1927) is more liberal and gives the dose of lithium carbonate as five to 15 grains and of the citrate as 10 to 30 grains.
In practice one finds that some patients can tolerate lithium citrate 20 grains three times a day for weeks without toxic symptoms, but that a high proportion show toxic symptoms in one to three weeks on such a dose.
It seems advisable to keep the patient on a maximum dose - that is, lithium citrate 20 grains three times a day or lithium carbonate 10 grains three times a day - well he continues to improve. Once normal emotional tone is attained the dose is progressively reduced: lithium citrate to 10 grains three times a day for one to two weeks, to 10 grains twice a day for a further one to two weeks, and then a maintenance dose of 10 grains after the evening meal indefinitely. The corresponding doses of lithium carbonate are half those for the citrate. In view of their liability to produce gastric upsets lithium salts are given after meals.
The reason for using two alternative preparations is that the citrate is very soluble and appears to be better absorbed than the carbonate, whereas the carbonate must be put up suspended in mucilage or given in capsules. However, the carbonate has the advantage that it is better tolerated by some patients and appears less liable to produce either gastric disturbances or other toxic symptoms.
The symptoms of over-dosage are referable mainly to the alimentary and nervous systems. Abdominal pain, anorexia, nausea and vomiting occur and occasionally mild diarrhoea. The nervous symptoms are giddiness, tremor, ataxia, slurring speech, myoclonic twitching, asthenia and depression. The patient looks ill - pinched, drawn, grey and cold.
Unless such symptoms are followed by immediate cessation of intake there is little doubt that they can progress to a fatal issue. It is therefore of the utmost importance that when a patient is on maximum doses he should be seen each day and that the nursing staff should be instructed to look for early symptoms of saturation.
If toxic symptoms develop, they disappear quickly - that is, in two to four days - when the drug is completely withdrawn. Treatment may then be resumed with a smaller dose, or, if it is still desirable to use a maximum dose, by substituting the carbonate for the citrate.
There is no doubt that in mania patients’ improvement has closely paralleled treatment and that this criterion has been fulfilled in the chronic and subacute cases just as closely as in the cases of more recent onset. The quietening effect of restless, non-manic psychotics is additional strong evidence of the efficacy of lithium salts, especially as such restlessness returned on cessation of treatment.
Lithium salts have no apparent hypnotic effect; the result is purely sedative. The effect on patients with pure psychotic excitement - that is, true manic attacks - is so specific that it inevitably leads to speculations as to the possible etiological significance of a deficiency in the body of lithium ions in the genesis of this disorder.
Lithium may well be an essential trace element. It is widely distributed, has been detected in sea-water and in many spring and river waters, in the ash of many plants, and in animal ash.
Pre-frontal leucotomy has been performed lately on restless and psychopathic mental defectives (Mackay, 1948; Engler, 1948) in an attempt to control their restless impulses and ungovernable tempers. It is likely that lithium medication would be effective in such cases and would be much preferred to leucotomy.
Culbreth, D. M. R. (1927), “Materia Medica and Pharmacology”, Seventh Edition, page 73.
Engler, M. (1948), “Prefrontal Leucotomy in Mental Defectives”, The Journal of Mental Science, Volume XCVIV, page 844.
Garrod, A. B. (1859), “Gout and Rheumatic Gout”, page 438.
Henderson, D. K., and Gillespie, R. D. (1944), Textbook of Psychiatry, Sixth Edition, page 3.
Mackay, F. W. (1948), “Leucotomy in the Treatment of Psychopathic Feeble-Minded Patients in a State Mental Institution”, The Journal of Mental Science, Volume XCIV, page 834.
Squires’s “Companion to British Pharmacopoeia”, quoted in The Practitioner (1907), Volume I, page 166, quoted in The Practitioner (1909), Volume II, page 130, quoted by Squires, loc. cit.
Transcribed from the uploaded scan. Some words may remain uncertain where the original print is faint or partially obscured.