M a r i o n T. Doig, Ill, Michael G. Heyl, and D e a n F. Martin'
Universitv of South Florida
Lithium and Mental Health
Lithium, although one of the less familiar elements, is also one of the most ubiquitous. Traces of it are found in nearly all igneous rocks and as a constituent of water from many mineral springs. Beneficient effects of these springs have been recognized about as long as the element has been known. Its medical applications have been varied, as have the degrees of success of the treatment. A current application, lithium therapy, is considered here. Lithium Therapy
Lithium carbonate is used in treatment of mental patients with manic-deoressive disorders. The illness usuallv begins without warning or apparent cause, though som;.. times a preceding stress can be recoenized. Manic-de~ressive are characterized b y alternating extremes of mania (over-excitement) and depression, with periods of normalcy between. Still another feature is the tendency to spontaneous disappearence and recurrence. An Australian psychiatrist, J. F. J. Cade, M.D., is credited with being the first to try administering lithium compounds to control mania. Cade had, in fact, assembled all the pieces of a scientific jig-saw puzzle. He had noted lithium chemicals in medicine had "enjoyed a heyday" in the latter half of the century (Table 1). For example, lithia tablets were taken to alleviate gout as well as a range of ailments, before the method of treatment fell into disfavor. Later, Cade learned of a 1944 observation that water from certain English wells was helpful in treatment of mental illness. He concluded, on the basis of his experiments that demonstrated a sedative effect of lithium carbonate with guinea pigs, that the "supposed efficacy of the famous well water was a real efficacy and directional to the lithium content of the waters." Case Histories
Early in 1948, Dr. Cade used lithium carbonate to treat the limited number of patients available to him. The results with Case I, Mr. W. B., were perhaps the most dramatic ( 1 ) . He was 51. and had been in a state of chronic manic excitement for five years. M. W. B. was "restless, dirty, destructive. mischievous, and interferine. had long been regarded a s t h e most troublesome in the chronic ward." After three weeks of lithium administration, Mr. W. B. had settled down, and was transferred to a convalescent ward. He was kept under observation, and on a maintenance dosage of lithium for two months, was discharged and was soon working a t his old job. Since 1949, many investigators, particularly in Denmark, have confirmed Cade's observations. Accounts of his work and that of others have appeared in many popular and technical publications. The popular accounts mention the optimistic aspects, that it is possible that lithium carbonate therapy might help as many as 100,000 persons currently suffering from manic-depressive disorders (2. :I). Popular accounts of lithium therapy usually fail to mention some of the complications and implications. 'To whom all correspondence concerning this article may be addressed.
Table 1 . Medical History of Lithium SaltP Year
Event
1817 1859
Discovery of lithium by Arfvedsan. Use of lithium salts for treatment of rheumatism and gout by Garrod. Lithia tablets cause cardiac depression. Lithia salts cause upset stomach very easily. Pfeiffer showed lithia actually retarded elimination of uric acid in gouty patients (13). Hvonatic effect of lithium bromide noted by Culbreth.
1907 1909 1912 1927
.~~ .. importance of "minor" elements, hut significance of ~~~
l i t h m not discussed
1970
Lithium carbonate approved by FDA for treating manic (121 Correlatmn does not ohtam formental retardation, drug abuse, alcoholism, or schizophrenia.
=SeeCade ( I ) for specificreferences, unless otherwise noted Table 2. Properties of Some Lithium Salts
Lithium Salt
Molecular Formula
Acetate Carbonate Chloride Citrate Sulfate
LiC?HzO? ~ i z C 0 jLiCl LiaCeHs07 LLSOL
Water % hv Soh Molec- Weiiht bility ular Lith- (g/100 HygroWeight ium cc) scop~c 66 74 42 210 110
10.6 18.9 16.6 10.0 12.7
300 2 64 74 26
no no
very no no
First, why should any U.S. drug manufacturer produce lithium carbonate? It's a common chemical that can not be patented and could be marketed only a t a low profit. But three firms will produce it as a public service, with the approval of the U.S. Food and Drug Administration. Lithium carbonate, acetate, citrate, or sulfate are equally useful in lithium therapy. They are not hygroscopic in contrast to lithium chloride (Table 2). But lithium carbonate contains a greater percentage of lithium by weight and is more efficient to use (Table 2). The carbonate is also the least likely to upset the stomach. Clinical Aspects
There are many unanswered questions about lithium therapy, including such obvious ones as: How does it work? How effective is the treatment? What is its future? We don't know the answer to the first question, but we do know it does not alter thought content or cause memory disturbance, a s some treatment may (e.g., tranquilizers and electroshock). The mechanism by which lithium exerts its antimanic action has been the object of extensive research (4. -i). Although the exact mechanism is still unknown, several inVolume 50, Number 5, May 1973 / 343
Table 3. Properties of Group I Elements
Element
Atomic No.
Atomic Weight
Crystal Radii (A)
Hydration Energy (kcal male(
Table 4. Cyclic Polyethers Having Specificity for Given Alkali Metal Ions (16)
Bracelet representation of Kf-valinomycin structure with K+ represented by central sphere and planes described by six oxygen donor atoms represented by two dashed circles. (After Hassall and Thomas) 116). teresting effects have been noted. For example, lithium has been shown to alter the levels of norepinephrine, serotonin, and cyclic AMP; however, these effects could be secondary to an ionic effect. Lithium is in the same group (Table 3) of metals as sodium and potassium, ions which are basic to nerve cell operations. We are also uncertain about the numerical effectiveness of lithium therapy because 'most studies have been of the open type, i.e., both patient and doctor knew it was being administered, so the possibility exists that a psychological effect is involved in the absence of relapse during treatment. Few experiments have been of the "double-blind" type in which neither investigators nor patients really know which medication (i.e., lithium or a placebo or another medication) is given and in which random assignment of patients is an important methodological consideration. In addition, as Davis and Fann note 15). most double-blind experiments in lithium therapy have been of short duration and in an artificial situation. Lithium therapy can be tedious and cumbersome. It may take months for stabilization to occur, and some patients have been on maintenance doses for over five years. Some may need to take lithium carbonate tablets every day for the rest of their lives. At first glance this may not seem to be a major problem, but it is tedious and patients become lackadaisical about taking the tablets or become forgetful. Mr. W. B., mentioned earlier, was the first example of this (also the first patient to he treated) and had to be readmitted to the mental hospital; within two weeks of treatment, he had settled down again and was a t work within a month. The cumbersome aspect of lithium therapy arises because the patient must be watched carefully and have blood samples taken daily (especially at early stages) and analyzed for lithium. Careful monitoring is necessary because poisoning can occur if the amount of lithium in the blood becomes too high. This has rarely happened with careful monitoring, but a few patients have tried to commit suicide by taking too many tablets I . Also, in 1949, some fatal intoxications occurred when lithium chloride was used as a salt substitute for patients with heart trouble on a salt-free diet 171. It was then tragically evident that excessive build-up of lithium can occur when the sodium (as table salt) intake is reduced. For maintenance on lithium therapy, serum levels of 0.5-1.0 meq!l are optimum. Mild adverse reactions to lithium occur a t serum levels above 1.5 meqil. These minor side effects include drowsiness, muscular weakness, loss of appetite, nausea, vomiting, abdominal pain, and diarrhea 18. 91. Disorders involving the nervous system occur at high serum lithium levels. Clinical signs of these 344 /Journal
of Chemical Education
Cation
Ionic Diameter (A)
Cvclic Polvether
Ratio of metal ion diameter to hole diameter
Lithium
1.20
bis-tert-butylcyclohexyl-
0.89
Sodium
1.90
tert-hutyleyclahexyl-15-
0.97
Potassium Rubidium
2.66 2.96
Cesium
3.34
14-crown-4
crown-5 dieyclohexyl-lbcrown-6 asym-dieyclohexyl-21crown-7 dicyclohexyl-24-crown-8
0.90 0.77 0.83
more serious side effects include mental confusion, hyperreflexia, tremulousness, dysarthria, and seizures, progressing tocoma and death ( 5 ) . Presently, there is no effective way of removing lithium rapidly from the blood, though it is obvious that we need some such procedure. "Water loading" has been tried, but the techniqueZ was unsuccessful. However, i t appears that selective lithium ion binding by chelating agents or macrocyclic compounds may provide a method of accelerated lithium removal. Certain &diketones are chelating agents that are known to have some degree of specificity toward lithium and, therefore, may prove suitable as lithium control agents. The specificity of these compounds [RCOCH(R")COR'] is the result of three steric effects. First, coordination with a smaller metal ion, such as lithium, is favored by bulky R and R' groups which hold the oxygen atoms closer together (B-strain) 1101. Second, it becomes less likely that two ligands can fit around the same metal ion if R and R' are sufficiently large (F-strain) 1101. Finally, the presence of hydrophobic groups (R, R' and R") will shield the M - 0 bond from solvation and favor coordination (entropy effect) 11). Also, the size and nature of the groups can favorably influence the lithium transport properties of the chelating agents. Several macrocyclic compounds show specificity in coordinating sodium ions (e.g., crown compounds, see Table 4) 1161 or with potassium ions (e.g. valinomycin, see figure) 117). Typically, binding of the cation induces a conformational change in the macrocyclic compound such that a central hydrophillic cavity is formed with a hydrophobic exterior (figure). The hydrophobic exteriors allow these complexed ions to pass readily through biological membranes. Apparentlv verv few macrocvclic comnounds show specifity toward lithium; however, ckrtain polyethers may prove suitable and should be investigated (Table 4). The future of lithium therapy must surely be uncertain if the past is an accurate guide. We are iustified in taking an optimistic view if contemporary research and clinicai practice is successful. A sinister aspect also appears, though no one seems to mention it. It will surely occur to some one that if the citizens of El Paso have low admissions to mental hospitals because of the lithium content 'One liter of water per hour for seven hours
in their drinking water (121 then maybe lithium treatment of all drinking water should be considered. At that point, the battles over fluoridation will seem minor by comparison, and we must have accurate answers to the questions that will inevitablv be asked. We acknowledge with gratitude the support of the National Institute of Mental Health (1 R03 MH 20078-01) and D,F, M, is grateful for a PHS career ~~~~d from the National Institute of General Medical Sciences (KOCGM
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Publication acoIIpy, A h,i,w of 1951-1967,.. 1836, U. S.~ o v e m m c n~t r i n t i n goffice, washington, D.c., 1968.701. (61 Davis. 3. M.. and Fmn. W. E., " A n ~ u a IReview of Pharmacology.ll Annual Rev. h e . , Palo Alto. Calif., 1971. V o l l 1 . p 297. G. U..N ~ C U E MJ.. ~ ~ dZR1.. 1369 . 119691. 161 H.mwit.. L.C., and (71 coreoran. A. c.. ~ a y l o r ,R. D.. and page. I. H.. J ~ m ~ m d Aaan.. . 11% 685 (19491. ,,,A,,,.J PublieHenlfh. 59,466(19491. (91 sehou, M., A ~ ~ ~ AS , aD n d~ ~,r a p - ~ e n s eJn . , A ~ ~JP ~. s ~ c h m t1%,520(1%81. .. (lo) Brown. H. C.. Barthdom~y.H.. and Taylor. M . D., J. Amor. Chem. Sot. 66.435 (19441. IIII Martin. ~ . ~ . a ~ d ~ a B.B.. r t i nhen. . chem., I. 40111962).
Volume 50, Number 5, May 1973 / 345
