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.

Marion T. Doig, Ill, Michael G. Heyl,

and Dean F. Martin' Universitv of South Florida

Lithium Therapy

Lithium and Mental Health

Lithium carbonate is used in treatment of mental pa- tients with manic-deoressive disorders. The illness usuallv begins without warning or apparent cause, though som;.. times a preceding stress can be recoenized. Manic-de~res- sive 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 cred- ited with being the first to try administering lithium com- pounds 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, lith- ia tablets were taken to alleviate gout as well as a range of ailments, before the method of treatment fell into disfa- vor. 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 experi- ments that demonstrated a sedative effect of lithium car- bonate 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 admin- istration, Mr. W. B. had settled down, and was trans- ferred to a convalescent ward. He was kept under observa- tion, 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 Den- mark, have confirmed Cade's observations. Accounts of his work and that of others have appeared in many popu- lar 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 disor- ders (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 Discovery of lithium by Arfvedsan. 1859 Use of lithium salts for treatment of rheumatism and

gout by Garrod. 1907 Lithia tablets cause cardiac depression. 1909 Lithia salts cause upset stomach very easily. 1912 Pfeiffer showed lithia actually retarded elimination of

uric acid in gouty patients (13). 1927 Hvonatic effect of lithium bromide noted by Culbreth.

.~~ ~~~ . . 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 retarda- tion, drug abuse, alcoholism, or schizophrenia.

=See Cade ( I ) for specific references, unless otherwise noted

Table 2. Properties of Some Lithium Salts

Water % hv S o h

Molec- Weiiht bility Lithium Molecular ular Lith- (g/100 Hygro-

Salt Formula Weight ium cc) scop~c

Acetate LiC?HzO? 66 10.6 300 no Carbonate ~ i z C 0 j - 74 18.9 2 no Chloride LiCl 42 16.6 64 very Citrate LiaCeHs07 210 10.0 74 no Sulfate LLSOL 110 12.7 26 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 car- bonate 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, as 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). Al- though the exact mechanism is still unknown, several in-

Volume 50, Number 5, May 1973 / 343

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 un- certain about the numerical effectiveness of lithium ther- apy 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 in- volved in the absence of relapse during treatment. Few ex- periments have been of the "double-blind" type in which neither investigators nor patients really know which medi- cation (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 pa- tients 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 ex- ample 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 be- cause the patient must be watched carefully and have blood samples taken daily (especially at early stages) and analyzed for lithium. Careful monitoring is necessary be- cause 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 com- mit suicide by taking too many tablets I . Also, in 1949, some fatal intoxications occurred when lithium chlo- ride was used as a salt substitute for patients with heart trouble on a salt-free diet 171. It was then tragically evi- dent 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

Table 3. Properties of Group I Elements

Hydration Energy

Atomic Crystal (kcal Element No. Atomic Weight Radii (A) male(

Table 4. Cyclic Polyethers Having Specificity for Given Alkali Metal Ions (16)

Ratio of metal ion

Ionic diameter Diameter to hole

Cation ( A ) Cvclic Polvether diameter

Lithium 1.20 bis-tert-butylcyclohexyl- 0.89 14-crown-4

Sodium 1.90 tert-hutyleyclahexyl-15- 0.97 crown-5

Potassium 2.66 dieyclohexyl-lbcrown-6 0.90 Rubidium 2.96 asym-dieyclohexyl-21- 0.77

crown-7 Cesium 3.34 dicyclohexyl-24-crown-8 0.83

more serious side effects include mental confusion, hyper- reflexia, tremulousness, dysarthria, and seizures, progres- sing 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 ma- crocyclic 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 togeth- er (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 ef- fect) 11 ). Also, the size and nature of the groups can fa- vorably 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 hydro- phobic 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 admis- sions to mental hospitals because of the lithium content

'One liter of water per hour for seven hours

344 /Journal of Chemical Education

in their drinking water (121 then maybe lithium treat- j:; $':'';;,?:;$:;f;;PL acoIIpy, A h,i,w of 1951-196 7,.. Publication ment of all drinking water should be considered. At that 1836, U. S. ~ o v e m m c n t ~r in t ing office, washington, D.c., 1968.701. point, the battles over fluoridation will seem minor by (61 Davis. 3. M.. and Fmn. W. E., " A n ~ u a I Review of Pharmacology.ll Annual Rev.

h e . , Palo Alto. Calif., 1971. Vo l l 1 . p 297. comparison, and we must have accurate answers to the 161 H.mwit.. L. C., and G. U.. N ~ C U E M . J . ~ ~ d . . ZR1. 1369 119691. questions that will inevitablv be asked. (71 coreoran. A. c.. ~ a y l o r , R. D.. and page. I. H.. J ~ m m ~ d . Aaan.. 11% 685

(19491. We acknowledge with gratitude the support of the Na- ,,,A,,,.J PublieHenlfh. 59,466(19491. tional Institute of Mental Health (1 R03 MH 20078-01) (91 sehou, M., A ~ ~ ~ S D ~ , A , a n d ~ r a p - ~ e n s e n . J . , A ~ ~ P . J ~ s ~ c h m t . . 1%,520(1%81.

and D, F, M, is grateful for a PHS career ~~~~d from the ( lo) Brown. H. C.. Barthdom~y. H.. and Taylor. M. D., J. Amor. Chem. Sot. 66.435 (19441.

National Institute of General Medical Sciences (KOCGM IIII Martin. ~ . ~ . a ~ d ~ a r t i n . B.B.. hen. chem., I . 40111962).

Volume 50, Number 5, May 1973 / 345