Therapeutic drug monitoring:
Lithium levels
NORMAN B. COFFMAN, PhD
JOHN J. FERNANDES, DO
Lithium has been used in the
treatment of mania since 1949. Although
its effectiveness is well recognized, the
mechanism by which it stabilizes manic be-
havior is not well understood. In addition,
it has some serious toxic properties com-
bined with a narrow therapeutic range.
For this reason, monitoring of serum lith-
ium levels is mandatory. Suggested mecha-
nisms of action and protocols for monitor-
ing of serum levels are presented.
(Key words: Drug monitoring, lith-
ium, toxicity, therapeutic index)
In the late 1940s, Cadel(p41S) in Australia
was looking for toxic nitrogenous substances
in the urine of mental patients. He was aware
that lithium urate was quite soluble and that
lithium salts actually had been used in the
19th century as a treatment for gout. Subse-
quently, he gave lithium to the experimental
animals he was using and, surprisingly, ob-
served an induced lethargy in his guinea pigs.
He deduced from this observation that lithium
salts might make manic humans less agitated.
He then gave lithium carbonate to several
From the Department of Pathology and Laboratory Medi-
cine, Philadelphia College of Osteopathic Medicine, Phila-
delphia, Pa, where Dr Coffman was associate professor
of pathology and laboratory medicine and Dr Fernandes
was formerly chairman. Dr Fernandes is currently at
the Department of Pathology, Olympia Fields Osteo-
pathic Hospital and Medical Center, Olympia Fields, Ill.
Reprint requests to Norman B. Coffman, PhD, Abing-
ton Memorial Hospital , 1200 Old York Rd, Abington,
PA 19001.
Clinical practice/Laboratory medicine • Coffman and Fernandes
manic psychiatric patients. The patients re-
sponded as the guin'e a pigs had, and a new treat-
ment for mania was discovered.
Lithium is useful in the treatment of manic
episodes of bipolar disorder and also as a main-
tenance treatment in patients with bipolar dis-
order. Lithium does have serious toxic proper-
ties combined with a narrow therapeutic in-
dex. For these reasons, the serum lithium lev-
els must be monitored routinely.
Indications for the use of lithium
Lithium and the tricyclic antidepressants rep-
resent two of the major classes of drugs used
in the treatment of mood disorders. Lithium
is useful for the treatment of the manic phase
of manic-depressive psychosis. It can also be
used successfully in the treatment and man-
agement of recurrent severe depression with-
out manic episodes, schizoaffective psychosis,
episodic alcoholism, periodic antisocial behav-
ior, and periodic schizophrenic illness. Also,
maintenance doses can be used to prevent or
decrease the intensity of recurring episodes in
manic-depressive patients who have a history
ofmania. 2
Acute mania is often used as a rationale for
the immediate use of lithium. However, it is
probably more appropriate to begin treatment
with one of the tricyclic antidepressants and
to then start treatment with lithium salts once
the patient is stabilized. When the patient's
cooperativeness and intake offood and liquids
have become more nearly uniform, lithium ther-
apy can be gradually instituted with a greater
degree of safety. Lithium also appears to be
JAOA • Vol 92 • No 7 • July 1992 • 907
effective in preventing recurrence of bipolar
affective disorders and depression. For the for-
mer disorder, lithium is often used in conjunc-
tion with antidepressive agents. Dosage must
be managed well or serious toxicity can re-
sult. 1(p421)
Absorption and mechanisms of action
Lithium carbonate and lithium citrate are the
lithium compounds currently used in the
United States. The lithium ion is water sol-
uble. It is almost completely absorbed from the
gut and is rather evenly distributed in tissues.
One study of autopsy cases showed the average
lithium concentrations for various tissues to
be as follows: blood, 1.9 mmollL; brain, 2.0
mmollL; liver, 2.8 mmollL; kidney, 3.6 mmoll
L; and urine, 6.7 mmol/L. 3(p465)
Although the passage oflithium across most
membranes is rapid, equilibration across the
blood-brain barrier is slow: at steady state, the
lithium level in cerebrospinal fluid is about
40% to 50% of that in plasma. Peak plasma
concentrations occur 2 to 4 hours after an oral
dose. Lithium's volume of distribution, 0.7 LI
kg to 0.9 L/kg, is slightly higher than the vol-
ume of total body water.
Excretion is almost entirely urinary with
about 99% renal excretion. Excretion is bipha-
sic. Approximately two thirds of a dose is rap-
idly excreted over 10 to 14 days. The half-life
of excretion averages about 20 to 24 hours
(range, 17 to 58 hours).3(p463) In dehydrated pa-
tients, proximal tubular reabsorption of lith-
ium is increased and lithium retention may
result (decreased clearance).
In mentally healthy persons, the presence
of the lithium ion has little psychotropic ef-
fect. It appears to have no sedative, depres-
sant, or euphoric effects in them. The mecha-
nism by which it exerts its effects in mentally
ill persons is not understood-note its "acci-
dental" discovery. There is some thought that
lithium alters sodium ion transport in nerve
and muscle cells or that it alters the normal
pharmacology of catecholamine neurotransmit-
ters (or both). Investigators are also accumu-
lating evidence oflithium's ability to influence
the intracellular activity of certain phosphat-
idylinositide second messengers. 1(p419)
908 • JAOA • Vol 92 • No 7 • July 1992 Clinical practice/Laboratory medicine • Coffman and Fernandes
Toxicologic properties
Lithium is a pervasive toxin. With increasing
serum levels, the symptoms of toxicity become
more severe and widespread. Diarrhea, vom-
iting, drowsiness, muscle weakness, and lack
of coordination may become evident at plasma
levels below 2.0 mmol/L, and some people may
even show signs of toxicity at levels lower than
1.5 mmoliL. At levels higher than 2.0 mmoll
L, giddiness, ataxia, blurred vision, tinnitus,
and the production of large amounts of dilute
urine may occur.
When levels increase above 3.0 mmol/L, tox-
icity to multiple organs becomes evident. Or-
gan systems involved may include the neu-
romuscular, central nervous, cardiovascular,
neurologic, gastrointestinal, genitourinary, der-
matologic, autonomic nervous, and thyroid sys-
tems. Lithium does decrease the tubular reab-
sorption of sodium; it may also be teratogenic. 4
Patients and their families should be alert
for symptoms such as diarrhea, vomiting,
tremor, mild ataxia, drowsiness, or muscular
weakness. Decreased alertness may make per-
formance of certain attention-demanding tasks
hazardous. With long-term use, nephrotoxicity
can be a serious side effect. Glomerular, tubu-
lar, and interstitial renal changes have been
observed although lithium has not been seen
to cause end-stage renal disease. 4 Renal func-
tion tests should be monitored to detect renal
damage.
This pervasive and serious nature of lith-
ium's toxic properties combined with its nar-
row therapeutic index mandates the careful
monitoring of the serum levels in patients tak-
ing lithium.
Monitoring protocols
Serum lithium levels must be monitored be-
cause this toxic substa:p.ce has a narrow effec-
tive therapeutic range of 1.0 mmoliL to 1.5
mmol/L (some sources give 0.6 mmoliL to 1.2
mmoliL or 0.8 mmoliL to 1.2 mmollL, espe-
cially for long-term maintenance),5,6 and seri-
ous toxic side effects that initially become ap-
parent in some patients (especially the elderly)
at levels lower than 1.5 mmol/L. For the test
results to be intelligible, samples for analysis
must be drawn at appropriate times within the
dosing schedule, and these sampling times
must be known to those interpreting the test
results.
One source 6 recommends that a 12-hour post-
dose serum level be used to assess dosage ef-
fectiveness. This sample would be obtained
just before the next dose in a twice-per-day dos-
ing schedule. In any event, the trough levels
should be monitored. Levels should be deter-
mined twice per week during acute phases of
lithium therapy and at least every 2 months
during long-term therapy in patients without
complications.
Monitoring of serum lithium levels must be
done concomitantly with good clinical moni-
toring. Both serum lithium levels and clinical
observations must be assessed to determine
that excessive doses of lithium are not being
Clinical practice/Laboratory medicine • Coffman and Fernandes
given and that the patient is complying with
the desired dosage schedule.
References
1. Gilman AG, Ra il TW, Nies AS, et al (eds): Goodman and
Gilman's The Pharmacological Basis of Therapeutics, ed 8. New
York, NY, Pergamon Press, 1990, pp 418, 419 , 42l.
2. Gennaro AR (ed): Remmington's Pharmaceutical Sciences, ed
18. Easton, Pa, Mack Publishing Co, 1990, p 1086.
3. BaseltRC, Cr a vey RC: Disposition ofToxic Drugs andChemi-
cals in Man , ed 3. Chicago, Ill, Year Book Medical Publishers,
Inc, 1989, pp 463 , 465 .
4. Roxane Laboratories, Inc : Lithium carbonate tablets
package insert. Columbus, Ohio, No. 4055500, revised June
1989.
5. Tietz NW (ed): Clinical Guide to Laboratory Tests. Philadel-
phia, Pa, WB Saunders Co, 1983, pp 590-59l.
6. Tietz NW: Textbook of Clinical Chemistry. Philadelphia, Pa,
WB Saunders Co, 1986, p 1657.
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