TEACHERS' TOPICS Therapeutic Drug Management of Lithium
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American Journal of Pharmaceutical Education 2005; 69 (5) Article 88.
TEACHERS’ TOPICS
Therapeutic Drug Management of Lithium
Marshall E. Cates, PharmD, and Pamela J. Sims, PharmD, PhD
McWhorter School of Pharmacy, Samford University
Submitted February 2, 2005; accepted March 18, 2005.
Lithium continues to be a mainstay in the treatment of bipolar disorder. Aside from understanding the
basic pharmacokinetics of lithium and the factors that influence serum lithium concentrations, the
student should understand the clinical usefulness of serum lithium concentrations, the reasons for
obtaining them, and how to interpret them. Significant emphasis is placed on the student being able
to apply the information to clinical scenarios and becoming an inquisitive problem solver. To that end,
case studies are used to promote a deeper understanding of lecture material.
Keywords: lithium, pharmacokinetics, therapeutic drug monitoring, bipolar disorder
INTRODUCTION INSTRUCTIONAL DESIGN
Therapeutic Drug Management (TDM) is a 2-course Clinical Use of Lithium
sequence that emphasizes the application of pharmacoki- Despite the introduction of many other mood stabil-
netic principles to the individualization of drug regimens. izers, lithium continues to be considered first-line therapy
The course philosophy is that students should learn to be for treatment of acute mania and long-term prophylaxis
problem solvers. They should be able to identify the prob- of bipolar disorder. It is also used in a variety of other
lem, identify and retrieve missing information, apply conditions, such as schizoaffective disorder, major
appropriate principles, choose realistic solutions, and rec- depressive disorder (adjunctive therapy), schizophrenia
ommend appropriate follow up. The TDM of lithium ther- (adjunctive therapy), aggression, premenstrual dyspho-
apy is taught via a traditional 80-minute lecture using ria, and cluster headaches.1-3
PowerPoint slides. Students then complete case studies
in an independent manner, followed by a 2-hour small- Basic Pharmacokinetics of Lithium
group work session in which students discuss their find- Lithium is available in regular-release tablets and
ings with peers and the instructor. After completing the capsules (as carbonate salt), extended-release tablets (as
course, students should be able to: carbonate salt), and syrup (as citrate salt).1-4 The
1. Describe the basic pharmacokinetic parameters extended-release tablet has a slower absorption rate, a
of lithium; lower peak level, and lower bioavailability relative to
2. Recognize factors that influence serum lithium the other dosage forms.1,2,5 Patients may prefer capsules
concentrations; if they cannot tolerate the taste of tablets. Extended-
3. List the important drug interactions of lithium; release tablets are more expensive and are usually
4. State the usual therapeutic range for lithium in reserved for patients who are experiencing peak-concen-
the acute and maintenance treatment of mania; tration related side effects such as tremor, nausea, or pol-
5. Recognize the various signs/symptoms of lith- yuria. The syrup is used primarily for patients who refuse
ium toxicity; to take medication or who have difficulty swallowing
6. Discuss reasons for obtaining a serum lithium tablets or capsules.2
concentration; Lithium is widely distributed into most body tissues
7. Interpret serum lithium concentrations that differ and fluids. However, it is unevenly distributed among
from expected values; and several tissue compartments, so for instance, the lithium
8. Describe and apply lithium dosing methods. concentration is higher in saliva and in the thyroid than in
Corresponding Author: Marshall E. Cates, PharmD. serum.1 Lithium initially distributes into an apparent vol-
Address: Department of Pharmacy Practice, Samford ume that is about 25%-40% of body weight, and later into
University McWhorter School of Pharmacy, 800 Lakeshore a volume that is about 50%-100% of body weight. The
Drive, Birmingham, AL 35229. Tel: 205-726-2457. apparent volume of distribution at steady state ranges
Fax: 205-726-2669. E-mail: mecates@samford.edu from 0.5 L/kg to 1.2 L/kg. Lithium has a smaller volume
1American Journal of Pharmaceutical Education 2005; 69 (5) Article 88.
of distribution in elderly patients. Lithium is not bound to inhibition.6,7 Distal tubule diuretics, such as hydrochlor-
plasma proteins.1,2,5 othiazide, have been reported to increase serum lithium
Lithium is not metabolized. It is filtered by the glo- concentrations by approximately 25%.6 The purported
meruli and eliminated renally as the free ion. Although mechanism of this interaction is the induction of natriu-
small amounts are eliminated via sweat, saliva, and feces, resis, which leads to a compensatory increase in the reab-
lithium is excreted almost entirely in the urine. Its clear- sorption of sodium (and thus lithium) in the proximal
ance is directly proportional to a patient’s glomerular tubule.6,7 Angiotensin-converting enzyme (ACE) inhibi-
filtration rate and renal blood flow. About 80% of lithium tors, such as captopril, enalapril, and lisinopril, can in-
filtered by the glomeruli is reabsorbed in the proximal crease serum lithium concentrations through volume
tubules (in parallel with sodium); thus, clearance of lith- depletion and reduction in glomerular filtration rate or a
ium is about 20% of the patient’s glomerular filtration decrease in aldosterone levels that leads to sodium deple-
rate. Renal clearance of lithium is affected by several tion and subsequent lithium retention. The onset of this
factors, including circadian rhythms (day . night), affec- interaction appears to be delayed (3-5 weeks), and elderly
tive phase (manic . nonmanic), age (younger . elderly), patients may be predisposed.6
and pregnancy (pregnant . nonpregnant).1,2,5 The approx- Drugs that have been reported to decrease serum lith-
imate half-life of lithium is 24 hours in adults, 36 hours in ium concentrations include carbonic anhydrase inhibitors
elderly patients, and 40-50 hours in patients with impaired (eg, acetazolamide), osmotic diuretics (eg, mannitol, urea),
renal function.4 methylxanthines (eg, caffeine, theophylline), and sodium
bicarbonate.6 Drugs that have minor, variable effects
Serum Lithium Concentration on serum lithium concentrations include loop diuretics
Important considerations in how the body handles (eg, furosemide) and potassium-sparing diuretics (eg,
lithium are three-fold: water balance, sodium balance, amiloride).5
and renal function.2,5 A decreased water balance would
be expected to result in increased serum lithium concen- Usefulness of Serum Lithium Concentrations
trations, whereas an increased water balance would be Because lithium concentrations vary widely during
expected to result in decreased serum lithium concentra- a dosing interval, a representative single time point for
tions. Because of the manner in which the body handles serum lithium concentration monitoring was established
lithium renally, a decreased sodium balance would be for standardization. Although somewhat arbitrary, the 12-
expected to result in increased serum lithium concentra- hour post-dose time point was selected for this purpose
tions, whereas an increased sodium balance would be because it avoids the highly variable absorption and dis-
expected to result in decreased serum lithium concentra- tribution phases. The usual practice is to obtain the sample
tions. Renal function plays an obvious role in influencing in the morning before the first lithium dose and 12 hours
serum lithium concentrations, as almost all lithium is after the previous evening dose.1,5,7
excreted renally. Through these mechanisms, many dif- Acute mania typically presents with a combination of
ferent factors can affect serum lithium concentrations. mood (eg, euphoria, elation, lability, irritability), hyper-
Examples include such things as alterations in diet (eg, active (eg, decreased need for sleep, rapid speech, psy-
low salt diet, slimming diets) or physical activity (eg, chomotor agitation, racing thoughts), and behavioral (eg,
excessive sweating), drug-drug interactions (eg, nonster- intrusiveness, challenging, hypersexual) symptoms, and
oidal anti-inflammatory drugs [NSAIDs], diuretics), occasionally psychotic (eg, hallucinations, delusions)
medical illnesses (eg, renal dysfunction, diarrhea or vom- symptoms. Most clinicians advocate a serum concentra-
iting), and pregnancy and delivery. tion of 0.8-1.2 mEq/L during initial treatment of acute
mania.1,8 On the other hand, during long-term mainte-
Drug Interactions With Lithium nance treatment, serum concentrations of 0.6-1.0 mEq/L
Some of the most clinically relevant drug interactions are usually adequate to prevent the recurrence of a manic
involving lithium are those that result in increased serum episode.1,8 Some patients may require serum lithium con-
lithium concentrations. Some NSAIDs, such as indome- centrations outside the usual ranges. For instance, elderly
thacin and ibuprofen, can increase serum lithium concen- patients may require lower levels.1
trations by approximately 40%, but aspirin and sulindac Unfortunately, lithium possesses a narrow therapeu-
have only minimal effects.6 Possible mechanisms of this tic index.9 Toxic effects of lithium become more likely
interaction include decreased renal blood flow secondary as serum concentrations rise, and most patients will expe-
to prostaglandin inhibition and enhanced reabsorption of rience some toxic effects with concentrations above
sodium (and thus lithium) secondary to prostaglandin 1.5 mEq/L.9 Symptoms of mild toxicity include such
2American Journal of Pharmaceutical Education 2005; 69 (5) Article 88.
things as nausea, diarrhea, tremors, muscle weakness, 12-hour serum lithium concentration by about 0.2 mEq/L
and fatigue. Symptoms of moderate toxicity include relative to twice-daily or thrice-daily dosing regimens.2,7
such things as sedation, confusion, lethargy, ataxia, Recommendations for therapeutic concentrations (as noted
coarse tremors, dysarthria, nystagmus, and increased above) are based on multiple daily dosing regimens.
deep tendon reflexes. Severe toxicity (.2.5 mEq/L) may Finally, the accuracy and reliability of the laboratory can
result in permanent neurological impairment, seizures, certainly impact the interpretability of serum lithium con-
coma, and death. The severity of lithium toxicity is related centration determinations. Therefore, guidelines for ensur-
to both serum concentrations and the duration at which ing the accuracy and reliability of standardized 12-hour
concentrations have remained high.1,3,4,9 serum lithium concentrations include: optimal compli-
ance; sample obtained 12 6 1/2 hours after the last evening
dose; sample obtained after at least 4-5 days at a given
Reasons for Monitoring Serum
dose; twice-daily or thrice-daily dosing schedule; and appro-
Lithium Concentrations
priate precision of laboratory analyses.1
There are many clinical reasons to obtain serum lith-
When interpreting unexpected serum lithium concen-
ium concentration measurements. When lithium therapy
tration values, the clinician must consider various explan-
is initiated, or anytime that the lithium dosage is changed,
ations. Perhaps the serum concentration measurement
serum concentrations are helpful in determining optimal
reveals a ‘‘true’’ concentration, so the clinician should look
dosing.4 During maintenance therapy for prophylaxis of
for those factors that alter serum lithium concentrations,
bipolar disorder, most clinicians obtain serum concentra-
such as changes in water balance, sodium balance, and
tion measurements every 3-6 months.4 Signs/symptoms
renal function. On the other hand, the clinician should
of either manic or depressive symptoms, or symptoms of
consider whether the measurement is actually inaccurate
possible lithium toxicity, necessitate serum lithium con-
or unreliable, and thus may be due to a missed or extra
centration determinations. When situations arise that may
dose, improper timing, non–steady-state, dosing sched-
alter steady-state serum concentrations, such as develop-
ule, or laboratory error. Regardless, the clinician should
ment of medical disease (eg, diarrhea), significant increases
not make hasty decisions based on aberrant values, rather
in sweating, initiation/dosage alteration/discontinuation
he or she should consider obtaining another measurement
of drugs that may interact with lithium, and change in salt
for verification.
intake or diet, then the clinician is wise to obtain serum
lithium concentration measurements.1,4 Finally, sus-
Lithium Dosing Methods
pected noncompliance with prescribed lithium regimens
The lithium dosage must be individualized according
frequently dictates the need for serum lithium concentra-
to serum lithium concentrations, clinical response, and
tion measurements.1
adverse effects. Various prospective dosing methods exist
in order to minimize the number of serum lithium con-
Interpreting Serum Lithium Concentrations centration determinations and decrease the amount of
There are various factors that can affect the accuracy time required to achieve a therapeutic dose. However,
and reliability of serum lithium concentration measure- there is no empirical evidence that these strategies
ments. Certainly patient compliance with the lithium reg- actually result in a more rapid clinical response.8 In the
imen, especially the doses immediately prior to the serum Cooper method,11,12 a 600-mg test dose is given and the
concentration determination, can affect the accuracy of serum lithium concentration is determined 24 hours later.
the results.7 Because the standard concentration is con- Depending upon that concentration, a chart reveals the
sidered a 12-hour post-dose determination, samples predicted daily dose to yield a steady-state concentration
obtained before that timeframe result in falsely increased of 0.6-1.2 mEq/L. Another example is the Perry
concentrations, while samples obtained after that time- method,13,14 which utilizes a 1200-mg test dose, with
frame result in falsely decreased concentrations. Due to subsequent serum lithium measurement 24 hours later.
the approximate 24-hour half-life in most patients, The clinician then plots the 24-hour concentration against
steady-state concentrations are obtained in about 4-5 a desired steady-state concentration on a nomogram,
days.10 Thus, samples obtained prior to that timeframe revealing the approximate daily dose needed for that
after increasing or decreasing the lithium dosage will patient. Despite the availability of such prospective meth-
result in falsely decreased or increased steady-state con- ods, the traditional (‘‘retrospective’’) method is almost
centrations, respectively. The dosing interval can also always used by clinicians because of its ease and familiar-
affect the interpretation of lithium concentrations. Once- ity, as well as the fact that it minimizes initial adverse
daily (ie, bedtime) dosing of lithium typically increases the effects, which may increase the likelihood of long-term
3American Journal of Pharmaceutical Education 2005; 69 (5) Article 88.
compliance. In this method, lithium therapy is usually improved tolerability of therapy. Since CS is acutely
initiated at 300-mg given 2 or 3 times daily, and the dos- manic, the most appropriate serum lithium concentration
age is adjusted utilizing serum concentration determinations range is 0.8-1.2 mEq/L. First-order linear kinetics mean
once or twice a week until the desired serum concentration is that the patient’s dosage should be increased to 1500 mg/
obtained. Since lithium follows first-order linear kinetics, day. Assuming no other reasons for more frequent mon-
as the dose is changed, the steady-state serum lithium itoring, serum lithium concentration measurements
concentration changes proportionately.1,2,9,10 should be made every 3-6 months, with a desired concen-
tration of 0.6-1.0 mEq/L.
CASE STUDIES Case Study #2. The outpatient psychiatrist in the
Case Study #1. CS is a 45-year-old woman who was mood disorders clinic has called you for consultation con-
brought to the state psychiatric facility by the police. She cerning one of his patients, LS, a 46-year-old black male
was causing a disturbance at a local television station by patient with a long history of bipolar disorder. He is rather
insisting on addressing the city during a news broadcast. well-known for being compliant with therapy overall, yet
She is euphoric and grandiose. She exhibits rapid speech very absent-minded; for instance, he always shows up for
and psychomotor agitation. She admits to racing thoughts his clinic appointments but is frequently very early or very
and decreased need for sleep. CS denies that she has a late because he cannot remember when the appointment
mental illness and states that she does not need any med- is. You have known LS for quite some time, and recall that
ication. CS is diagnosed with bipolar disorder, manic epi- he was receiving lithium, 600 mg twice daily, and nifedi-
sode. Her only medical illness is hepatitis C. pine, 30 mg three times daily, the last time you checked
1. The psychiatrist is considering lithium or val- his profile several months ago.
proate to treat CS’s mania. Why might lithium The reason the psychiatrist has called you is because
be the best choice for CS? of LS’s serum lithium concentration. LS generally has a
2. Lithium is available in several different dosage serum lithium concentration of approximately 0.9 mEq/L.
forms. What would be your advice to the psy- A routine level was drawn this morning and was just
chiatrist concerning choice(s) of dosage forms reported as 1.6 mEq/L. The psychiatrist states that
and why? although he has made some recent adjustments to LS’s
3. Describe the various dosing techniques that lithium therapy, he has not altered the daily dose for many
could be utilized to treat CS’s manic episode. years. He also states that LS appears as usual, except that
Which would you prefer and why? he complains of ‘‘not feeling good lately,’’ which LS
4. What is the most appropriate serum lithium con- attributes to either a ‘‘stomach virus caught from my
centration range to treat CS’s condition? nephew’’ or ‘‘side effects from that new pill they gave
5. CS is started on 300 mg of lithium 3 times daily me in hypertension clinic.’’
and has a steady-state lithium concentration of Based upon the information above:
0.6 mEq/L. If the desired lithium concentration 1. What are the possible factors, which may, individ-
is 1.0 mEq/L, what should the dosage be ually or collectively, explain why LS’s serum lith-
adjusted to? ium concentration is so much higher than usual?
6. Describe the maintenance treatment of CS with 2. What information would you need to gather from
lithium, including desired steady-state serum various sources (eg, patient, psychiatrist, labora-
concentrations and frequency of serum concen- tory studies, medication profile) in order to either
tration monitoring. rule out or further substantiate each of the afore-
Comments: The student should recognize that lithium mentioned factors as the etiology for the high
would be preferred over valproate in a patient with active level?
liver disease, as lithium is not metabolized and is renally Comments: The student should consider that the
excreted. The syrup formulation should be used, at least serum lithium concentration may or may not be accurate
initially, owing to the patient’s lack of insight into the and reliable. The patient may, in fact, be lithium toxic, as
need for medication and consequent likelihood of non- he describes gastrointestinal distress. It is important to
compliance. Although prospective dosing methods would note that symptoms such as diarrhea and vomiting may
yield quicker therapeutic serum concentrations, and thus be the cause or effect of lithium toxicity. So perhaps he
possibly a quicker response, the increased likelihood of really does have a stomach virus that has indirectly caused
adverse effects, with resultant effects on compliance, is the serum lithium concentration to increase. It is also
a major drawback. The retrospective dosing method important to rule out a drug interaction as the cause of
is slower, but conventional and easy and allows for an elevated lithium concentration, which may be the case
4American Journal of Pharmaceutical Education 2005; 69 (5) Article 88.
if the new medication prescribed in the hypertension 2. Perry PJ, Alexander B, Liskow BI. Psychotropic Drug
clinic is hydrochlorothiazide or an ACE inhibitor. On Handbook. 7th ed. Washington, DC: American Psychiatric Press,
Inc.; 1997:221-56.
the other hand, the concentration may be falsely elevated
3. Bezchlibnyk-Butler KZ, Jeffries JJ. Clinical Handbook of
due to the forgetfulness of the patient (eg, may have taken Psychotropic Drugs. 12th ed. Seattle, Wash: Hogrefe & Huber
a dose in the morning), a change to bedtime dosing by the Publishers; 2002:133-9.
psychiatrist, or simply laboratory error. Regardless, the 4. Fankhauser MP. Bipolar Disorder. In: DiPiro JT, Talbert RL, Yee
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