Lithium has been used for the treatment of acute bipolar mania
for over 50 years. Five studies have demonstrated that lithium is
superior to placebo (176–180). Pooled data from these studies
reveal that 87 (70%) of 124 patients displayed at least
partial reduction of mania with lithium. However, the use of a crossover
design in four of these trials (176–179), nonrandom assignment
in two studies (177, 178), and variations in diagnostic criteria
and trial duration limit interpretation of the results of all but one
trial (180). Nevertheless, in the only placebo-controlled, parallel-design
trial in which lithium served as an active comparator to divalproex,
lithium and divalproex exerted comparable efficacy (180). In active
comparator trials, lithium displayed efficacy comparable to that
of carbamazepine (181, 182), risperidone (183), olanzapine (184),
and chlorpromazine and other typical antipsychotics (185–190).
Among active comparator trials, however, only three (185, 186, 189)
were likely to be of sufficient size to detect possible differences
in efficacy between treatments. Open studies (191–194) and
randomized, active comparator-controlled studies (195–197)
indicate that lithium is likely to be effective for treatment of
pure or elated mania but is less often effective in the treatment
of mixed states.
Up to 75% of patients treated with lithium experience
some side effects (41, 198). These side effects vary in clinical
significance; most are either minor or can be reduced or eliminated
by lowering the lithium dose or changing the dosage schedule. For
example, Schou (199) reported a 30% reduction in side effects
among patients treated with an average lithium level of 0.68 meq/liter
compared with those treated with an average level of 0.85 meq/liter.
Side effects that appear to be related to peak serum levels (e.g.,
tremor that peaks within 1 to 2 hours of a dose) may be reduced
or eliminated by using a slow-release preparation or changing to
a single bedtime dose.
Dose-related side effects of lithium include polyuria, polydipsia,
weight gain, cognitive problems (e.g., dulling, impaired memory,
poor concentration, confusion, mental slowness), tremor, sedation or
lethargy, impaired coordination, gastrointestinal distress (e.g.,
nausea, vomiting, dyspepsia, diarrhea), hair loss, benign leukocytosis,
acne, and edema (200). Side effects that persist despite dosage
adjustment may be managed with other medications (e.g., beta-blockers
for tremor; diuretics for polyuria, polydipsia, or edema; topical
antibiotics or retinoic acid for acne). Gastrointestinal disturbances
can be managed by administering lithium with meals or changing lithium
preparations (especially to lithium citrate).
Lithium may cause benign ECG changes associated with repolarization.
Less commonly, cardiac conduction abnormalities have been associated
with lithium treatment. Anecdotal reports have linked lithium with
other ECG changes, including the exacerbation of existing arrhythmias
and, less commonly, the development of new arrhythmias (201).
The most common renal effect of lithium is impaired concentrating
capacity caused by reduced renal response to ADH, manifested as
polyuria, polydipsia, or both (202, 203). Although the polyuria associated
with early lithium treatment may resolve, persistent polyuria (ranging
from mild and well tolerated to severe nephrogenic diabetes insipidus)
may occur. Polyuria can frequently be managed by changing to a once-daily
bedtime dose. If the polyuria persists, management includes ensuring that
fluid intake is adequate and that the lithium dose is as low as
possible. If these measures do not ameliorate the problem, then
concurrent administration of a thiazide diuretic (e.g., hydrochlorothiazide
at a dose of 50 mg/day) may be helpful. The lithium dose
will usually need to be decreased (typically by 50%) to
account for the increased reabsorption induced by thiazides (198).
In addition, potassium levels will need to be monitored, and potassium
replacement may be necessary. Amiloride, a potassium-sparing diuretic,
is reported to be effective in treating lithium-induced polyuria
and polydipsia (203). Its advantages are that it does not alter
lithium levels and does not cause potassium depletion. Amiloride
may be started at 5 mg b.i.d. and may be increased to 10 mg b.i.d.
as needed (204).
Hypothyroidism occurs in 5%–35% of
patients treated with lithium. It occurs more frequently in women,
tends to appear after 6–18 months of lithium treatment,
and may be associated with rapid cycling (41, 80, 198, 205). Lithium-induced
hypothyroidism is not a contraindication to continuing lithium and
is easily treated by the administration of levothyroxine (198, 205).
In addition to the other signs and symptoms of hypothyroidism, patients
with bipolar disorder are at risk of developing depression or rapid
cycling. If these symptoms occur in the presence of laboratory evidence
of suboptimal thyroid functioning, then thyroid supplementation,
discontinuation of lithium, or both should be considered (206–208).
Hyperparathyroidism has also been noted with lithium treatment (209–211).
A small number of case reports have described exacerbation
or first occurrences of psoriasis associated with lithium treatment
(212). Some of these patients improved with appropriate dermatologic
treatment or when the lithium dose was lowered. In some cases, however,
lithium seemed to block the effects of dermatologic treatment, with
psoriasis clearing only after lithium was discontinued. In addition,
patients occasionally experience severe pustular acne that does
not respond well to standard dermatologic treatments and only resolves
once the lithium treatment is discontinued (212). This is in contrast
to the more common mild to moderate acne that can occur with lithium
treatment, which is usually responsive to standard treatments (198).
Approximately 10%–20% of patients
receiving long-term lithium treatment (i.e., for more than 10 years)
display morphological kidney changesusually interstitial
fibrosis, tubular atrophy, and sometimes glomerular sclerosis. These
changes may be associated with impairment of water reabsorption
but not with reduction in glomerular filtration rate or development
of renal insufficiency (41, 198, 213–216). Although irreversible
renal failure caused by lithium has not been unequivocally established,
there are a number of case reports of probable lithium-induced renal
insufficiency (215, 217, 218). Additionally, several studies have
shown that a small percentage of patients treated with lithium may
develop rising serum creatinine concentrations after 10 years or
more of treatment (215, 218).
Toxic effects of lithium become more likely as the serum level
rises (219). Most patients will experience some toxic effects with
levels above 1.5 meq/liter; levels above 2.0 meq/liter
are commonly associated with life-threatening side effects. For
many patients, the therapeutic range within which beneficial effects
outweigh toxic effects is quite narrow, so that small changes in
serum level may lead to clinically significant alterations in the
beneficial and harmful effects of lithium. Elderly patients may
experience toxic effects at lower levels and have a correspondingly
narrower therapeutic window (138).
Signs and symptoms of early intoxication (with levels above
1.5 meq/liter) include marked tremor, nausea and diarrhea,
blurred vision, vertigo, confusion, and increased deep tendon reflexes.
With levels above 2.5 meq/liter, patients may experience
more severe neurological complications and eventually experience
seizures, coma, cardiac dysrhythmia, and permanent neurological
impairment. The magnitude of the serum level and the duration of
exposure to a high level of lithium are both correlated with risk
of adverse effects (219). Therefore, rapid steps to reduce the serum
level are essential. In addition, during treatment for severe intoxication,
patients may experience "secondary peaks" during
which the serum level rises after a period of relative decline;
the clinician must therefore continue to monitor serum levels during
treatment for severe intoxication. The patient with lithium intoxication
should be treated with supportive care (e.g., maintenance of fluid
and electrolyte balance), and steps should be taken to prevent further
absorption of the medication (e.g., gastric lavage or, in the alert
patient, induction of emesis).
Hemodialysis is the only reliable method of rapidly removing
excess lithium from the body and is more effective than peritoneal
dialysis for this purpose (220). Criteria for the use of hemodialysis in
lithium intoxication are not firmly established, and the decision
to dialyze must take into account both the patient's clinical
status and the serum lithium level (219, 221). When serum lithium
levels are below 2.5 meq/liter, hemodialysis usually is
unnecessary. The need for hemodialysis differs in patients who have
developed toxicity after an acute overdose compared with those who
have developed gradual toxicity or have an acute overdose superimposed
on long-term lithium treatment. In acute poisoning, hemodialysis
is generally required with serum lithium levels over 6–8
meq/liter, whereas hemodialysis may be needed with serum
levels over 4 meq/liter in those who have been on long-term
regimens of lithium treatment. Hemodialysis may also be necessary
at lower serum levels in patients who are more susceptible to complications
because of underlying illnesses (e.g., cardiac disease, renal impairment).
Regardless of serum lithium level, hemodialysis is generally indicated in
patients with progressive clinical deterioration or severe clinical
signs of intoxication such as coma, convulsions,
cardiovascular symptoms, or respiratory failure (219, 221). Because
serum levels of lithium may rebound after initial hemodialysis,
repeat dialysis may be needed (219, 222).
In cases of overdose with sustained-release preparations of
lithium, development of toxicity is likely to be delayed, and the
duration of toxicity is likely to be prolonged (223, 224). This
should be taken into consideration in decisions about the need for
initial or repeat hemodialysis (219).
c) Implementation and dosing
Before beginning lithium treatment, the patient's
general medical history should be reviewed, with special reference
to those systems that might affect or be affected by lithium therapy
(e.g., renal, thyroid, and cardiac functioning). In addition, pregnancy
or the presence of a dermatologic disorder must be ascertained.
Patient education should address potential side effects of lithium
treatment as well as the need to avoid salt-restricted diets or
concomitant medications that could elevate serum lithium levels
(e.g., diuretics, angiotensin-converting enzyme inhibitors, nonsteroidal
anti-inflammatory drugs, cyclooxygenase-2 inhibitors).
Patients should be cautioned, particularly if nephrogenic diabetes
insipidus is present, that lithium toxicity might occur with dehydration
from environmental heat, gastrointestinal disturbance, or inadequate
Laboratory measures and other diagnostic tests are generally
recommended on the basis of pathophysiological knowledge and anticipated
clinical decisions rather than on empirical evidence of their clinical
utility. The decision to recommend a test is based on the probability
of detecting a finding that would alter treatment as well as the
expected benefit of such alterations in treatment. Recommended tests
fall into three categories: 1) baseline measures to facilitate subsequent
interpretation of laboratory tests (e.g., ECG, CBC); 2) tests to
determine conditions requiring different or additional treatments
(e.g., pregnancy, thyroid-stimulating hormone level); and 3) tests
to determine conditions requiring alteration of the standard dosage
regimen of lithium (e.g., creatinine level).
On the basis of these considerations, the following procedures
are generally recommended before beginning lithium therapy: a general
medical history, a physical examination, BUN and creatinine level
measurement, a pregnancy test, thyroid function evaluation, and,
for patients over age 40, ECG monitoring with rhythm strip. Some
authorities also suggest a CBC.
Lithium is usually started in low, divided doses to minimize
side effects (e.g., 300 mg t.i.d. or less, depending on the patient's
weight and age), with the dose titrated upward (generally to serum concentrations
of 0.5–1.2 meq/liter) according to response and
side effects (225). Lithium levels should be checked after each
dose increase and before the next. Steady-state levels are likely
to be reached approximately 5 days after dose adjustment, but levels
may need to be checked sooner if a rapid increase is necessary (e.g.,
in the treatment of acute mania) or if toxicity is suspected. As
levels approach the upper limits of the therapeutic range (i.e., '¥1.0
meq/liter), they should be checked at shorter intervals
after each dose increase to minimize the risk of toxicity.
Serum concentrations required for prophylaxis may be, in some
cases, as high as those required for treatment of the acute episode.
A controlled study by Gelenberg et al. (225) found that patients randomly
assigned to a "low" lithium level (0.4–0.6
meq/liter) had fewer side effects but more illness episodes
than patients in the "standard" lithium group
(0.8–1.0 meq/liter). However, the lithium levels of
some of the patients in the low-lithium group decreased relatively
rapidly from their previous treatment levels, a decrease that could
have increased their risk of relapse. Although the prophylactic efficacy
of lithium levels between 0.6 and 0.8 meq/liter has not
been formally studied, this range is commonly chosen by patients
and their psychiatrists (226). Despite the lack of formal study,
it is likely that for many patients, increases in maintenance lithium
levels will result in a trade-off between greater protection from
illness episodes at the cost of an increase in side effects. The "optimal" maintenance
level may therefore vary somewhat from patient to patient. Some
patients find that a single, daily dose facilitates treatment compliance
and reduces or does not change side effects.
The clinical status of patients receiving lithium needs to
be monitored especially closely. The frequency of monitoring depends
on the individual patient's clinical situation but generally
should be no less than every 6 months for stable patients. The optimal
frequency of serum level monitoring in an individual patient depends
on the stability of lithium levels over time for that patient and
the degree to which the patient can be relied upon to notice and
In general, renal function should be tested every 2–3
months during the first 6 months of treatment, and thyroid
function should be evaluated once or twice during the first 6 months
of lithium treatment. Subsequently, renal and thyroid function may
be checked every 6 months to 1 year in stable patients or whenever
clinically indicated (e.g., in the presence of breakthrough affective
symptoms, changes in side effects, or new medical or psychiatric
signs or symptoms) (198, 214).