Side Effects

CASE 87-1, QUESTION 7: What are the potential side effects of VPA therapy? How should T.R. be

monitored for these possible effects?

T.R. should be monitored for potential dose-related adverse reactions of VPA

including various gastrointestinal complaints (nausea, diarrhea, dyspepsia, anorexia),

sedation, ataxia, tremor, transaminase elevations, and thrombocytopenia. Reducing

the dosage, changing to an extended-release preparation,

90 or administering an

antacid or histamine H2-antagonist may mitigate gastrointestinal complaints. Central

nervous system effects such as ataxia and sedation may respond to dosage reduction,

although sedation may resolve with continued treatment. If a tremor is bothersome or

interferes with the patient’s functioning, a dosage reduction or change to the

extended-release preparation may provide relief.

86 Small elevations in transaminases

are considered benign; however, VPA should be discontinued if elevations are more

than 2 to 3 times the upper limit of normal.

91

Weight gain occurs in up to 20% of patients receiving VPA.

83 The increase in body

weight is particularly distressing to some patients and may contribute to medication

non-adherence. Weight gain has been associated with VPA at different

concentrations, so a dosage reduction may not be helpful.

83,92

In women, VPA

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has been associated with the development of polycystic ovary syndrome.

93 Core

features of polycystic ovary syndrome include oligomenorrhea and

hyperandrogenism, which develop in about 10% of women with BD taking VPA.

Alopecia occurs in 0.5% to 12% of patients and may improve with dose reduction.

94

There are several reports of VPA-induced hyperammonemic encephalopathy in

psychiatric patients.

95,96 Patients presenting with coma or mental status changes

should have serum ammonia and liver functions tests ordered. If VPA-induced

hyperammonemic encephalopathy is suspected, then VPA should be discontinued.

Other serious adverse events with VPA include fulminant hepatic failure,

agranulocytosis, and pancreatitis. All of these adverse events require immediate

discontinuation of therapy.

In January 2008, the U.S. Food and Drug Administration (FDA) issued a warning

to healthcare professionals about the potential for an increased risk of suicidality

associated with antiepileptic drugs (AEDs), including VPA. For its analysis, FDA

used data from 199 randomized clinical trials of 11 AEDs involving 43,892 study

participants with either psychiatric or neurologic disorders. In the “Warnings and

Precautions” section of AED product labels, it is stated that the risk of suicidality for

those treated with AEDs during clinical trials was approximately twice that of

placebo treatment (0.43% vs. 0.24%; adjusted relative risk = 1.8, 95% CI = 1.2, 2.7;

number needed to harm = 530). In these clinical trials, there were a total of four

suicides in AED-treated patients, and zero suicides in placebo-treated patients. As a

result, practitioners are advised to inform patients and caregivers to be vigilant about

the emergence or worsening of signs and symptoms of depression or mood/behavior

changes, especially if they involve thoughts or behaviors centered on self-harm when

patients receive AED treatment.

97

Once VPA therapy is initiated, liver function tests, VPA serum levels, and CBCs

with differential and platelets should be monitored at least monthly for the first 3

months and every 3 to 6 months thereafter.

11 Body weight should also be determined

at baseline and monitored monthly during therapy.

CASE 87-1, QUESTION 8: T.R. was titrated to a total daily VPA dosage of 2,500 mg/day and determined to

have a steady-state plasma concentration of 95 mcg/mL after 1 month of treatment. A routine CBC with

differential and platelet count was ordered at this time, and the following data were reported:

Red blood cells, 5.2 × 106/μL

Hemoglobin, 14.5 g/dL

Hematocrit, 43%

White blood cell count, 8.5 × 103/μL

Neutrophils, 59%

Lymphocytes, 27%

Monocytes, 6%

Eosinophils, 2%

Basophils, 0.5%

Platelets, 75 × 10

3

/μL

How should T.R.’s VPA-induced thrombocytopenia be managed?

VPA-induced thrombocytopenia occurs in 18% of patients and is associated with

female gender and higher VPA levels (>100 mcg/mL in women and >130 mcg/mL in

men).

98 Clinicians should educate patients to look for signs such as easy bruising or

bleeding. In most patients, thrombocytopenia is asymptomatic and responds to a

lowering of the VPA dosage; complete discontinuation of the drug is usually

unnecessary.

99 T.R.’s dosage should be reduced, and his platelet count should be

monitored closely. In addition, he should be observed for reemerging symptoms of

mania.

LITHIUM

Prelithium Workup

CASE 87-2

QUESTION 1: C.N., a 21-year-old woman, was diagnosed with her first episode of mania 3 weeks ago. At

that time, she was hospitalized and treated with olanzapine 15 mg daily. C.N.’s was stabilized, and after 10

days, she was discharged from the hospital. She was scheduled to see an outpatient psychiatrist for follow-up 1

week later, but she failed to keep the appointment. Today, C.N. arrives at the emergency department at the

request of her mother. C.N. is grabbing her mother’s hair and kicking wildly as she is pulled from the car. She

can be heard screaming “The FBI is after me, Mom! You want them to find me, don’t you? I would have made

it out of the country if you hadn’t gotten in the way! I was going to marry Prince Charles and become the new

queen of England.” On evaluation, C.N.’s mood is irritable, and she is pacing around the interviewer. She is

dressed in a short skirt and high heels and is wearing an excessive amount of makeup and costume jewelry.

During the interview, she interrupts the examiner, smiles, and says in a loud, provocative voice, “Let’s you and

me get out of here!” Her mother states that after C.N. was discharged from the hospital, she stopped taking

her olanzapine due to gaining some weight and, within several days, stopped attending her classes at the local

community college. She began staying out late, playing her radio loudly, and driving recklessly, finally hitting the

side of the garage while parking early this morning. The clinician would like to admit C.N. to the inpatient unit

and initiate lithium treatment. What laboratory tests are required before initiating lithium therapy for C.N.?

Because lithium can affect many organ systems, baseline laboratory values must be

evaluated before therapy is initiated. Baseline laboratory tests are useful in

determining contraindications to the use of lithium or conditions that may require an

adjustment in dosage. As a young, healthy female, C.N.’s prescreening laboratory

battery should include electrolytes, blood urea nitrogen, creatinine, urine specific

gravity, thyroid-stimulating hormone (TSH), thyroxine (T4

), and a CBC (Table 87-3).

Also, a pregnancy test should be obtained before starting therapy since lithium is a

known teratogen.

Table 87-3

Routine Monitoring During Lithium Therapy

Baseline Every 1–3 Months Yearly

CBC X

Electrolytes X X

Renal function

a X X

ECG

b X X

Urine X

Thyroid function X X

Lithium level

c X

Weight or BMI X X

Pregnancy

d X

aMonitor more often in patients with history of kidney disease.

bPatients ≥45 years or those with history of cardiac disease.

cWeekly monitoring during the first month of treatment is often recommended.

dWomen of childbearing potential.

BMI, body mass index; CBC, complete blood count; ECG, electrocardiogram.

Dosing

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CASE 87-2, QUESTION 2: C.N.’s baseline laboratory parameters were normal, and her pregnancy test was

negative. How should lithium treatment for C.N. be initiated?

Although there are many strategies for calculating lithium dosage requirements, it

is simplest to begin C.N. at a dosage of 300 mg twice daily. This is a common

starting dose for a healthy adult patient.

Patients experiencing an acute manic episode require higher lithium levels

compared with maintenance therapy. The goal for the acute management of C.N. is a

serum level between 0.8 and 1.2 mEq/L.

11 Because lithium is not immediately

effective, C.N.’s lithium dosage can be adjusted based on the results of lithium serum

levels checked weekly until the manic episode resolves. As she recovers and enters

the maintenance phase of treatment, both C.N.’s lithium dosage and her lithium levels

will require re-evaluation (see Case 87-8, Question 1).

CASE 87-2, QUESTION 3: How long will it take for C.N. to get the full effect of lithium?

The half-life of lithium in a young patient with normal renal function is

approximately 24 hours; therefore, steady-state concentrations are typically achieved

in approximately 5 days. The onset of action is slow, taking as long as 1 to 2 weeks

to fully exert its therapeutic effects.

11 Because of the delay in onset, it is appropriate

to use an adjunctive medication to help reduce C.N.’s acute symptoms. Both

benzodiazepines and antipsychotics have been used in this manner.

11 AAPs are

preferred over typical antipsychotics (see also Chapter 85, Schizophrenia) and have

been demonstrated to enhance efficacy and accelerate time to response when used in

combination with lithium in acute mania.

48 Benzodiazepines work rapidly to reduce

agitation, anxiety, and decreased need for sleep.

100

Adverse Effects

CASE 87-2, QUESTION 4: After 3 weeks of lithium therapy, C.N. is demonstrating significant improvement

in her sleep, impulsivity, delusions, and activity level. She has achieved a lithium carbonate dose of 1,200

mg/day, and her lithium level is 0.8 mEq/L. Today she is complaining to the clinical staff that she has developed

a hand tremor. Soon after her clinician arrives to evaluate her, C.N. asks to be excused so that she can go to

the bathroom. How might C.N.’s presentation be related to her medication?

When considering adverse effect management early in lithium therapy, it becomes

important to monitor lithium levels closely. When patients start to recover from acute

mania, the rate of lithium clearance may decrease and patients may demonstrate an

increase in lithium levels and worsening side effects (Table 87-4). This does not

seem to be the case with C.N. because her lithium level is within the accepted range

for the management of acute mania.

C.N. is complaining of a hand tremor. She should be interviewed and examined to

determine its origin. Lithium-induced tremor occurs in 10% to 65% of treated

patients and is characteristically rapid, regular, and fine in amplitude.

100,101 Often, this

tremor occurs early in therapy and improves with time. Caffeine, personal or family

history of tremor, alcoholism, anxiety, antidepressants, antipsychotics, and possibly

older age enhance the risk of lithium-induced tremor.

101 The tremor is more common

in patients with higher serum concentrations and may be worse at times of peak

lithium levels.

11

If C.N. is not bothered by the tremor and suffers no impairment,

treatment is not necessary. If the tremor becomes problematic, her lithium dosage

may be reduced or a β-adrenergic blocking agent can be added. Propranolol is the

most commonly used. Additionally, switching to a sustained-release lithium

preparation may reduce peak serum levels and ameliorate tremors if associated with

peak concentrations.

11 Because it is early in treatment and C.N. has only a moderate

lithium level, it is reasonable to add propranolol 10 mg 3 times a day rather than to

reduce the lithium dosage (if an intervention is required). Propranolol usually is

effective at dosages less than 160 mg/day.

101 C.N. should be educated about her

tremor, the adverse effects of propranolol (see Chapter 9, Essential Hypertension)

and instructed to minimize her caffeine consumption.

Table 87-4

Lithium Adverse Effects

Adverse Effect Considerations

ECG changes T-wave suppression, delayed or irregular rhythm, increase in

PVCs; SSNS; myocarditis

Edema Primarily ankles and feet; transient or intermittent; secondary to

effects on sodium and carbohydrate metabolism; caution about

diuretics and sodium restriction to avoid lithium toxicity

Acne Worsens

Psoriasis Treatment-refractory worsening

Rashes Maculopapular and follicular

Hypothyroidism About 5% goiter; about 30% clinically significant hypothyroidism;

may diminish sex drive

Hyperparathyroidism Clinically not significant

Teratogenicity Ebstein anomaly (tricuspid valve malformation, atrialseptal

defect); educate female patients, encourage advanced planning

regarding pregnancy.

Anorexia, nausea (10%–30%) Usually early in treatment and usually transient; may be early sign

of toxicity

Diarrhea (5%–20%) Slow-release preparations may help

Leukocytosis May be useful in disorders such as Felty syndrome, iatrogenic

neutropenia

Tremor (10%–65%) Dose-related; men > women; worse with antidepressants and

antipsychotics; reduce dose or use β-blocker

Cognitive disruption (10%) Worsens compliance; perceived as “mental dulling”

Fatigue or weakness May be early toxicity; may mimic depression

Polyuria-polydipsia (nephrogenic diabetes

insipidus)

May be an indication of morphological changes; requires adequate

hydration

CBZ, carbamazepine; ECG, electrocardiogram; PVC, premature ventricular contraction; SSNS, sick sinus node

syndrome.

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In addition, C.N. should be asked about her trip to the bathroom during this clinic

visit because lithium may cause both diarrhea and polyuria. Polyuria and polydipsia

are common, occurring in up to 60% of patients.

102 Nephrogenic diabetes insipidus is

less common, affecting about 10% of patients on long-term treatment.

103 Nephrogenic

diabetes insipidus (see Chapter 53, Diabetes Mellitus) is dose dependent, so C.N.

can be told that a lower lithium dose may minimize the symptoms. Although the

advantages of once-daily administration of lithium are not universally accepted,

switching a stabilized patient to this schedule with its lower trough levels may help

to reduce urine volume.

11

If C.N. were to fail to respond to either of these

interventions, amiloride could be administered, which minimizes lithium’s effect on

free water clearance.

11,104

If C.N.’s trip to the bathroom was because of diarrhea, lithium should be evaluated

as a possible cause; up to 20% of patients started on lithium experience diarrhea,

epigastric bloating, and sometimes stomach pain early in therapy.

105 Diarrhea from

lithium is associated with high serum levels, once-daily dosing, and rapidly absorbed

preparations; therefore, divided doses may help to alleviate the problem. Use of

lower doses and switching to sustained-release preparations are alternative

strategies that could be used if C.N. is experiencing diarrhea or polyuria. Her fluid

status and lithium level also should be monitored closely. Dehydration leads to

increased lithium reabsorption in the proximal tubule and could result in

accumulation and lithium toxicity.

CASE 87-2, QUESTION 5: What should C.N. be told regarding potential renal damage from lithium?

C.N. should be informed that lithium could adversely affect her kidneys. Long-term

treatment has been associated with reduced kidney function and, rarely, end-stage

renal disease.

106 Routine monitoring of renal function (Table 87-3) allows for the

identification of patients with precipitous declines in glomerular filtration. In such

patients, lithium should be discontinued to prevent progression to end-stage renal

disease. Risk factors for renal insufficiency include episodes of lithium intoxication,

medical conditions that impair glomerular filtration (e.g., hypertension, diabetes

mellitus), and concurrent medications that are damaging to the kidney.

107

Communication with her physician about situations that increase the risk of lithium

toxicity (see Case 87-2, Question 7) and cooperation with regular lithium and renal

function monitoring can vastly reduce the risk of renal disease. Finally, C.N. must be

informed that polyuria is not related to any of the more serious renal side effects.

Patient Education

CASE 87-2, QUESTION 6: What lithium education should C.N. receive prior to discharge from the hospital?

As with all medications, C.N. should be instructed to disclose all medications she

is taking to each of her healthcare providers. She should be informed that

dehydration, fever, vomiting, or sodium-restricted diets could lead to increases in her

lithium level. Therefore, she needs to drink plenty of fluids and should avoid

restricting sodium.

C.N. should be instructed to contact her physician if she starts to experience any

symptoms of lithium toxicity, including worsening tremor, slurred speech, muscle

weakness or twitches, or difficulty walking. C.N. should be told to use caution in

selecting over-the-counter medications. Specifically, she should be warned to avoid

the use of preparations containing nonsteroidal anti-inflammatory drugs, which can

increase lithium levels.

108 C.N. should know that caffeine can sometimes be

troublesome in patients taking lithium, worsening tremor on a short-term basis and

lowering lithium levels during the long term.

108 With regard to serum lithium level

monitoring, C.N. needs to know that lithium levels usually are drawn approximately

12 hours after a dose of lithium. If she is taking lithium in the evening and the

morning, she should take her evening dose and then report for a blood sample to be

drawn in the morning before taking her morning dose.

Toxicity

CASE 87-2, QUESTION 7: About 6 months after discharge, C.N.’s mother calls, concerned that C.N. has

been complaining of nausea, vomiting, and diarrhea for several days. During the past few hours, C.N. has

become confused and has developed a coarse tremor and slurred speech. It has been 4 months since C.N.’s

lithium level has been checked. The only change is that C.N. recently started taking naproxen for headaches.

What action should be taken?

There is a strong possibility that C.N. is suffering from lithium toxicity, which can

occur acutely from an overdose or insidiously from reduced lithium clearance. Mild

toxicity at levels less than 1.5 mEq/L causes feelings of apathy, lethargy, and muscle

weakness accompanied by nausea and irritability. Moderate toxicity occurs between

1.5 and 2.5 mEq/L with symptoms progressing to coarse tremor, slurred speech,

unsteady gait, drowsiness, confusion, muscle twitches, and blurred vision. Severe

toxicity at levels greater than 2.5 mEq/L can result in seizures, stupor, coma, renal

failure, and cardiovascular collapse. C.N. seems to be experiencing moderate lithium

toxicity. She should stop any medications that can decrease lithium clearance and the

lithium itself until instructed to resume it. She should be taken to the emergency

department immediately, where stat laboratory tests, including a lithium level,

electrolytes, and renal function tests, should be ordered. There is no antidote for

lithium intoxication. Intravenous solutions should be started to ensure that C.N. is

hydrated adequately, and electrolyte abnormalities should be corrected promptly.

Depending on the results of physical examination and laboratory tests, cardiac

monitoring should be instituted and hemodialysis should be considered.

Hemodialysis is used to shorten the exposure of different tissues of the body to the

elevated lithium concentration and to lower the lithium level to 1.0 mEq/L.

Mohandas and Ramjmohan suggest that candidates for hemodialysis include those

with: compromised renal function, severe (irreversible) neurological symptoms,

acute lithium ingestions where symptoms are clear and serum levels are greater than

4.0 mEq/L, or a chronic toxicity where lithium levels exceed the therapeutic values

with a clearly manifested clinical picture.

109

Hypothyroidism

CASE 87-2, QUESTION 8: After receiving lithium 1,200 mg/day for 1 year, C.N. returns complaining that

the lithium is slowing her down. She is tired and has gained weight in recent weeks and thinks that she is

becoming depressed. In the examining room, C.N. complains that the temperature is too cold. What is the most

likely cause of C.N.’s complaints? What treatment should be instituted?

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C.N.’s symptoms are consistent with those of hypothyroidism.

Lithium affects the incorporation of iodine into thyroid hormone, interferes with

secretion of thyroid hormones, and may interfere with the peripheral conversion of T4

to T3

(triiodothyronine).

110 According to laboratory indices, the incidence of

hypothyroidism in lithium-treated patients with BD ranges from 28% to 32%

compared with 6% to 11% in patients not taking lithium.

111 Risk factors for lithiuminduced hypothyroidism include female gender, family history of hypothyroidism or

thyroid illness in first-degree relatives, weight gain, elevated baseline TSH,

preexisting autoantibodies, an iodine-deficient diet, rapid cycling, and elevated

lithium levels.

112 For women, the first 2 years of treatment is a period of heightened

risk as well as for any middle-aged patient starting lithium.

112

Thyroid function tests should be ordered to evaluate C.N.’s current symptoms. If

she is found to be hypothyroid, discontinuation of lithium is not necessary. She should

receive levothyroxine in doses that normalize her thyroid function tests. Even if she

has an elevated TSH with normal levels of T3 and T4

, low-dose thyroid

supplementation may help to resolve her symptoms, and prevent breakthrough

depression.

110

Drug and Dietary Interactions

CASE 87-3

QUESTION 1: T.J., a 35-year-old man, is hospitalized and treated with lithium for a severe manic episode. He

had a stable lithium level of 0.84 mEq/L for several weeks, but his last two levels were 0.65 and 0.61 mEq/L

without any change in his drug therapy. T.J. insists that he is taking the medication as prescribed. The nursing

staff believes that he is adherent with his medication but notes that he is spending more time off the unit and in

the cafeteria. What factors could contribute to a decrease in T.J.’s lithium levels?

Drug interactions are a common cause of changes in lithium levels, but there have

been no changes in T.J.’s regimen (Table 87-5 provides a list of clinically significant

drug interactions). Changes in formulation or brand may sometimes have an impact

on lithium levels. Nevertheless, lithium is relatively well absorbed and has a long

elimination half-life, so this usually does not result in large changes in the 12-hour

postdose lithium level. Occasionally, patients switched from lithium citrate to solid

dosage forms experience small changes in lithium levels.

T.J. should be questioned about his visits to the cafeteria because diet can have a

major influence on lithium excretion. If T.J. is consuming large amounts of

caffeinated beverages or salty snacks, a reduction in lithium levels could occur.

Increases in dietary sodium intake and the ingestion of methylxanthines (e.g., caffeine,

theophylline) can increase lithium clearance.

108

Finally, acute mania can increase lithium clearance.

7

If T.J. was showing signs of a

relapse, his decrease in lithium levels might be attributable to his return to a manic

state.

Lithium in Pregnancy

CASE 87-4

QUESTION 1: A.J., a 36-year-old woman, has been maintained successfully on lithium therapy for 5 years

for BD. She asks whether she should stay on lithium because she plans to become pregnant in the near future.

While there is considerable disagreement about the importance of lithium as a

teratogen, it has been associated with a variety of congenital malformations,

including the rare cardiac malformation, Ebstein anomaly.

113 Lithium was originally

thought to increase the risk of Ebstein anomaly 400 times; however, the risk is more

likely 20 to 40 times higher than in the general population.

114 The current estimated

overall risk for congenital malformations related to lithium treatment is

approximately 4% to 12% (compared with 2%–4% in controls).

115 Because

malformations are most likely to occur in the first trimester of pregnancy, it is

advisable for patients to avoid lithium, when possible, during this high-risk period.

Table 87-5

Lithium Drug Interactions of Clinical Significance

Drugs That Increase Lithium Levels

NSAIDs

Many NSAIDs have been reported to increase lithium levels as much as 50%–60%. This probably is owing

to an enhanced reabsorption of sodium and lithium secondary to inhibition of prostaglandin synthesis.

Diuretics

All diuretics can contribute to sodium depletion. Sodium depletion can result in an increased proximal tubular

reabsorption of sodium and lithium. Thiazide-like diuretics cause the greatest increase in lithium levels,

whereas loop diuretics and potassium-sparing diuretics seem to be somewhat safer.

Angiotensin-Converting Enzyme (ACE) inhibitors

ACE inhibitors and lithium both result in volume depletion and a reduction in glomerular filtration rate. This

results in reduced lithium excretion.

Angiotensin II Receptor Blockers (ARBs)

ARBs decrease in sodium and reabsorption via AT1

blockade results in reduced lithium excretion.

Drugs That Decrease Lithium Levels

Theophylline, caffeine

Theophylline and caffeine may increase renal clearance of lithium and result in a decrease in levels in the

range of 20%.

Acetazolamide

Acetazolamide may impair proximal tubular reabsorption of lithium ions.

Sodium

High dietary sodium intake promotes the renal clearance of lithium.

Drugs That Increase Lithium Toxicity

Methyldopa

Cases of sedation, dysphoria, and confusion owing to the combined use of lithium and methyldopa have been

reported.

Carbamazepine

Cases of neurotoxicity involving the combined use of lithium and carbamazepine have been reported in

patients with normal lithium levels.

Calcium-channel antagonists

Cases of neurotoxicity involving the combined use of lithium and the calcium-channel blockers verapamil and

diltiazem have been reported. Lithium interferes with calcium transport across cells.

Antipsychotics

Cases of neurotoxicity (encephalopathic syndrome, extrapyramidal effects, cerebellar effect, EEG

abnormalities) have been reported owing to the combined use of lithium and various antipsychotics. The

interaction may be related to increase in phenothiazine levels, changes in tissue uptake of lithium, or

dopamine-blocking effects of lithium. Studies attempting to demonstrate this effect have yielded differing

results.

Serotonin-selective reuptake inhibitors

Fluvoxamine and fluoxetine have been reported to result in toxicity when added to lithium. Sertraline has been

reported to cause nausea and tremor in lithium recipients.

ACE, angiotensin-converting enzyme; EEG, electroencephalogram; NSAIDs, nonsteroidal anti-inflammatory

drugs.

In addition to cardiac malformations, infants exposed to lithium have been

reported to have hypotonia, nephrogenic diabetes insipidus, and thyroid

abnormalities.

113 Lithium administration during pregnancy increases the risk of

premature delivery by a factor of two to three.

116 Unfortunately, the relative safety of

other

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