Lithium is still the first-line choice for symptoms of manic episodes, although other agents are available from the category of anticonvulsants. When lithium is not tolerated because of its side effects, divalproex (Depakote) or carbamazepine (Tegretol) can be tried (Box 21-4 Mood Stabilizers and Anticonvulsants). Other newer anticonvulsants such as gabapentin (Neurontin) or lamotrigine (Lamictal) are being tested.

Hypotheses on Mechanisms of Action

Lithium (Eskalith, Lithobid) Lithium's exact mechanisms of action are unknown. It appears to enhance the serotonergic transmissions. It also affects the norepinephrine system by increasing its function in some parts of the brain and decreasing it in others. It also affects membrane permeability and ionic transport. Its inhibition of intracellular enzymes is also studied as a possible mechanism of action.

Carbamazepine (Tegretol) The mechanism of action of carbamazepine is unknown. It may be related to GABA level changes.

Divalproex (Depakote) Divalproex decreases GABA metabolism to result in increased GABA in the CNS.

Efficacy in Treating Symptoms

Lithium (Eskalith, Lithobid) The therapeutic effect of lithium may take 4 to 8 weeks to achieve. Serum levels of 0.5 to 1.2 mEq/L are recommended.

Carbamazepine (Tegretol) The therapeutic effect of carbamazepine may take 2 to 4 weeks. The correlation between clinical responses and serum levels is not established, although plasma levels of 8 to 12 mcg/ml are suggested.

Divalproex (Depakote) The therapeutic effect of divalproex may take 2 to 4 weeks after plasma levels of 50 to 120 mcg/ml are reached.

Common Side Effects

Lithium (Eskalith, Lithobid) Toxic reactions to lithium can occur even within the therapeutic range (Box 21-5 Possible Side Effects and Toxic Effects of Lithium). It may produce toxic effects in patients who use diuretics or who have renal failure, hyponatremia, diarrhea, and/or dehydration. Long-term toxic effects can include diabetes insipidus, hypothyroidism, leukocytosis, hypotension.

Carbamazepine (Tegretol) Toxic effects with carbamazepine include leukopenia, aplastic anemia, gastrointestinal (GI) disturbances, sedation, blurred vision, vertigo, rash, arrhythmia, and hepatitis.

Divalproex (Depakote) Toxic effects with divalproex include sedation, nausea, vomiting, tremor, GI upset, weight gain, ataxia, headache, hair loss, rash, clotting abnormalities, transient transaminase elevation, and false abnormality in thyroid function test.

Related Clinical Concerns

Children

Divalproex therapy for children younger than 2 years of age is associated with increased risk of hepatotoxicity. Safety and effectiveness of lithium therapy in patients younger than the age of 12 have not been established.

Adolescents

Divalproex, lithium, carbamazepine are contraindicated in pregnancy, so sexually active teens need to be advised about this risk. Side effects of acne, weight gain, tremors, and polyuria may be particularly upsetting for this age group.

Older Adults

Divalproex may increase the risk of somnolence and dehydration. Risk of side effects with lithium are pronounced in this population as excretion may be reduced due to impaired kidney function. Signs of toxicity may be exhibited within normal therapeutic ranges.

Other Clinical Concerns

Managing Safety in Lithium Therapy Lithium use must be monitored closely to prevent complications. Patients need an initial laboratory screening including complete blood count (CBC), thyroid levels, creatinine, blood urea nitrogen (BUN), electrolytes, glucose level, and an ECG. For the first month on lithium, blood levels are drawn weekly, then biweekly, and then every 2 to 3 months for maintenance once a stable level is achieved.

Causes of increased lithium levels include the following:

• Decreased intake of dietary sodium
• Sweating or dehydration
• Concurrent medications such as thiazides, amiloride, furosemide, ibuprofen, tetracyclines, methyldopa, and metronidazole

Additional contraindications include pregnancy, lactation, and history of myocardial infraction.

Managing Safety in Carbamazepine Therapy For patients starting on carbamazepine therapy, the initial work-up should include CBC with platelets, liver function tests, electrolytes and BUN, and an ECG in patients older than 40 years of age or with a history of cardiac problems.

Dosing should not increase by more than 200 mg/day until 800 mg/day is reached. These patients need to be monitored for possible blood dyscrasias with periodic CBCs, liver function tests, and drug level tests. Many drugs contribute to increased blood levels of carbamazepine. Concurrent medications need to be reviewed with the treatment team. MAOIs should not be prescribed for 2 weeks before or after carbamazepine. Monitor closely for signs of infection.

Contraindications include a history of bone marrow suppression; glaucoma; cardiac, hepatic, or renal impairment; pregnancy and breast-feeding; and a history of allergic reactions to TCAs.

Managing Safety in Divalproex Therapy Initial screening should include CBC, liver function tests, and prothrombin time/partial thromboplastin time. A major concern is the risk for hepatic failure; therefore, the patient needs to have periodic liver function tests and be monitored for symptoms such as jaundice and weakness during the first 6 months of therapy. Because clotting problems can also occur, patients need to be advised to avoid aspirin products and warfarin. In addition, some drugs such as cimetidine, fluoxetine, and amitriptyline can increase the blood levels of this drug. Divalproex is contraindicated during pregnancy and lactation and in the presence of any liver disease.

Patient and Family Education

• Teach patient to adhere strictly to lithium or carbamazepine therapy regimen.
• Advise patient to consult prescriber before starting any new medications or nutritional supplements.
• Teach patient how to avoid possible adverse interactions.
• Advise patient and family that lithium should be taken with food or milk to avoid GI irritation.
• Teach patient the lithium side effects that should be reported to the treatment team.
• Teach patient to avoid any significant changes in diet patterns or salt intake when taking lithium.
• Teach patient how to replace loss of fluids and electrolytes after diarrhea or vigorous exercise.
• Teach patient that over-the-counter analgesics (e.g., ibuprofen and other nonsteroidal anti-inflammatory agents) should be avoided while taking lithium.
• Advise pregnant patient that no mood stabilizers should be taken during pregnancy because of the risk of birth defects.
• Teach patient that flu-like symptoms that occur while taking carbamazepine should be reported to the treatment team.
• Teach patient that easy bruising or bleeding, pallor, or weakness should be reported to the treatment team.