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C. Additional Information About Pharmacotherapeutic Agents

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1. Lithium

  • Side effects

    • Up to 75% of patients experience some side effects, but most side effects either are minor or can be reduced or eliminated by lowering the lithium dose or changing the dosage schedule.

    • Side effects related to peak serum levels (e.g., tremor 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.

    • Side effects include polyuria, polydypsia, weight gain, cognitive problems, tremor, sedation or lethargy, impaired coordination, gastrointestinal distress, hair loss, benign leukocytosis, acne, and edema.

    • With long-term lithium treatment (>10 years), 10% to 20% of patients display morphological kidney changes. These changes are not generally associated with renal failure, although there are some case reports of renal insufficiency probably induced by lithium.

    • Most patients experience some toxic effects with levels above 1.5 meq/L; levels above 2.0 meq/L are commonly associated with life-threatening side effects. At higher serum levels, hemodialysis may be needed to minimize toxicity.

  • Implementation

    • Initial workup

      • The following are generally recommended before beginning lithium therapy:

        • General medical history and physical examination

        • Blood urea nitrogen (BUN) and creatinine levels

        • Tests of thyroid function

        • Electrocardiogram (ECG) with rhythm strip for patients over age 40

        • Pregnancy test (in women of childbearing age)

    • Dosing

      • Start in low divided dosages to minimize side effects (e.g., 300 mg t.i.d. or less, depending on the patient's weight and age).

      • Titrate dosage upward (generally to serum concentrations of 0.5 to 1.2 meq/L) according to response and side effects.

      • Check lithium level after each dosage increase (steady-state levels are likely to be reached approximately 5 days after a dosage adjustment).

      • Check at shorter intervals after dosage increase as levels approach upper limits of the therapeutic range (i.e., greater than 1.0 meq/L).

      • The "optimal" maintenance level may vary from patient to patient. Some patients require the level used to treat acute mania; others can be satisfactorily maintained at lower levels.

    • Long-term monitoring of laboratory values

      • Serum lithium levels

        • - At minimum, check every 6 months in stable patients and whenever the clinical status changes.

        • - The optimal frequency of monitoring depends on the stability of lithium levels over time for that patient and the degree to which the patient can be relied on to notice and report symptoms.

      • Renal function

        • - In general, during the first 6 months of treatment, test every 2 to 3 months.

        • - Subsequently, check every 6 to 12 months in stable patients as well as whenever the clinical status changes.

      • Thyroid function

        • - In general, during the first 6 months of treatment, test once or twice.

        • - Subsequently, check every 6 to 12 months in stable patients and whenever the clinical status changes.

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2. Divalproex/Valproate/Valproic Acid

  • Side effects

    • Common dose-related side effects of valproate include gastrointestinal distress, benign hepatic transaminase elevations, osteoporosis, tremor, and sedation.

    • Patients with past or current hepatic disease may be at increased risk for hepatotoxicity.

    • Mild, asymptomatic leukopenia and thrombocytopenia occur less frequently and are reversible on drug discontinuation.

    • Other side effects include hair loss, increased appetite, and weight gain.

    • Although risks are unclear, female patients should be monitored for possible development of polycystic ovarian syndrome.

    • Rare, idiosyncratic, but potentially fatal adverse events include irreversible hepatic failure, hemorrhagic pancreatitis, and agranulocytosis; patients should be educated about the signs and symptoms of hepatic and hematological dysfunction and warned to contact their physician immediately if symptoms develop.

  • Implementation

    • Initial workup

      • The following are generally recommended before beginning valproate therapy:

        • Before treatment, take a general medical history with special attention to hepatic, hematological, and bleeding abnormalities.

        • Obtain liver function tests and hematological measures.

    • Dosing

      • For hospitalized patients with acute mania, valproate can be administered at an initial dosage of 20 to 30 mg/kg per day in inpatients. After obtaining a valproate level, adjust the dose to achieve a serum level between 50 and 125 g/mL.

      • For outpatients, elderly patients, or patients with hypomania or euthymia, start at 250 mg t.i.d. Titrate the dose upward by 250 to 500 mg/day every few days, depending on clinical response and side effects, generally to a serum concentration of 50 to 125 g/mL, with a maximum adult daily dosage of 60 mg/kg per day. Once the patient is stable, simplify to once- or twice-daily dosing.

      • Bioavailability of the extended-release preparation, divalproex ER, is about 15% less than that of the immediate-release preparation; doses of divalproex ER will need to be increased proportionately.

    • Drug interactions

      • Valproate displaces highly protein-bound drugs from their protein binding sites. Dosage adjustments will be needed.

      • Because valproate inhibits lamotrigine metabolism, lamotrigine must be initiated at less than half the usual dose.

    • Long-term monitoring of laboratory values

      • Patients should be educated about the signs and symptoms of hepatic and hematological dysfunction and instructed to report these symptoms if they occur.

      • Most psychiatrists perform clinical assessments, including tests of hematological and hepatic function, at a minimum of every 6 months for stable patients who are taking valproate.

      • Serum levels of valproic acid should be checked when clinically indicated (e.g., when another medication may change the metabolism of valproic acid).

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3. Lamotrigine

  • Side effects

    • The most common side effects are headache, nausea, infection, and xerostomia.

    • In early clinical trials with patients with epilepsy, rapid titration of lamotrigine dosage was associated with a risk of serious rash, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Risk was approximately 0.3% in adults and approximately 1% in children.

    • Patients should be informed of the risk of rash and of the need to contact the psychiatrist or primary care physician immediately if any rash occurs.

    • Rash can occur at any time during treatment but is more likely early in treatment.

    • At rash onset, it is difficult to distinguish between a serious and a more benign rash.

    • Particularly worrisome, however, are rashes accompanied by fever or sore throat, those that are diffuse and widespread, and those with prominent facial or mucosal involvement. In such circumstances, lamotrigine (and valproate, if administered concurrently) should be discontinued.

    • In clinical trials, use of a slow dosage titration schedule (see below) reduced the risk of serious rash in adults to 0.01% (comparable to other anticonvulsants).

    • Rash may be more likely if lamotrigine and valproate are administered concomitantly.

  • Implementation

    • Lamotrigine should be administered at 25 mg/day for the first 2 weeks, then at 50 mg for weeks 3 and 4.

    • After that, 50 mg/week can be added as clinically indicated.

    • To minimize the risk of potentially serious rash in patients who are receiving valproate, the dose or the dosage schedule should be halved (i.e., 12.5 mg/day or 25 mg every other day for 2 weeks, then 25 mg daily for weeks 3 and 4).

    • Concurrent carbamazepine treatment will lead to increased metabolism of lamotrigine and will require that dosing be doubled.

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4. Carbamazepine

  • Side effects

    • Up to 50% of patients receiving carbamazepine experience side effects.

    • The most common side effects include fatigue, nausea, and neurological symptoms such as diplopia, blurred vision, and ataxia.

    • Less frequent side effects include skin rashes, mild leukopenia, mild liver enzyme elevations, mild thrombocytopenia, hyponatremia, and (less commonly) hypo-osmolality.

    • Rare, idiosyncratic, but serious and potentially fatal side effects include agranulocytosis, aplastic anemia, thrombocytopenia, hepatic failure, exfoliative dermatitis (e.g., Stevens-Johnson syndrome), and pancreatitis.

    • In addition to careful monitoring of clinical status, it is essential to educate patients about the signs and symptoms of hepatic, hematological, or dermatological reactions and instruct them to report symptoms if they occur.

    • Other rare side effects include systemic hypersensitivity reactions; cardiac conduction disturbances; psychiatric symptoms, including sporadic cases of psychosis; and, very rarely, renal effects, including renal failure, oliguria, hematuria, and proteinuria.

    • The carbamazepine analogue oxcarbazepine may be a useful alternative to carbamazepine based on its superior side effect profile.

  • Implementation

    • Initial workup

      • The following are generally recommended before beginning carbamazepine therapy:

        • Minimum baseline evaluation should include a complete blood count (CBC) with differential and platelet count, a liver profile (LDH, SGOT, SGPT, bilirubin, alkaline phosphatase), and renal function tests. Serum electrolytes may also be obtained, especially in the elderly, who may be at higher risk for hyponatremia.

        • Before treatment, a general medical history and a physical examination should be done, with special emphasis on prior history of blood dyscrasias or liver disease.

    • Dosing

      • Carbamazepine is usually begun at a total daily dose of 200 to 600 mg, in three to four divided doses.

      • In hospitalized patients with acute mania, the dosage may be increased in increments of 200 mg/day up to 800 to 1000 mg/day (unless side effects develop), with slower increases thereafter as indicated.

      • In less acutely ill outpatients, dose adjustments should be slower to minimize side effects.

      • Maintenance dosages average about 1000 mg/day but may range from 200 to 1600 mg/day in routine clinical practice.

      • Levels established for treatment of seizure disorders (serum concentration between 4 and 12 g/mL) are generally applied to patients with bipolar disorder.

      • Use trough levels (drawn prior to the first morning dose) 5 days after a dose change.

    • Long-term monitoring of laboratory values

      • CBC, platelet, and liver function tests should be performed every 2 weeks during the first 2 months of carbamazepine treatment.

      • Thereafter, if laboratory tests remain normal and no symptoms of bone marrow suppression or hepatitis appear, blood counts and liver function tests should be obtained at least every 3 months; more frequent monitoring is necessary if there are hematological or hepatic abnormalities.

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5. Antipsychotic Medications

  • Implementation and relative side effects of second-generation antipsychotic medications with FDA indications for treatment of acute manic or mixed episodes are described in Table 1.

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Table Reference Number
TABLE 1. Dosing and Relative Side Effects of Second-Generation Antipsychotic Agents for the Treatment of Acute Mania or Mixed Episodes
Table Reference Number
TABLE 1. Dosing and Relative Side Effects of Second-Generation Antipsychotic Agents for the Treatment of Acute Mania or Mixed Episodes

References

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