Acute bipolar mania: Aggressive initial dosing provides faster symptom relief

Patients who develop a manic episode while taking lithium pose a therapeutic dilemma. If they stop taking lithium—especially abruptly—manic symptoms can return in as few as 2 days. For these patients, consider increasing the usual dosage by 50% to 100% on the first day of mania treatment,⁴ then continue a dosage that maintains efficacy and achieves a therapeutic blood level.

To avoid GI upset, avoid any single dose of >1,500 mg; if a greater dosage is needed, divide it for improved tolerance. Obtain lithium blood levels at baseline, after 4 days, and thereafter as clinically relevant to monitor for drug interactions that may affect serum levels.

Side effects—GI irritation, tremor, muscle weakness, thirst, polyuria—are common in the first week, and weight gain may occur after prolonged treatment.

DIVALPROEX

In a study by Keck et al¹ of 19 adults with acute bipolar mania, aggressive initial dosing of divalproex sodium, 20 mg/kg/d, was well-tolerated and shortened hospitalization. Side effects including sedation and nausea occurred at a rate similar to that seen with more-gradual titration.

To calculate the initial dose, the authors used a conversion factor of 20 mg/kg/d or added a zero to the patient’s weight in pounds. This amount was given in single or divided doses the first day, then continued for 4 to 7 days. Blood levels were measured on day 4, and all 15 patients who completed the study achieved serum valproate levels >50 mcg/mL.

In a double-blind study by Hirschfeld et al,⁵ 59 adults with Young Mania Rating Scale (YMRS) scores >14 were randomly assigned to receive divalproex oral loading; divalproex nonloading (250 mg tid on days 1 and 2, followed by standard titration on days 3 to 10); or lithium carbonate (300 mg tid, followed by standard titration on days 3 to 10).

Divalproex loading—30 mg/kg/d on days 1 and 2, followed by 20 mg/kg on days 3 to 10— yielded valproate levels >50 mcg/mL in 84% of patients by day 3. Rapid loading appeared to increase antimanic efficacy, as measured by YMRS endpoint scores, without increasing adverse effects. For Table 1, we converted this study’s metric values to patient weight in pounds.

Side effects. Divalproex can inhibit metabolism of other drugs (including anticonvulsants such as lamotrigine) and increase their blood levels. Side effects such as sedation, alopecia, abdominal pain, diarrhea, and tremor may require observation and treatment. Pancreatitis, hepatitis, and allergic reactions are rare but may require discontinuation.

Recommendation. Aggressive initial dosing and loading for patients with acute mania has been reported with enteric-coated delayed-release and extended-release⁶ divalproex sodium tablets. With identical dosages, the extended-release form produces 11% lower serum levels than the delayed-release form.⁷

Aggressive dosing of oral valproic acid preparations is not recommended and is likely to be poorly tolerated.⁸ A pilot study evaluating IV valproate loading in acute mania found no changes in mania in the 2 hours that followed loading.⁹

CARBAMAZEPINE

Carbamazepine is used off-label to treat mania and mixed phases of bipolar disorder.^4,9,10 Excessive absorption rates are associated with dizziness, ataxia, and nausea. Side effects may occur when the plasma level is therapeutic for epilepsy (4 to 12 mcg/mL).¹¹

In mania, the relationship between carbamazepine levels and clinical response is not always clear. Lerer et al¹² found a correlation between acute mania response and a serum level of 8.8 mcg/mL (range 4.7 to 14.0 mcg/mL).

Patients with acute mania may require 600 to 1,600 mg/d. Carbamazepine is available in immediate-release and controlled-release preparations. Because generic preparations might not be bio-equivalent,¹³ use the same formulation throughout treatment to maintain consistent serum levels.

Enzymatic auto-induction—in which carbamazepine gradually increases the activity of its metabolic enzyme—is likely to occur at 3 to 5 weeks of administration, often after hospital discharge. An aggressive initial rescue adjustment can be used if a patient develops mania after having been stabilized on carbamazepine for >6 weeks. Because these patients are past the point of auto-induction, a target blood level of 8.8 mcg/mL can be used and the dosage adjusted proportionally.

For example, if mania recurs in a patient who is stabilized on carbamazepine, 400 mg/d (plasma level 4.5 mcg/mL), carbamazepine can be loaded up to 800 mg/d. Measure the plasma level within 4 days; the target level would be 9.0 mcg/mL (2 times 4.5 mcg/mL), which closely approximates steady state and sets up a ratio to reach the target level of 8.8 mcg/mL.

Side effects include ataxia, diplopia, and dizziness. Complete blood counts, liver function studies, plasma levels, and serum chemistries require regular monitoring.

Recommendation. Carbamazepine is not recommended for oral loading in patients who have never taken it or for those with hyponatremia, hepatic dysfunction, or history of intolerance or agranulocytosis.