Pharmacokinetic interactions and side effects resulting from concomitant administration of lithium and divalproex sodium

BACKGROUND: Valproic acid is added to the lithium regimens of many patients with bipolar disorder, especially those with mania refractory to lithium treatment. METHOD: We evaluated the pharmacokinetic effects and safety of coadministration of lithium and valproate in 16 healthy volunteers in this randomized, placebo-controlled, two-period (12 days each) crossover trial. Valproate or placebo was given twice daily. On Days 6-10, lithium was added. Blood samples drawn on Days 5 and 10 were analyzed for valproate by high-pressure liquid chromatography (HPLC) and for lithium by atomic absorption spectrophotometry. RESULTS: Lithium pharmacokinetics were unchanged by valproate, but valproate C(max), C(min), and AUC rose slightly during lithium coadministration. Adverse events did not change significantly. CONCLUSION: Concomitant administration of lithium and valproate appears to be safe in patients with bipolar disorder.