Lithium + Antiepileptics; Valproate - Drug Interactions

Clinical evidence,mechanism, importance and management

In a crossover study,16 healthy subjects were given valproate (as valproate semisodium) or a placebo twice daily for 12 days, to which lithium carbonate 300mg three times daily was added on days 6 to 10. The valproate-serum levels and AUC rose slightly, while serum-lithium levels were unaltered. Adverse events did not change significantly. It was concluded that concurrent use of these drugs is safe (See reference number 1). A review on efficacy of lithium/anticonvulsant combinations in bipolar disorder lists several studies in which combination of valproate (as valproate semi-sodium) and lithium was used. On whole combination was considered safe and well tolerated, although a few patients discontinued treatment due to adverse effects, which included gastrointestinal symptoms and raised liver transaminases. It was, however, difficult to know if these adverse effects were due to individual drugs or result of an interaction. Other adverse effects that have been reported with combined treatment include tremor, cognitive impairment and alopecia (See reference number 2).

Granneman GR,Schneck DW, Cavanaugh JH, Witt GF. Pharmacokinetic interactions and sideeffects resulting from concomitant administration of lithium and divalproex sodium. J Clin Psychiatry (1996) 57, 204–6.

Pies R. Combining lithium and anticonvulsants in bipolar disorder: a review. Ann Clin Psychiatry (2002) 14,223–32.