Valproic acid dose response

Adjunctive therapy - Divalproex sodium or valproic acid may be added to the patient s regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/wk to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses less than 60 mg/kg/day. If satisfactory clinical response has not been achieved, measure plasma levels to determine whether they are in the usually accepted therapeutic range (50 to 100 mcg/mL). If the total daily dose exceeds 250 mg, administer in divided doses. 

Theimissen PT et al (2012) Dose-response toxicogenomic evaluation of valproic acid, cyproconazole and hexaconazole in the neural embryonic stem cell test (ESTn). Toxicol Sci 125(2) 430 38... 

The primary route of valproic acid metabolism is /3-oxidation, although up to 40% of a dose may be excreted as the glucuronide. At least 10 metabolites of valproic acid have been identified. Some of these may have weak anticonvulsant activity, and at least one metabolite may be responsible for the hepatotoxicity reported with valproic acid. One of the lesser oxidative metabolites, 4-en-valproic acid, causes significant hepatotoxicity in rats. The formation of this metabolite is increased when valproic acid is given with enzyme-inducing drugs. ... 

Recommended baseline and routine laboratory tests for valproate are listed in Table 68-12. Data from clinical trials in acutely manic patients indicated that there was an earlier response when trough serum levels were greater than 45 mcg/mL during the Hrst week of treatment. Although therapeutic serum concentrations of valproic acid have not been established in bipolar disorder, most clinicians use the anticonvulsant therapeutic range of 50 to 125 mcg/mL taken 12 hours after the last dose. Patients with cyclothymia or mild bipolar II disorder may have a therapeutic response to lower doses and blood levels, whereas some patients with a more severe form of bipolar disorder may require up to 150 mcg/mL. Serum valproic acid levels are usually determined every 1 to 2 weeks during the first 2 months, and then every 3 to 6 months during maintenance therapy. ... 

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