Valproate/divalproex: optimal therapeutic serum levels. Two randomized controlled trials have shown valproate(Drug information on valproate)/divalproex to be effective in the treatment of acute mania, but the relationship between serum levels and efficacy was not fully established.29,30 The American Psychiatric Association’s practice guidelines describe a broad therapeutic range for trough valproate/divalproex serum concentrations between 50 and 125 µg/mL.31 A number of studies have shown a significant positive relationship between valproate serum levels and clinical response.32-34
A recent study by Allen and colleagues12 examined 374 patients with mania and found that the efficacy of valproate was significantly higher than that of placebo beginning at 71.4 to 85.0 µg/mL and for all higher valproate levels. In addition, the 94.1 to 107.0 µg/mL and greater than 107.0 µg/mL groups were superior to the lowest valproate serum level group (less than 55.0 µg/mL group). The mean discontinuation rate for adverse events across all groups was 3%, suggesting similar tolerability. Taken together, the data suggest that a valproate/divalproex serum concentration of 94.1 µg/mL or higher provides optimal efficacy without increased side effects.
Active comparator trials
Active comparator trials are useful in distinguishing the head-to-head efficacy of medications. Studies have compared lithium versus many mood stabilizers and antipsychotics, haloperidol(Drug information on haloperidol) versus all SGAs except for ziprasidone(Drug information on ziprasidone), and olanzapine versus risperidone(Drug information on risperidone) and valproate/divalproex. In general, all agents have shown similar efficacy relative to each other, although one study found that olanzapine(Drug information on olanzapine) was associated with a greater reduction in YMRS scores than valproate/divalproex.35
Two head-to-head studies of olanzapine and divalproex assessed their relative efficacy in the treatment of bipolar disorder. The initial dosing in both studies differed. The study by Zajecka and colleagues36 started olanzapine at 10 mg/d on days 1 through 2 and titrated, at the discretion of the investigator, to a maximum of 20 mg/d. Divalproex was orally loaded at 20 mg/kg/d. The study by Tohen and colleagues37 started olanzapine at 15 mg/d and used a standard-titration divalproex dose of 750 mg/d. The mean YMRS score changes in this study were significantly greater with olanzapine (–13.4) than with divalproex (–10.4, P = .028). No significant differences between olanzapine (–17.2) and divalproex (–14.8, P = .210) were seen in the study by Zajecka and colleagues.36 The difference may be explained by the smaller group of 120 patients compared with 251 patients in the study by Tohen and colleagues,37 or by the orally loaded36 versus standard-titration37 dosing of divalproex.