Divalproex sodium extended-release (ER) was examined for the treatment of acute mania in adults in 2 randomized, placebo-controlled clinical trials. One study demonstrated statistically significant improvements in mania symptoms compared to placebo, while an earlier study did not. Results of the earlier study are presented here.
A total of 225 DSM-IV-diagnosed bipolar I disorder patients were randomly assigned in a 2:1 ratio to 21 days of double-blind treatment with divalproex ER (n = 147) or placebo (n = 78). The daily divalproex ER dosage was initiated at 20 mg/kg. The primary efficacy variable was the change from baseline to final evaluation in Mania Rating Scale (MRS) score. Subjects were discontinued from the study if they were discharged from the hospital or if they met prespecified improvement criteria. The study was conducted from May 1998 to July 1999 at centers in the United States.
There was no statistically significant difference in MRS score change from baseline to final for patients treated with divalproex ER compared with those treated with placebo. With the exception of back pain and constipation, adverse event rates between placebo and divalproex ER were very similar. A large proportion of patients prematurely discontinued study treatment (divalproex ER: 83%, placebo: 82%). The mean daily dose of divalproex ER was 2,211 mg with a mean maximum serum valproic acid concentration of 77.9 microg/mL.
The results of the current study did not demonstrate statistically significant improvement in mania symptoms associated with divalproex ER treatment compared to placebo. A number of methodological considerations may have contributed to the negative findings, including allowance for early study discontinuation and lower than optimal dosing.
clinicaltrials.gov Identifier: NCT00060905.
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"Placeboassociated improvement in mean mania ratings relative to baseline varied greatly, from À19% (Zarate et al, 2007) or + 0.63% (Pope et al, 1991) to + 38% (McIntyre et al, 2009a). Likewise, study drop-out rates ranged from 13–15% (Kushner et al, 2006; Smulevich et al, 2005, respectively) to 82% (Hirschfeld et al, 2010) with placebo, and from 11–14% (Bowden et al, 2005; Khanna et al, 2005; Smulevich et al, 2005) to 83% (Hirschfeld et al, 2010) with drug. The impact of these sources of variance lie beyond this study and are reported separately (Yildiz et al, 2010). "
"For example, in a 3-week study comparing placebo, valproate, and lithium (Bowden et al., 1994), response rates were 25% for placebo, 48% for valproate (P=0.004 vs. placebo), and 49% for lithium (P=0.025 vs. placebo). A subsequent placebo-controlled trial of valproate patients (Bowden et al., 2006) reported response rates of 48% for valproate and 34% for placebo. In a three-arm study comparing quetiapine and lithium with placebo (Bowden et al., 2005), response rates were 27.4% at 3 weeks and 41.1% at 3 months for placebo, 53.3% at 3 weeks and 72.0% at 3 months for quetiapine, and 53.1% at 3 weeks and 75.5% at 3 months for lithium. "
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to compare the efficacy and safety of valproate and lithium in bipolar I patients experiencing a manic or a mixed episode. This international, randomized, open-label, parallel-group, equivalence study included 268 patients with bipolar I disorder. The starting dose of valproate was 20 mg/kg/day and that of lithium was 800 mg/day. Treatment duration was 12 weeks. The primary outcome measure was mean change in Young Mania Rating Scale score between baseline and study end. Secondary outcome measures were response and remission rates, change in Montgomery and Asberg Depression Rating Scale and Clinical Global Impression Bipolar Disorder instrument score, and occurrence of adverse events. The mean change from baseline in Young Mania Rating Scale score was 15.8+/-5.3 in the lithium group and 17.3+/-9.4 in the valproate group. The 90% confidence interval of the intergroup difference (-0.69; 3.31) was within prespecified equivalence limits. Response rates were 72.6% in the lithium group and 79.5% in the valproate group. Remission rates were 58.5 and 71.9%, respectively. No intergroup differences were observed in median time to treatment response (21 days) or change in Clinical Global Impression Bipolar Disorder instrument or Montgomery and Asberg Depression Rating Scale scores. Adverse events were reported in 42.8% of patients in the lithium group and 41.5% in the valproate group. Valproate and lithium showed comparable efficacy and tolerability in the treatment of acute mania over 12 weeks.
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