A Randomized, Placebo-Controlled, Multicenter Study of Divalproex Sodium Extended-Release in the Acute Treatment of Mania

The University of Texas Medical Branch, Department of Psychiatry, 301 University Blvd, Galveston, TX 77555, USA.
The Journal of Clinical Psychiatry (Impact Factor: 5.5). 03/2010; 71(4):426-32. DOI: 10.4088/JCP.08m04960yel
Source: PubMed


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. Identifier: NCT00060905.

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Available from: Charles L Bowden, Dec 16, 2015
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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). "

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    • "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. "
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