The Safety and Early Efficacy of Oral-Loaded Divalproex Versus Standard-Titration Divalproex, Lithium, Olanzapine, and Placebo in the Treatment of Acute Mania Associated With Bipolar Disorder
J Clin Psychiatry 2003;64(7):841-846
© Copyright 2016 Physicians Postgraduate Press, Inc.
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Background: Previous studies have examined the
safety and tolerability of oral-loaded divalproex sodium in the
treatment of acute mania, but not the early efficacy of this
dosing strategy. The purpose of this study was to evaluate the
early efficacy of oral-loaded divalproex.
Method: In this pooled analysis, 348 subjects
from 3 randomized, double-blind, parallel-group, active- or
placebo-controlled studies were used to compare the efficacy,
safety, and tolerability of oral-loaded divalproex with
standard-titration divalproex, lithium, olanzapine, or placebo.
Subjects were inpatients diagnosed with acute mania associated
with bipolar I disorder (DSM-III-R or -IV and SADS-Change
Version). Patients were administered oral-loaded divalproex (20
or 30 mg/kg/day on days 1 and 2 followed by 20 mg/kg/day, and
increased at physician's discretion), standard-titration
divalproex initiated at 250 mg t.i.d. and titrated to 40-150
mg/mL, lithium (300 mg t.i.d. initial dose) titrated to 0.4 to
1.5 mEq/L, olanzapine (10 mg q.d. initial dose) up to 20 mg/day,
Results: The results demonstrate an early
efficacy advantage for oral-loaded divalproex compared to
standard-titration divalproex at days 5, 7/8, and 10. Efficacy
was improved over lithium on day 7/8. There were no efficacy
differences between divalproex loading and olanzapine. Divalproex
loading showed greater efficacy than placebo at all time points.
Divalproex loading was as well tolerated or better tolerated than
the other active treatments as measured by adverse events and
changes in laboratory parameters.
Conclusion: These results suggest the oral
loading of divalproex leads to a more rapid antimanic effect when
compared with standard-titration divalproex, lithium, or placebo
and is better tolerated than olanzapine and as well tolerated as
lithium or standard-titration divalproex.