A randomized, placebo-controlled, multicenter study of divalproex sodium extended-release in the acute treatment of mania.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
clinicaltrials.gov Identifier: NCT00060905.
Hirschfeld
Robert M A
RM
The University of Texas Medical Branch, Department of Psychiatry, 301 University Blvd, Galveston, TX 77555, USA. rohirsch@utmb.edu
Bowden
Charles L
CL
Vigna
Namita V
NV
Wozniak
Patricia
P
Collins
Michelle
M
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D018692:Antimanic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology*; D003692:Delayed-Action Preparations; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011569:Psychiatric Status Rating Scales; D011795:Surveys and Questionnaires; D016896:Treatment Outcome; D014635:Valproic Acid / Q000008:administration & dosage / Q000627:therapeutic use*
D018692:Antimanic Agents; D003692:Delayed-Action Preparations; D010919:Placebos; D014635:Valproic Acid