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A pilot study of loading versus titration of valproate in the treatment of acute mania


OJ Oluboka, MD, Acute Care Program, North Bay Psychiatric Hospital, Box 3010 Hyw 11 North, North Bay, Ontario, Canada, P1B 8L1. Fax: 705 495 7890; e-mail:


Objective:  This double-blind pilot study compares the effectiveness and incidence of adverse effects of oral loading versus titration schedules of valproate in acute mania.

Method:  Consecutive new admissions for an acute manic episode were prescribed either an oral loading dose (20 mg/kg/day; n=5; mean age=33.4) or slower titration dose (10 mg/kg/day; n=6, mean age=30.6) of valproate for 7 days without other psychotropic agents, with the exception of benzodiazepines. Daily outcome measures included: serum valproic acid levels, the Young Mania Rating Scale (YMRS), the Brief Psychiatry Rating Scale (BPRS), the Clinical Global Impression Scale (CGI) and the Adverse Effect Rating Scale.

Results:  The mean serum valproic acid levels were significantly higher in the loading group when compared with the titration group after 1 and 2 days following the initiation of treatment (p < 0.05). After 3 days of treatment there was a trend for the group that received the loading regimen to have slightly more improvement in YMRS scores compared with the titration group. Side-effects were minor for both treatments, however, a higher incidence of side-effects was reported in the titration group, with 50% of patients reporting sedation most likely because of increased use of benzodiazepines.

Conclusion:  This suggests that a loading dose of valproate is likely safe and may provide an earlier onset of antimanic effects in patients with bipolar disorder. Future studies with larger sample sizes are indicated.