Bipolar Disorder: Increasing the Effectiveness and Decreasing the Side Effects of Treatment: Page 3 of 11

Bipolar Disorder: Increasing the Effectiveness and Decreasing the Side Effects of Treatment: Page 3 of 11

Although not considered a primary end point in acute mania studies, completion rates may be an important measure of treatment effectiveness. An active medication may separate from placebo in clinical response, but a low completion rate raises questions as to the real-world effectiveness of the medication. Completion rates can be affected by the use of concomitant medications. The quetiapine study by Bowden and colleagues19 that employed concomitant use of lorazepam, chloral hydrate, and zolpidem reported the highest rates of completion. More than 90% of patients in the quetiapine arm and 69% of patients in the placebo arm completed the study. The aripiprazole study by Keck and colleagues23 reported the lowest completion rates with only 42% of patients in the aripiprazole arm and 21% of patients in the placebo arm finishing the study.

Response rate. Response to treatment is typically defined as a 50% or greater reduction on the primary efficacy measure (YMRS or MRS) or “much or very much improvement” on the Clinical Global Impression Improvement (CGI-I) scale.11 An estimate of the true response to the medication (placebo-corrected response rate) is the difference in the response rates between the active agent and placebo.25 The average placebo-corrected response rate in all SGA studies ranged from 16% to 23% (olanzapine 23%, risperidone 23%, quetiapine 17%, ziprasidone 16%, and aripiprazole 21%). The placebo-corrected response rates were similar for the olanzapine studies (24.4% and 21.9%), aripiprazole studies (21% in each study), risperidone studies (15% and 19%), and ziprasidone studies (15% and 16.8%). However, the placebo-corrected response rates were quite different in the quetiapine studies (26% and 8%).

Oral loading in acute mania. In order to obtain rapid results in the treatment of mania, it is important to quickly reach a therapeutic level of medication. Numerous studies have analyzed this concept with valproate/divalproex. Several studies showed that when oral (“rapid”) loading doses of valproate/divalproex are used, most patients have significant improvement in manic symptoms by day 5, with the greatest percent change on the MRS occurring in the first 3 days of treatment.18,25-28 This approach is generally well tolerated. An open-label trial examining valproate oral loading (20 mg/kg/d) showed a therapeutic serum level (of 50 µg/mL or higher) in patients within 24 hours.27

In a randomized, double-blind study, Hirschfeld and colleagues25compared oral-loaded valproate (30 mg/kg/d on days 1 and 2, followed by 20 mg/kg/d on days 3 through 10) to standard-titration valproate or lithium and reported that the oral-loaded patients achieved therapeutic serum levels more quickly than the standard-titration group. By day 3, 84% of oral-loaded patients and 30% of standard-titration patients achieved therapeutic serum levels of valproate, while neither group differed statistically in the number and types of adverse events. The oral-loaded group showed a statistically significant improvement relative to the standard-titration group at days 5, 7/8, and 10 in the MRS, Manic Syndrome Scale, and Behavior and Ideation Scale.24

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