A pilot trial of quetiapine, lithium, or placebo added to divalproex sodium for hypomanic or manic episodes in ambulatory adults with bipolar I disorder

Victoria E Cosgrove, Santiago Allende, Iola Gwizdowski, E Grace Fischer, Michael Ostacher, Trisha Suppes, Victoria E Cosgrove, Santiago Allende, Iola Gwizdowski, E Grace Fischer, Michael Ostacher, Trisha Suppes

Abstract

Background: Many patients with bipolar I disorder do not respond to monotherapy treatment with mood-stabilizing medications, and combination regimens are commonly used in both inpatient and outpatient settings for the acute and maintenance treatment of bipolar disorder. We studied whether combination therapy is more effective than monotherapy for the acute treatment of subjects with bipolar I disorder currently experiencing manic symptoms. The primary hypothesis was that combination treatments would be associated with greater reductions in symptoms of mania and hypomania than monotherapy alone. The secondary hypothesis was that combination therapies would be associated with lower depression levels than monotherapy alone. Last, a post-hoc exploratory aim was used to examine whether the effect of side effect severity on risk-of-dropout would be greater in combination therapies than in monotherapy alone.

Results: In this 12-week, double-blind, placebo-controlled ambulatory pilot trial, participants (n = 75) with bipolar I disorder were randomly assigned to: (1) monotherapy divalproex plus placebo (DVP + PBO), (2) combination therapy of divalproex plus blinded lithium (DVP + Li) or (3) divalproex plus blinded quetiapine (DVP + QTP). Combination therapies (vs. monotherapy) were not associated with improved symptoms of mania, hypomania or depression. The effect of side effect severity on study retention did not differ between combination therapies and monotherapy. However, the risk-of-dropout was significantly greater in the DVP + Li arm versus the DVP + PBO arm.

Conclusions: No longitudinal differences in mania, hypomania or depression were found between combination therapies and monotherapy. The effect of side effect severity on study retention did not differ between groups. Due to the small sample size and differential rates of attrition between treatment arms, results of this pilot trial must be interpreted with caution. Trial registration ClinicalTrials.gov identifier: NCT00183443.

Keywords: Divalproex plus blinded lithium; Divalproex plus blinded quetiapine; Monotherapy divalproex.

Conflict of interest statement

TS in the past 36 months has reported grants from Pathway Genomics, Stanley Medical Research Institute, Elan Pharma International Limited, Merck and Co., and Sunovion Pharmaceuticals; consulting fees from Allergan, Impel NeuroPharma Inc., Intraceluular Therapies, and Sunovion Pharmaceuticals; honoraria from CME Institute, Health and Wellness Partners Inc., and CMEology; royalties from Wolters Kluwer Health (UpToDate), Jones and Bartlett, American Psychiatric Association Press, and Hogrefe Publishing. MO in the past 36 months has reported consulting fees from Johnson & Johnson, Sage Therapeutics, and Alkermes; and grant support from Palo Alto Health Sciences, Inc. VC in the past 36 months has reported grants from the National Cancer Institute and royalties from UpToDate. SA, IG, and GF declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Consort diagram
Fig. 2
Fig. 2
Kaplan–Meier time-to-event curves
Fig. 3
Fig. 3
Frequency of dropout per study arm

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