Efficacy and safety of long-term fluoxetine versus lithium monotherapy of bipolar II disorder: a randomized, double-blind, placebo-substitution study

Abstract

Objective: The authors examined the safety and efficacy of long-term fluoxetine monotherapy, lithium monotherapy, and placebo therapy in preventing relapse and recurrence of bipolar type II major depressive episode. The authors hypothesized that fluoxetine monotherapy would be superior to lithium monotherapy with a similar hypomanic mood conversion rate.

Method: Patients at least 18 years old who recovered from their major depressive episode during initial open-label fluoxetine monotherapy were randomly assigned to receive 50 weeks of double-blind monotherapy with fluoxetine at 10-40 mg/day, lithium at 300-1200 mg/day, or placebo. The primary outcome measure was time to relapse or recurrence. Secondary outcome measures included the proportion of patients remaining well and the frequency of hypomanic symptoms.

Results: There were no significant differences in clinical or demographic characteristics among the fluoxetine (N=28), lithium (N=26), and placebo (N=27) groups. The mean time to relapse was 249.9 days for the fluoxetine group, 156.4 days for the lithium group, and 186.9 days for the placebo group. The hazard of relapse was significantly lower with fluoxetine compared with lithium, and the estimated hazard of relapse with lithium was 2.5 times greater than with fluoxetine. There were no statistically significant or clinically meaningful differences in hypomanic symptoms among treatment groups over time. One patient taking fluoxetine and one patient taking placebo discontinued treatment because of hypomania.

Conclusions: These findings suggest that long-term fluoxetine monotherapy may provide superior relapse-prevention benefit relative to lithium monotherapy after recovery from bipolar II major depressive episode without an increase in hypomanic mood conversion episodes.

Trial registration: ClinicalTrials.gov NCT00044616.

FIGURE 1

CONSORT Diagram for a Study of Patients With Bipolar II Disorder in a Randomized Controlled Study of Fluoxetine or Lithium Monotherapy

FIGURE 2. Kaplan-Meier Survival Curves for Relapseor Recurrence During Long-Term Fluoxetine, Lithium, or Placebo Monotherapy^a

^aThe x-axis displays measurement beyond the 50-week protocol because of delays in scheduling study visits for several patients, which resulted in some measurements being obtained after 50 weeks. In the lower part of the figure, the number of patients at risk is displayed for each group at 0, 100, 200, 300, and 400 days.

FIGURE 3. Individual-Level Overlaid Profile Plots of Young Mania Rating Scale (YMRS) Scores During Long-Term Fluoxetine, Lithium, and Placebo Monotherapy^a

^aThe time along the x-axis is based on the actual date of the measurement. The horizontal dashed lines indicate the cut-points scores of 8 and 12.