During SP1, a mean change of −20.0 ± 10.0 in the MADRS total score (OFC treatment at a starting once-daily dose of 12/25 mg; mean modal daily dosage, 10.8/27.8) was observed, with 71% completing the study period and a few patients experiencing an emergence of mania. The mean weight increase (SP1) was 4.8 ± 6.8 lb, and 17% had a 7% or higher weight increase. Our data also suggests that OFC treatment for an additional 12 weeks may be more effective than switching to OLZ monotherapy in maintaining response in patients with BD with similar tolerability.
These results in Latinos supplement evidence from 2 white population studies. In one, 86 patients were randomized to OFC for 8 weeks starting at 6/25 (mean modal dose was 7.4/39.3 mg/d).7
Results included an MADRS mean change of −18.5; response and remission rates of 56% and 49%, respectively; a mania emergence of 6.4%; 64% completing the study; a mean weight gain of 7.09 ± 8.20 lb; and 19.5% having a 7% or higher weight gain. The other study used OFC (n = 205; mean modal dosage, 10.7/38.3 mg/d; 25% of the patients on the 12/25 mg/d dosage) and lamotrigine (n = 205)12
for 7 weeks. Results included an MADRS mean change of −14.91; response and remission rates of approximately 69% and 56%, respectively; a rate of affective switch of 4%; 67% completing the study; a mean weight gain of 3.1 ± 3.4 kg; and 23% of the patients having a 7% or higher weight gain. In the 25-week study extension phase,16
the completion rate was 33%, 64% responded, 56% remitted, and the incidence of mania emergence was 5%. The MADRS and CGI-S improvements were maintained over the extension phase.
Acknowledging differences in study characteristics, there were similar MADRS reductions, response and remission rates, mania emergence rates, and study completion rates. However, numerically less weight increase in our Puerto Rican study contrasts a previous analysis where Latinos had significantly higher weight increases with OLZ than in whites.10
Reasons for the worsening MADRS in SP2 in those switched from OFC could (1) suggest an advantage of OFC over OLZ in maintenance of response, (2) indicate a worsening with OLZ, (3) be specific to the Latinos studied, or (4) be a biased assessment due to the open-label design.
Our study outcomes differ from the recent effectiveness study (Systematic Treatment Enhancement Program for Bipolar Disorder)17
in which antidepressants plus mood stabilizers neither improved the depressive symptoms nor increased the risk of a switch to mania in 366 patients with BD. This was likely because of options for psychotherapy and different drugs and objectives. Still, the antidepressant plus mood stabilizer combination in BD maintenance has shown encouraging results,14,18,19
and our study clearly supports OFC treatment. In addition, we found that the continuation treatment with this combination is more effective than switching to OLZ monotherapy, and concerns about induction of mania or rapid cycling are not warranted if fluoxetine is combined with OLZ. In light of currently available data, there is strong support for future large clinical studies to elucidate the role of antidepressants in the treatment of a bipolar depressive episode.19
There were several limitations to our study. First, the open-label design may have led to investigator and patient expectation effects and biases. Second, all SP1 nonresponders were excluded from SP2, which produced an enriched sample that would not generalize to the population of all patients with BD but to those who would meet the response criteria to OFC treatment. In addition, the exclusion of nonresponders from SP2 prevented an investigation of patients who might have reached the response criteria with longer than 7 weeks of exposure to OFC. Third, psychotic and rapid-cycling patients were excluded. Fourth, the Young Mania Rating Scale was not collected; thus, remission was defined as a single pole assessment measure. Nevertheless, only 1 patient demonstrated an emergence of mania defined as a CGI-S-Mania score of 3 or more or hospitalization for mania during SP2, suggesting that many patients were in mania remission. Lastly, the unique characteristics of care/support in Puerto Rico may limit the generalizability of results in other regions.
This study suggests that acute treatment gains and safety in Puerto Rican patients with BD treated with OFC are maintained for up to 19 weeks. Patients switched to OLZ after 7 weeks demonstrated significantly worse outcomes on depressed mood, relapse rates, times to relapse, and SF-12 scores. Future double-blind, controlled, long-term studies with OFC treatment of BD in Latinos or switching from OFC to OLZ in other populations are needed to confirm these findings.