Abstract
Background: Bipolar (BP) I disorder affects 1.6% of the US adult population and results in estimated healthcare costs of $40 billion annually. It is characterized by a predominance of major depressive episodes interspersed with manic and hypomanic episodes. Most current practice guidelines are based upon expert consensus and generally recommend using mood stabilizer monotherapy for initial treatment of BP I depression, while avoiding antidepressants and using only mood stabilizer monotherapy for prevention of relapse and recurrence of depression. We hypothesize that long-term mood stabilizer plus antidepressant therapy will result in fewer depressive relapses and recurrences versus mood stabilizer monotherapy. Methods/design: 200 patients with BP I depression will receive initial lithium plus fluoxetine therapy for 12 weeks. Responders will be randomized to double-blind maintenance therapy with either: (i) lithium plus fluoxetine, or (ii) lithium monotherapy (following fluoxetine taper and discontinuation) for an additional 50 weeks. The primary outcome is the proportion of subjects in each condition who have a depressive relapse or recurrence during maintenance therapy. Depressive relapse or recurrence is defined as a return of moderate depressive symptoms. Discussion: We believe that evidence-based medicine will eventually support the use of concurrent antidepressant therapy for prevention of depressive relapse and recurrence in patients with BP I disorder. The paucity of modern controlled clinical trials studying the best method for preventing depressive relapse and recurrence of BP I disorder has led to contradictory practice guidelines and confusion as to the best treatment for BP I disorder. This study seeks to determine whether subjects who respond to initial mood stabilizer plus antidepressant therapy will have a superior longterm efficacy and fewer depressive relapses and recurrences if they continue therapy with maintenance mood stabilizer plus antidepressant therapy versus mood stabilizer therapy alone. Trial registration: ClinicalTrials.gov Trials Register - NCT00961961.
Highlights
Bipolar (BP) I disorder affects 1.6% of the US adult population and results in estimated healthcare costs of $40 billion annually
Phase IIa is a 2-week consolidation period during which remitted patients with a 17-item Hamilton Rating Scale for Depression (HRSD) [13] score ≤ 8 continue on initial therapy
We anticipate that the significance level of the statistical tests will change due to the reduced power to detect possible site differences between conditions, these stratified analyses will be important to assess whether the direction and magnitude of differences is similar between conditions, and whether subjects at each site are comparable with regard to basic demographics
Summary
Patients with BP I disorder spend a disproportionate amount of time in the depressive phase of their illness. Poor functional outcome in BP disorder is more highly correlated with the depressive, rather than the manic, phase [40,41,42]. These observations support the need for developing new strategies for treating and preventing BP I MDE relapse and recurrence. A recent 18-month, placebo-controlled trial of lamotrigine versus lithium monotherapy examined the time to relapse or recurrence of depressive and manic episodes after remission from an acute BP MDE found that depressive occurrences were 3-times more frequent than mania, and that the proportion of patients who remained depression-free for 12 months was not significantly different for lamotrigine (57%) or lithium (46%) versus placebo (45%) [56]
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