Antidepressant Augmentation of Bipolar Disorder
From MindLinc Wiki
Background: This study represents the first randomized trial of competing options for treatment-resistant bipolar depression and assesses the effectiveness and safety of antidepressant augementation with lamotrigine, inositol, and risperidone. This study is part of the larger Systematic Treatment Endhancement Program for Bipolar Disorder which was conceived in response to NIMH initiative seeking a public health intervention model that could generate externally valid answers to treatment effectiveness questions related to bipolar disorder.
Objective: To assess the effectiveness of antidepressant augementation with lamotrigine, inositol, and risperidone in treatment-resistant bipolar depression
METHODS:
Design/Setting-this study is part of the larger multi-center STEP-BD study
Inclusion Criteria->18 yo, met criteria for bipolar 1 or 2 with current MDD episode at least 8 weeks of duration and had not responded to treatment in first 12 weeks of standard or randomized care pathways or had documented failure to respond to 2 trials of antidepressant or antidepressant and mood stabilizer. Pts were required to be taking a mood stabilizer or agree to start. Pt had to have refused ECT.
Exclusion Criteria-history of nonresponse to, intolerance of, or any medical contraindications to at least two of the study medications, met criteria for mixed episode, hypomania, or substance abuse/dependence.
Population-66 subjects in all, mostly white, mostly female
Treatment Protocol-Subjects were randomized, treatments using equipoise randomization meaning that there were allowed to choose one of the following pairings: 1) accept all meds, 2)accept only lamotrigine or risperidone, 3) accept only lamotrigine or inositol, and 4)accept only risperidone or inositol. Pt were randomly assigned to receive on of the active agents under open-label conditions within the chosen strata. Mood stabilizer therapy was optimized (lithium:0.6-0.9; VPA: 45-90; carbamazepine: 4-10). Pts were followed weekly for the first 4 weeks. The 3 agents being study were titrated up per clinical guidelines to max doses as follows: Lamotrigine 150-250mg/day, Risperidone up to 6mg, Inositol 10-25 g daily. Tx lasted up to 16 weeks.
Outcomes-Primary outcome was the recovery rate within equipoise randomization strata. Recovery rate was defined as 1) no more than 2 symptoms meeting DSM-IV threshold criteria for MDD, manic or hypomanic episode and no significant symptoms present for 8 weeks. Secondary outcome measures included CGI, SUM-D, SUM-M and GAF and were done across equipoise randomization strata rather than within.
Analysis-For each 2-drug comparison, analyses were conducted twice:once including only those pts willing to accept the 2 drugs in the comparison and a second with those willing to accept all 3 drugs. Fisher's exact test was used for the secondary outcomes due to the fact they were based on discrete rating scales.
Validity:
Pts randomized? Yes, Randomization Blinded? No, Analyzed to Groups to Which Randomized? Yes, Similar pts w/ respect to known prognostic factors? Yes, Groups treated equally outside of intervention? Yes, F/u complete? Yes
Results:
For the primary outcome, there is no significant difference in treatment response. Table 2. In raw data, lamotrigine trends toward doing better than the other agents. This study is not adequately powered to show a significant difference. For the secondary outcomes, see Table 3, there is no differences in treatment response across equipoise randomization strata except for lower SUM-D scores for lamotrigine vs inositol and higher GAF for lamotrigine vs risperidone. Finally Table 4 shows the comparisons across equipoise randomization strata and indicates that subjects assigned to lamotrigine had significantly lower SUM-D exit scores, CGI, GAF improvement, and stayed in the study longer.
Comments:
Strenghts-this is the first randomized, open-label medication augmentation trial for treatment-resistant bipolar depression. It also focuses on effectiveness rather than efficacy and points to generalizability to a real world population. Weaknesses-Under powered to show statistical significance within equipoise groups, many details surrounding the study are missing (ie: what mood stabilizer the pt is on or anti-depressant).
Presented by Jennifer Farmer, May 1, 2006
