Pooled analysis assessing the efficacy and safety of amphetamine derivative adjunctive therapy for bipolar depression

OBJECTIVE: The bipolar pharmacopoeia targeting depression is significantly underdeveloped. Despite high rates of attention deficit symptoms, there has been inadequate investigation of stimulants as a treatment intervention for adults with bipolar depression. METHODS: Data were pooled from two, 8-week, randomized, placebo-controlled trials of adjunctive mixed d-amphetamine/l-amphetamine salt (MAS) and lisdexamfetamine (LDX). The primary outcome measure was baseline-to-endpoint change in the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included treatment response and remission (50%MADRS reduction, MADRS < 10), and improvement as measured by the Clinical Global Impression for Bipolar Disorder (CGI-BP). The primary safety assessment was the Young Mania Rating Scale (YMRS). RESULTS: Fifty-seven bipolar [BD-I: n = 23 (40.4%); BD-II: n = 34 (59.6%); male: n = 17 (29.8%); female: n = 40 (70.2%); mean age = 40.1 ± 11.3 years] depressed participants were randomized. There were no significant group differences in baseline demographics (all p ≥ 0.14). In age-adjusted analysis, participants receiving adjunctive LDX/MAS (n = 26) in comparison to placebo (n = 31) showed greater improvement in MADRS (mean % reduction: 54.6% vs. 25.6%; 95% CI: 9.1, 48.9; p = 0.005), with higher response (65.7% vs. 16.7%; p < 0.001), remission (48.8 vs. 15.3%; p = 0.007) and CGI-BP improvement rates (65.0% vs. 23.5%; p = 0.001). There was no between-group difference in YMRS scores at baseline or endpoint (p ≥ 0.36). CONCLUSIONS: In this pooled controlled analysis, 8-week adjunctive amphetamine was associated with reduction in depressive symptoms in carefully selected patients with bipolar depression, with no increased risk of treatment-emergent mania/hypomania. Further studies are encouraged to identify clinical correlates of treatment response guiding clinicians when to consider this potentially effective treatment.