Effect of symptom severity on efficacy and safety of aripiprazole adjunctive to antidepressant monotherapy in major depressive disorder: a pooled analysis.

BACKGROUND: There is a paucity of evidence for outcome predictors in patients with major depressive disorder (MDD) not responding to initial antidepressant therapy (ADT). This post-hoc analysis evaluated whether MDD severity affects response to adjunctive aripiprazole. METHODS: Data from 3 randomized, double-blind, placebo-controlled trials of adjunctive aripiprazole in adults with MDD and inadequate response to 1 to 3 ADT trials were pooled and stratified based on Montgomery-Åsberg Depression Rating Scale (MADRS) total score (mild, ≤24; moderate, 25-30; severe, ≥31). Treatment differences in change in MADRS total score and rates of response (≥50% MADRS improvement) and remission (response with MADRS total score ≤10) were analyzed at endpoint. Adverse events were assessed within each subgroup. RESULTS: Aripiprazole produced greater improvement than placebo in the MADRS total score regardless of MDD severity at baseline (between-treatment difference [95% CI]: mild, -2.5 [-4.0 to -1.1]; moderate, -3.2 [-4.9 to -1.6]; severe, -4.5 [-6.8 to -2.2]). Compared with placebo, adjunctive aripiprazole increased the likelihood of response in all subgroups (risk ratio [95% CI]: mild, 1.50 [1.15, 1.95]; moderate, 1.51 [1.09, 2.11]; severe, 1.95 [1.23, 3.10]). Common treatment-emergent adverse events included akathisia and restlessness. LIMITATIONS: The original studies were not designed to assess the efficacy of adjunctive aripiprazole by baseline severity, and this post-hoc analysis was not powered to evaluate differences in severity subgroups. CONCLUSIONS: In patients who failed to respond to initial ADT, adjunctive aripiprazole was more effective than placebo in mild, moderate, and severe MDD strata. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov: NCT00095823, NCT00105196, and NCT00095758.

Efficacy of aripiprazole versus placebo as adjuncts to lithium or valproate in relapse prevention of manic or mixed episodes in bipolar I patients stratified by index manic or mixed episode.

BACKGROUND: Differences in response to treatment have been observed for bipolar disorder (BPD) patients with manic or mixed episodes. This post-hoc analysis examined the maintenance effect of aripiprazole in combination with lithium or valproate in subpopulations of patients entering a relapse prevention study with either manic or mixed bipolar episodes. METHODS: A long-term relapse prevention study of BPD patients with manic or mixed episodes included a single-blind stabilization phase, in which patients were stabilized with single-blind aripiprazole plus lithium or valproate (maintaining stability for 12 weeks), and a double-blind relapse assessment phase, where patients were randomized to aripiprazole or placebo plus lithium or valproate for up to 52 weeks. Lithium and valproate groups were pooled. RESULTS: The time to relapse of any mood episode was longer in the adjunctive aripiprazole group versus the lithium/valproate monotherapy group for the manic (p<0.01) but not mixed population (p=0.59). The LOCF analysis indicated a significantly greater reduction in YMRS total score from baseline with continued aripiprazole versus placebo at 52 weeks in both manic (treatment difference=-3.32, p<0.01) and mixed episode populations (treatment difference=-2.56, p=0.02). Overall, adverse event profiles were similar between the populations. LIMITATION: The lithium and valproate subgroups were combined. CONCLUSIONS: The continuation of aripiprazole in stabilized BPD patients treated with lithium or valproate increased the time to relapse of any mood episode for manic but not mixed patients; both groups achieved greater stability in YMRS total score with adjunctive aripiprazole. Thus, adjunctive aripiprazole may be more appropriate for stabilized patients with manic episodes.

Investigation into the long-term metabolic effects of aripiprazole adjunctive to lithium, valproate, or lamotrigine.

BACKGROUND: Bipolar I disorder (BPD) patients are often overweight or obese, and likely to have metabolic syndrome. Several medications used to treat BPD are associated with increased body weight and/or worsening metabolic parameters. METHODS: Metabolic data were analyzed from two efficacy studies of aripiprazole plus the mood stabilizers, lithium/valproate (Study CN138-189), or lamotrigine (Study CN138-392), in the long-term treatment (52 weeks) of BPD. Changes in body weight, individual metabolic parameters, and incidence of metabolic syndrome were assessed. RESULTS: In the lithium/valproate study, modest increases in body weight were observed at Week 52 in both groups: 1.7 ± 0.8 kg in the lithium/valproate group, and 1.6 ± 0.7 kg in the adjunctive aripiprazole group; this difference was nonsignificant. In the lamotrigine study, decreases in body weight were observed at Week 52 with lamotrigine alone (-2.2 ± 1.0 kg), whereas a modest increase was observed when combined with aripiprazole (0.4 ± 1.0 kg). In both studies, rates of metabolic syndrome at 52 weeks did not increase from baseline with aripiprazole, and median changes from baseline in individual metabolic syndrome parameters were similar with both mood stabilizer monotherapy and the addition of aripiprazole as an adjunctive therapy. LIMITATIONS: This was a post-hoc analysis, and a low percentage of patients completed the lamotrigine study. CONCLUSIONS: Aripiprazole plus a mood stabilizer has minimal impact on metabolic changes in predominantly overweight/obese BPD patients over a 52-week period. In both studies, modest mean increases in weight with the addition of aripiprazole were not accompanied by increased rates of metabolic syndrome or changes in metabolic parameters.