Effects of asenapine on depressive symptoms in patients with bipolar I disorder experiencing acute manic or mixed episodes: a post hoc analysis of two 3-week clinical trials

Abstract

BackgroundAsenapine demonstrated superiority over placebo for mania in bipolar I disorder patients experiencing acute current manic or mixed episodes in 2 randomized, placebo-and olanzapine-controlled trials. We report the results of exploratory pooled post hoc analyses from these trials evaluating asenapine's effects on depressive symptoms in patients from these trials with significant baseline depressive symptoms.MethodsIn the original trials (A7501004 [NCT00159744], A7501005 [NCT00159796]), 977 patients were randomized to flexible-dose sublingual asenapine (10 mg twice daily on day 1; 5 or 10 mg twice daily thereafter), placebo, or oral olanzapine 5-20 mg once daily for 3 weeks. Three populations were defined using baseline depressive symptoms: (1) Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥20 (n = 132); (2) Clinical Global Impression for Bipolar Disorder-Depression (CGI-BP-D) scale severity score ≥4 (n = 170); (3) diagnosis of mixed episodes (n = 302) by investigative site screening. For each population, asenapine and olanzapine were independently compared with placebo using least squares mean change from baseline on depressive symptom measures.ResultsDecreases in MADRS total score were statistically greater with asenapine versus placebo at days 7 and 21 in all populations; differences between olanzapine and placebo were not significant. Decreases in CGI-BP-D score were significantly greater with asenapine versus placebo at day 7 in all categories and day 21 in population 1; CGI-BP-D score reductions were significantly greater with olanzapine versus placebo at day 21 in population 1 and day 7 in populations 2 and 3.ConclusionsThese post hoc analyses show that asenapine reduced depressive symptoms in bipolar I disorder patients experiencing acute manic or mixed episodes with clinically relevant depressive symptoms at baseline; olanzapine results appeared to be less consistent. Controlled studies of asenapine in patients with acute bipolar depression are necessary to confirm the generalizability of these findings.

Efficacy and Tolerability of Asenapine Compared with Olanzapine in Borderline Personality Disorder: An Open-Label Randomized Controlled Trial

“…These trends are inconsistent with results of other two clinical trials of subjects with bipolar disorder [52], where asenapine was found superior to olanzapine in improving depressive symptoms during manic or mixed episodes. A possible reason for this inconsistency may be that, whilst in our sample HAM-D scores at baseline were rather low (with a mean lower than 13) as patients with concomitant major depression had been excluded, in the other two studies of bipolar disorder patients [52] depressive symptoms were rated as "clinically relevant".…”

Efficacy of pharmacotherapy in bipolar disorder: a report by the WPA section on pharmacopsychiatry

“…In these studies, asenapine but not olanzapine was reported to reduce 'clinically relevant depressive symptoms' in the frame of a manic/mixed episode [483].…”

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013

“…A post-hoc analysis of two asenapine RCTs in patients with manic or mixed episodes demonstrated statistically significant decreases in depression scores with asenapine versus placebo in patients with severe baseline depressive symptoms (n = 604); differences between the active comparator olanzapine and placebo were not significant, which makes the interpretation of these results more difficult as it raises the possibility of a negative study (80). Pharmacological management of acute bipolar depressive episodes should follow the algorithm outlined in Figure 4.1 (1-3).…”