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Effect of asenapine on manic and depressive symptoms in bipolar I patients with mixed episodes: Results from post hoc analyses

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Abstract

Background

The efficacy of agents useful for mania is largely unproven in patients with mixed episodes.

Methods

The efficacy of asenapine in the treatment of mixed episodes was assessed using post hoc analyses on pooled data from two identically designed 3-week, randomized, double-blind, flexible dose, placebo- and olanzapine-controlled trials and their 9-week, double-blind olanzapine-controlled extension study. Efficacy was measured by changes on Young Mania Rating Scale (YMRS) and Montgomery-Åsberg Depression Rating Scale (MADRS) total scores, and was analysed through analysis of covariance on observed cases of the intent-to-treat dataset.

Results

In the intent-to-treat population, 295 patients had a DSM-IV-TR mixed episode (placebo: 66; olanzapine: 122; asenapine: 107) in the 3-week trials. Of these, 102 patients (olanzapine: 56; asenapine: 46) entered the 9-week extension study.

At week 3, decreases in YMRS and MADRS total scores, were significantly (p<0.01) greater with asenapine (YMRS: −15.0; MADRS: −8.2) versus placebo (YMRS: −11.5; MADRS: −4.5); olanzapine did not separate from placebo (YMRS: −13.3; MADRS: −6.5). At week 12, further decreases in YMRS and MADRS total scores were observed with asenapine (YMRS: −22.4; MADRS: −11.9); non-statistically different from olanzapine (YMRS: −20.2; MADRS: −7.9).

Limitations

Results are from post hoc analyses of trials that were not designed to specifically evaluate mixed episodes.

Conclusions

These exploratory analyses provide supportive evidence for the efficacy of asenapine in treating the associated symptoms of mania and depression in bipolar I patients with mixed episodes.

Introduction

The concept of mixed states is old, predating that of bipolar disorder itself (Swann, 2011). Various definitions have been and are still being proposed, but the concept always refers to a combination of depressive and manic features in the same episode. The DSM-IV-TR criteria require that patients have both full syndromal mania and depression. Depending on the definition, there is a wide range of reported rates of mixed states in the literature; from 5% to 75% (Hantouche et al., 2006). Mixed episodes represent a severe presentation of bipolar disorder. Mixed patients are characterized by an earlier appearance of bipolar symptoms, a higher risk of suicide, a higher occurrence of manic and depressive episodes, higher rates of rapid cycling, and more co-morbidities related to substance abuse and dependence, as well as anxiety disorders (Azorin et al., 2009, Swann, 2011).

The treatment of mixed states is made difficult by the fact that the efficacy of drugs shown useful for pure manias is largely unproven in the subset of patients with mixed episodes (Stahl et al., 2010).

Usually the magnitude of response to manic symptoms' treatment exceeds that of depression symptoms. Valproate and carbamazepine have shown some effectiveness, but the efficacy of lithium appears questionable. A small number of atypical antipsychotics were found to improve both manic and depressive symptoms, used as monotherapy or in combination to mood stabilizers (Fountoulakis et al., 2012).

Asenapine has been shown to be effective in the treatment of patients with manic or mixed episodes associated with bipolar I disorder, in two companion randomized, double-blind, placebo -and olanzapine-controlled 3-week trials (McIntyre et al., 2009a, McIntyre et al., 2010). Across trials, reductions in Young Mania Rating Scale (YMRS) total score were significantly greater with asenapine and olanzapine compared with placebo. In a 9-week extension of these trials (McIntyre et al., 2009b), asenapine met the criteria for non-inferiority to olanzapine. The effect of asenapine on depressive symptoms in subgroups of patients who participated in the same 3-week lead-in trials, but experienced clinically relevant depressive symptoms, was assessed by Szegedi et al. (2011). Three populations were selected: (1) Montgomery-Åsberg Depression Rating scale (MADRS) total score≥20; (2) Clinical Global Impression for Bipolar Disorder-Depression (CGI-BP-D) scale severity score≥4; (3) diagnosis of mixed episode according to DSM-IV-TR. The decreases in MADRS total scores were found to be statistically greater with asenapine versus placebo at days 7 and 21 in all populations, whereas differences between olanzapine and placebo were not significant. In conclusion, the authors state the need for randomized controlled studies of asenapine in patients with bipolar depression to confirm the generalizability of their findings.

Nonetheless, there is still a lack of data on the efficacy of asenapine in mixed patients in the studies that have been conducted so far. For example, changes in YMRS scores in the specific population of DSM-IV-TR mixed patients were analyzed in only one of the two short-term trials (McIntyre et al., 2009a), response and remission rates were defined as percentage improvement on the YMRS only and threshold scores on YMRS were missing in both trials for the subpopulation of mixed patients. Data for this subpopulation were also completely absent in the 9-week extension study. In the analyses carried out by Szegedi et al. (2011), the efficacy of asenapine on manic symptoms and response rates based on percent improvement on the MADRS in the population of mixed patients were not assessed, neither was the tolerability of asenapine assessed. The latter may be worth considering as side effects such as extrapyramidal (Goodwin, 2009) or metabolic symptoms (Fagiolini et al., 2005) may worsen depressive features in bipolar patients.

Moreover, before implementing randomized controlled studies of asenapine in bipolar depression, it may be of interest to get some signal as to whether the efficacy of asenapine on depressive symptomatology is driven by its impact on the core features of depression.

The objective of these post hoc analyses is to try to yield further information on those missing data in order to better evaluate the efficacy and tolerability of asenapine in the treatment of manic and depressive symptoms in a cohort of patients with mixed episode defined according to DSM-IV-TR criteria.

Section snippets

Methods

These post hoc analyses include data from two identically designed 3-week, randomized, double-blind, flexible dose, placebo- and olanzapine-controlled trials (NCT00159744; NCT00159796) and their 9-week, double-blind olanzapine-controlled extension study (NCT00143182).

Each study was conducted in compliance with the Declaration of Helsinki, the principles of Good Clinical Practice and was approved by the appropriate institutional review boards. All enrolled patients provided written informed

Disposition and demographics

The intent-to-treat population for these post hoc analyses consisted of 295 bipolar I patients experiencing mixed episodes: asenapine, n=107, olanzapine, n=122 and placebo, n=66 (Fig. 1). Of these, 102 patients entered the 9-week extension study: asenapine, n=46 and olanzapine, n=56. The lead-in trials were completed by 63%, 75%, and 65% of asenapine-, olanzapine-, and placebo-treated mixed episode patients, respectively (p=0.093). The completion rate in the extension study was 50% for

Discussion

These post hoc analyses show the efficacy of asenapine in the treatment of symptoms associated with DSM IV-defined mixed episodes as measured by changes on the YMRS and MADRS total scores, or by composite responder or composite remission (that is, achieving response or remission on both the YMRS and MADRS). The efficacy of asenapine was found to be significantly greater than placebo at week 3. Szegedi et al. (2011) assessed the effect of asenapine on depressive symptoms in bipolar I disorder

Role of funding source

These analyses were supported by H. Lundbeck A/S (Copenhagen, Denmark). The studies used in these analyses were sponsored by Merck (Whitehouse Station, New Jersey, USA).

Conflict of interest

J–M Azorin receives, or has received, research support and has acted as a consultant and/or served on a speaker's bureau for Bristol-Myers Squibb, Janssen, Eli Lilly, Lundbeck, Novartis, Pfizer, Servier and Sanofi-Aventis.

C. Sapin and E. Weiller are employees of H. Lundbeck A/S.

Acknowledgements

J.K. Simonsen (H. Lundbeck A/S) provided support in the preparation, revision, and editing of the methods and results sections of the manuscript.

References (21)

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