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Asenapine: a review of acute and extension phase data in bipolar disorder.

ABSTRACT: The second generation atypical antipsychotic, asenapine (Saphris), was approved by the US FDA (August 2009) for the acute treatment of manic or mixed episodes with or without psychotic features associated with bipolar I disorder in adults as well as the acute treatment of schizophrenia. Asenapine exhibits a high affinity for and antagonism at several serotonergic (5-HT(2A-C), 5HT(5A), 5HT(6), 5HT(7)), dopaminergic (D(2), D(3)), alpha-adrenergic (?(1) and ?(2)), and histaminergic (H1, H2) receptor subtypes. Asenapine is the first atypical antipsychotic formulated as a fast-dissolving, rapidly absorbed sublingual tablet. Asenapine was evaluated in adults with bipolar I disorder, manic or mixed episodes with or without psychotic features. Two identically designed 3-week registration trials confirmed the efficacy of asenapine relative to placebo in studies that included olanzapine as an active control. The placebo-subtracted rate of EPS (excluding akathisia) is 5% whereas the placebo-subtracted rate of akathisia was 2%. The placebo-subtracted rate of clinically significant weight gain (?7%) with asenapine was approximately 5% during the 3-week acute mania trials. A 9- extension trial indicated that 19% of asenapine patients will experience clinically significant weight gain. Clinically significant metabolic abnormalities were not observed during the acute and/or extension trials. Asenapine can be associated with somnolence (asenapine 24%, placebo 6%) and does not appear to be associated with clinically significant changes in vital signs, laboratory parameters, or electrocardiographic changes. Bipolar depression and recurrence prevention studies are required to fully characterize this novel agent's position in the treatment of bipolar disorder.

SUBMITTER: McIntyre RS

PROVIDER: S-EPMC6493886 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Asenapine: a review of acute and extension phase data in bipolar disorder.

McIntyre Roger S RS

CNS neuroscience & therapeutics 20101015 6

The second generation atypical antipsychotic, asenapine (Saphris), was approved by the US FDA (August 2009) for the acute treatment of manic or mixed episodes with or without psychotic features associated with bipolar I disorder in adults as well as the acute treatment of schizophrenia. Asenapine exhibits a high affinity for and antagonism at several serotonergic (5-HT(2A-C), 5HT(5A), 5HT(6), 5HT(7)), dopaminergic (D(2), D(3)), alpha-adrenergic (α(1) and α(2)), and histaminergic (H1, H2) recepto ...[more]

PMID: 20950326

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Project description:Asenapine (Saphris(®)) is an atypical antipsychotic drug which has been approved by the US Food and Drug Administration for the treatment of schizophrenia in adults, as well as the treatment of acute manic or mixed episodes of bipolar I in both adult and pediatric populations. Asenapine is a tetracyclic drug with antidopaminergic and antiserotonergic activity with a unique sublingual route of administration. In this review, we examine and summarize the available literature on the safety, efficacy, and tolerability of asenapine in the treatment of bipolar disorder (BD). Data from randomized, double-blind trials comparing asenapine to placebo or olanzapine in the treatment of acute manic or mixed episodes showed asenapine to be an effective monotherapy treatment in clinical settings; asenapine outperformed placebo and showed noninferior performance to olanzapine based on improvement in the Young Mania Rating Scale scores. There are limited data available on the use of asenapine in the treatment of depressive symptoms of BD, or in the maintenance phase of BD. The available data are inconclusive, suggesting the need for more robust data from prospective trials in these clinical domains. The most commonly reported adverse effect associated with use of asenapine is somnolence. However, the somnolence associated with asenapine use did not cause significant rates of discontinuation. While asenapine was associated with weight gain when compared to placebo, it appeared to be modest when compared to other atypical antipsychotics, and its propensity to cause increases in hemoglobin A1c or serum lipid levels appeared to be similarly modest. Asenapine does not appear to cause any clinically significant QTc prolongation. The most commonly reported extra-pyramidal symptom associated with asenapine was akathisia. Overall, asenapine appears to be a relatively well-tolerated atypical antipsychotic, effective in the treatment of acute manic and mixed episodes of BD.

Project description: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.

Project description:Sublingually administered asenapine was approved in March 2015 by the United States Food and Drug Administration for patients aged 10-17 years with an acute manic or mixed episode associated with bipolar I disorder (BP-1). This is the first long-term safety and tolerability study of asenapine in this population.Following the 3-week randomized, double-blind, placebo-controlled trial of patients aged 10-17 years with an acute manic or mixed episode associated with BP-1, patients could enroll in this flexible-dose (2.5-10 mg twice daily) open-label extension (OLE) study for an additional 50 weeks, conducted from August 2011 to September 2014 in the United States and Russia. Treatment-emergent adverse events (TEAEs) were assessed and predefined TEAEs of interest reported in addition to metabolic and anthropometric parameters. The Young Mania Rating Scale (YMRS) and Clinical Global Impressions scale in bipolar illness (CGI-BP) were used to assess effectiveness.A total of 321 patients (lead-in study treatment: placebo, n = 80; asenapine, n = 241) were included; 267 (83.2 %) reported one or more TEAE and 181 (56.4 %) discontinued early, 48 (15.0 %) due to TEAEs. Of the predefined TEAEs of interest, combined somnolence/sedation/hypersomnia occurred most frequently (42.4 %) followed by oral hypoesthesia/dysgeusia (7.5 %). In total, 109 (34.8 %) patients experienced clinically significant weight gain (?7 % increase). No clinically meaningful changes were noted for laboratory parameters measured. Eighteen patients met the criteria for new-onset metabolic syndrome (MBS) post-baseline during the extension study, whereas 10 patients who met MBS criteria at baseline did not meet MBS criteria at endpoint. A total of 12 patients met MBS at baseline and endpoint. Mean change in YMRS total score from OLE baseline was -9.2 points at week 50, and change in CGI-BP severity overall score was similar among all treatment groups (those who initially received asenapine and those who initially received placebo). After 26 weeks of treatment in the OLE, 79.2 % of patients were classified as YMRS 50 % responders relative to acute trial baseline.Asenapine was generally well tolerated in pediatric patients with BP-1 during ?50 weeks of open-label treatment; among predefined TEAEs of interest, the combination of somnolence/sedation/hypersomnia was the most common. Trial registration ClinicalTrials.gov: NCT01349907.

Project description:BackgroundActigraphy could be an objective alternative to clinical ratings of motor activity in bipolar disorder (BD), which is of importance now that increased activity and energy are added as cardinal symptoms of (hypo)mania in the DSM-5 and commonly used rating scales give inadequate information about motor symptoms. To date, most actigraphy studies have been conducted in groups and/or used mean activity levels as the variable of interest. The novelty of this case series is therefore to indicate the potential of actigraphy and non-parametric analysis as an objective and personalized marker of intra-individual activity patterns in different phases of BD. To our knowledge, this is the first case series that provides an objective assessment of non-linear dynamics in within-person activity patterns during acute BD episodes.ResultsWe report on three cases of bipolar I disorder with 24-h actigraphy recordings undertaken during the first few days of two or more separate admissions for an acute illness episode, including admissions for individuals in different phases of BD, or with different levels of severity in the same phase of illness. For each recording, we calculated mean activity levels over 24 h, but especially focused on key measures of variability and complexity in activity. Intra-individual activity patterns were found to be different according to phase of illness, but showed consistency within the same phase. With increasing psychotic symptoms, there was evidence of a lower overall level and greater irregularity in activity. As such, sample entropy (a measure of irregularity) may have particular utility in characterizing mania and psychotic symptoms, while assessment of the distribution of rest versus activity over 24 h may distinguish between phases of BD within an individual.ConclusionsThis case series indicates that objective, intra-individual, real-time recordings of patterns of activity may have clinical impact as a valuable adjunct to clinical observation and symptom ratings. We suggest that actigraphy combined with detailed mathematical analysis provides a biological variable that could become an important tool for developing a personalized approach to diagnostics and treatment monitoring in BD.

Dataset Information

Asenapine: a review of acute and extension phase data in bipolar disorder.

Publications

Asenapine: a review of acute and extension phase data in bipolar disorder.

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