Mary Mackle

Asenapine as adjunctive treatment for acute mania associated with bipolar disorder: results of a 12-week core study and 40-week extension.

Abstract In a 12-week randomized, placebo-controlled study evaluating the efficacy and safety of adjunctive asenapine, bipolar I disorder patients experiencing manic or mixed episodes despite pretreatment with lithium or valproate monotherapy were treated with flexible-dose, twice-daily asenapine 5 or 10 mg (n = 158) or placebo (n = 166). The primary efficacy end point was change from baseline Young Mania Rating Scale (YMRS) total score at week 3. Secondary outcomes included YMRS response and remission and Clinical Global Impression for Bipolar Disorder and Montgomery-Asberg Depression Rating Scale score changes. Patients completing the core study were eligible for a 40-week double-blind extension assessing safety and tolerability. Adjunctive asenapine significantly improved mania versus placebo at week 3 (primary end point) and weeks 2 to 12. The YMRS response rates were similar at week 3 but significantly better with asenapine at week 12. The YMRS remission rates and changes from baseline on Clinical Global Impression for Bipolar Disorder for mania and overall illness were significantly better with asenapine at weeks 3 and 12. No other statistically significant differences on secondary outcomes were observed. Only a small number of patients entered the extension, making firm statistical conclusions on efficacy difficult. Treatment-emergent adverse events reported by 5% or more of asenapine patients and at twice the incidence of placebo were sedation, somnolence, depression/depressive symptoms, oral hypoesthesia, and increased weight in the 12-week core study. Adjunctive asenapine to lithium or valproate was more effective than mood stabilizer monotherapy in the core study and was well tolerated for up to 52 weeks.

A randomized placebo-controlled trial of asenapine for the prevention of relapse of schizophrenia after long-term treatment.

OBJECTIVE Long-term efficacy of asenapine in preventing schizophrenia relapse was assessed in a 26-week double-blind, placebo-controlled trial that followed 26 weeks of open-label treatment. METHOD Stable schizophrenia patients (DSM-IV-TR criteria) who were cross-titrated from previous medication to sublingual asenapine and remained stable during 26 weeks of open-label treatment were eligible for 26 weeks of double-blind treatment, with randomization to continued asenapine or switch to placebo. Time to relapse/impending relapse (primary endpoint, as usually determined by specific scores on the Positive and Negative Syndrome Scale and the Clinical Global Impressions-Severity of Illness Scale) and discontinuation for any reason (key secondary endpoint) were assessed by survival analyses for asenapine versus placebo. The study was conducted from May 2005 through June 2008. RESULTS Of 700 enrolled patients treated with open-label asenapine, 386 entered (asenapine, n = 194; placebo, n = 192) and 207 completed (n = 135; n = 72) the double-blind phase. Times to relapse/impending relapse and discontinuation for any reason were significantly longer with asenapine than with placebo (both P < .0001). Incidence of relapse/impending relapse was lower with asenapine than placebo (12.1% vs 47.4%, P < .0001). The modal dosage of asenapine was 10 mg twice daily in both phases. During the double-blind phase, the incidence of adverse events (AEs) considered serious with asenapine and placebo was 3.1% and 9.9%, respectively; incidence of extrapyramidal symptom-related AEs was 3.1% and 4.7%, respectively. The most frequently reported AEs with asenapine versus placebo were anxiety (8.2%; 10.9%), increased weight (6.7%; 3.6%), and insomnia (6.2%; 13.5%). The incidence of clinically significant weight gain (≥ 7% increase from double-blind baseline) was 3.7% with asenapine and 0.5% with placebo. CONCLUSIONS Long-term treatment with asenapine was more effective than placebo in preventing relapse of schizophrenia and appeared to be safe and well tolerated. TRIAL REGISTRATION clinicaltrials.gov Identifier NCT00150176.

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

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 asenapines 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.

Meta-Analyses of the Efficacy of Asenapine for Acute Schizophrenia: Comparisons With Placebo and Other Antipsychotics

CONTEXT Asenapine is an approved treatment for schizophrenia in the United States. OBJECTIVE Meta-analyses were conducted to evaluate the efficacy of asenapine in acute schizophrenia compared with placebo and other antipsychotics. DATA SOURCES Four asenapine trials from the asenapine development program were pooled for the meta-analysis. To compare asenapine versus placebo treatment effect with other antipsychotics, we added integrated asenapine data to a previously published meta-analysis. For comparative efficacy of asenapine versus other second-generation antipsychotics (SGAs), data from a second published meta-analysis were combined with the 4 asenapine trials. DATA ANALYSES To evaluate efficacy, mean change in Positive and Negative Syndrome Scale (PANSS) total score was examined in asenapine and other antipsychotics. To assess clinical relevance, PANSS response rates and associated odds ratios (ORs) for treatment response were assessed. To assess the relative efficacy of SGAs, a network meta-analysis with PANSS total score change was conducted by using data from the 2 published meta-analyses together with asenapine data. RESULTS Asenapine was superior to placebo with regard to mean change in PANSS total score (last observation carried forward [LOCF]: -3.6, P = .002; mixed model for repeated measures [MMRM]: -4.1, P = .001), an effect comparable to active controls from the same trials (LOCF: -4.0, P = .002; MMRM: -4.8, P = .001). PANSS responder rates were significantly better with asenapine versus placebo (OR, 1.9; P < .001) and comparable to active controls (OR, 1.7; P = .002). Effect sizes for asenapine were somewhat lower than those reported in the literature for other SGAs. Network meta-analysis also demonstrated that the efficacy of asenapine was comparable to that of other SGAs; estimated differences between asenapine and other SGAs ranged from 3.9 points (95% CI, 0.3 to 7.4) greater than ziprasidone to 2.9 points (95% CI, -0.1 to 5.9) less than olanzapine. CONCLUSIONS These meta-analyses indicate that the efficacy of asenapine for acute schizophrenia is superior to placebo and comparable to several other SGAs.

Weight change and metabolic effects of asenapine in patients with schizophrenia and bipolar disorder

OBJECTIVE To describe weight changes and metabolic effects of asenapine compared with placebo and olanzapine in adults. METHOD Post hoc analyses were performed using data from 17 asenapine trials (13 schizophrenia and 4 bipolar mania trials) with placebo (5-10 mg twice daily; n = 1,748; 1-6 weeks) and/or olanzapine (5-20 mg, once daily; n = 3,430; 3-100 weeks). Data were pooled based on treatment into placebo-controlled and olanzapine-controlled trials. For trials with placebo and olanzapine treatment groups, the asenapine population was included in both pools. Changes from baseline for weight, body mass index, and fasting lipid and glucose levels were determined. The Medical Dictionary for Regulatory Activities was used to define metabolic adverse events. RESULTS Mean (standard error [SE]) weight change was greater with asenapine than with placebo (1.2 [0.2] vs 0.14 [0.2] kg; P < .0001) and similar in schizophrenia and bipolar disorder. Mean changes differed for asenapine versus placebo in triglycerides (1.8 [6.3] vs -12.2 [5.9] mg/dL; P < .01) and fasting glucose (1.9 [1.7] vs -1.6 [1.5] mg/dL; P < .05). In the olanzapine-controlled trials, weight change was significantly lower with asenapine than with olanzapine (0.9 [0.1] vs 3.1 [0.2] kg; P < .0001). Changes associated with asenapine were lower than those with olanzapine in fasting glucose (2.0 vs 3.3 mg/dL), total cholesterol (-0.4 [1.1] vs 6.2 [1.2] mg/dL; P < .0001), low-density lipoprotein cholesterol (-0.3 [1.1] vs 3.1 [1.2] mg/dL; P < .01), and triglycerides (-0.9 [5.4] vs 24.3 [5.8] mg/dL; P < .0001). CONCLUSIONS Asenapine was associated with greater weight gain and glucose changes than placebo and not associated with a meaningful change in triglycerides or cholesterol levels. Asenapine was not significantly different from olanzapine in change in glucose levels and lower than olanzapine with respect to triglycerides, weight gain, and increased cholesterol.

Comparison of somnolence associated with asenapine, olanzapine, risperidone, and haloperidol relative to placebo in patients with schizophrenia or bipolar disorder

Background Patients with schizophrenia or bipolar disorder (BPD) may be differentially sensitive to antipsychotics. This study assessed the median time to onset, duration, and rate of somnolence associated with asenapine and other antipsychotics in both indications. Methods Ten clinical trials (n = 4786) were analyzed as five cohorts pooled according to indication and study design. Results In the short-term schizophrenia cohort, the incidence of somnolence was 13.1%, 19.1%, 8.5% 5.2%, and 6.9% with asenapine, olanzapine, risperidone, haloperidol, and placebo, respectively. Median time to onset of somnolence was 2 days for asenapine and olanzapine, and 6, 3, and 7 days for risperidone, haloperidol, and placebo, respectively. Median duration was 15 days for asenapine and olanzapine, and 3, 22.5, and 4.5 days for risperidone, haloperidol, and placebo, respectively. In the long-term schizophrenia cohort, the incidence, time to onset, and duration of somnolence with asenapine and olanzapine were 18.4% versus 19.6%, 9.0 days versus 12 days, and 22 days versus 21 days, respectively. In schizophrenia with persistent negative symptoms, the incidence, median time to onset, and duration of somnolence with asenapine and olanzapine were 18.5% versus 21.1%, 9.0 days versus 7.5 days, and 25.0 days versus 41.5 days, respectively. In the monotherapy for BPD cohort, the incidence of somnolence with asenapine, olanzapine, and placebo was 23.8%, 26.4%, and 6.4%, respectively. Median time to onset and duration of somnolence with asenapine, olanzapine, and placebo were 1, 2, and 2 days, respectively, and 7, 8.5, and 5 days. In the adjunctive therapy for BPD cohort, the incidence, median time to onset, and duration of somnolence with asenapine and placebo were 24.0% versus 10.2%, 1.5 days versus 2 days, and 12.5 days versus 7 days, respectively. Conclusion In the short-term schizophrenia cohort, time to onset and duration of somnolence with asenapine was similar to that with olanzapine and haloperidol. Only asenapine and olanzapine had significantly higher rates of somnolence relative to placebo. The time to onset, duration, and incidence of somnolence with asenapine and olanzapine was similar in patients with long-term schizophrenia and those with BPD. Patients with BPD were more sensitive than those with schizophrenia to asenapine and olanzapine.

Safety and tolerability of switching to asenapine from other antipsychotic agents: pooled results from two randomized multicenter trials in stable patients with persistent negative symptoms in schizophrenia

Background In clinical practice, clinicians often need to switch antipsychotic medications in patients with schizophrenia to optimize treatment outcomes. Here, we describe the safety and tolerability of switching existing antipsychotic treatments to asenapine or olanzapine monotherapy using various switching regimens. Methods Data were pooled from 949 patients in two 26-week randomized double-blind studies. Patients with persistent negative symptoms of schizophrenia, stable for at least 5 months prior to screening and 1 additional month before randomization, were randomized to and treated with either asenapine (n = 485) or olanzapine (n = 464), and were tapered off existing antipsychotic(s) at variable rates within 28 days. Results Prior to randomization, most patients were treated with second-generation antipsychotics (SGAs) (asenapine: 79.6%; olanzapine: 78.2%) and first-generation antipsychotics (FGAs) (31.1%; 29.7%), while depot formulations were used by 12.4% and 11.4%, respectively. Median time to taper off previous antipsychotics was 7 days, with approximately 40% of patients abruptly discontinuing their previous medication. Similar percentages of patients in each group reported at least one adverse event (AE) (asenapine: 76.9%; olanzapine: 75.2%). The majority of AEs occurred within the first 28 days. The most frequently reported AEs were somnolence, insomnia, and headache. The incidence of AEs in patients switching from SGAs, FGAs, or depot medications was similar between asenapine and olanzapine (77.5% vs 74.6%, 75.5% vs 79.7%, 85.0% vs 86.8%, respectively). AEs were more frequent in subjects previously treated with two antipsychotics (asenapine: 79.4%; olanzapine: 83.9%) versus one antipsychotic (asenapine: 76.3%; olanzapine: 72.2%) in the switch period. Conclusion The presented data from post hoc pooled analyses may provide practical guidance for physicians switching partially stabilized patients with schizophrenia and persistent negative symptoms to asenapine or olanzapine.

Safety and Efficacy from an 8 Week Double-Blind Trial and a 26 Week Open-Label Extension of Asenapine in Adolescents with Schizophrenia.

OBJECTIVE The purpose of this study was to evaluate the safety and efficacy of asenapine in adolescents with schizophrenia. METHODS In an 8 week, randomized, double-blind placebo-controlled trial, subjects (12-17 years of age) meeting Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria for schizophrenia were randomized 1:1:1 to placebo, asenapine 2.5 mg b.i.d., or asenapine 5 mg b.i.d. Subjects who completed the 8 week acute study could participate in a 26 week flexible-dose asenapine-only open-label extension (OLE). RESULTS A similar percentage of subjects completed treatment on day 56 (2.5 mg b.i.d. (n=98): 83%; 5 mg b.i.d. [n=106]: 79%; placebo [n=102]: 79%). In the mixed model for repeated measures analysis of the primary end-point (with Hochberg correction for multiplicity), least squares (LS) mean differences between asenapine and placebo on the Positive and Negative Syndrome Scale (PANSS) total score at day 56 were not significant (-4.8 for 2.5 mg b.i.d., p=0.070; -5.6 for 5 mg b.i.d., p=0.064). Significant improvement in the Clinical Global Impressions-Severity score was observed in the 5 mg b.i.d. group versus placebo on day 56 (LS mean -0.3, p=0.024). In the acute phase, ≥7% weight gain and the composite event of somnolence, sedation, and hypersomnia were more common in both asenapine groups than in the placebo group. Akathisia, fasting glucose elevation, and extrapyramidal syndrome were more common in the 5 mg b.i.d. group than in the placebo group. There were no unexpected adverse events in the OLE, and PANSS total scores decreased by -16.1 points in the group previously treated with placebo (n=62) and by -11.2 points in the continuous asenapine group (n=131) from OLE baseline to week 26. CONCLUSIONS Although improvements in PANSS total score at day 56 of the acute phase were numerically greater for both asenapine 2.5 and 5 mg b.i.d. than for placebo and were maintained in the OLE, the primary end-point did not achieve statistical significance in the acute phase. No new or unexpected safety concerns were detected during the acute phase or after an additional 26 weeks of asenapine treatment in the adolescent population with schizophrenia. CLINICAL TRIALS REGISTRY NCT01190254 and NCT1190267 at ClinicalTrials.gov.

Asenapine: Efficacy and safety of 5 and 10 mg bid in a 3-week, randomized, double-blind, placebo-controlled trial in adults with a manic or mixed episode associated with bipolar I disorder

BACKGROUND Asenapine is an atypical antipsychotic for acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. The recommended asenapine starting dose is 10mg bid with the option to reduce the dose to 5mg bid if needed due to adverse effects/tolerability. METHODS Phase IIIb, international, double-blind, fixed-dose, parallel-group, 3-week placebo-controlled trial of asenapine 5 and 10mg bid in adults with an acute bipolar I disorder manic or mixed episode. Primary outcome was difference in asenapine versus placebo in mean change from baseline to day 21 in the Young-Mania Rating Scale (YMRS) total score. Others included difference in asenapine versus placebo in the Clinical Global Impression Scale for Bipolar Severity (CGI-BP-S) and rate of YMRS responders. RESULTS Both asenapine doses were statistically superior to placebo in mean change from baseline to day 21 in YMRS total score (-10.9, -14.4, and -14.9 for placebo, asenapine 5mg bid, 10mg bid, respectively). Both asenapine doses had statistically superior improvement in mean change in CGI-BP-S score at day 21. Neither asenapine dose had significantly more YMRS responders at day 21 than placebo. LIMITATIONS Results may not be generalizable to the entire population with bipolar I disorder owing to strict inclusion criteria. CONCLUSIONS This study evaluated, by a fixed-dose design, the efficacy and safety of asenapine versus placebo in patients with bipolar I disorder. Both asenapine 5 and 10mg bid were efficacious in treating mania associated with bipolar I disorder and were generally well tolerated.

Asenapine effects on individual Young Mania Rating Scale items in bipolar disorder patients with acute manic or mixed episodes: a pooled analysis

Background An exploratory post hoc analysis was conducted to evaluate the potential differential effects over time of asenapine and olanzapine compared with placebo on the eleven individual items comprising the Young Mania Rating Scale (YMRS) in patients with manic or mixed episodes in bipolar I disorder. Methods Data were pooled from two 3-week randomized, controlled trials in which the eleven individual items comprising the YMRS were measured over 21 days. An analysis of covariance model adjusted by baseline value was used to test for differences in changes from baseline in YMRS scores between groups. Results Each of the eleven individual YMRS item scores was significantly reduced compared with placebo at day 21. After 2 days of treatment, asenapine and olanzapine were superior to placebo for six of the YMRS items: disruptive/aggressive behavior, content, irritability, elevated mood, sleep, and speech. Conclusion Reduction in manic symptoms over 21 days was associated with a broad-based improvement across all symptom domains with no subset of symptoms predominating.