Thomas A. Macek

A 3-week, randomized, placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states.

OBJECTIVE Asenapine is approved for bipolar disorder and schizophrenia. This was a 3-week, randomized, double-blind, placebo-controlled trial of asenapine for treating acute bipolar mania. METHODS After a single-blind placebo run-in period, adults (n = 488) experiencing manic or mixed episodes were randomized to flexible-dose sublingual asenapine (10 mg BID on day 1; 5 or 10 mg BID thereafter; n = 194), placebo (n = 104), or oral olanzapine (15 mg BID on day 1; 5-20 mg QD thereafter; n = 191). Primary efficacy, change in Young Mania Rating Scale (YMRS) total score from baseline to day 21, was assessed using analysis of covariance with last observation carried forward [(LOCF); primary analysis]. A mixed model for repeated measures [(MMRM); prespecified secondary analysis] was also used to assess efficacy. Tolerability and safety assessments included adverse events, physical examinations, extrapyramidal symptom ratings, and laboratory values. RESULTS Mean daily dosages were asenapine 18.2 mg and olanzapine 15.8 mg. Significantly greater least squares (LS) mean +/- SE changes in YMRS scores were observed on day 2 with asenapine (-3.0 +/- 0.4) and olanzapine (-3.4 +/- 0.4) versus placebo (-1.5 +/- 0.5, both p < 0.01) and were maintained until day 21 (-10.8 +/- 0.8 with asenapine, -12.6 +/- 0.8 with olanzapine; both p < or = 0.0001 versus placebo, -5.5 +/- 1.1) with LOCF. The results of MMRM analyses were consistent with those of LOCF. Asenapine had a modest impact on weight and metabolic measures. CONCLUSIONS These results indicate that asenapine is rapidly acting, efficacious, and well tolerated for patients with bipolar I disorder experiencing an acute manic episode.

Asenapine in the treatment of acute mania in bipolar I disorder: A randomized, double-blind, placebo-controlled trial

BACKGROUND Asenapine is indicated in adults for acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features. This randomized, double-blind, placebo-controlled trial assessed the efficacy, safety, and tolerability of asenapine in bipolar I disorder. METHODS Adults experiencing manic or mixed episodes were randomized to 3 weeks of flexible-dose treatment with sublingual asenapine (day 1: 10mg BID, 5 or 10mg BID thereafter; n=185), placebo (n=98), or oral olanzapine (day 1: 15 mg QD, 5-20mg QD thereafter; n=205). Primary efficacy, YMRS total score change from baseline to day 21, was assessed using ANCOVA with last observation carried forward. RESULTS Mean daily doses were 18.4 mg asenapine and 15.9mg olanzapine. Least squares mean changes in YMRS total score on day 21 were significantly greater with asenapine than placebo (-11.5 vs -7.8; P<0.007), with advantage seen as early as day 2 (-3.2 vs -1.7; P=0.022). Changes with olanzapine on days 2 and 21 also exceeded placebo (both P<0.0001). YMRS response and remission rates with olanzapine, but not asenapine, exceeded those of placebo. Incidence of EPS-related adverse events was 10.3%, 3.1%, and 6.8% with asenapine, placebo, and olanzapine, respectively; incidence of clinically significant weight gain (7.2%; 1.2%; 19.0%). Mean weight change (baseline to endpoint) was 0.9, 0.1, and 2.6 kg with asenapine, placebo, and olanzapine, respectively. LIMITATIONS As this short-term study was designed for comparisons with placebo, any comparisons between asenapine and olanzapine should be interpreted cautiously. CONCLUSIONS Asenapine was superior to placebo in reducing YMRS total score and was well tolerated.

Asenapine versus olanzapine in acute mania: a double-blind extension study

OBJECTIVE To assess the efficacy and tolerability of asenapine versus olanzapine in the extended treatment of bipolar mania. METHODS Patients with bipolar I disorder experiencing acute manic or mixed episodes who completed either of two 3-week, double-blind trials with asenapine 5 or 10 mg twice daily, olanzapine 5 to 20 mg once daily, or placebo were eligible for this 9-week, double-blind extension study. Patients receiving active medication in the 3-week trials continued the same regimen; those who had received placebo were blindly switched to asenapine but were assessed for safety outcomes only. The primary efficacy measure was the change from baseline to day 84 on the Young Mania Rating Scale (YMRS) total score in the per-protocol population. Results on the primary efficacy outcome were used to determine the noninferiority of asenapine versus olanzapine. RESULTS A total of 504 patients (placebo/asenapine, n = 94; asenapine, n = 181; olanzapine, n = 229) were enrolled in the extension study. At day 84, the mean (SD) change from baseline in YMRS total score was -24.4 (8.7) for asenapine and -23.9 (7.9) for olanzapine. Prespecified statistical analysis for noninferiority indicated no significant difference between asenapine and olanzapine. The overall incidence of treatment-emergent adverse events was similar across treatment groups (77% placebo/asenapine, 77% asenapine, 78% olanzapine). Clinically significant weight gain occurred in 10%, 19%, and 31% of the placebo/asenapine, asenapine, and olanzapine groups, respectively. CONCLUSIONS Asenapine was efficacious, showed noninferiority to olanzapine, and was well tolerated in the extended treatment of patients experiencing manic symptoms associated with bipolar I disorder.

Asenapine for long-term treatment of bipolar disorder: A double-blind 40-week extension study

BACKGROUND Asenapine is approved in the United States for acute treatment of manic or mixed episodes of bipolar I disorder with or without psychotic features. We report the results of long-term treatment with asenapine in patients with bipolar I disorder. METHODS Patients completing either of two 3-week efficacy trials and a subsequent 9-week double-blind extension were eligible for this 40-week double-blind extension. Patients in the 3-week trials were randomized to flexible-dose asenapine (5 or 10mg BID), placebo, or olanzapine (5-20mg QD; included for assay sensitivity only). Patients entering the extension phase maintained their preestablished treatment; those originally randomized to placebo received flexible-dose asenapine (placebo/asenapine). Safety and tolerability endpoints included adverse events (AEs), extrapyramidal symptoms, laboratory values, and anthropometric measures. Efficacy, a secondary assessment, was measured as change in Young Mania Rating Scale (YMRS) total score from 3-week trial baseline to week 52 with asenapine or olanzapine; the placebo/asenapine group was assessed for safety only. RESULTS Incidence of treatment-emergent AEs was 71.9%, 86.1%, and 79.4% with placebo/asenapine, asenapine, and olanzapine, respectively. The most frequent treatment-emergent AEs were headache and somnolence with placebo/asenapine; insomnia, sedation, and depression with asenapine; and weight gain, somnolence, and sedation with olanzapine. Among observed cases, mean ± SD changes in YMRS total score at week 52 were -28.6 ± 8.1 and -28.2 ± 6.8 for asenapine and olanzapine, respectively. LIMITATIONS The study did not have a long-term placebo group. CONCLUSIONS In this 52-week extension in patients with bipolar mania, asenapine was well tolerated and long-term maintenance of efficacy was supported.

Activation of PKC Disrupts Presynaptic Inhibition by Group II and Group III Metabotropic Glutamate Receptors and Uncouples the Receptor from GTP‐Binding Proteins

hroughout the central nervous system, cell excitability and fast synaptic transmission are modulated by the activation of a family of G protein–coupled receptors termed metabotropic glutamate receptors (mGluRs). Eight mGluR subtypes have been cloned and have been classified into three major groups. Group I mGluRs (mGluR1 and mGluR5) couple primarily to phosphoinositide hydrolysis, whereas group II (mGluR2 and mGluR3) and group III (mGluRs 4,6,7, and 8) couple to inhibition of adenylyl cyclase in expression systems. One of the primary functions of mGluRs seen throughout the central nervous system (CNS) is to serve as presynaptic receptors involved in reducing transmission at glutamatergic synapses. A diversity exists within the CNS as to which mGluR subtypes serve this role at a given synapse. For example, different complements of mGluR subtypes serve this role at each of the three major excitatory synapses in the hippocampal formation. We now report that activation of protein kinase C (PKC) inhibits the function of presynaptic mGluR’s at three major hippocampal synapses. At the Schaffer collateral (SC)-CA1 synapse, this effect can be elicited by activation of A3 adenosine receptors. Furthermore, we provide biochemical evidence that suggests that PKC elicits this effect by inhibiting coupling of mGluR’s to GTP-binding proteins. Regulation of presynaptic mGluRs by PKC could play a critical role in fine-tuning transmission at glutamatergic synapses.

P01-69 - Long-term asenapine treatment for bipolar disorder: a double-blind 40-week extension study

Objectives Asenapine is indicated in adults for acute treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder with or without psychotic features. We report the safety, tolerability, and efficacy of asenapine in patients with bipolar I disorder completing up to 52 weeks of treatment. Methods Patients completing either of two 3-week efficacy trials and a 9-week double-blind extension were eligible for this 40-week double-blind extension. Patients in the 3-week trials were randomized to flexible-dose asenapine (5 or 10 mg BID), placebo, or olanzapine (5-20 mg QD; included for assay sensitivity only). Patients entering the extension continued their preestablished treatment; those originally randomized to placebo received flexible-dose asenapine (placebo/asenapine, 5 or 10 mg BID). Safety and tolerability endpoints included adverse events (AEs), extrapyramidal symptoms, laboratory values, and anthropometric measures. Efficacy was measured as the change in Young Mania Rating Scale (YMRS) total score from 3-week trial baseline to week 52; the placebo/asenapine group was included in the safety analyses. Results Incidence of treatment-emergent AEs was 71.9%, 86.1%, and 79.4% with placebo/asenapine, asenapine, and olanzapine, respectively. The most frequent AEs included headache and somnolence (placebo/asenapine); insomnia, sedation, and depression (asenapine); and weight gain, somnolence, and sedation (olanzapine). Mean ± SD changes in YMRS score at week 52 among observed cases in the intent-to-treat population were -28.6±8.1 for asenapine and -28.2±6.8 for olanzapine. Conclusions In this 52-week study, asenapine was well tolerated and long-term maintenance of efficacy was supported in patients initially presenting with bipolar mania.