Asenapine is an atypical antipsychotic that acts as an antagonist at dopaminergic, serotonergic and alpha-adrenergic receptors. Although the exact mechanism of action is not understood, its activity at D2 and 5-HT2A receptors is thought to be important in treating bipolar disorder. Actions at 5-HT1A, 5-HT1B, 5-HT2C, 5-HT6, 5-HT7, D3 and alpha2-adrenergic receptors may also contribute to the therapeutic effect. Unlike many other antipsychotics, asenapine has a low affinity for muscarinic receptors, which may be beneficial in patients where antimuscarinic effects are undesirable.1
The bioavailability of asenapine administered orally is low (2%), owing to extensive first-pass metabolism. When formulated as a sublingual tablet, asenapine is rapidly absorbed and achieves peak plasma concentrations within 90 minutes. To ensure optimal absorption, the manufacturer recommends avoiding eating or drinking for 10 minutes after the tablet has completely dissolved.1
The short-term efficacy of asenapine in the treatment of acute manic or mixed episodes in bipolar I disorder was evaluated in two 3-week randomised, double-blind phase 3 trials of similar design, which included placebo and olanzapine as controls. Patients with rapid cycling were excluded from both studies.1–3
Following a placebo run-in period, participants were randomised to receive flexible-dose sublingual asenapine (10mg twice daily on day 1, then 5mg or 10mg twice daily), oral olanzapine (15mg once daily on day 1, then 5–20mg once daily) or placebo. Young Mania Rating Scale (YMRS) was assessed at baseline and at day 21 as the primary efficacy measure.2,3
In the first study (n=488), patients receiving asenapine showed a significantly greater reduction in YMRS score as early as day 2 compared with patients on placebo (-3.0 vs -1.5; p<0.01), and this difference was maintained at day 21 (-10.8 vs -5.5; p≤0.0001).2 Similar results were observed in the second study (n=489), with a significantly greater reduction in YMRS score for asenapine than placebo after 2 days (-3.2 vs -1.7; p=0.022) and at 21 days (-11.5 vs -7.8; p<0.007).3
Olanzapine was also significantly more effective than placebo at days 2 and 21 in both studies. The studies were not designed to directly compare asenapine and olanzapine.2,3
Patients who completed either short-term study were eligible to join a double-blind 9-week extension study investigating the longer term safety and efficacy of asenapine. A total of 504 patients were enrolled and continued their assigned treatment with asenapine or olanzapine; those originally assigned to receive placebo were switched to asenapine. The treatment effect was maintained, with asenapine displaying non-inferiority to olanzapine in terms of reduction in YMRS score after 12 weeks (-24.4 vs -23.9).4
Asenapine was generally well tolerated in the trials, with the most common adverse events being somnolence, dizziness and sedation. Extrapyramidal symptoms were observed more frequently in patients receiving asenapine than in those receiving olanzapine. However, weight gain was more common and more pronounced with olanzapine than asenapine. The effects of asenapine on blood glucose and lipids were minimal.2–4
1. Sycrest Summary of Product Characteristics, October 2011.
2. McIntyre RS et al. Bipolar Disord 2009;11:673-86.
3. McIntyre RS et al. J Affect Disord 2010;122:27-38.
4. McIntyre RS et al. Bipolar Disord 2009;11:815-26.
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Further information: Lundbeck Ltd