Asenapine for schizophrenia and bipolar disorder: a review of the efficacy and safety profile for this newly approved sublingually absorbed second-generation antipsychotic.

Summary Objective: To describe the efficacy and safety of asenapine for the treatment of schizophrenia and bipolar disorder. Data sources: The pivotal registration trials were accessed by querying http://www.pubmed.gov, http://www.fda.gov and http://www.clinicaltrials.govfor the search terms ‘asenapine’ or ‘ORG 5222’. Study selection: All available clinical reports of studies were identified, as well as preclinical animal and receptor affinity studies that describe potential mechanisms of action. Extensive documents available from the US Food and Drug Administration and Schering-Plough Corporation as posted on http://www.fda.gov provided much of this data. Product labelling also provided additional information. Data extraction: Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the study reports and synopses. Additional safety outcomes subject to NNH analysis were obtained from product labelling. Data synthesis: A sublingual formulation of asenapine has received regulatory approval for the acute treatment of schizophrenia and manic/mixed episodes of bipolar I disorder. Bioavailability is 35% when taken sublingually, but < 2% if ingested. Similar to other second-generation antipsychotics, asenapine’s binding profile includes 5-HT2A and D2 antagonism. Binding at the alpha-1 adrenergic and histamine H1 receptors predicts asenapine’s propensity to cause orthostasis and sedation in some patients. Efficacy in the treatment of acute schizophrenia is supported by 2 of 4 completed phase II/III randomised, placebo and active-controlled 6-week trials, principally at a dose of 5 mg bid. Responder analysis for one of the studies reveals a NNT of asenapine vs. placebo of six for response as defined by a minimum of a 20% decrease in the Positive and Negative Syndrome Scale total score from baseline, and a NNT of 8 for the threshold of a 30% decrease. Efficacy in the treatment of manic or mixed episodes of bipolar I disorder is supported by 2 of 2 completed phase III randomised, placebo and active-controlled 3-week trials and by a 9-week extension trial. The dose tested in the bipolar trials was 10 mg bid. Longer-term studies have been completed in patients with schizophrenia or bipolar disorder, but complete results have not yet been published. Asenapine has a relatively favourable tolerability profile. For the patients with schizophrenia, the NNH values for asenapine vs. placebo for commonly observed adverse reactions were 13 (95% CI 8–30) for akathisia (10 mg bid), 20 (95% CI 13–50) for oral hypoesthesia (5 mg bid) and 13 (95% CI 8–32) for somnolence (5 mg bid). For patients with bipolar disorder, the NNH values for asenapine 5–10 mg bid vs. placebo were 6 (95% CI 5–9) for somnolence, 13 (95% CI 9–25) for dizziness, 20 (95% CI 13–56) for extra-pyramidal symptoms (EPS) other than akathisia and 25 (95% CI 16–71) for increased weight. Asenapine is associated with a lower frequency for EPS than haloperidol. Asenapine has a mild effect on the ECG QT interval similar to that seen with quetiapine. Asenapine’s effect on prolactin is similar to that observed with olanzapine. Asenapine has a more favourable weight gain and metabolic profile compared with olanzapine. Conclusions: Asenapine sublingual tablets are a new option for the treatment of acute episodes of schizophrenia and for the treatment of acute manic or mixed episodes of bipolar I disorder. Although there is no evidence for asenapine’s efficacy to be superior to currently available agents, asenapine’s favourable weight and metabolic profile are of clinical interest. A caveat is that the data reviewed regarding asenapine are from its manufacturer. No independent studies of asenapine’s efficacy or safety are available. Obstacles to the use of asenapine are the recommendations for twice daily dosing and the need to avoid food or liquids for 10 min after administration. As asenapine’s bioavailability is very low if ingested, asenapine is unique among the antipsychotics, in that it needs to be swallowed to be covertly ‘cheeked’.