14 de noviembre de 2011

Patient Prefer Adherence. 2011; 5: 333–341.
Published online 2011 July 1. doi: 10.2147/PPA.S10968
PMCID: PMC3140314
Copyright © 2011 Gonzalez et al, publisher and licensee Dove Medical Press Ltd
Review of the safety, efficacy, and side effect profile of asenapine in the treatment of bipolar 1 disorder
Jodi M Gonzalez,1 Peter M Thompson,1 and Troy A Moore1,2
1University of Texas Health Science Center, San Antonio, TX, USA;
2South Texas Veterans Health Care System, TX, USA
Correspondence: Jodi M Gonzalez, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA, Tel +1 210 567 5424, Fax +1 210 567 3759, Email gonzalezjm1@uthscsa.edu
Received June 30, 2011

Asenapine is a recently FDA-approved atypical antipsychotic which has shown benefits in treating manic and mixed states as monotherapy in bipolar disorder up to one year after initiation of treatment. In two 3-week trials, asenapine had a higher dropout rate than olanzapine, often due to continuing manic symptoms. After 3 weeks, asenapine performs as well as olanzapine on primary efficacy outcomes. In a trial to assess the adjunctive effects of asenapine on manic and mixed states, there were short-term benefits on manic symptoms, but no additional benefits in the long-term for asenapine versus placebo as adjunctive therapy.20 Asenapine is FDA approved to treat manic and mixed episodes in bipolar disorder. However, asenapine may be less effective for mixed states in the short-term. Only one asenapine 3-week trial reported by subgroup, and they noted significant improvements at day 2 compared to placebo, with the improvement not statistically significant compared to placebo by day 21. Additional subgroup analyses on mixed states would be beneficial.
Asenapine did not show improvement on depressive symptoms in the short term or long term. During the 40-week extension period, 15% of subjects had worsening of depression symptoms while 8% of the olanzapine group had worsening symptoms. Thus, one of the primary interests of new pharmaceuticals from a patient’s perspective (ie, treating depressive symptoms)15 is not addressed by asenapine. Weight gain was the other patient-expressed concern. Greater weight gain in the olanzapine group emerged in the initial 3-week trials. In a year’s time, 31% of the asenapine group had clinically significant weight gain, as compared with 55% with olanzapine. Compared with olanzapine, asenapine has a more favorable weight gain side effect profile although both compounds have a significant impact on weight. Elevated fasting blood glucose levels were comparable in asenapine and olanzapine in the long-term trial. Monitoring of lab values and metabolic outcomes with asenapine is crucial.
Long-term side effects reported by at least 10% of the asenapine group are sedation, somnolence, insomnia, headache, dizziness, nausea, and akathisia. Tremor and parkinsonism were reported by 8% of subjects. None of the clinical trials reported the frequency or seriousness of sexual dysfunction while taking asenapine. Sexual dysfunction may be a hidden cause of nonadherence to antipsychotic medication28,29 as clinicians may underestimate the frequency of sexual side effects. Further attention to this topic in future trials is warranted. A consideration of these side effects in prescribing asenapine will be essential to adherence to the treatment regimen. Table 3 provides an overview of side effect profiles across medications used to treat bipolar disorder
Clinical situations where asenapine may be the preferred agent
Asenapine was recently introduced and the clinical indications, which may distinguish it from other treatments of mania, are lacking. The pharmacology of asenapine offers a commonsense approach to guide its use. One benefit of asenapine for some patients is the sublingual application, a preferred option for patients who cannot take medications by tablet because of medical or behavioral reasons, for example, a patient who cannot swallow pills due to an esophageal stricture, gastric bypass surgery, or general unwillingness to swallow pills. Other areas where sublingual medication is especially important include crisis intervention requiring rapid onset, or with patients who may be reluctant to take medication, such as an inpatient setting or forensic setting where patients may not swallow medication but rather hold it in their mouth (ie, “cheek it”).
The other treatment guidance comes from asenapine’s pharmacological profile.35 Asenapine has relatively low histamine receptor 1 (H1) affinity. Histamine receptor blockade is often implicated in atypical antipsychotic-induced weight gain and sedation, suggesting less weight gain and sedation liability than atypical antipsychotics with high H1 affinity (such as olanzapine or quetiapine). Additionally, it has lower affinity for dopamine receptors 1,2 (D1,2) suggesting it will have less extrapyramidal and hyperprolactinemia effects than haloperidol. These attributes should be considered with individuals who are at risk for developing metabolic syndrome and when other medications were stopped due to intolerable side effects, eg, akathisia. Another clinical situation where asenapine may be a good choice is with QT prolongation, which asenapine is less apt to produce than ziprasidone.36 Finally, there is a growing awareness that anxiety in mood disorders increases the severity of the illness.37,38 While there are no published trials of asenapine treatment of bipolar disorder and anxiety, asenapine acts as an inverse agonist at the serotonin 1 A (5HT1A) receptor, similar to anxiolytic busperoine39 suggesting that patients with anxiety may benefit from its use.
Potential asenapine contraindications
Patients who have demonstrated nonadherence in the initial 3 weeks of treatment due to slow medication effects may fare better with a faster acting medication such as olanzapine. For patients who have cognitive deficits interfering with adherence to a slightly more complex regimen than other atypical antipsychotics (ie, twice daily and food intake restrictions) asenapine may not be the preferred agent. As there is increased risk of metabolic syndrome for asenapine, consideration of comorbid medical conditions is essential, that is, diabetes and any indications of metabolic syndrome. In these cases, other antipsychotics should be considered first (eg, aripiprazole, ziprasidone). Other comorbid conditions to carefully consider are any hepatic impairment or any comorbid conditions, which include medication regimens that may be contraindicated in asenapine administration. Asenapine may be less indicated for mixed states only, for long-term use as adjunctive therapy, or for those patients and clinicians who may also be looking for a medication with a potential antidepressant effect.
In this review we provide information on reasons for dropout, typical side effects to expect with asenapine, and discuss issues related to adherence to antipsychotics in general. However, this report is limited by the current lack of studies examining patient preferences and issues related to adherence with asenapine.

Asenapine is an atypical antipsychotic indicated for the treatment of schizophrenia and for the acute treatment of manic or mixed episodes, with or without psychotic features, associated with bipolar disorder. Asenapine is approved as monotherapy and as adjunctive therapy. The initial recommended dose of asenapine monotherapy for bipolar disorder is 20 mg total daily dose (10 mg sublingually twice daily), which is also the recommended target dose. For adjunctive therapy, the recommended dose is 10–20 mg. The safety of total daily doses above 20 mg has not been evaluated in clinical trials. Ninety percent of bipolar patients in registration trials required 10 mg twice daily for a clinical response.
The exact mechanism by which asenapine reduces manic symptoms associated with bipolar disorder is unknown. Asenapine has high affinity for serotonin receptors (5-HT1a, 5-HT1b, 5-HT2a, 5-HT2b, 5-HT2c, 5-HT5, 5-HT6, and 5-HT7), dopamine receptors (D1, D2, D3, and D4), Alpha 1 and 2 receptors, and histamine (H1) receptors. It also has moderate affinity for histamine (H2) receptors. Asenapine acts as an antagonist at all these receptors. Unlike some other antipsychotics (eg, olanzapine) asenapine has no appreciable binding to muscarinic receptors. The mean half-life of asenapine is 24 hours and steady state concentrations are achieved in 3 days with multiple dosing. Absorption pharmacokinetics are very important with asenapine as the absolute bioavailability of asenapine taken sublingually is approximately 35%, but if swallowed the bioavailability is less than 2%.17 Patients must be properly counseled on the importance of taking asenapine sublingually with no drinking or eating 10 minutes after administration. Asenapine is metabolized via direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2).
Asenapine has been found to be a weak inhibitor of cytochrome P-450 2D6, so major drug interactions are not expected; but it should be used with caution with other agents that are metabolized by CYP 2D6 (eg, paroxetine, most tricyclic antidepressants, amoxapine, captopril, duloxetine, fluoxetine, fluvoxamine, haldol). Co-administration of a single 20-mg dose of paroxetine during treatment with 5 mg asenapine twice daily in 15 healthy male subjects resulted in an almost 2-fold increase in paroxetine exposure.17 Asenapine may enhance the inhibitory effects of paroxetine on its own metabolism. Also since asenapine is metabolized by CYP 1A2, caution should be used with co-administration with agents/conditions that induce CYP 1A2 (eg, smoking, carbamazepine, or rifampin) or inhibit CYP 1A2 (eg, fluvoxamine, ciprofloxacin, or ketoconazole).
Asenapine does not require any dosage adjustment in renal impairment. In severe hepatic impairment (Child–Pugh C), asenapine is not recommended. Asenapine levels were 7-fold higher in patients with Child–Pugh C classified hepatic impairment versus patients with normal hepatic function.
Black box warning
As is the case for all antipsychotic medications prescribed to elderly individuals, there is a black box warning for asenapine. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death, due to cerebrovascular adverse reactions including fatalities.
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