|Trade names||Saphris, Sycrest|
|Bioavailability||35% (sublingual), <2% (Oral)|
|Metabolism||hepatic (glucurinodation by UGT1A4 and oxidative metabolism by CYP1A2)|
|Elimination half-life||24 hours|
|Excretion||Renal (50%), Faecal (40%; ~5-16% as unchanged drug in faeces)|
|Chemical and physical data|
|Molar mass||285.77 g/mol g·mol−1|
|3D model (JSmol)|
|(what is this?)|
Asenapine has been approved by the FDA for the acute treatment of adults with schizophrenia and acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features in adults. In Australia asenapine's approved (and also listed on the PBS) indications include the following:
- Treatment, for up to 6 months, of an episode of acute mania or mixed episodes associated with bipolar I disorder
- Maintenance treatment, as monotherapy, of bipolar I disorder
In a Cochrane systemic review, senior researcher for the McPin Foundation, Ben Gray found that while Asenapine has some preliminary evidence that it improves positive, negative, and depressive symptoms, it does not have enough research to merit a certain recommendation of Asenapine for the treatment of schizophrenia. Likewise, as stated, Aspenapine isn't approved for schizophrenia treatment in the UK where Cochrane organization and that reviewer is located.
As for its efficacy in the treatment of acute mania, a recent meta-analysis showed that it produces comparatively small improvements in manic symptoms in patients with acute mania and mixed episodes than most other antipsychotic drugs (with the exception of ziprasidone) such as risperidone and olanzapine. Drop-out rates (in clinical trials) were also unusually high with asenapine. According to a post-hoc analysis of two 3-week clinical trials it may possess some antidepressant effects in patients with acute mania or mixed episodes.
Very common (>10% incidence) adverse effects include:
Common (1-10% incidence) adverse effects include:
- Weight gain
- Increased appetite
- Extrapyramidal side effects (EPS; such as dystonia, akathisia, dyskinesia, muscle rigidity, parkinsonism)
- Oral hypoaesthesia
- Increased alanine aminotransferase
Uncommon (0.1-1% incidence) adverse effects include:
- Hyperglycaemia — elevated blood glucose (sugar)
- sinus bradycardia
- Bundle branch block
- QTc interval prolongation (has a relatively low risk for causing QTc interval prolongation.)
- sinus tachycardia
- Orthostatic hypotension
- Swollen tongue
- Dysphagia (difficulty swallowing)
- Oral paraesthesia
Rare (0.01-0.1% incidence) adverse effects include:
- Neuroleptic malignant syndrome (Combination of fever, muscle stiffness, faster breathing, sweating, reduced consciousness, and sudden change in blood pressure and heart rate)
- Tardive dyskinesia
- Speech disturbance
- Blood dyscrasias such as agranulocytosis, leukopenia and neutropenia
- Accommodation disorder[clarification needed]
- Pulmonary embolism
Unknown incidence adverse effects
- Allergic reaction
- Restless legs syndrome
- Oral mucosal lesions (ulcerations, blistering and inflammation)
- Salivary hypersecretion
Asenapine seems to have a relatively low weight gain liability for an atypical antipsychotic (which are notorious for their metabolic side effects) and according to a recent meta-analysis it produces significantly less weight gain (SMD [standard mean difference in weight gained in those on placebo vs. active drug]: 0.23; 95% CI: 0.07-0.39) than, paliperidone (SMD: 0.38; 95% CI: 0.27-0.48), risperidone (SMD: 0.42; 95% CI: 0.33-0.50), quetiapine (SMD: 0.43; 95% CI: 0.34-0.53), sertindole (SMD: 0.53; 95% CI: 0.38-0.68), chlorpromazine (SMD: 0.55; 95% CI: 0.34-0.76), iloperidone (SMD: 0.62; 95% CI: 0.49-0.74), clozapine (SMD: 0.65; 95% CI: 0.31-0.99), zotepine (SMD: 0.71; 95% CI: 0.47-0.96) and olanzapine (SMD: 0.74; 95% CI: 0.67-0.81) and approximately (that is, no statistically significant difference at the p=0.05 level) as much as weight gain as aripiprazole (SMD: 0.17; 95% CI: 0.05-0.28), lurasidone (SMD: 0.10; 95% CI: –0.02-0.21), amisulpride (SMD: 0.20; 95% CI: 0.05-0.35), haloperidol (SMD: 0.09; 95% CI: 0.00-0.17) and ziprasidone (SMD: 0.10; 95% CI: –0.02-0.22). Its potential for elevating plasma prolactin levels seems relatively limited too according to this meta-analysis. This meta-analysis also found that asenapine has approximately the same odds ratio (3.28; 95% CI: 1.37-6.69) for causing sedation [compared to placebo-treated patients] as olanzapine (3.34; 95% CI: 2.46-4.50]) and haloperidol (2.76; 95% CI: 2.04-3.66) and a higher odds ratio (although not significantly) for sedation than aripiprazole (1.84; 95% CI: 1.05-3.05), paliperidone (1.40; 95% CI: 0.85-2.19) and amisulpride (1.42; 95% CI: 0.72 to 2.51) to name a few and is hence a mild-moderately sedating antipsychotic. Being a second-generation (atypical) antipsychotic its liability for causing extrapyramidal side effect is comparatively low compared to first-generation antipsychotics such as haloperidol as is supported by the aforementioned meta-analysis (although this meta-analysis did reveal it had a relatively high EPS liability for an atypical antipsychotic drug).
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a felling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.
There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.
Asenapine shows high affinity (pKi) for numerous receptors, including the serotonin 5-HT1A (8.6), 5-HT1B (8.4), 5-HT2A (10.2), 5-HT2B (9.8), 5-HT2C (10.5), 5-HT5A (8.8), 5-HT6 (9.5), and 5-HT7 (9.9) receptors, the adrenergic α1 (8.9), α2A (8.9), α2B (9.5), and α2C (8.9) receptors, the dopamine D1 (8.9), D2 (8.9), D3 (9.4), and D4 (9.0) receptors, and the histamine H1 (9.0) and H2 (8.2) receptors. It has much lower affinity (pKi < 5) for the muscarinic acetylcholine receptors. Asenapine behaves as a partial agonist at the 5-HT1A receptors. At all other targets asenapine is an antagonist. As of November 2010 asenapine is also in clinical trials at UC Irvine to treat stuttering.
Based on its exceptionally high, unequaled (among antipsychotics) affinity for the 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors, and very high affinity for the α2 and H1 receptors, asenapine, given normal tolerability, should theoretically demonstrate among the highest improvements in the negative symptomology of schizophrenia among all current antipsychotics (August 2017), such as high cognitive improvements and positive, stable mood maintenance.
It was developed by Schering-Plough after its November 19, 2007 merger with Organon International. Though Phase III trials began while Organon was still a part of Akzo Nobel. Preliminary data indicate that it has minimal anticholinergic and cardiovascular side effects, as well as minimal weight gain. Over 3000 people have participated in clinical trials of asenapine, and the FDA approved the manufacturer's NDA in August 2009.
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