asenapine

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:{{cite book | editor = Rossi, S | isbn = 978-0-9805790-9-3 | title = Australian Medicines Handbook | place = Adelaide | publisher = The Australian Medicines Handbook Unit Trust | year = 2013 | edition = 2013 }}

• Schizophrenia
• 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 the European Union and the United Kingdom, asenapine is only licensed for use as a treatment for acute mania in bipolar I disorder.

Asenapine is absorbed readily if administered sublingually, asenapine is poorly absorbed when swallowed.{{cite journal | vauthors = Stoner SC, Pace HA | title = Asenapine: a clinical review of a second-generation antipsychotic | journal = Clinical Therapeutics | volume = 34 | issue = 5 | pages = 1023–1040 | date = May 2012 | pmid = 22494521 | doi = 10.1016/j.clinthera.2012.03.002 }} A transdermal formulation of asenapine was approved in the United States in October 2019 under the brand name Secuado.{{cite journal | vauthors = Carrithers B, El-Mallakh RS | title = Transdermal Asenapine in Schizophrenia: A Systematic Review | journal = Patient Preference and Adherence | volume = 14 | pages = 1541–1551 | date = 18 March 2020 | pmid = 32943849 | pmc = 7468370 | doi = 10.2147/PPA.S235104 | doi-access = free }}

===Schizophrenia===

A Cochrane systematic review 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.{{cite journal | vauthors = Hay A, Byers A, Sereno M, Basra MK, Dutta S | title = Asenapine versus placebo for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 2015 | issue = 11 | pages = CD011458 | date = November 2015 | pmid = 26599405 | pmc = 6464872 | doi = 10.1002/14651858.CD011458.pub2 }}

For the medium-term and long-term management and control of both depressive and manic features of bipolar disorder asenapine was found to be equally effective as olanzapine, but with a substantially superior side effect profile.{{cite journal | vauthors = Vita A, De Peri L, Siracusano A, Sacchetti E | title = Efficacy and tolerability of asenapine for acute mania in bipolar I disorder: meta-analyses of randomized-controlled trials | journal = International Clinical Psychopharmacology | volume = 28 | issue = 5 | pages = 219–227 | date = September 2013 | pmid = 23719049 | doi = 10.1097/YIC.0b013e32836290d2 | s2cid = 20871442 }}

In acute mania, asenapine was found to be significantly superior to placebo. 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 such as risperidone and olanzapine (with the exception of ziprasidone). Drop-out rates (in clinical trials) were also unusually high with asenapine.{{cite journal | vauthors = Cipriani A, Barbui C, Salanti G, Rendell J, Brown R, Stockton S, Purgato M, Spineli LM, Goodwin GM, Geddes JR | title = Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis | journal = Lancet | volume = 378 | issue = 9799 | pages = 1306–1315 | date = October 2011 | pmid = 21851976 | doi = 10.1016/S0140-6736(11)60873-8 | s2cid = 25512763 }} 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.{{cite journal | vauthors = Szegedi A, Zhao J, van Willigenburg A, Nations KR, Mackle M, Panagides J | title = Effects of asenapine on depressive symptoms in patients with bipolar I disorder experiencing acute manic or mixed episodes: a post hoc analysis of two 3-week clinical trials | journal = BMC Psychiatry | volume = 11 | pages = 101 | date = June 2011 | pmid = 21689438 | pmc = 3152513 | doi = 10.1186/1471-244X-11-101 | doi-access = free }}

Adverse effect incidence

Very common (>10% incidence) adverse effects include:

• Somnolence

Common (1–10% incidence) adverse effects include:

• Weight gain^{{dagger}}
• Increased appetite
• Extrapyramidal side effects (EPS; such as dystonia, akathisia, dyskinesia, muscle rigidity, parkinsonism)
• Sedation
• Dizziness
• Dysgeusia (altered taste)
• Oral hypoaesthesia (numbness), only when taken sublingually. Transdermal asenapine was shown to eliminate this side effect.
• Increased alanine aminotransferase
• Dyspepsia, stomach discomfort, and/or vomiting{{efn|The Phase III trials used for FDA approval in the US used lists of "elicited side effects", asking all subjects about each side effect on the list, and "nausea" was not included. The elicited side effects list included the related symptoms of "dyspepsia", "stomach discomfort", and "vomiting", and the incidence of each was higher than placebo and in the range of 1 to 10% of asenapine-treated subjects.}}
• Fatigue

Uncommon (0.1–1% incidence) adverse effects include:

• Hyperglycaemia — elevated blood glucose (sugar)
• Syncope
• Seizure
• Dysarthria
• sinus bradycardia
• Bundle branch block
• QTc interval prolongation (has a relatively low risk for causing QTc interval prolongation.{{cite journal| vauthors = Washington NB, Brahm NC, Kissack J |title=Which psychotropics carry the greatest risk of QTc prolongation?|journal=Current Psychiatry |date=October 2012 |volume=11 |issue=10 |pages=36–39 |url= http://www.mdedge.com/currentpsychiatry/article/64870/anxiety-disorders/which-psychotropics-carry-greatest-risk-qtc |access-date=14 April 2017}}{{cite book | isbn = 978-0-470-97948-8 | title = The Maudsley prescribing guidelines in psychiatry | vauthors = Taylor D, Paton C, Shitij K | year = 2012 | publisher = Wiley-Blackwell | location = West Sussex }})
• sinus tachycardia
• Orthostatic hypotension
• Hypotension
• Swollen tongue
• Dysphagia (difficulty swallowing)
• Glossodynia
• 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
• Rhabdomyolysis
• Angioedema
• Blood dyscrasias such as agranulocytosis, leukopenia and neutropenia
• Accommodation disorder{{clarify|date=February 2016}}
• Pulmonary embolism
• Gynaecomastia
• Galactorrhoea

Unknown incidence adverse effects

• Allergic reaction
• Restless legs syndrome
• Oral mucosal lesions (ulcerations, blistering and inflammation)
• Salivary hypersecretion
• Hyperprolactinaemia

^{{dagger}} Asenapine seems to have a relatively low weight gain liability for an atypical antipsychotic (which are notorious for their metabolic side effects) and a 2013 meta-analysis found 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.{{cite journal | vauthors = Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM | title = Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis | journal = Lancet | volume = 382 | issue = 9896 | pages = 951–962 | date = September 2013 | pmid = 23810019 | doi = 10.1016/S0140-6736(13)60733-3 | s2cid = 32085212 }} The same meta-analysis suggested that asenapine had a relatively high risk of extrapyramidal symptoms compared to other atypical antipsychotics but a lower risk than first-generation or typical antipsychotics.

For all antipsychotics, the British National Formulary recommends a gradual dose reduction when discontinuing to avoid acute withdrawal syndrome or rapid relapse.{{cite book |editor1-first=BMJ | editor = Joint Formulary Committee | title = British National Formulary | edition = 57 | date = March 2009 |publisher=Royal Pharmaceutical Society of Great Britain |location=United Kingdom |isbn=978-0-85369-845-6 |page=192 |chapter=4.2.1 |quote=Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.}} Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.{{cite book | vauthors = Haddad P, Haddad PM, Dursun S, Deakin B |title=Adverse Syndromes and Psychiatric Drugs: A Clinical Guide |date=2004 |publisher=OUP Oxford |isbn=9780198527480 |pages=207–216 |url=https://books.google.com/books?id=CWR7DwAAQBAJ&pg=PA207 |language=en}} Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling 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 as a transient withdrawal symptom.{{cite journal | vauthors = Moncrieff J | title = Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse | journal = Acta Psychiatrica Scandinavica | volume = 114 | issue = 1 | pages = 3–13 | date = July 2006 | pmid = 16774655 | doi = 10.1111/j.1600-0447.2006.00787.x | s2cid = 6267180 }} It may also result in recurrence of the condition that is being treated.{{cite book | vauthors = Sacchetti E, Vita A, Siracusano A, Fleischhacker W |title=Adherence to Antipsychotics in Schizophrenia |date=2013 |publisher=Springer Science & Business Media |isbn=9788847026797 |page=85 |url=https://books.google.com/books?id=odE-AgAAQBAJ&pg=PA85 |language=en}} Rarely tardive dyskinesia can occur when the medication is stopped.

{{See also|Atypical antipsychotic#Pharmacodynamics|Antipsychotic#Comparison of medications}}

Asenapine shows high affinity (pKi) for numerous receptors, including the serotonin 5-HT_1A (8.6), 5-HT_1B (8.4), 5-HT_2A (10.2), 5-HT_2B (9.8), 5-HT_2C (10.5), 5-HT_5A (8.8), 5-HT₆ (9.5), and 5-HT₇ (9.9) receptors, the adrenergic α₁ (8.9), α_2A (8.9), α_2B (9.5), and α_2C (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-HT_1A receptors.{{cite journal | vauthors = Ghanbari R, El Mansari M, Shahid M, Blier P | title = Electrophysiological characterization of the effects of asenapine at 5-HT(1A), 5-HT(2A), alpha(2)-adrenergic and D(2) receptors in the rat brain | journal = European Neuropsychopharmacology | volume = 19 | issue = 3 | pages = 177–187 | date = March 2009 | pmid = 19116183 | doi = 10.1016/j.euroneuro.2008.11.001 | s2cid = 140204044 }} At all other targets asenapine is an antagonist.{{cite journal | vauthors = Shahid M, Walker GB, Zorn SH, Wong EH | title = Asenapine: a novel psychopharmacologic agent with a unique human receptor signature | journal = Journal of Psychopharmacology | volume = 23 | issue = 1 | pages = 65–73 | date = January 2009 | pmid = 18308814 | doi = 10.1177/0269881107082944 | s2cid = 206489515 }}

Even relative to other atypical antipsychotics, asenapine has unusually high affinity for the 5-HT_2A, 5-HT_2C, 5-HT₆, and 5-HT₇ receptors, and very high affinity for the α₂ and H₁ receptors.

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{{Reflist}}

• {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/asenapine | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Asenapine }}
• {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/asenapine%20maleate | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Asenapine maleate }}

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