Asenapine, sold under the brand name Saphris among others, is an atypical antipsychotic medication used to treat schizophrenia and acute mania associated with bipolar disorder as well as the medium to long-term management of bipolar disorder.[2]
It was chemically derived via altering the chemical structure of the tetracyclic (atypical) antidepressant, mianserin.[8]
It was initially approved in the United States in 2009[9] and approved as a generic medication in 2020.[10]
Medical uses
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.[9] In Australia asenapine's approved (and also listed on the PBS) indications include the following:[11]
In the European Union and the United Kingdom, asenapine is only licensed for use as a treatment for acute mania in bipolar I disorder.[5][6][2]
Asenapine is absorbed readily if administered sublingually, but is poorly absorbed when swallowed.[12]
† 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),
Pharmacology
Pharmacodynamics
Asenapine shows high affinity (pKi) for numerous receptors, including the serotonin5-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 adrenergicα1 (8.9), α2A (8.9), α2B (9.5), and α2C (8.9) receptors, the dopamineD1 (8.9), D2 (8.9), D3 (9.4), and D4 (9.0) receptors, and the histamineH1 (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.[25] At all other targets asenapine is an antagonist.[26]
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
Schizophrenia
A Cochranesystematic 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.[14]
Bipolar disorder
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.[15]
In acute mania, asenapine was found to be significantly superior to placebo.[15] 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.[16] 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.[17]
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.[20] 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.[20]
Somnolence
Weight gain†
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.[13]
Increased alanine aminotransferase
Dyspepsia, stomach discomfort, and/or vomiting
Fatigue
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.[18][19])
sinus tachycardia
Orthostatic hypotension
Hypotension
Swollen tongue
Dysphagia (difficulty swallowing)
Glossodynia
Oral paraesthesia
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
Pulmonary embolism
Gynaecomastia
Galactorrhoea
Allergic reaction
Restless legs syndrome
Oral mucosal lesions (ulcerations, blistering and inflammation)
Salivary hypersecretion
Hyperprolactinaemia
Discontinuation
For all antipsychotics, the British National Formulary recommends a gradual dose reduction when discontinuing to avoid acute withdrawal syndrome or rapid relapse.[21] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[22] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[22] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[22] Symptoms generally resolve after a short period of time.[22]
There is tentative evidence that discontinuation of antipsychotics can result in psychosis as a transient withdrawal symptom.[23] It may also result in recurrence of the condition that is being treated.[24] Rarely tardive dyskinesia can occur when the medication is stopped.[22]
Even relative to other atypical antipsychotics, asenapine has unusually high affinity for the 5-HT2A, 5-HT2C, 5-HT6, and 5-HT7 receptors, and very high affinity for the α2 and H1 receptors.[26]
TGA eBusiness Services, Merck Sharp & Dohme (Australia) Pty Limited, 14 January 2013, retrieved 23 October 2013
11.Australian Medicines Handbook The Australian Medicines Handbook Unit Trust, 2013^
12.Asenapine: a clinical review of a second-generation antipsychotic Clinical Therapeutics, May 2012^
13.Transdermal Asenapine in Schizophrenia: A Systematic Review Patient Preference and Adherence, 18 March 2020^
14.Asenapine versus placebo for schizophrenia The Cochrane Database of Systematic Reviews, November 2015^
15.Efficacy and tolerability of asenapine for acute mania in bipolar I disorder: meta-analyses of randomized-controlled trials International Clinical Psychopharmacology, September 2013^
16.Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis Lancet, October 2011^
17.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 BMC Psychiatry, June 2011^
23.Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse Acta Psychiatrica Scandinavica, July 2006^
25.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 European Neuropsychopharmacology, March 2009^
26.Asenapine: a novel psychopharmacologic agent with a unique human receptor signature Journal of Psychopharmacology, January 2009^
