Asenapine is a second generation (atypical) antipsychotic agent that is taken sublingually and used in the treatment of schizophrenia and manic or mixed episodes associated with bipolar 1 disorder. Asenapine is associated with a low rate of transient and mild serum aminotransferase elevations during therapy but has not been linked to instances of clinically apparent acute liver injury.


Asenapine (a sen' a peen) is a second generation antipsychotic agent which appears to act as a dopamine type 2 (D2) and serotonin (5-HT)-2A receptor antagonist. It is a somewhat unique antipsychotic agent that has a tetracyclic structure similar to that of mirtazapine, and it is administered as a sublingual tablet, being poorly absorbed by the oral route. Several randomized controlled trials have shown that sublingual asenapine improves symptoms of schizophrenia with effects comparable to risperidone and olanzapine. It also has beneficial activity in acute manic and mixed episodes associated with bipolar 1 disorder. Asenapine was approved for use in the United States in 2009 and is available in sublingual tablets of 2.5, 5 and 10 mg generically and under the brand name Saphris. The typical maintenance dose in adults is 2.5 to 10 mg twice daily. Asenapine is also available for treatment of schizophrenia as a transdermal formulation available in doses of 3.8, 5.7 and 7.6 mg per 24 hours under the brand name Secuado. The recommended initial dose of the transdermal patch is 3.8/24 hours, which can be increased to 5.7/24 hours and 7.6 mg/24 hours based upon effect and tolerance. Common side effects of asenapine include dizziness, somnolence, fatigue, nausea, anxiety, restlessness (akathisia) and weight gain. Rare, but potentially severe adverse reactions (mentioned in most antipsychotic and antidepressant product labels) include tardive dyskinesia, major neurologic events, neuroleptic malignant syndrome, orthostatic hypotension, seizures, neutropenia, hypersensitivity reactions, prolongation of the QTc interval, increased cerebrovascular events, and suicidal ideation or behavior. Asenapine also has a boxed warning of increased mortality in elderly patients with dementia-related psychosis.


Liver test abnormalities occur in 1% to 2.5% of patients receiving asenapine, but similar rates are reported with placebo therapy (0.6% to 1.3%) and with comparator agents. The ALT elevations are usually mild, transient and often resolve even without dose modification or drug discontinuation. There has been a single case report of cholestatic serum enzyme elevations arising 3 to 4 weeks after starting asenapine, resolving within a month of stopping. Thus, asenapine may be a rare cause of mild cholestatic liver injury.

Likelihood score: D (possible rare cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which asenapine might cause serum enzyme elevations or liver injury is not known. Asenapine is metabolized to some extent by the cytochrome P450 system (CYP 2D6 and 3A4), but is an uncommon cause of significant drug-drug interactions with agents that inhibit or induce these microsomal enzymes.

Outcome and Management

The serum aminotransferase elevations that occur with asenapine therapy are usually self-limited and often do not require dose modification or discontinuation. No instances of acute liver failure, chronic hepatitis or vanishing bile duct syndrome have been attributed to asenapine. Cross sensitivity to liver related or other hypersensitivity reactions between asenapine and other antipsychotic agents have not been demonstrated.

Drug Class: Antipsychotic Agents, Atypicals



Asenapine – Saphris®, Secuado®


Antipsychotic Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 05 June 2023

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    (Among 367 patients with a manic or mixed episode associated with bipolar 1 disorder treated with asenapine [5 or 10 mg] or placebo twice daily for 3 weeks, symptoms were somewhat more improved with asenapine than placebo, while adverse events were more frequent, particularly somnolence [20% and 26% vs 4%] and oral hypoesthesia [16% and 29% vs 2%], although “no patients had elevated liver enzymes that met criteria for potential drug-induced liver injury”).
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    (Among 306 adolescents with schizophrenia treated with asenapine [2.5 or 5 mg] or placebo twice daily for 8 weeks, some symptom scores improved with the higher dose of asenapine compared to placebo, but adverse events were also more common including akathisia, dizziness, oral hypoesthesia, insomnia and weight gain; no mention of ALT elevations or hepatotoxicity).
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  • Citrome L, Walling DP, Zeni CM, Starling BR, Terahara T, Kuriki M, Park AS, et al. Efficacy and safety of HP-3070, an asenapine transdermal system, in patients with schizophrenia: a phase 3, randomized, placebo-controlled study. J Clin Psychiatry. 2020;82:20m13602. [PubMed: 33326711]
    (Among 614 patients with an acute exacerbation of schizophrenia treated with transdermal asenapine [3.8 or 7.6 mg/24 hours] or placebo for 6 weeks, symptom scores improved more with both doses of asenapine compared with placebo and adverse event rates were similar with no serious adverse events; no mention of ALT elevations or hepatotoxicity).
  • In brief: An asenapine patch (Secuado) for schizophrenia. Med Lett Drugs Ther. 2021;63(1615):7–8. [PubMed: 33647000]
    (Concise review of the mechanism of action, clinical efficacy, toxicity and cost of transdermal asenapine shortly after its approval as therapy of schizophrenia in the US; no mention of ALT elevations or hepatotoxicity).
  • Zeiss R, Hafner S, Schönfeldt-Lecuona C, Connemann BJ, Gahr M. Drug-associated liver injury related to antipsychotics: exploratory analysis of pharmacovigilance data. J Clin Psychopharmacol. 2022;42:440–444. [PubMed: 35730552]
    (Review of the VigiBase data base of individual case safety reports on antipsychotics and liver injury found positive hepatic safety signals for olanzapine and clozapine but none for risperidone, quetiapine, ziprasidone, asenapine, aripiprazole, brexpiprazole, and cariprazine).