Iloperidone is a second generation (atypical) antipsychotic agent that is used for treatment of schizophrenia. Iloperidone is associated with a low rate of serum aminotransferase elevations during therapy and has not been linked to instances of clinically apparent acute liver injury.


Iloperidone (eye" loe per' i done) is a second-generation antipsychotic agent which appears to act as a dopamine type 2 (D2) and serotonin (5-HT)-2A receptor antagonist whose structure and mechanism of action are similar to risperidone. Several randomized controlled trials have shown that iloperidone improves symptoms of schizophrenia with effects comparable to risperidone and ziprasidone. Iloperidone was approved for use in adults with schizophrenia in the United States in 2009 and is available as tablets of 1, 2, 4, 6, 8, 10 and 12 mg generically and under the brand name Fanapt. The recommended dose regimen is a slow escalation to a maintenance dose in adults is 6 to 12 mg twice daily. Common side effects of include dizziness, dry mouth, somnolence, fatigue, nasal congestion, anxiety, restlessness (akathisia), peripheral edema, sexual dysfunction, weight gain and changes in glucose and lipid levels. Iloperidone therapy is also associated with postural hypotension and prolongation of the QTc interval. Rare, but potentially severe adverse reactions (mentioned in most antipsychotic and antidepressant product labels) include increased mortality in elderly patients with dementia-related psychosis and suicidal thoughts and behaviors. Other rate adverse reactions are tardive dyskinesia, major neurologic events, neuroleptic malignant syndrome, priapism, orthostatic hypotension, seizures, suicidal thoughts and behaviors, and neutropenia.


Liver test abnormalities occur in 1% to 3% of patients on long term therapy with iloperidone, but similar rates are reported with placebo therapy and with comparator agents. The ALT elevations are usually mild, transient and usually resolve even without dose modification or drug discontinuation. There have been no published reports of clinically apparent liver injury with symptoms or jaundice attributed to iloperidone therapy.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which iloperidone might cause serum ALT elevations or liver injury is not known. Iloperidone is extensively metabolized by the cytochrome P450 system (CYP 2D6 and 3A4) to its active metabolite and is susceptible to drug-drug interactions with agents that inhibit or induce these microsomal enzymes.

Outcome and Management

The serum aminotransferase elevations that occur on iloperidone therapy are usually self-limited and usually do not require dose modification or discontinuation. No instances of acute liver failure, chronic hepatitis or vanishing bile duct syndrome have been attributed to iloperidone. Cross sensitivity to liver related or other hypersensitivity reactions between iloperidone and structurally related antipsychotic agents (such as lurasidone, paliperidone, risperidone and ziprasidone) have not been demonstrated, but may well occur.

Drug Class: Antipsychotic Agents, Atypicals



Iloperidone – Generic, Fanapt®


Antipsychotic Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 06 June 2023

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    (Textbook of pharmacology and therapeutics).
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    (Review of hepatotoxicity of psychiatric agents does not discuss iloperidone).
  • Kane JM, Lauriello J, Laska E, Di Marino M, Wolfgang CD. Long-term efficacy and safety of iloperidone: results from 3 clinical trials for the treatment of schizophrenia. J Clin Psychopharmacol. 2008;28(2) Suppl 1:S29–35. [PubMed: 18334910]
    (Among 371 adults with schizophrenia who were continued on iloperidone for 46 weeks after their participation in a controlled trial, adverse events included insomnia [18%] and anxiety [11%], but “there were no significant effects on liver function tests”).
  • Cutler AJ, Kalali AH, Weiden PJ, Hamilton J, Wolfgang CD. Four-week, double-blind, placebo- and ziprasidone-controlled trial of iloperidone in patients with acute exacerbations of schizophrenia. J Clin Psychopharmacol. 2008;28(2) Suppl 1:S20–8. [PubMed: 18334909]
    (Among 593 patients with schizophrenia treated with iloperidone [24 mg daily], ziprasidone [160 mg daily] or placebo for 4 weeks, symptom scores improved in both the active treatment groups and side effects from iloperidone included dizziness, sedation, weight gain, dry mouth, tachycardia and nasal congestion; “mean changes in laboratory values from baseline to end point were similar across treatment groups”).
  • Weiden PJ, Cutler AJ, Polymeropoulos MH, Wolfgang CD. Safety profile of iloperidone: a pooled analysis of 6-week acute-phase pivotal trials. J Clin Psychopharmacol. 2008;28(2) Suppl 1:S12–9. [PubMed: 18334908]
    (Among 1943 adults with schizophrenia treated with various doses of iloperidone, haloperidol, risperidone or placebo for 6 weeks, side effects of iloperidone included dizziness, dry mouth, fatigue, nasal congestion, somnolence and tremor; 1 of 1044 patients on iloperidone, but none of 440 on placebo had a serious adverse event related to serum enzyme elevations; no specific details given).
  • Potkin SG, Litman RE, Torres R, Wolfgang CD. Efficacy of iloperidone in the treatment of schizophrenia: initial phase 3 studies. J Clin Psychopharmacol. 2008 Apr;28(2) Suppl 1:S4–11. [PubMed: 18334911]
    (Among 1943 adults with schizophrenia enrolled in 3 controlled trials of various doses of iloperidone versus haloperidol, risperidone or placebo for 6 weeks, symptom scores improved more with iloperidone than placebo and to a similar extent as with the comparator arms; side effects were not discussed [Weiden 2008]).
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    (Brief review of efficacy and safety of iloperidone shortly after its approval in the US; common side effects are restlessness, nausea, extrapyramidal symptoms, agitation, and somnolence; no mention of liver injury).
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    (Systematic review of safety of iloperidone in schizophrenia found 12% rate of significant weight gain, but low rates of akathisia and extrapyramidal symptoms: no mention of ALT elevations or hepatotoxicity).
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    (24 year old African-American man developed hypersensitivity reaction [angioedema] within 24 hours of starting haloperidol and, after recovery, developed a similar reaction 3 days after starting iloperidone, both episodes responding rapidly to antihistamines and corticosteroids).
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    (Among 72 patients with schizophrenia who were continued on iloperidone for 25 weeks after participation in a 4-week controlled trial, side effects included headache, weight gain, dizziness, nausea, sedation and insomnia; no mention of ALT elevations or hepatotoxicity).
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    (Concise review of safety, efficacy and role of drugs for psychiatric disorders, mentions that iloperidone is a second-generation antipsychotic agent whose adverse side effects include orthostatic hypotension, prolongation of the QTc interval, somnolence, dizziness, dry mouth and weight gain, but rarely has extrapyramidal effects; no mention of ALT elevations or hepatotoxicity).
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    (Review of the efficacy and safety of iloperidone makes no mention of ALT elevations or hepatotoxicity).
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    (Extensive systematic review of the literature on the problem of weight gain during therapy with antipsychotic agents, mentions that weight gain of 7% or more occurs in 9-47% of patients on iloperidone, the rates being lower than with olanzapine, but higher than with aripiprazole).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterology. 2015;148:1340–52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury seen over a ten year period at 8 US medical centers, one was attributed olanzapine, but none to iloperidone or other antipsychotic medications).
  • Weiden PJ, Manning R, Wolfgang CD, Ryan JM, Mancione L, Han G, Ahmed S, et al. A randomized trial of iloperidone for prevention of relapse in schizophrenia: the REPRIEVE Study. CNS Drugs. 2016;30:735–47. [PMC free article: PMC4982888] [PubMed: 27379654]
    (Among 303 patients with schizophrenia who were placed on iloperidone and stabilized, those continued on iloperidone were less likely to relapse than those switched to placebo [20% vs 64%], while adverse event rates were similar; no mention of ALT elevations or hepatotoxicity).
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    (Concise review of medications available in the US for therapy of psychotic disorders; mentions that olanzapine can cause aminotransferase elevations, and that olanzapine and ziprasidone can cause DRESS syndrome, but does not mention ALT elevations or hepatotoxicity for any of agents discussed, including aripiprazole, brexpiprazole, cariprazine, clozapine, quetiapine, risperidone, asenapine, iloperidone, paliperidone and lurasidone).
  • Solmi M, Murru A, Pacchiarotti I, Undurraga J, Veronese N, Fornaro M, Stubbs B, et al. Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review. Ther Clin Risk Manag. 2017;13:757–77. [PMC free article: PMC5499790] [PubMed: 28721057]
    (Extensive review of the safety of antipsychotic medications mentions that significant liver enzyme elevations are rare, but have been reported with olanzapine, quetiapine, and risperidone and that clinically apparent acute liver injury has been reported with phenothiazines, halothane and clozapine; no mention of hepatotoxicity associated with iloperidone).
  • Subeesh V, Maheswari E, Singh H, Beulah TE, Swaroop AM. Novel adverse events of iloperidone: A disproportionality analysis in US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Curr Drug Saf. 2019;14:21–26. [PubMed: 30362421]
    (Data mining of the FDA’s Adverse Event Reporting System for adverse events associated with iloperidone, identified signals for akathisia, dyskinesia, peripheral edema, priapism and sexual disfunction, but not for ALT elevations or clinically apparent liver injury).
  • Nair A, Salem A, Asamoah AL, Gosal R, Grossberg GT. An update on the efficacy and safety of iloperidone as a schizophrenia therapy. Expert Opin Pharmacother. 2020;21:1793–1798. [PubMed: 32735148]
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    (Among 246 cases of severe liver injury due to antipsychotic medications identified in a prospective registry of German psychiatric hospitals between 1993 and 2016, 46 arose in 38,349 patients [0.12%] who received clozapine [34 as a single antipsychotic agent]; other commonly implicated agents being olanzapine [n=90 of 54,822: 0.16%], quetiapine [34 of 66,209: 0.05%] and risperidone [27 of 51,683: 0.05%]; two fatal cases occurred in olanzapine-treated patients; low rates were found for ziprasidone [no cases among 3568 patients treated] and aripiprazole [6 cases of 15,988 patients treated: 0.01%]; iloperidone not listed).