Ziprasidone is an atypical antipsychotic used in the treatment of adults with schizophrenia and bipolar disorder. Use of ziprasidone has not been consistently associated with serum enzyme elevations but has been linked to rare instances of hypersensitivity reactions accompanied by mild-to-moderate acute liver injury.


Ziprasidone (zi pras' i done) is a benzisothiazolyl piperazine-type atypical antipsychotic that appears to act as both a dopamine type 2 (D2) and a serotonin (5-HT2) receptor antagonist. It also has moderate activity against α-adrenergic and histamine receptors. Ziprasidone is indicated for the therapy of schizophrenia and as either monotherapy or adjunctive therapy for acute manic episodes and maintenance therapy for manic and mixed episodes in bipolar 1 disorder. Ziprasidone was approved for use in the United States in 2001 and is widely used with more than a million prescriptions written yearly in the United States. Ziprasidone is available as capsules of 20, 40, 60 and 80 mg generically and under the brand name Geodon. It is also available as an oral suspension and as a solution for intramuscular injection. The typical initial dose is 20 mg twice daily, which can be increased to a maintenance dose in the range of 40 to 80 mg twice daily. Common side effects include somnolence, dizziness, restlessness, fatigue, headache, nausea, dyspepsia, anorexia, dry mouth and blurred vision. Weight gain is uncommon and extrapyramidal symptoms occur in about 5% of patients. Uncommon but potentially severe adverse events include neuroleptic malignant syndrome, tardive dyskinesia, rash, DRESS syndrome, metabolic changes with weight gain, hyperglycemia and dyslipidemia, orthostatic hypotension, leukopenia, neutropenia, seizures, suicidal ideation and behaviors, increased risk of cerebral vascular incidents and death in the elderly dementia related psychosis.


Liver test abnormalities have been reported in patients taking ziprasidone, but they have not been well characterized in the literature and the frequency of elevations appears to be similar to placebo therapy. Several instances of hypersensitivity reactions have been reported in patients taking ziprasidone, arising within 1 to 4 weeks of starting therapy and with rapid recurrence on reexposure in at least one case. In several instances, the hypersensitivity reaction qualified as DRESS syndrome with rash, eosinophilia and an accompanying liver injury either in the form of moderate serum enzymes or a mixed hepatitis with jaundice. In all instances, the symptoms, signs and laboratory abnormalities resolved rapidly with stopping ziprasidone. Thus, on rare occasions, ziprasidone can cause acute hypersensitivity reactions that can be accompanied by hepatitis, but the liver injury is usually mild and self-limited.

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

Mechanism of Injury

Ziprasidone is largely excreted unchanged in the urine and its hepatic metabolism is minimal, perhaps accounting for why hepatotoxicity is rare. The liver injury caused by ziprasidone is likely due to hypersensitivity and is idiosyncratic in nature. Ziprasidone is less likely to cause weight gain than other atypical antipsychotics and has not been linked to cases of steatosis.

Outcome and Management

The hypersensitivity reactions to ziprasidone are likely to recur with reexposure and rechallenge should be avoided. Ziprasidone has not been reported to cause acute liver failure, chronic hepatitis or vanishing bile duct syndrome in the published literature. Persons with hypersensitivity to ziprasidone are likely to tolerate other atypical antipsychotic medications, but prospective monitoring is warranted if other such agents are used.

Drug Class: Antipsychotic Agents, Atypicals



Ziprasidone – Generic, Geodon®


Antipsychotic Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 10 June 2023

Abbreviations: DRESS, drug reaction with eosinophilia and systemic symptoms.

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    (Controlled trial of clozapine [300 mg] vs ziprasidone [80-160 mg] daily for 18 weeks; similar efficacy; weight gain +0.8 kg with clozapine vs -2.6 kg with ziprasidone; “no detrimental effects for either drug were observed with regard to liver functions…”).
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    (Open label study in 196 inpatients given ziprasidone; no mention of ALT levels or hepatotoxicity).
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    (27 year old woman developed pharyngitis, facial swelling, rash and fever 2 weeks after starting ziprasidone [bilirubin 2.6 mg/dL, ALT 688 U/L, Alk P 812 U/L, eosinophils 19%], with recurrence 2 days after ziprasidone was restarted [bilirubin 11.5 mg/dL, ALT 2061 U/L], responding to high doses of prednisone and then tolerating risperidone).
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    (Concise summary of current therapies for psychiatric disorders, mentions that ziprasidone can cause prolongation of QT interval and extrapyramidal symptoms, but does not mention liver injury or ALT elevations).
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    (33 year old Korean woman developed rash and fever 3 weeks after starting ziprasidone and lithium, with resolution of stopping both and recurrence one day after restarting ziprasidone [ALT 141, atypical lymphocytes 12%], resolving within 2 weeks of stopping).
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    (Review of the efficacy and safety of ziprasidone does not discuss 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).
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    (25 year old man was found to have marked serum enzyme elevations two years after starting valproate and ziprasidone [ALT 334 U/L, AST 1040 U/L, CPK 34,270] and a month after starting a muscle building agent “Code Red” containing DMAA, resolving rapidly with stopping the supplement and interpreted as rhabdomyolysis due to DMAA).
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    (48 year old man with bipolar disorder and NASH underwent liver transplantation and developed confusion, dyskinesia, rigidity, hyperthermia and tachycardia/tachypnea postoperatively having been given lithium, lamotrigine, promethazine and ziprasidone, responding to therapy of neuroleptic malignant syndrome with benzodiazepines and propofol).
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    (Among 216 children and adolescents starting atypical antipsychotics, mean weight gain at 6 months was 6.5 kg and mean ALT levels increased by 8.6 U/L, while among 37 taking olanzapine mean weight gain was 10.3 kg and ALT increase 2.6 U/L; increases in ALT associated with development of the metabolic syndrome, mean ALT increasing by 27.8 U/L at 6 months; results using ziprasidone not included).
  • Girard TD, Exline MC, Carson SS, Hough CL, Rock P, Gong MN, Douglas IS, et al. MIND-USA Investigators. Haloperidol and ziprasidone for treatment of delirium in critical illness. N Engl J Med. 2018;379:2506–2516. [PMC free article: PMC6364999] [PubMed: 30346242]
    (Among 566 adults who developed delirium during therapy for respiratory failure or shock and were treated with ziprasidone [maximum dose 40 mg daily], haloperidol [maximum dose 20 mg daily], or placebo, duration of delirium and major outcomes were similar in the three groups; no mention of ALT elevations or hepatotoxicity but QTc prolongation was more frequent with ziprasidone).
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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%).
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    (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).
  • Atkinson S, Bachinsky M, Raiter Y, Abreu P, Ianos C, Chappell P, Findling RL. 26-Week open-label extension study evaluating the safety and tolerability of flexible doses of oral ziprasidone in children and adolescents with bipolar I disorder (Most Recent Episode Manic). J Child Adolesc Psychopharmacol. 2022;32:453–458. [PubMed: 36282771]
    (Among 23 adolescents treated with ziprasidone in a 4 week controlled trial who were started or continued on therapy for up to 26 weeks, side effects included fatigue, somnolence, nausea and extrapyramidal symptoms, usually transiently shortly after starting; no mention of ALT levels or hepatotoxicity).
  • Gunther M, Dopheide JA. Antipsychotic safety in liver disease: a narrative review and practical guide for the clinician. J Acad Consult Liaison Psychiatry. 2023;64:73–82. [PubMed: 36180017]
    (Review of the literature on hepatotoxicity of antipsychotic medications and guidance on their use in patients with liver disease characterizes chlorpromazine, clozapine, and olanzapine as having the greatest risk for causing liver injury, quetiapine and risperidone as having moderate risk, haloperidol as having low risk and paliperidone, aripiprazole, lurasidone, loxapine, and ziprasidone as having low risk).