Thioridazine is a phenothiazine and antipsychotic agent that is no longer in common use. Thioridazine has been linked to rare instances of clinically apparent acute cholestatic liver injury.


Thioridazine is a piperazine phenothiazine derivative which acts by postsynaptic inhibition of dopamine receptors. Thioridazine has other peripheral and central nervous system effects, producing both alpha adrenergic stimulation and blocking histamine- and serotonin-mediated effects. Thioridazine is indicated for the therapy of acute and chronic psychosis. Thioridazine was approved for use in the United States in 1978 and was formerly a commonly prescribed antipsychotic medication, but in recent years has been replaced in large part by the atypical antipsychotics, which have fewer extrapyramidal side effects. Use of thioridazine is also restricted because of its propensity to cause prolongation of the QTc interval and increased risk of sudden death. Thioridazine is available as tablets of 10, 25, 50 and 100 mg in generic forms and previously under the brand name Mellaril. The usual recommended dose in adults is 50 to 100 mg three times daily, increasing based upon effect and tolerance to a maximum of 800 mg daily. Common side effects include drowsiness, dizziness, headache, blurred vision, dry mouth, constipation, tremor, restlessness, muscle spasms and weight gain. Uncommon but potentially severe adverse events include increased mortality in elderly patients with dementia-associated psychosis, neuroleptic malignant syndrome, tardive dyskinesia, hypotension and falls.


Liver test abnormalities have been reported to occur in a high proportion of patients on long term phenothiazine therapy, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. Rare instances of clinically apparent acute liver injury have been reported due to thioridazine, with some resemblance to cases of chlorpromazine jaundice. The onset of jaundice occurred within a few weeks to several months of therapy and the pattern of serum enzyme elevations was typically cholestatic, although hepatocellular patterns have also been reported. Immunoallergic manifestations (fever, rash and eosinophilia) were not prominent and autoantibodies were not detected. Some cases were associated with agranulocytosis which is a rare but known complication of the phenothiazines.

Likelihood score: B (likely but rare cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which the phenothiazines cause serum aminotransferase elevations is not known. Thioridazine is extensively metabolized by the liver via sulfoxidation and oxidation, and some instances of serum aminotransferase elevations as well as more clinical apparent liver injury may be caused by production of a toxic intermediate of its metabolism.

Outcome and Management

The serum aminotransferase elevations that occur on thioridazine therapy are usually self-limited and do not require dose modification or discontinuation of therapy. The acute clinically apparent liver injury caused by thioridazine is typically self-limited and benign. Instances of chronic cholestasis and vanishing bile duct syndrome have not been reported with thioridazine, but many cases have been attributed to other phenothiazines. Rechallenge with thioridazine usually causes a prompt recurrence of the liver injury and should be avoided. Patients with thioridazine induced liver injury may have cross sensitivity to other phenothiazines, but generally tolerate the atypical antipsychotics.

Drug Class: Antipsychotic Agents

Other Drugs in the Subclass, Phenothiazines: Chlorpromazine, Fluphenazine, Perphenazine, Prochlorperazine, Trifluoperazine



Thioridazine – Generic, Mellaril®


Antipsychotic Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 01 July 2020

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