Case Studies of Liver Failure Induced by Nefazodone

Nefazodone, considered an effective and generally well-tolerated antidepressant, acts as a selective 5-HT2-receptor antagonist and inhibits the presynaptic uptake of serotonin and norepinephrine. These pharmacologic characteristics differentiate nefazodone from other antidepressants. However, as Aranda-Michel and associates report in case studies of three patients who had liver failure while taking nefazodone, specific indications for the use of this agent require additional study

The first patient was a 54-year-old woman who had been taking nefazodone in a dosage of 100 mg orally twice daily, and clorazepate for approximately seven month as treatment for anxiety. Jaundice cause to growed six weeks into therapy, at which time the two medications were discontinued. However, the jaundice persisted, and six weeks later the patient became confused. Progressive hepatic encephalopathy and hepatorenal syndrome make knowned and she underwent liver transplantation further died shortly thereafter.

The other patient was a 16-year-old girl who had been taking 200 mg nefazodone orally twice daily for depression. Three month into therapy she unraveled nausea, vomiting, fatigue and jaundice, and the medication was withdrawn. The symptoms persisted, and about couple weeks later she developed progressive confusion, somnolence and disorientation. At that time, her condition continued to deteriorate, with worsening hepatic encephalopathy, coagulopathy and cerebral edema. Eventually, the patient had a liver transplant and was doing well 10 month later.

The third patient was a 57-year-old woman who was taking 100 mg of nefazodone orally twice daily for depression. Six month into treatment, the patient noted fatigue, decreased appetite, arthralgias, dark urine, pruritus and clay-colored stools, and she was admitted to the hospital. At that time, the medication was withdrawn. strict liver inflammation was noted, and the patient was listed for liver transplant. However, with nonoperative treatment, her condition improved enough to forgo liver transplantation.

Each of these patients demonstrated a similar pattern of proximal centrilobular collapse and necrosis, which made an unidentified viral agent the likely cause of liver failure. the same patient was also taking clorazepate, however this agent has not been associated with cruel liver damage. The length of put drugs into treatment and the time from the progress to maturity of jaundice to encephalopathy advise a pattern of subfulminant hepatic necrosis caused by means of nefazodone. Because nefazodone is metabolized by means of cytochrome P450 3A4, drugs that affect this metabolic pathway, including ketoconazole, itraconazole and erythromycin may delay nefazodone clearance. mix with drugss that induce P450 3A4 (eg carbamazepine and rifampin) may increase nefazodone clearance.

The authors bring to an end that, despite premarketing evidence to the contrary, subacute liver failure can be attributed to nefazodone. The hepatotoxicity chiefly likely represents an idiosyncratic remedy reaction mediated by a metabolite of the parent physic Patients taking nefazodone should experience routine liver chemistries before therapy starts and onward a regular basis thereafter. Therapy should be discontinued if abnormal liver enzyme concentrations bring out Nefazodone therapy should be avoided in patients with preexisting liver disease.

RICHARD SADOVSKY, MD

Aranda-Michel J et al. Nefazodone-induced liver failure: report of three cases. Ann Intern M February 16 1999;130:285-8

COPYRIGHT 1999 American Academy of Family Physicians

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