Nefazodone is a serotoninergic modulating antidepressant that is used in therapy of depression, aggressive behavior and panic disorder. Nefazodone therapy has been associated with transient, usually asymptomatic elevations in serum aminotransferase levels and has been linked to several instances of clinically apparent acute liver injury some of which have been fatal.
Nefazodone (ne faz' oh done) is a phenylpiperazine derivative whose mechanism of action is believed to be inhibition of serotonin and norepinephrine reuptake, which results in increased levels and activity of these neurotransmitters. However, the actual mechanism of action is unknown and nefazodone also is a weak serotonin and alpha-1 adrenergic antagonist. Nefazodone was approved for use in moderate and severe depression in the United States in 1988, but was subsequently linked to many cases of acute liver injury, some of which were fatal, and is no longer in common use. Nefazodone is available in tablets of 50, 100, 150, 200 and 250 mg in several generic forms and formerly under the brand name of Serzone. The recommended dosage for depression in adults is 200 mg daily that can be increased in 100 mg amounts to a maximum of 600 mg daily. Common side effects of nefazodone are drowsiness, dizziness, headache, dry mouth, blurred vision, nausea, constipation or diarrhea, decreased libido, abnormal dreams, increased appetite and weight gain.
Liver test abnormalities occur in a proportion of patients on nefazodone, but elevations are usually modest and usually do not require dose modification or discontinuation. Soon after its general availability, nefazodone was linked to several instances of acute, clinically apparent liver injury, some of which were fatal. The onset of injury varied from 6 weeks to 8 months and the pattern of serum enzyme elevations was typically hepatocellular. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) were uncommon. Liver biopsy usually demonstrated an acute hepatitis with cholestasis and variable degrees of centrolobular (zone 3) necrosis. Systematic reviews suggested that the incidence of hepatic failure due to nefazodone is 1 per 250,000 to 300,000 patient-years of exposure. Because of this complication, nefazodone was withdrawn from use in many countries. Nefazodone, however, can be effective in patients with otherwise resistant forms of severe depression. For this reason, it remains available in the United States with the recommendation that it be used only if other antidepressants have been found to be ineffective and after full disclosure and discussion of the risks.
Mechanism of Injury
The mechanism by which nefazodone causes liver injury is not known. Nefazodone is extensively metabolized by the liver, mainly via the cytochrome P450 system (CYP3A4), and hepatotoxicity may be mediated by toxic intermediates of its metabolism.
Outcome and Management
The serum aminotransferase elevations that occur on nefazodone therapy are usually self-limited, but require careful monitoring because of the risk of clinically apparent liver injury which can be severe and even fatal. Several instances of acute liver failure have been attributed to nefazodone therapy and it is often mentioned in case series of acute liver failure due to medications. Persons with intolerance to nefazodone may have similar reactions to other antidepressants and careful monitoring is warranted if other such agents are used.
Other Drugs in the Subclass: Trazodone
Case 1. Acute liver failure due to nefazodone.
[Modified from: Ehrentraut S, Rothenhäusler HB, Gerbes AL, Rau HG, Thiel M, Schirren CA,
Kapfhammer HP. [Acute liver failure in nefazodone therapy? A case report].
Nervenarzt 2002; 73: 686-9. PubMed Citation]
A 52 year old man developed fatigue and nausea 6 weeks after starting nefazodone (300 mg daily) for a long standing depression that had not responded adequately to conventional antidepressants. He had no previous history of liver disease, did not drink alcohol and had no risk factors for viral hepatitis. His liver enzymes were known to be normal in the past. Other medications included an herbal sleeping aid (valerian and passionflower) and ergotamines for occasional headaches. Laboratory test results included marked elevations in serum aminotransferase levels (ALT 1947 U/L, AST 836 U/L), with minimal increases in GGT (88 U/L) and normal bilirubin levels. All medications were stopped and he was observed. Over the next week, he became jaundiced and his prothrombin index (Quick) fell (from 53% of normal to 27%). He was transferred to a liver transplant center. Tests for hepatitis A, B and C were negative as were serologic tests for acute cytomegalovirus, herpes simplex and Ebstein Barr Virus infection. Abdominal imaging initially showed a normal appearing liver, but a slight amount of ascites. Two weeks later, magnetic resonance imaging demonstrated a shrunken liver and worsening ascites. A liver biopsy showed a cellular and canalicular cholestasis with marked portal inflammation and periportal necrosis and fibrosis with lobular collapse. He remained markedly jaundiced and developed marked ascites and hepatic encephalopathy. Fourteen weeks after starting nefazodone and 8 weeks after stopping it, he underwent liver transplantation. Despite this, he developed postoperative complications and died of disseminated aspergillosis 4 weeks later.
|Medication:|| Nefazodone (300 mg daily)|
|Pattern:|| Hepatocellular (R=26) |
|Severity:||5+ (liver transplantation, death) |
|| 6 weeks
|Other medications:|| Passionflower, valerian, ergotamines|
|Time After Starting
||Time After Stopping
|5 weeks ||Pre||Normal||Normal||Normal|
|6 weeks||0 ||1947||88||Normal||Admission|
|7 weeks||7 days||1031||89||13.9||Transfer l|
|8 days||1108||85||18.9||Prothrombin time: 30%|
|9 weeks||3 weeks ||87||29||34.9|
|10 weeks||4 weeks ||45||28||41.4|
|12 weeks||6 weeks||22||11||41.4
|14 weeks||8 weeks||14||18||43.9||Prothrombin time 25%|
|8 weeks||Liver transplantation|
Nefazodone has been linked to several instances of severe acute hepatocellular injury arising 2 to 24 weeks after starting therapy. The injury is typically hepatocellular and can be severe. Autoimmune and immunoallergic features are not common. In the current instance, nefazodone was discontinued promptly, but the liver injury was severe enough that hepatic failure arose that did not resolve over the next 4 to 8 weeks, leading to a liver transplant but subsequent death from complications. The sleeping aid that was started at the same time as nefazodone is a commonly used herbal mixture that has not been specifically linked to liver injury.
REPRESENTATIVE TRADE NAMES
– Generic, Serzone®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 30 January 2014
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