Introduction to Nefazodone (Serzone)
Nefazodone, first introduced for medical use in 1994 under the brand name Serzone, is an antidepressant medication used for the treatment of depression [1.7.2]. It belongs to a class of drugs known as serotonin antagonists and reuptake inhibitors (SARIs) [1.2.7]. Its unique mechanism of action, which involves blocking serotonin 5-HT2A receptors and inhibiting the reuptake of serotonin and norepinephrine, set it apart from other antidepressants like SSRIs [1.6.1, 1.6.3]. This profile was believed to offer effective treatment for depression with a lower incidence of certain side effects, such as sexual dysfunction and sleep impairment, commonly associated with SSRIs [1.6.2, 1.6.5].
The Emergence of Severe Liver Toxicity
Shortly after its approval, concerns about nefazodone's safety began to emerge. The first reports of serious liver toxicity surfaced in 1998 [1.7.2]. Over the next several years, the number of reported cases of severe liver injury, including acute liver failure requiring transplantation and even death, grew significantly [1.7.6]. By early 2002, the U.S. Food and Drug Administration (FDA) had received enough data to act. Postmarketing experience revealed a rate of liver failure resulting in death or transplant of about 1 case per 250,000 to 300,000 patient-years of treatment [1.3.4]. This prompted the FDA to mandate a "black box" warning—the agency's most serious type of warning—on nefazodone's labeling to alert both physicians and patients to the risk of life-threatening liver failure [1.3.1, 1.7.1]. The warning advised discontinuing the drug if signs of liver dysfunction, such as jaundice, anorexia, or malaise, appeared [1.3.1].
Manufacturer Discontinuation and Market Withdrawal
Despite the black box warning, safety concerns persisted. Consumer advocacy groups like Public Citizen petitioned the FDA to ban the drug entirely, citing the continued risks and the availability of safer alternatives [1.2.1, 1.7.6]. While the FDA denied the petition, stating the data did not justify a complete market removal, the manufacturer, Bristol-Myers Squibb (BMS), took its own action [1.2.1, 1.7.3]. BMS had already withdrawn nefazodone from markets in Europe, Canada, Australia, and New Zealand [1.2.6]. On May 19, 2004, BMS announced it would discontinue all sales and manufacturing of the brand-name drug Serzone in the United States, effective June 14, 2004 [1.2.1]. The company cited "commercial business reasons," specifically declining sales and increased competition from generic versions, as the motivation for their decision [1.2.1].
Comparison of Antidepressant Classes
Nefazodone's risk profile stands in contrast to other commonly prescribed antidepressants.
| Feature | Nefazodone (SARI) | SSRIs (e.g., Prozac, Zoloft) | SNRIs (e.g., Cymbalta, Effexor) |
|---|---|---|---|
| Primary Mechanism | Serotonin receptor antagonist and reuptake inhibitor [1.2.7] | Selective Serotonin Reuptake Inhibitor [1.5.4] | Serotonin and Norepinephrine Reuptake Inhibitor [1.5.4] |
| Liver Toxicity Risk | High; Black box warning for liver failure [1.3.3] | Generally lower risk, though some cases reported [1.3.7] | Generally lower risk [1.5.4] |
| Common Side Effects | Drowsiness, dizziness, dry mouth, nausea [1.2.7] | Sexual dysfunction, insomnia, anxiety [1.6.2] | Nausea, dry mouth, increased blood pressure [1.5.5, 1.5.6] |
| Sleep Impact | Can increase total sleep and REM sleep [1.6.4] | Can cause insomnia or sleep disturbances [1.6.2] | Can cause insomnia [1.5.6] |
Is Nefazodone Still Available?
A common misconception is that nefazodone was banned by the FDA. The agency never formally removed it from the market [1.7.3]. While the brand-name Serzone was discontinued by its manufacturer, generic versions of nefazodone hydrochloride remain available in the United States [1.2.5, 1.4.7]. Teva Pharmaceuticals is one manufacturer that produces generic nefazodone [1.8.1]. However, its use is significantly restricted. It is no longer considered a first-line treatment and is generally reserved for patients with major depression who have not responded to other, safer antidepressant therapies [1.2.4, 1.7.4]. Prescribing it requires careful patient screening for pre-existing liver conditions and a thorough discussion of the significant risks involved [1.3.5].
Conclusion
The story of nefazodone is a critical case study in pharmacovigilance. The brand-name drug Serzone was not taken off the market by an FDA ban, but rather was discontinued by its manufacturer, Bristol-Myers Squibb, in 2004 due to a combination of mounting safety concerns over life-threatening liver toxicity and declining sales [1.2.1]. The drug carries a prominent black box warning for hepatotoxicity, a risk that led to its withdrawal from most countries [1.3.4, 1.7.2]. While generic versions are still available in the U.S. for treatment-resistant depression, its use is limited, underscoring the importance of balancing therapeutic benefit with patient safety [1.4.1, 1.2.4].
For more information from the U.S. National Library of Medicine on drug-induced liver injury, see the LiverTox database.
