The Complicated History of Nefazodone
Nefazodone, an antidepressant originally marketed under the brand name Serzone, was first introduced for medical use in 1994 [1.2.2]. It was developed to treat major depressive disorder [1.2.1]. As a phenylpiperazine compound, it is chemically related to trazodone and works as a serotonin antagonist and reuptake inhibitor (SARI) [1.2.2, 1.4.2]. Its unique mechanism, which involves blocking serotonin 5-HT2A receptors while also inhibiting the reuptake of serotonin and norepinephrine, offered an alternative to other antidepressants, with a reputation for causing fewer sexual side effects and less weight gain [1.4.2, 1.3.4].
However, the drug's trajectory shifted dramatically when reports of severe hepatotoxicity (liver damage) began to surface in 1998 [1.2.2]. These weren't minor side effects; the FDA received reports of at least 55 cases of liver failure, including 20 deaths [1.3.9]. This led the FDA to issue its strongest caution, a "black box" warning, in 2002, highlighting the risk of life-threatening liver failure [1.6.3, 1.6.4]. The incidence of such severe outcomes was estimated to be about 1 case for every 250,000 to 300,000 patient-years of use [1.6.6].
Discontinuation and Lingering Availability
Following the black box warning and mounting pressure, Bristol-Myers Squibb (BMS), the original manufacturer, withdrew Serzone from the market in most countries, including Canada and those in Europe, by 2004 [1.2.2, 1.3.2]. The company cited declining sales and competition from generic versions as the reason for discontinuing sales in the United States in June 2004 [1.2.8]. However, the FDA determined that the brand-name drug was not withdrawn for reasons of safety or effectiveness, which allowed generic manufacturers to continue producing the medication [1.2.5]. As of late 2021, Teva Pharmaceuticals made generic nefazodone available again in the U.S. after a temporary shortage [1.2.6, 1.2.2]. Therefore, while the brand name Serzone is long gone, generic nefazodone remains a prescription option in the United States [1.2.3, 1.2.4].
Understanding Nefazodone's Pharmacology and Risks
Nefazodone is classified as a Serotonin Antagonist and Reuptake Inhibitor (SARI) [1.4.5]. Its primary action involves a dual mechanism: it potently blocks the serotonin 5-HT2A receptor and weakly inhibits the reuptake of serotonin and norepinephrine [1.4.6, 1.4.3]. This action increases the amount of serotonin available to interact with other receptors, like the 5-HT1A receptor, which is thought to contribute to its antidepressant and anti-anxiety effects [1.4.4].
The Black Box Warning: Hepatotoxicity
The most significant risk associated with nefazodone is severe liver injury. The FDA mandates a black box warning on its label, stating that cases of life-threatening hepatic failure have been reported [1.6.1]. Treatment should not be started in individuals with active liver disease or elevated liver enzymes [1.6.1]. Patients are advised to be alert for symptoms like jaundice (yellowing skin/eyes), dark urine, loss of appetite, and malaise [1.6.7]. If such symptoms appear, the medication must be stopped immediately [1.6.3].
In addition to the liver warning, nefazodone also carries a black box warning for an increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults, a warning common to many antidepressants [1.6.1, 1.6.8]. Other common side effects include drowsiness, dry mouth, nausea, dizziness, constipation, and blurred vision [1.4.1].
Comparison of Nefazodone and Its Alternatives
Given its risk profile, nefazodone is not a first-choice treatment [1.2.3]. Clinicians typically turn to other classes of antidepressants first, such as Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) [1.5.3, 1.5.4]. Trazodone is another SARI that is structurally similar to nefazodone [1.4.1].
| Feature | Nefazodone | Trazodone | SSRIs (e.g., Sertraline) | SNRIs (e.g., Duloxetine) |
|---|---|---|---|---|
| Class | SARI [1.4.2] | SARI [1.4.1] | SSRI [1.5.4] | SNRI [1.5.4] |
| Primary Use | Depression (not first-line) [1.2.3] | Depression, Insomnia [1.4.5] | Depression, Anxiety Disorders [1.5.6] | Depression, Anxiety, Nerve Pain [1.5.1, 1.5.6] |
| Key Risk | Severe Liver Toxicity [1.6.5] | Priapism (rare), Sedation [1.6.7] | Sexual Dysfunction, Withdrawal Syndrome [1.5.7] | Nausea, Increased Blood Pressure [1.5.6] |
| Common Side Effects | Drowsiness, dry mouth, nausea [1.2.2] | Sedation, dizziness, headache [1.4.5] | Nausea, insomnia, diarrhea [1.5.8] | Nausea, dry mouth, constipation [1.5.6] |
| Availability | Generic only in US [1.2.3] | Brand and Generic [1.5.6] | Brand and Generic [1.5.6] | Brand and Generic [1.5.6] |
Conclusion
To answer the question, "Is nefazodone still available?"—yes, it is available in the United States as a generic medication [1.2.2]. It has been discontinued in many other parts of the world due to the significant risk of severe, and sometimes fatal, liver damage [1.3.4]. Its continued availability in the U.S. is a source of controversy [1.3.7]. Today, it is considered a second or third-line treatment, reserved for patients with major depressive disorder who have not responded to other, safer antidepressants [1.6.5]. Any use of nefazodone requires careful patient selection, full disclosure of the risks, and vigilant monitoring for any signs of liver dysfunction [1.6.5].
For more information on the liver toxicity of this drug, you can review materials provided by the National Institutes of Health. [An authoritative outbound link could be placed here, for example: [Nefazodone - LiverTox](https://www.ncbi.nlm.nih.gov/books/NBK548179/)]
