Nefazodone
Nefazodone, sold formerly under the brand names Serzone, Dutonin, and Nefadar among others, is an atypical antidepressant which was first marketed by Bristol-Myers Squibb (BMS) in 1994 but has since largely been discontinued. BMS withdrew it from the market by 2004 due to decreasing sales due to the rare incidence of severe liver damage and the onset of generic competition. The incidence of severe liver damage is approximately 1 in every 250,000 to 300,000 patient-years. Generic versions were introduced in 2003. Nefazodone is a phenylpiperazine compound and is related to trazodone. It has been described as a  serotonin antagonist and reuptake inhibitor (SARI) due to its combined actions as a potent serotonin 5-HT receptor and 5-HT receptor antagonist and weak serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI). Medical uses. Nefazodone is used to treat major depressive disorder, aggressive behavior, anxiety, and panic disorder. Available forms. Nefazodone is available as 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg tablets for oral ingestion. Side effects. Nefazodone can cause severe liver damage, leading to a need for liver transplant, and death. The incidence of severe liver damage is approximately 1 in every 250,000 to 300,000 patient -years. By the time that it started to be withdrawn in 2003, nefazodone had been associated with at least 53 cases of liver injury, with 11 deaths, in the United States, and 51 cases of liver toxicity, with 2 cases of liver transplantation, in Canada. In a Canadian study which found 32 cases in 2002, it was noted that databases like that used in the study tended to include only a small proportion of suspected drug reactions. Common and mild side effects of nefazodone reported in clinical trials more often than placebo include dry mouth (25%), sleepiness (25%), nausea (22 %), dizziness (17%), blurred vision (16%), weakness (11%), lightheadedness (10%), confusion (7%), and orthostatic hypotension (5%). Rare and serious adverse reactions may include allergic reactions, fainting, painful/prolonged erection, and jaundice. Nefazodone is not especially associated with increased appetite and weight gain. Interactions. Nefazodone is a potent inhibitor of CYP3A4, and may interact adversely with many commonly used medications that are metabolized by CYP3A4. Pharmacology. Pharmacodynamics. Nefazodone acts primarily as a potent antagonist of the serotonin 5-HT receptor and to a lesser extent of the serotonin 5-HT receptor. It also has high affinity for the α-adrenergic receptor and  serotonin 5-HT receptor, and relatively lower affinity for the α-adrenergic receptor and dopamine D receptor. Nefazodone has low but significant affinity for the serotonin, norepinephrine, and dopamine transporters as well, and therefore acts as a weak serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI). It has low but potentially significant affinity for the histamine H receptor, where it is an antagonist, and hence may have some antihistamine activity. Nefazodone has negligible activity at muscarinic acetylcholine receptors, and accordingly, has no anticholinergic effects. Pharmacokinetics. The bioavailability of nefazodone is low and variable, about 20%. Its plasma protein binding is approximately 99 %, but it is bound loosely. Nefazodone is metabolized in the liver, with the main enzyme involved thought to be CYP3A4. The drug has at least four active metabolites, which include hydroxynefazodone, "para"-hydroxynefazodone, triazoledione, and "meta"-chlorophenylpiperazine. Nefazodone has a short elimination half-life of about 2 to 4 hours. Its metabolite hydroxynefazodone similarly has an elimination half-life of about 1.5 to 4 hours, whereas the elimination half-lives of triazoledione and mCPP are longer at around 18 hours and 4 to 8 hours, respectively. Due to its long elimination half-life, triazole is the major metabolite and predominates in the  circulation during nefazodone treatment, with plasma levels that are 4 to 10 times higher than those of nefazodone itself. Conversely, hydroxynefazodone levels are about 40% of those of nefazodone at steady state. Plasma levels of mCPP are very low at about 7% of those of nefazodone; hence, mCPP is only a minor metabolite. mCPP is thought to be formed from nefazodone specifically by CYP2D6. The ratios of brain-to-plasma concentrations of mCPP to nefazodone are 47:1 in mice and 10:1 in rats, suggesting that brain exposure to mCPP may be much higher than plasma exposure. Conversely, hydroxynefazodone levels in  the brain are 10% of those in plasma in rats. As such, in spite of its relatively low plasma concentrations, brain exposure to mCPP may be substantial, whereas that of hydroxynefazodone may be minimal. Chemistry. Nefazodone is a phenylpiperazine; it is an alpha-phenoxyl derivative of etoperidone which in turn was a derivative of trazodone. History. Nefazodone was discovered by scientists at Bristol-Myers Squibb (BMS) who were seeking to improve on trazodone by reducing its sedating qualities. BMS obtained marketing approvals worldwide for nefazodone in 1994. It was marketed in the US under the brand name Serzone and in  Europe under the brand name Dutonin. In 2002 the FDA obligated BMS to add a black box warning about potential fatal liver toxicity to the drug label. Worldwide sales in 2002 were $409 million. In 2003 Public Citizen filed a citizen petition asking the FDA to withdraw the marketing authorization in the US, and in early 2004 the organization sued the FDA to attempt to force withdrawal of the drug. The FDA issued a response to the petition in June 2004 and filed a motion to dismiss, and Public Citizen withdrew the suit. Generic versions were introduced in the  US in 2003 and Health Canada withdrew the marketing authorization that year. Sales of nefazodone were about $100 million in 2003. By that time it was also being marketed under the additional brand names Serzonil, Nefadar, and Rulivan. In April 2004, BMS announced that it was going discontinue the sale of Serzone in the US in June 2004 and said that this was due to declining sales. By that time BMS had already withdrawn the drug from the market in Europe, Australia, New Zealand and Canada. As of 2012 generic nefazodone was available in the US. In August 2020 , Teva Pharmaceuticals placed nefazodone in shortage due to a shortage of a raw ingredient. On December 20, 2021 Nefazodone was again made available in all strengths. Society and culture. Generic names. "Nefazodone" is the generic name of the drug and its and , while "néfazodone" is its and "nefazodone hydrochloride" is its and . Brand names. Nefazodone has been marketed under a number of brand names including "Dutonin" (, , , ), Menfazona (), "Nefadar" (, , , ), Nefazodone BMS (), Nefazodone Hydrochloride Teva (), Reseril (), Rulivan (), and "Serzone" (, , ). Research. The use of nefazodone to prevent migraine has been studied, due to its antagonistic effects on the 5-HT and 5-HT  receptors.