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Nefazodone, sold formerly under the brand namesSerzone,Dutonin, andNefadar among others, is anatypical antidepressant medication which is used in the treatment ofdepression and for other uses.[4][5][6][7] Nefazodone was withdrawn in most countries by 2004[8][9] (due to liver toxicity[10]), but was, as of December 2021, still available in the United States.[11] The medication is takenby mouth.[10]
Nefazodone was introduced for medical use in 1994.[7][12][8]Generic versions were introduced in 2003.[13] Serious liver toxicity was first reported with nefazodone in 1998, and it was withdrawn from most markets by 2004.[8][9] However, as of 2023, it continues to be available in the United States in generic from one manufacturer,Teva Pharmaceuticals[citation needed][14][failed verification] and is manufactured in Israel.[15]
Contraindications include the coadministration ofterfenadine,astemizole,cisapride,pimozide, orcarbamazepine. Nefazodone is contraindicated in patients who were withdrawn from nefazodone because of evident liver injury as well as those that have shown hypersensitivity to the drug, its inactive ingredients, or otherphenylpiperazine antidepressants. Furthermore, the coadministration oftriazolam and nefazodone should be avoided for all patients, including the elderly, since it causes a significant increase in the plasma level of triazolam and not all commercially available dosage forms of triazolam permit a sufficient dosage reduction. If coadministrated, a 75% reduction in the initial dosage of triazolam is recommended.[18]
Nefazodone can cause severeliver damage which may lead to the need for liver transplantation or to death. The incidence of severe liver damage is approximately 1 in every 250,000 to 300,000patient-years.[7][10] By the time it started to be withdrawn from the markets in 2003, nefazodone had been associated with at least 53 cases of liver injury (of which 11 led to death) in theUnited States,[22] and 51 cases of liver toxicity (of which 2 led to transplantation) inCanada.[23][24] In a 2002 Canadian study of 32 cases, it was noted that databases like those used in the study tended to include only a small proportion of suspected drug reactions.[24]
Treatment protocols suggest screening for pre-existingliver disease before initiating nefazodone, and those with known liver disease should not be prescribed nefazodone. If serumAST or serumALT levels are more than 3 times theupper limit of normal (ULN), treatment should be permanently withdrawn. Enzyme labs should be done every six months, and nefazodone should not be a first-line treatment.[25]
Nefazodone ismetabolized in theliver, with the mainenzyme involved thought to beCYP3A4.[3] The drug has at least fouractive metabolites, which includehydroxynefazodone,para-hydroxynefazodone,triazoledione, andmeta-chlorophenylpiperazine (mCPP).[2] Nefazodone has a shortelimination half-life of about 2 to 4hours.[2] Its metabolite hydroxynefazodone similarly has an elimination half-life of about 1.5 to 4hours, whereas the elimination half-lives of triazoledione and mCPP are longer at around 18hours and 4 to 8hours, respectively.[2] Due to its long elimination half-life, triazoledione is the major metabolite and predominates in the circulation during nefazodone treatment, with plasma levels that are 4 to 10times higher than those of nefazodone itself.[2][35] Conversely, hydroxynefazodone levels are about 40% of those of nefazodone atsteady state.[2] Plasma levels of mCPP are very low at about 7% of those of nefazodone; hence, mCPP is only a minor metabolite.[2][35] mCPP is thought to be formed from nefazodone specifically byCYP2D6.[3][35]
The ratios ofbrain-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.[2] Conversely, hydroxynefazodone levels in the brain are 10% of those in plasma in rats.[2] As such, in spite of its relatively low plasma concentrations, brain exposure to mCPP may be substantial, whereas that of hydroxynefazodone may be minimal.[2]
Nefazodone was discovered by scientists atBristol-Myers Squibb (BMS) who were seeking to improve on trazodone by reducing its sedating qualities.[37]
BMS obtained marketing approvals for nefazodone worldwide, including in the United States and Europe, in 1994.[7][12][8] It was marketed in the United States under the brand name Serzone[38] and in Europe under the brand name Dutonin.[39]
The first reports of serious liver toxicity with nefazodone were published in 1998 and 1999.[40][41] These instances were quickly followed by many additional cases.[42][22][23][24]
In 2003Public Citizen filed acitizen petition asking the FDA to withdraw the marketing authorization in the United States, and in early 2004 the organization sued the FDA to attempt to force withdrawal of the drug.[43][44] The FDA issued a response to the petition in June 2004 and filed a motion to dismiss, and Public Citizen withdrew the suit.[44]
Sales of nefazodone were about $100 million in 2003.[45] By that time, it was also being marketed under the additional brand names Serzonil, Nefadar, and Rulivan.[7]
Generic versions were introduced in the United States in 2003[13] andHealth Canada withdrew the marketing authorization that same year.[46]
In April 2004, BMS announced that it was going to discontinue the sale of Serzone in the United States in June 2004 and said that this was due to declining sales and generic versions being available in the United States.[13][9][45] By that time, BMS had already withdrawn the drug from the market in Europe, Australia, New Zealand, and Canada.[9]
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.[11][47]
Nefazodone is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name andBANTooltip British Approved Name, whilenéfazodone is itsDCFTooltip Dénomination Commune Française andnefazodone hydrochloride is itsUSANTooltip United States Adopted Name andUSPTooltip United States Pharmacopeia.[4][5][48][6]
Nefazodone was under development for the treatment ofpanic disorder, and reachedphase 3clinical trials for this indication, but development was discontinued in 2004.[49]
The use of nefazodone to preventmigraine has been studied, due to its antagonism of the serotonin 5-HT2A and 5-HT2C receptors.[50][51][52]
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^abc"Nefazodone". Drug Patent Watch.Archived from the original on 27 January 2018. Retrieved3 June 2017.
^Sussman N, Ginsberg DL, Bikoff J (April 2001). "Effects of nefazodone on body weight: a pooled analysis of selective serotonin reuptake inhibitor- and imipramine-controlled trials".The Journal of Clinical Psychiatry.62 (4):256–260.doi:10.4088/JCP.v62n0407.PMID11379839.
^Ferguson JM, Shrivastava RK, Stahl SM, Hartford JT, Borian F, Ieni J, et al. (January 2001). "Reemergence of sexual dysfunction in patients with major depressive disorder: double-blind comparison of nefazodone and sertraline".The Journal of Clinical Psychiatry.62 (1):24–29.doi:10.4088/jcp.v62n0106.PMID11235924.
^Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F (2001). "Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction".The Journal of Clinical Psychiatry.62 (Suppl 3):10–21.PMID11229449.
^Spina E, Santoro V, D'Arrigo C (July 2008). "Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update".Clinical Therapeutics.30 (7):1206–1227.doi:10.1016/S0149-2918(08)80047-1.PMID18691982.
^Roth BL, Driscol J."PDSP Ki Database".Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health.Archived from the original on 28 October 2021. Retrieved14 August 2017.
^abcdeTatsumi M, Groshan K, Blakely RD, Richelson E (December 1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters".European Journal of Pharmacology.340 (2–3):249–258.doi:10.1016/s0014-2999(97)01393-9.PMID9537821.
^abcdOwens MJ, Morgan WN, Plott SJ, Nemeroff CB (December 1997). "Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites".The Journal of Pharmacology and Experimental Therapeutics.283 (3):1305–1322.doi:10.1016/S0022-3565(24)37161-7.PMID9400006.
^abcdefghijCusack B, Nelson A, Richelson E (May 1994). "Binding of antidepressants to human brain receptors: focus on newer generation compounds".Psychopharmacology.114 (4):559–565.doi:10.1007/bf02244985.PMID7855217.S2CID21236268.
^abcdRoth BL, Kroeze WK (2006). "Screening the receptorome yields validated molecular targets for drug discovery".Current Pharmaceutical Design.12 (14):1785–1795.doi:10.2174/138161206776873680.PMID16712488.
^Aranda-Michel J, Koehler A, Bejarano PA, Poulos JE, Luxon BA, Khan CM, et al. (February 1999). "Nefazodone-induced liver failure: report of three cases".Ann Intern Med.130 (4 Pt 1):285–8.doi:10.7326/0003-4819-130-4-199902160-00013.PMID10068386.
^Millan MJ (2005). "Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies".Therapie.60 (5):441–460.doi:10.2515/therapie:2005065.PMID16433010.
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