View source for Nefazodone

{{Short description|Atypical antidepressant drug}}
{{lead rewrite|reason = to remove redundant and discrepant information in the first and last paragraph of the lead, regarding the U.S. on-market status of the drug | date = April 2025}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
| verifiedrevid      = 462258980
| IUPAC_name         = 1-(3-[4-(3-chlorophenyl)piperazin-1-yl]propyl)-3-ethyl-4-(2-phenoxyethyl)-1''H''-1,2,4-triazol-5(4''H'')-one
| image              = Nefazodone.svg
| image_class        = skin-invert-image
| width              = 250px
| image2             = File:Nefazodone ball-and-stick model.png
| width2             = 250px

<!--Clinical data-->| tradename          = Serzone, Dutonin, Nefadar, others
| Drugs.com          = {{drugs.com|monograph|nefazodone-hydrochloride}}
| MedlinePlus        = a695005
| licence_US         = 
| pregnancy_category = C
| legal_AU           = S4
| legal_BR           = C1
| legal_BR_comment   = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>
| legal_US           = Rx-only
| legal_status       = Rx-only
| routes_of_administration = [[Oral administration|By mouth]]

<!--Pharmacokinetic data-->| bioavailability    = 20% (variable)<ref name="SchatzbergNemeroff2017">{{cite book| vauthors = Schatzberg AF, Nemeroff CB |title=The American Psychiatric Association Publishing Textbook of Psychopharmacology, Fifth Edition|url=https://books.google.com/books?id=KfHEDgAAQBAJ&pg=PA460|year=2017|publisher=American Psychiatric Pub|isbn=978-1-58562-523-9|pages=460–}}</ref>
| protein_bound      = 99% (loosely)<ref name="SchatzbergNemeroff2017" />
| metabolism         = [[Liver]] ([[CYP3A4]], [[CYP2D6]])<ref name="PacificiPelkonen2001">{{cite book| vauthors = Pacifici GM, Pelkonen O |title=Interindividual Variability in Human Drug Metabolism|url=https://books.google.com/books?id=mNKWjla41qUC&pg=PA103|date=24 May 2001|publisher=CRC Press|isbn=978-0-7484-0864-1|pages=103–}}</ref>
| metabolites        = • [[Hydroxynefazodone]]<ref name="SchatzbergNemeroff2017" /><br />• {{abbrlink|mCPP|meta-Chlorophenylpiperazine}}<ref name="SchatzbergNemeroff2017" /><br />• ''p''-Hydroxynefazodone<ref name="PacificiPelkonen2001" /><br />• [[Triazoledione]]<ref name="SchatzbergNemeroff2017" />
| elimination_half-life = • Nefazodone: 2–4 hours<ref name="SchatzbergNemeroff2017" /><br />• [[Hydroxynefazodone]]: 1.5–4 hours<ref name="SchatzbergNemeroff2017" /><br />• [[Triazoledione]]: 18 hours<ref name="SchatzbergNemeroff2017" /><br />• {{abbrlink|mCPP|meta-Chlorophenylpiperazine}}: 4–8 hours<ref name="SchatzbergNemeroff2017" />
| excretion          = [[Urine]]: 55%<br />[[Feces]]: 20–30%

<!--Identifiers-->| CAS_number_Ref     = {{cascite|correct|??}}
| CAS_number         = 83366-66-9
| CAS_supplemental   = <br />82752-99-6 ([[hydrochloride]])
| ATC_prefix         = N06
| ATC_suffix         = AX06
| PubChem            = 4449
| DrugBank_Ref       = {{drugbankcite|correct|drugbank}}
| DrugBank           = DB01149
| ChemSpiderID_Ref   = {{chemspidercite|correct|chemspider}}
| ChemSpiderID       = 4294
| UNII_Ref           = {{fdacite|correct|FDA}}
| UNII               = 59H4FCV1TF
| KEGG_Ref           = {{keggcite|correct|kegg}}
| KEGG               = D08257
| ChEBI_Ref          = {{ebicite|correct|EBI}}
| ChEBI              = 7494
| ChEMBL_Ref         = {{ebicite|correct|EBI}}
| ChEMBL             = 623
| IUPHAR_ligand      = 7247
| synonyms           = BMY-13754-1; MJ-13754-1; MJ-13754; MS-13754

<!--Chemical data-->| C                  = 25
| H                  = 32
| Cl                 = 1
| N                  = 5
| O                  = 2
| SMILES             = Clc4cccc(N3CCN(CCCN1/N=C(\N(C1=O)CCOc2ccccc2)CC)CC3)c4
| StdInChI_Ref       = {{stdinchicite|correct|chemspider}}
| StdInChI           = 1S/C25H32ClN5O2/c1-2-24-27-31(25(32)30(24)18-19-33-23-10-4-3-5-11-23)13-7-12-28-14-16-29(17-15-28)22-9-6-8-21(26)20-22/h3-6,8-11,20H,2,7,12-19H2,1H3
| StdInChIKey_Ref    = {{stdinchicite|correct|chemspider}}
| StdInChIKey        = VRBKIVRKKCLPHA-UHFFFAOYSA-N
}}
<!-- Definition and medical uses -->
'''Nefazodone''', sold formerly under the brand names '''Serzone''', '''Dutonin''', and '''Nefadar''' among others, is an [[atypical antidepressant]] medication which is used in the treatment of [[depression (mood)|depression]] and for other uses.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Drugs.com" /><ref name=WHOPN2004>{{cite journal|title=Drugs of Current Interest: Nefazodone|journal=WHO Pharmaceuticals Newsletter|date=2003|issue=1|url=http://apps.who.int/medicinedocs/en/d/Js4944e/3.html|archive-url=https://web.archive.org/web/20150403165029/http://apps.who.int/medicinedocs/en/d/Js4944e/3.html|url-status=dead|archive-date=April 3, 2015}}</ref> Nefazodone was withdrawn in most countries by 2004<ref name="pmid29609830" /><ref name="CBS2004" /> (due to liver toxicity<ref name="USlabel2005" />), but was, as of December 2021, still available in the United States.<ref name="Teva Nefazodone Statement" /> The medication is taken [[oral administration|by mouth]].<ref name="USlabel2005" />

<!-- Side effects and mechanism of action -->
[[Side effect]]s of nefazodone include [[dry mouth]], [[sleepiness]], [[nausea]], [[dizziness]], [[blurred vision]], [[weakness]], [[lightheadedness]], [[confusion]], and [[orthostatic hypotension|postural low blood pressure]], among others.<ref name="USlabel2005" /> Rarely, nefazodone can cause serious [[liver damage]], with an incidence of death or [[liver transplantation]] of about 1 in every 250,000 to 300,000 patient years.<ref name=USlabel2005>{{cite web|title=Serzone (Nefazodone): Side Effects, Interactions, Warning, Dosage & Uses|url=http://www.rxlist.com/serzone-drug.htm|publisher=RxList|access-date=3 June 2017|language=en|date=January 2005|archive-date=6 June 2017|archive-url=https://web.archive.org/web/20170606013304/http://www.rxlist.com/serzone-drug.htm|url-status=live}}</ref> Nefazodone is a [[phenylpiperazine]] [[chemical compound|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 [[potency (pharmacology)|potent]] [[receptor antagonist|antagonist]] of the [[serotonin]] [[5-HT2A receptor|5-HT<sub>2A</sub>]] and [[5-HT2C receptor|5-HT<sub>2C</sub> receptor]]s and weak [[serotonin–norepinephrine–dopamine reuptake inhibitor]] (SNDRI).

<!-- History, society, and culture -->
Nefazodone was introduced for medical use in 1994.<ref name="WHOPN2004" /><ref name="pmid8748566" /><ref name="pmid29609830">{{cite journal | vauthors = Babai S, Auclert L, Le-Louët H | title = Safety data and withdrawal of hepatotoxic drugs | journal = Therapie | volume = 76 | issue = 6 | pages = 715–723 | date = 2021 | pmid = 29609830 | doi = 10.1016/j.therap.2018.02.004 | url = }}</ref> [[Generic drug|Generic versions]] were introduced in 2003.<ref name="DPW">{{cite web |title=Nefazodone |url=https://www.drugpatentwatch.com/p/generic-api/nefazodone+hydrochloride |access-date=3 June 2017 |publisher=Drug Patent Watch |language=en |archive-date=27 January 2018 |archive-url=https://web.archive.org/web/20180127203138/https://www.drugpatentwatch.com/p/generic-api/nefazodone+hydrochloride |url-status=live }}</ref> Serious liver toxicity was first reported with nefazodone in 1998, and it was withdrawn from most markets by 2004.<ref name="pmid29609830" /><ref name="CBS2004" /> However, as of 2023, it continues to be available in the United States in generic from one manufacturer, [[Teva Pharmaceuticals]]{{cn|date=April 2025}}<ref name="Drugs@FDA">{{cite web | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process | title=Drugs@FDA: FDA-Approved Drugs | access-date=2023-02-11 | archive-date=2021-08-27 | archive-url=https://web.archive.org/web/20210827181002/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm | url-status=dead }}{{nonspecific|date=April 2025}}</ref>{{failed verification|date=April 2025}} and is manufactured in Israel.<ref>{{Cite web |title=DailyMed - NEFAZODONE HYDROCHLORIDE tablet |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=51ff7db5-aaf9-4c3c-86e6-958ebf16b60f |access-date=2023-10-29 |website=dailymed.nlm.nih.gov |archive-date=2016-09-16 |archive-url=https://web.archive.org/web/20160916034010/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=51ff7db5-aaf9-4c3c-86e6-958ebf16b60f |url-status=live }}</ref>

==Medical uses==
Nefazodone is used to treat [[major depressive disorder]], [[aggression|aggressive behavior]], [[anxiety]],<ref>{{Cite web|title=List of 54 Anxiety Medications Compared|url=https://www.drugs.com/condition/anxiety.html|access-date=2022-01-23|website=Drugs.com|language=en|archive-date=2022-01-23|archive-url=https://web.archive.org/web/20220123025418/https://www.drugs.com/condition/anxiety.html|url-status=live}}</ref> and [[panic disorder]].<ref name=LiverTox>{{cite book|title=Nefazodone|url=https://livertox.nih.gov/Nefazodone.htm|publisher=LiverTox (NIDDK)|date=2 June 2017|pmid=31643176 |access-date=3 June 2017|archive-date=2 July 2019|archive-url=https://web.archive.org/web/20190702154539/https://livertox.nih.gov/Nefazodone.htm|url-status=live}}</ref>

===Available forms===
Nefazodone is available as 50{{nbsp}}mg, 100{{nbsp}}mg, 150{{nbsp}}mg, 200{{nbsp}}mg, and 250{{nbsp}}mg [[tablet (pharmacy)|tablet]]s for [[oral administration|oral]] ingestion.<ref name="Drugs.com-2">{{Cite web|url=https://www.drugs.com/pro/nefazodone.html|title=Nefazodone Package insert / prescribing information|work=Drugs.com|access-date=2017-11-24|archive-date=2020-08-09|archive-url=https://web.archive.org/web/20200809062054/https://www.drugs.com/pro/nefazodone.html|url-status=live}}</ref>

==Contraindications==
[[Contraindication]]s include the coadministration of [[terfenadine]], [[astemizole]], [[cisapride]], [[pimozide]], or [[carbamazepine]]. 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 other [[phenylpiperazine]] antidepressants. Furthermore, the coadministration of [[triazolam]] 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.<ref name="Drugs.com-2" />

==Side effects==
Common and mild [[side effect]]s of nefazodone reported in [[clinical trial]]s 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, [[priapism|painful/prolonged erection]], and [[jaundice]].<ref name="USlabel2005" /> Nefazodone is not especially associated with increased appetite and weight gain.<ref name="pmid11379839">{{cite journal | vauthors = Sussman N, Ginsberg DL, Bikoff J | title = Effects of nefazodone on body weight: a pooled analysis of selective serotonin reuptake inhibitor- and imipramine-controlled trials | journal = The Journal of Clinical Psychiatry | volume = 62 | issue = 4 | pages = 256–260 | date = April 2001 | pmid = 11379839 | doi = 10.4088/JCP.v62n0407 }}</ref> It is also known for having low levels of [[Sexual side-effects of antidepressants|sexual side effects]] in comparisons to SSRIs.<ref>{{cite journal | vauthors = Ferguson JM, Shrivastava RK, Stahl SM, Hartford JT, Borian F, Ieni J, McQuade RD, Jody D | title = Reemergence of sexual dysfunction in patients with major depressive disorder: double-blind comparison of nefazodone and sertraline | journal = The Journal of Clinical Psychiatry | volume = 62 | issue = 1 | pages = 24–29 | date = January 2001 | pmid = 11235924 | doi = 10.4088/jcp.v62n0106 }}</ref><ref>{{cite journal | vauthors = Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F | title = 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 | journal = The Journal of Clinical Psychiatry | volume = 62 | issue = Suppl 3 | pages = 10–21 | date = 2001 | pmid = 11229449 | url = https://pubmed.ncbi.nlm.nih.gov/11229449/ | access-date = 2022-12-17 | archive-date = 2022-12-17 | archive-url = https://web.archive.org/web/20221217005305/https://pubmed.ncbi.nlm.nih.gov/11229449/ | url-status = live }}</ref>

Nefazodone can cause severe [[hepatotoxicity|liver 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 300,000 [[Incidence (epidemiology)|patient-years]].<ref name=WHOPN2004/><ref name=USlabel2005/> 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 the [[United States]],<ref name="pmid12699949">{{cite journal | vauthors = Edwards IR | title = Withdrawing drugs: nefazodone, the start of the latest saga | journal = Lancet | volume = 361 | issue = 9365 | pages = 1240 | date = April 2003 | pmid = 12699949 | doi = 10.1016/S0140-6736(03)13030-9 | s2cid = 39993080 }}</ref> and 51 cases of liver toxicity (of which 2 led to transplantation) in [[Canada]].<ref name="pmid14638657">{{cite journal | vauthors = Choi S | title = Nefazodone (Serzone) withdrawn because of hepatotoxicity | journal = CMAJ | volume = 169 | issue = 11 | pages = 1187 | date = November 2003 | pmid = 14638657 | pmc = 264962 | doi = }}</ref><ref name="pmid12025437">{{cite journal | vauthors = Stewart DE | title = Hepatic adverse reactions associated with nefazodone | journal = Canadian Journal of Psychiatry | volume = 47 | issue = 4 | pages = 375–377 | date = May 2002 | pmid = 12025437 | doi = 10.1177/070674370204700409 | doi-access = free }}</ref> 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.<ref name="pmid12025437" />

Treatment protocols suggest screening for pre-existing [[liver disease]] before initiating nefazodone, and those with known liver disease should not be prescribed nefazodone. If serum [[Aspartate transaminase|AST]] or serum [[Alanine transaminase|ALT]] levels are more than 3 times the [[Reference range|upper 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.<ref>{{Cite web |title=Nefazodone hydrochloride - Drug Summary |work=PDR.net |url=https://www.pdr.net/drug-summary/Nefazodone-nefazodone-hydrochloride-661 |access-date=2022-10-12 |archive-date=2022-10-12 |archive-url=https://web.archive.org/web/20221012154117/https://www.pdr.net/drug-summary/Nefazodone-nefazodone-hydrochloride-661 |url-status=live }}</ref>

==Interactions==
Nefazodone is a potent [[enzyme inhibitor|inhibitor]] of [[CYP3A4]], and may interact adversely with [[CYP3A4#Ligands|many commonly used medications]] that are metabolized by CYP3A4.<ref name=Lexi-Comp>{{cite web |url=http://www.merck.com/mmpe/lexicomp/nefazodone.html |title=Nefazodone |date=September 2008 |author=Lexi-Comp |work=[[Merck Manual of Diagnosis and Therapy|The Merck Manual Professional]] |access-date=2008-11-29 |archive-date=2010-09-04 |archive-url=https://web.archive.org/web/20100904010528/http://www.merck.com/mmpe/lexicomp/nefazodone.html |url-status=live }} Retrieved on November 29, 2008.</ref><ref>{{cite journal | vauthors = Spina E, Santoro V, D'Arrigo C | title = Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update | journal = Clinical Therapeutics | volume = 30 | issue = 7 | pages = 1206–1227 | date = July 2008 | pmid = 18691982 | doi = 10.1016/S0149-2918(08)80047-1 }}</ref><ref>{{cite journal | vauthors = Richelson E | title = Pharmacokinetic drug interactions of new antidepressants: a review of the effects on the metabolism of other drugs | journal = Mayo Clinic Proceedings | volume = 72 | issue = 9 | pages = 835–847 | date = September 1997 | pmid = 9294531 | doi = 10.4065/72.9.835 | doi-access = free }}</ref>

==Pharmacology==

===Pharmacodynamics===
{| class="wikitable floatright"
|+ Nefazodone<ref name="PDSP">{{cite web | title = PDSP K<sub>i</sub> Database | work = Psychoactive Drug Screening Program (PDSP) | author1-link = Bryan Roth | vauthors = Roth BL, Driscol J | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | access-date = 14 August 2017 | url = https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=nefazodone&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query | archive-date = 28 October 2021 | archive-url = https://web.archive.org/web/20211028141357/https://pdsp.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=nefazodone&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query | url-status = live }}</ref>
|-
! Site !! K<sub>i</sub> (nM) !! Species !! Ref
|-
| {{abbrlink|SERT|Serotonin transporter}} || 200–459 || Human || <ref name="pmid9537821">{{cite journal | vauthors = Tatsumi M, Groshan K, Blakely RD, Richelson E | title = Pharmacological profile of antidepressants and related compounds at human monoamine transporters | journal = European Journal of Pharmacology | volume = 340 | issue = 2–3 | pages = 249–258 | date = December 1997 | pmid = 9537821 | doi = 10.1016/s0014-2999(97)01393-9 }}</ref><ref name="pmid9400006">{{cite journal | vauthors = Owens MJ, Morgan WN, Plott SJ, Nemeroff CB | title = Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 283 | issue = 3 | pages = 1305–1322 | date = December 1997 | doi = 10.1016/S0022-3565(24)37161-7 | pmid = 9400006 }}</ref>
|-
| {{abbrlink|NET|Norepinephrine transporter}} || 360–618 || Human || <ref name="pmid9537821" /><ref name="pmid9400006" />
|-
| {{abbrlink|DAT|Dopamine transporter}} || 360 || Human || <ref name="pmid9537821" />
|-
| [[5-HT1A receptor|5-HT<sub>1A</sub>]] || 80 || Human || <ref name="pmid7855217">{{cite journal | vauthors = Cusack B, Nelson A, Richelson E | title = Binding of antidepressants to human brain receptors: focus on newer generation compounds | journal = Psychopharmacology | volume = 114 | issue = 4 | pages = 559–565 | date = May 1994 | pmid = 7855217 | doi = 10.1007/bf02244985 | s2cid = 21236268 }}</ref>
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]] || 26 || Human || <ref name="pmid7855217" />
|-
| [[5-HT2C receptor|5-HT<sub>2C</sub>]] || 72 || Human || <ref name="pmid16712488">{{cite journal | vauthors = Roth BL, Kroeze WK | title = Screening the receptorome yields validated molecular targets for drug discovery | journal = Current Pharmaceutical Design | volume = 12 | issue = 14 | pages = 1785–1795 | year = 2006 | pmid = 16712488 | doi = 10.2174/138161206776873680 }}</ref>
|-
| [[Alpha-1 adrenergic receptor|α<sub>1</sub>]] || 5.5–48 || Human || <ref name="pmid7855217" /><ref name="pmid9400006" />
|-
| [[Alpha-1A adrenergic receptor|α<sub>1A</sub>]] || 48 || Human || <ref name="pmid16712488" />
|-
| [[Alpha-2 adrenergic receptor|α<sub>2</sub>]] || 84–640 || Human || <ref name="pmid7855217" /><ref name="pmid9400006" />
|-
| [[Beta-adrenergic receptor|β]] || >10,000 || Rat || <ref name="pmid10379421">{{cite journal | vauthors = Sánchez C, Hyttel J | title = Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding | journal = Cellular and Molecular Neurobiology | volume = 19 | issue = 4 | pages = 467–489 | date = August 1999 | pmid = 10379421 | doi = 10.1023/A:1006986824213 | s2cid = 19490821 | pmc = 11545528 }}</ref>
|-
| [[Dopamine D2 receptor|D<sub>2</sub>]] || 910 || Human || <ref name="pmid7855217" />
|-
| [[Histamine H1 receptor|H<sub>1</sub>]] || ≥370 || Human || <ref name="pmid7855217" /><ref name="pmid16712488" />
|-
| {{abbrlink|mACh|Muscarinic acetylcholine receptor}} || >10,000 || Human || <ref name="pmid7855217" />
|- class="sortbottom"
| colspan="4" style="width: 1px;" | '''Notes:''' Values are K<sub>i</sub> (nM). The smaller the value, the more strongly the drug binds to the site.
|}

Nefazodone acts primarily as a potent [[receptor antagonist|antagonist]] of the [[serotonin]] [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]] and to a lesser extent of the serotonin [[5-HT2C receptor|5-HT<sub>2C</sub> receptor]].<ref name="pmid7855217" /> It also has high affinity for the [[α1-adrenergic|α<sub>1</sub>-adrenergic receptor]] and serotonin [[5-HT1A receptor|5-HT<sub>1A</sub> receptor]], and relatively lower affinity for the [[α2-adrenergic|α<sub>2</sub>-adrenergic receptor]] and [[dopamine]] [[D2 receptor|D<sub>2</sub> receptor]].<ref name="pmid7855217"/> Nefazodone has low but significant affinity for the [[serotonin transporter|serotonin]], [[norepinephrine transporter|norepinephrine]], and [[dopamine transporter]]s as well, and therefore acts as a weak [[serotonin–norepinephrine–dopamine reuptake inhibitor]] (SNDRI).<ref name="pmid9537821" /> It has low but potentially significant affinity for the [[histamine]] [[H1 receptor|H<sub>1</sub> receptor]], where it is an antagonist, and hence may have some [[antihistamine]] activity.<ref name="pmid7855217" /><ref name="pmid16712488" /> Nefazodone has negligible activity at [[muscarinic acetylcholine receptor]]s, and accordingly, has no [[anticholinergic]] effects.<ref name="pmid9537821"/>

===Pharmacokinetics===
The [[bioavailability]] of nefazodone is low and variable, about 20%.<ref name="SchatzbergNemeroff2017" /> Its [[plasma protein binding]] is approximately 99%, but it is bound loosely.<ref name="SchatzbergNemeroff2017" />

Nefazodone is [[metabolism|metabolized]] in the [[liver]], with the main [[enzyme]] involved thought to be [[CYP3A4]].<ref name="PacificiPelkonen2001" /> The drug has at least four [[active metabolite]]s, which include [[hydroxynefazodone]], ''para''-hydroxynefazodone, [[triazoledione]], and [[meta-chlorophenylpiperazine|''meta''-chlorophenylpiperazine]] (mCPP).<ref name="SchatzbergNemeroff2017" /> Nefazodone has a short [[elimination half-life]] of about 2 to 4{{nbsp}}hours.<ref name="SchatzbergNemeroff2017" /> Its metabolite hydroxynefazodone similarly has an elimination half-life of about 1.5 to 4{{nbsp}}hours, whereas the elimination half-lives of triazoledione and mCPP are longer at around 18{{nbsp}}hours and 4 to 8{{nbsp}}hours, respectively.<ref name="SchatzbergNemeroff2017" /> 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 10{{nbsp}}times higher than those of nefazodone itself.<ref name="SchatzbergNemeroff2017" /><ref name="PreskornStanga2012">{{cite book| vauthors = Preskorn SH, Stanga CY, Feighner JP, Ross R |title= Antidepressants: Past, Present and Future|url=https://books.google.com/books?id=Ue3uCAAAQBAJ&pg=PA68|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-18500-7|pages=68–}}</ref> Conversely, hydroxynefazodone levels are about 40% of those of nefazodone at [[steady state (pharmacokinetics)|steady state]].<ref name="SchatzbergNemeroff2017" /> Plasma levels of mCPP are very low at about 7% of those of nefazodone; hence, mCPP is only a minor metabolite.<ref name="SchatzbergNemeroff2017" /><ref name="PreskornStanga2012" /> mCPP is thought to be formed from nefazodone specifically by [[CYP2D6]].<ref name="PacificiPelkonen2001" /><ref name="PreskornStanga2012" />

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.<ref name="SchatzbergNemeroff2017" /> Conversely, hydroxynefazodone levels in the brain are 10% of those in plasma in rats.<ref name="SchatzbergNemeroff2017" /> As such, in spite of its relatively low plasma concentrations, brain exposure to mCPP may be substantial, whereas that of hydroxynefazodone may be minimal.<ref name="SchatzbergNemeroff2017" />

==Chemistry==
Nefazodone is a [[phenylpiperazine]];<ref>{{cite journal | vauthors = Davis R, Whittington R, Bryson HM | title = Nefazodone. A review of its pharmacology and clinical efficacy in the management of major depression | journal = Drugs | volume = 53 | issue = 4 | pages = 608–636 | date = April 1997 | pmid = 9098663 | doi = 10.2165/00003495-199753040-00006 | s2cid = 239077479 }}</ref> it is an alpha-phenoxyl derivative of [[etoperidone]] which in turn was a derivative of [[trazodone]].<ref name=DD>{{cite book| vauthors = Eison MS, Taylor DB, Riblet LA | veditors = Williams M, Malick JB |title=Drug Discovery and Development|date=1987|publisher=Springer Science & Business Media|isbn=978-1-4612-4828-6|page=390|chapter-url=https://books.google.com/books?id=O0LuBwAAQBAJ&pg=PA390|language=en|chapter=Atypical Psychotropic Agents}}</ref>

==History==
Nefazodone was discovered by scientists at [[Bristol-Myers Squibb]] (BMS) who were seeking to improve on trazodone by reducing its sedating qualities.<ref name=DD/>

BMS obtained marketing approvals for nefazodone worldwide, including in the United States and Europe, in 1994.<ref name=WHOPN2004/><ref name="pmid8748566">{{cite journal | vauthors = Ellingrod VL, Perry PJ | title = Nefazodone: a new antidepressant | journal = Am J Health Syst Pharm | volume = 52 | issue = 24 | pages = 2799–812 | date = December 1995 | pmid = 8748566 | doi = 10.1093/ajhp/52.24.2799 | url = }}</ref><ref name="pmid29609830" /> It was marketed in the United States under the brand name Serzone<ref>{{cite news|last1=Associated Press|title=Consumer group seeks ban on antidepressant|url=http://www.nbcnews.com/id/4536220/ns/health-mental_health/t/consumer-group-seeks-ban-antidepressant/|work=NBC News|date=16 March 2004|language=en|access-date=3 June 2017|archive-date=24 September 2020|archive-url=https://web.archive.org/web/20200924002552/http://www.nbcnews.com/id/4536220/ns/health-mental_health/t/consumer-group-seeks-ban-antidepressant/|url-status=dead}}</ref> and in Europe under the brand name Dutonin.<ref name=FirstWord>{{cite news|vauthors=Hoffmann C|title=Bristol-Myers to withdraw Dutonin in Europe|url=http://www.firstwordpharma.com/node/213988#axzz4iz3Sls6H|work=First Word Pharma|date=January 8, 2003|language=en|access-date=June 3, 2017|archive-date=September 12, 2017|archive-url=https://web.archive.org/web/20170912102209/http://www.firstwordpharma.com/node/213988#axzz4iz3Sls6H|url-status=live}}</ref>

The first reports of serious liver toxicity with nefazodone were published in 1998 and 1999.<ref name="pmid10068386">{{cite journal | vauthors = Aranda-Michel J, Koehler A, Bejarano PA, Poulos JE, Luxon BA, Khan CM, Ee LC, Balistreri WF, Weber FL | title = Nefazodone-induced liver failure: report of three cases | journal = Ann Intern Med | volume = 130 | issue = 4 Pt 1 | pages = 285–8 | date = February 1999 | pmid = 10068386 | doi = 10.7326/0003-4819-130-4-199902160-00013 | url = }}</ref><ref name="pmid10341782">{{cite journal | vauthors = Schrader GD, Roberts-Thompson IC | title = Adverse effect of nefazodone: hepatitis | journal = Med J Aust | volume = 170 | issue = 9 | pages = 452 | date = May 1999 | pmid = 10341782 | doi = 10.5694/j.1326-5377.1999.tb127827.x | s2cid = 1907139 | url = }}</ref> These instances were quickly followed by many additional cases.<ref name="pmid17609231">{{cite journal | vauthors = DeSanty KP, Amabile CM | title = Antidepressant-induced liver injury | journal = Ann Pharmacother | volume = 41 | issue = 7 | pages = 1201–11 | date = July 2007 | pmid = 17609231 | doi = 10.1345/aph.1K114 | s2cid = 24974828 | url = }}</ref><ref name="pmid12699949" /><ref name="pmid14638657" /><ref name="pmid12025437" />

In 2002 the [[Food and Drug Administration| United States Food and Drug Administration (FDA)]] obligated BMS to add a [[Boxed warning| black box warning]] about potential fatal liver toxicity to the drug label.<ref name=PL2004>{{cite news|title=Public Citizen to sue FDA over Serzone - Pharmaceutical industry news|url=https://www.thepharmaletter.com/article/public-citizen-to-sue-fda-over-serzone|work=The Pharma Letter|date=22 March 2004|language=en|access-date=3 June 2017|archive-date=5 August 2020|archive-url=https://web.archive.org/web/20200805005146/https://www.thepharmaletter.com/article/public-citizen-to-sue-fda-over-serzone|url-status=live}}</ref><ref name=CBS2004/> Worldwide sales in 2002 were $409 million.<ref name=FirstWord/>

In 2003 [[Public Citizen]] filed a [[citizen 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.<ref name=PL2004/><ref name=FDAcourt>{{cite web|title=Court Decisions and Updates|url=https://www.fda.gov/downloads/ICECI/EnforcementActions/EnforcementStory/EnforcementStoryArchive/UCM091483.pdf|publisher=FDA|access-date=3 June 2017|archive-date=10 May 2017|archive-url=https://web.archive.org/web/20170510034434/https://www.fda.gov/downloads/ICECI/EnforcementActions/EnforcementStory/EnforcementStoryArchive/UCM091483.pdf|url-status=dead}}</ref> The FDA issued a response to the petition in June 2004 and filed a [[Motion (legal)#To_dismiss| motion to dismiss]], and Public Citizen withdrew the suit.<ref name=FDAcourt/>

Sales of nefazodone were about $100 million in 2003.<ref name="WebMD">{{cite news|vauthors=DeNoon DJ|title=Company Pulls Antidepressant Off Market|url=http://www.webmd.com/depression/news/20040520/company-pulls-antidepressant-off-market|work=WebMD|date=May 4, 2004|access-date=June 3, 2017|archive-date=September 12, 2017|archive-url=https://web.archive.org/web/20170912055938/http://www.webmd.com/depression/news/20040520/company-pulls-antidepressant-off-market|url-status=live}}</ref> By that time, it was also being marketed under the additional brand names Serzonil, Nefadar, and Rulivan.<ref name="WHOPN2004" />

Generic versions were introduced in the United States in 2003<ref name=DPW /> and [[Health Canada]] withdrew the marketing authorization that same year.<ref name="pmid15767610">{{cite journal | vauthors = Lexchin J | title = Drug withdrawals from the Canadian market for safety reasons, 1963-2004 | journal = CMAJ | volume = 172 | issue = 6 | pages = 765–767 | date = March 2005 | pmid = 15767610 | pmc = 552890 | doi = 10.1503/cmaj.045021 }}</ref>

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 were available in the United States.<ref name="DPW" /><ref name="CBS2004" /><ref name="WebMD" /> By that time, BMS had already withdrawn the drug from the market in Europe, Australia, New Zealand, and Canada.<ref name="CBS2004">{{cite news|vauthors=Cosgrove-Mather B|title=Anti-Depressant Taken Off Market|url=http://www.cbsnews.com/news/anti-depressant-taken-off-market/|work=CBS News|date=April 15, 2004|language=en|access-date=June 3, 2017|archive-date=December 2, 2020|archive-url=https://web.archive.org/web/20201202053809/https://www.cbsnews.com/news/anti-depressant-taken-off-market/|url-status=live}}</ref>

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.<ref name="Teva Nefazodone Statement">{{Cite web|title=Teva Nefazodone Statement|url=https://www.tevausa.com/news-and-media/press-releases/teva-nefazodone-statement/|access-date=2022-01-23|website=www.tevausa.com|date=20 December 2021 |language=en|archive-date=2022-01-23|archive-url=https://web.archive.org/web/20220123024952/https://www.tevausa.com/news-and-media/press-releases/teva-nefazodone-statement/|url-status=live}}</ref><ref>{{Cite web|title=FDA Drug Shortages|url=https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Nefazodone%20Hydrochloride%20Tablets|access-date=2022-01-23|website=www.accessdata.fda.gov|archive-date=2024-01-17|archive-url=https://web.archive.org/web/20240117052141/https://www.accessdata.fda.gov/scripts/drugshortages/default.cfm|url-status=dead}}</ref>

==Society and culture==

===Generic names===
''Nefazodone'' is the [[generic term|generic name]] of the drug and its {{abbrlink|INN|International Nonproprietary Name}} and {{abbrlink|BAN|British Approved Name}}, while ''néfazodone'' is its {{abbrlink|DCF|Dénomination Commune Française}} and ''nefazodone hydrochloride'' is its {{abbrlink|USAN|United States Adopted Name}} and {{abbrlink|USP|United States Pharmacopeia}}.<ref name="Elks2014">{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA857|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=857–}}</ref><ref name="IndexNominum2000">{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA722|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=722–}}</ref><ref name="MortonHall2012">{{cite book|vauthors=Morton IK, Hall JM|title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA190|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=190–|access-date=24 November 2017|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110215032/https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA190|url-status=live}}</ref><ref name="Drugs.com">{{cite web|title=Nefazodone International Brands|url=https://www.drugs.com/international/Nefazodone.html|publisher=Drugs.com|access-date=1 June 2017|archive-date=1 December 2017|archive-url=https://web.archive.org/web/20171201044556/https://www.drugs.com/international/Nefazodone.html|url-status=live}}</ref>

===Brand names===
Nefazodone has been marketed under a number of brand names including ''Dutonin'' ({{abbrlink|AT|Austria}}, {{abbrlink|ES|Spain}}, {{abbrlink|IE|Ireland}}, {{abbrlink|UK|United Kingdom}}), Menfazona ({{abbrlink|ES|Spain}}), ''Nefadar'' ({{abbrlink|CH|Switzerland}}, {{abbrlink|DE|Germany}}, {{abbrlink|NO|Norway}}, {{abbrlink|SE|Sweden}}), Nefazodone BMS ({{abbrlink|AT|Austria}}), Nefazodone Hydrochloride Teva ({{abbrlink|US|United States}}), Reseril ({{abbrlink|IT|Italy}}), Rulivan ({{abbrlink|ES|Spain}}), and ''Serzone'' ({{abbrlink|AU|Australia}}, {{abbrlink|CA|Canada}}, {{abbrlink|US|United States}}).<ref name="IndexNominum2000" /><ref name="Drugs.com" />

==Research==
Nefazodone was under development for the treatment of [[panic disorder]], and reached [[Phases of clinical research#Phase III|phase 3]] [[clinical trial]]s for this indication, but development was discontinued in 2004.<ref name="AdisInsight">{{cite web | url=https://adisinsight.springer.com/drugs/800000656 | title=Nefazodone - AdisInsight | access-date=2023-02-12 | archive-date=2023-02-12 | archive-url=https://web.archive.org/web/20230212030233/https://adisinsight.springer.com/drugs/800000656 | url-status=live }}</ref>

The use of nefazodone to prevent [[migraine]] has been studied, due to its antagonism of the serotonin 5-HT<sub>2A</sub> and 5-HT<sub>2C</sub> receptors.<ref name="pmid11380644">{{cite journal | vauthors = Saper JR, Lake AE, Tepper SJ | title = Nefazodone for chronic daily headache prophylaxis: an open-label study | journal = Headache | volume = 41 | issue = 5 | pages = 465–474 | date = May 2001 | pmid = 11380644 | doi = 10.1046/j.1526-4610.2001.01084.x | s2cid = 32785110 }}</ref><ref name="pmid2045831">{{cite journal | vauthors = Mylecharane EJ | title = 5-HT2 receptor antagonists and migraine therapy | journal = Journal of Neurology | volume = 238 | issue = Suppl 1 | pages = S45–S52 | year = 1991 | pmid = 2045831 | doi = 10.1007/BF01642906 | s2cid = 5941834 }}</ref><ref name="pmid16433010">{{cite journal | vauthors = Millan MJ | title = Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies | journal = Therapie | volume = 60 | issue = 5 | pages = 441–460 | year = 2005 | pmid = 16433010 | doi = 10.2515/therapie:2005065 }}</ref>

==References==
{{Reflist}}

==External links==
* {{Commons category-inline}}

{{Antidepressants}}
{{Anxiolytics}}
{{Navboxes
| title = [[Pharmacodynamics]]
| titlestyle = background:#ccccff
| list1 = 
{{Adrenergic receptor modulators}}
{{Monoamine reuptake inhibitors}}
{{Serotonin receptor modulators}}
{{Xenobiotic-sensing receptor modulators}}
}}

[[Category:Alpha-1 blockers]]
[[Category:Alpha-2 blockers]]
[[Category:Antidepressants]]
[[Category:Anxiolytics]]
[[Category:5-HT1A agonists]]
[[Category:5-HT2A antagonists]]
[[Category:5-HT2C antagonists]]
[[Category:3-Chlorophenyl compounds]]
[[Category:CYP3A4 inhibitors]]
[[Category:H1 receptor antagonists]]
[[Category:Hepatotoxins]]
[[Category:Phenol ethers]]
[[Category:1-Phenylpiperazines]]
[[Category:Serotonin–norepinephrine–dopamine reuptake inhibitors]]
[[Category:1,2,4-Triazol-3-ones]]
[[Category:Ureas]]
[[Category:Withdrawn drugs]]