Nefazodone

Nefazodone is used to treat major depressive disorder, aggressive behavior, anxiety,{{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}} and panic disorder.{{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}}

Nefazodone is available as 50{{nbsp}}mg, 100{{nbsp}}mg, 150{{nbsp}}mg, 200{{nbsp}}mg, and 250{{nbsp}}mg tablets for oral ingestion.{{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}}

Contraindications 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 Nefazodone is contraindicated in patients who were withdrawn from nefazodone because of evident liver injury as well as those that have shown hypersensitivity to the drug, its inactive ingredients, or other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.

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.{{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 }} It is also known for having low levels of sexual side effects in comparisons to SSRIs.{{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 }}{{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 }}

Nefazodone can cause severe 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 patient-years. 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,{{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 }} and 51 cases of liver toxicity (of which 2 led to transplantation) in Canada.{{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 = }}{{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 }} 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.

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 AST or serum ALT levels are more than 3 times the 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.{{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 }}

Nefazodone is a potent inhibitor of CYP3A4, and may interact adversely with many commonly used medications that are metabolized by CYP3A4.{{cite web |url=http://www.merck.com/mmpe/lexicomp/nefazodone.html |title=Nefazodone |date=September 2008 |author=Lexi-Comp |work=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.{{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 }}{{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 }}

Nefazodone acts primarily as a potent antagonist of the serotonin 5-HT_2A receptor and to a lesser extent of the serotonin 5-HT_2C receptor. It also has high affinity for the α₁-adrenergic receptor and serotonin 5-HT_1A receptor, and relatively lower affinity for the α₂-adrenergic receptor and dopamine D₂ 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 H₁ 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.

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 (mCPP). Nefazodone has a short elimination half-life of about 2 to 4{{nbsp}}hours. 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. 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.{{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–}} 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.

Nefazodone is a phenylpiperazine;{{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 }} it is an alpha-phenoxyl derivative of etoperidone which in turn was a derivative of trazodone.{{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}}

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 for nefazodone worldwide, including in the United States and Europe, in 1994.{{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 = }} It was marketed in the United States under the brand name Serzone{{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}} and in Europe under the brand name Dutonin.{{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}}

The first reports of serious liver toxicity with nefazodone were published in 1998 and 1999.{{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 = }}{{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 = }} These instances were quickly followed by many additional cases.{{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 = }}

In 2002 the United States Food and Drug Administration (FDA) obligated BMS to add a black box warning about potential fatal liver toxicity to the drug label.{{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}} 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 United States, and in early 2004 the organization sued the FDA to attempt to force withdrawal of the drug.{{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}} The FDA issued a response to the petition in June 2004 and filed a motion to dismiss, and Public Citizen withdrew the suit.

Sales of nefazodone were about $100 million in 2003.{{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}} By that time, it was also being marketed under the additional brand names Serzonil, Nefadar, and Rulivan.

Generic versions were introduced in the United States in 2003 and Health Canada withdrew the marketing authorization that same year.{{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 }}

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. By that time, BMS had already withdrawn the drug from the market in Europe, Australia, New Zealand, and Canada.{{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}}

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.{{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}}{{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}}

Nefazodone is the 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}}.{{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–}}{{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–}}{{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}}{{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}}

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}}).

Nefazodone was under development for the treatment of panic disorder, and reached phase 3 clinical trials for this indication, but development was discontinued in 2004.{{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 }}

The use of nefazodone to prevent migraine has been studied, due to its antagonism of the serotonin 5-HT_2A and 5-HT_2C receptors.{{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 }}{{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 }}{{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 }}

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