Fluoxetine: Difference between revisions

{{Short description|SSRI antidepressant}}

{{Distinguish|Fluvoxamine}}

{{cs1 config |name-list-style=vanc |display-authors=6}}

{{Use dmy dates|date=January 2024}}

{{Infobox drug

| verifiedrevid = 456481815

| image = Fluoxetine.svg

| width =

| alt =

| image2 = R-and-S-fluoxetine-enantiomers-based-on-HCl-xtal-Mercury-3D-balls.png

| width2 = 250

| alt2 =

| caption = Fluoxetine (top),<br />(''R'')-fluoxetine (left), (''S'')-fluoxetine (right)

| chirality = [[Racemic mixture]]

<!-- Clinical data -->

| pronounce = {{IPAc-en|f|l|u|ˈ|ɒ|k|s|ə|t|iː|n}}<br>{{respell|floo|OKS|ə|teen}}

| tradename = Prozac, Sarafem, others

| Drugs.com = {{drugs.com|monograph|fluoxetine-hydrochloride}}

| MedlinePlus = a689006

| DailyMedID = Fluoxetine

| pregnancy_AU = C

| pregnancy_AU_comment =

| pregnancy_category =

| dependency_liability =

| addiction_liability = None<ref name=Hub2001>{{cite book | vauthors = Hubbard JR, Martin PR |title= Substance Abuse in the Mentally and Physically Disabled |date=2001 |publisher=CRC Press |isbn=978-0-8247-4497-7 |page=26 |url=https://books.google.com/books?id=MY1kFYk98mQC&pg=PA26 }}</ref>

| routes_of_administration = [[Oral administration|By mouth]]

| class = [[Selective serotonin reuptake inhibitor]] (SSRI)<ref name=AHFS2015/>

| ATC_prefix = N06

| ATC_suffix = AB03

| ATC_supplemental = {{ATCvet|N06|AB03}}

<!-- Legal status -->

| legal_AU = S4

| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-generic-medicines-and-biosimilar-medicines-2017 | access-date=30 March 2024}}</ref>

| legal_BR = C1

| legal_BR_comment = <ref>{{cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=31 March 2023 |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=3 August 2023 |access-date=16 August 2023 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=4 April 2023}}</ref>

| legal_CA = Rx-only

| legal_CA_comment = <ref>{{cite web | title=Mental health | website=[[Health Canada]] | date=9 May 2018 | url=https://www.canada.ca/en/services/health/drug-health-products/drug-medical-device-highlights-2017/approved-drugs/mental-health.html | access-date=13 April 2024}}</ref>

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = POM

| legal_UK_comment =

| legal_US = Rx-only

| legal_US_comment = <ref name="Prozac FDA label" /><ref name="Sarafem FDA label" />

| legal_EU = Rx-only

| legal_EU_comment =

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->

| bioavailability = 60–80%<ref name=AHFS2015/>

| protein_bound = 94–95%<ref name="Prozac FDA label" />

| metabolism = [[Liver]] (mostly [[CYP2D6]]-mediated)<ref name=TGA/>

| metabolites = Norfluoxetine, desmethylfluoxetine

| onset =

| elimination_half-life = 1–3 days (acute)<br />4–6 days (chronic)<ref name=TGA/><ref name=PK/>

| duration_of_action =

| excretion = Urine (80%), faeces (15%)<ref name=TGA>{{cite web|title=Prozac Fluoxetine Hydrochloride|work=TGA eBusiness Services|publisher=Eli Lilly Australia Pty. Limited|date=9 October 2013|access-date=23 November 2013|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04098-3|format=PDF|url-status=live|archive-url=https://web.archive.org/web/20170425231029/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04098-3|archive-date=25 April 2017}}</ref><ref name=PK>{{cite journal | vauthors = Altamura AC, Moro AR, Percudani M | title = Clinical pharmacokinetics of fluoxetine | journal = Clinical Pharmacokinetics | volume = 26 | issue = 3 | pages = 201–14 | date = March 1994 | pmid = 8194283 | doi = 10.2165/00003088-199426030-00004 | s2cid = 1406955 }}</ref>

<!-- Identifiers -->

| index2_label = as HCl

| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number = 54910-89-3

| CAS_number2_Ref = {{cascite|correct|CAS}}

| CAS_number2 = 56296-78-7

| CAS_supplemental =

| PubChem = 3386

| PubChem2 = 62857

| IUPHAR_ligand = 203

| DrugBank2_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank2 = DBSALT000087

| ChemSpiderID = 3269

| ChemSpiderID2_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID2 = 56589

| UNII = 01K63SUP8D

| UNII2_Ref = {{fdacite|correct|FDA}}

| UNII2 = I9W7N6B1KJ

| KEGG = D00326

| KEGG2_Ref = {{keggcite|correct|kegg}}

| KEGG2 = D00823

| ChEBI = 5118

| ChEBI2_Ref = {{ebicite|correct|EBI}}

| ChEBI2 = 5119

| ChEMBL = 41

| ChEMBL2_Ref = {{ebicite|correct|EBI}}

| ChEMBL2 = 1201082

| NIAID_ChemDB =

| PDB_ligand =

| synonyms =

<!-- Chemical and physical data -->

| IUPAC_name = ''N''-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine

| SMILES = CNCCC(c1ccccc1)Oc2ccc(cc2)C(F)(F)F

| StdInChI = 1S/C17H18F3NO/c1-21-12-11-16(13-5-3-2-4-6-13)22-15-9-7-14(8-10-15)17(18,19)20/h2-10,16,21H,11-12H2,1H3

| StdInChI_comment =

| StdInChIKey = RTHCYVBBDHJXIQ-UHFFFAOYSA-N

| density =

| density_notes =

| melting_point = 179

| melting_high = 182

| melting_notes =

| boiling_point = 395

| boiling_notes =

| solubility = 14

| sol_units =

| specific_rotation =

<!-- Definition and medical uses -->

'''Fluoxetine''', sold under the brand name '''Prozac''', among others, is an [[antidepressant]] of the [[selective serotonin reuptake inhibitor]] (SSRI) class.<ref name=AHFS2015>{{cite web|title=Fluoxetine Hydrochloride|url=https://www.drugs.com/monograph/fluoxetine-hydrochloride.html|publisher=The American Society of Health-System Pharmacists|access-date=2 December 2015|url-status=live|archive-url=https://web.archive.org/web/20151208193110/http://www.drugs.com/monograph/fluoxetine-hydrochloride.html|archive-date=8 December 2015}}</ref> It is used for the treatment of [[major depressive disorder]], [[obsessive–compulsive disorder]] (OCD), [[Anxiety disorder|anxiety]], [[bulimia nervosa]], [[panic disorder]], and [[premenstrual dysphoric disorder]].<ref name=AHFS2015/> It is also approved for treatment of major depressive disorder in adolescents and children 8 years of age and over.<ref>{{cite web|title=Depressive Disorders in Children and Adolescents – Pediatrics|url=https://www.merckmanuals.com/professional/pediatrics/mental-disorders-in-children-and-adolescents/depressive-disorders-in-children-and-adolescents|access-date=25 December 2020|website=Merck Manuals Professional Edition}}</ref> It has also been used to treat [[premature ejaculation]].<ref name=AHFS2015/> Fluoxetine is [[oral administration|taken by mouth]].<ref name=AHFS2015/>

<!-- Side effects -->

Common side effects include indigestion, trouble sleeping, sexual dysfunction, loss of appetite, nausea, diarrhea, dry mouth, and rash. Serious side effects include [[serotonin syndrome]], [[mania]], [[seizures]], an increased risk of [[suicidal behavior]] in people under 25 years old, and an increased risk of bleeding.<ref name=AHFS2015/> [[Antidepressant discontinuation syndrome]] is less likely to occur with fluoxetine than with other antidepressants, but it still happens in many cases. Fluoxetine taken during pregnancy is associated with significant increase in [[congenital heart defect]]s in the newborns.<ref name="pmid30415641"/><ref name="pmid33354752"/> It has been suggested that fluoxetine therapy may be continued during [[breastfeeding]] if it was used during pregnancy or if other antidepressants were ineffective.<ref name=PB2015>{{cite web|title=Fluoxetine Pregnancy and Breastfeeding Warnings|url=https://www.drugs.com/pregnancy/fluoxetine.html|access-date=2 December 2015|url-status=live|archive-url=https://web.archive.org/web/20170831221820/https://www.drugs.com/pregnancy/fluoxetine.html|archive-date=31 August 2017}}</ref>

<!-- History, society and culture-->

Fluoxetine was invented by [[Eli Lilly and Company]] in 1972, and entered medical use in 1986.<ref>{{cite book| vauthors = Myers RL |title=The 100 most important chemical compounds: a reference guide|date=2007|publisher=Greenwood Press|location=Westport, CN|isbn=978-0-313-33758-1|page=[https://archive.org/details/100mostimportant0000myer/page/128 128]|edition= 1st | url = https://archive.org/details/100mostimportant0000myer |url-access=registration}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref> It is available as a [[generic medication]].<ref name=AHFS2015/> In 2021, it was the 25th most commonly prescribed medication in the United States, with more than 22{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title=Fluoxetine – Drug Usage Statistics | website=ClinCalc | url=https://clincalc.com/DrugStats/Drugs/Fluoxetine | access-date=14 January 2024}}</ref> Lilly also markets fluoxetine in a fixed-dose combination with [[olanzapine]] as [[olanzapine/fluoxetine]] (Symbyax).<ref>{{cite web | title=Symbyax- olanzapine and fluoxetine hydrochloride capsule | website=DailyMed | date=23 December 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6b28c424-0b7e-4b75-b090-f116b113554e | access-date=8 October 2022}}</ref><ref>{{cite press release |url=https://investor.lilly.com/news-releases/news-release-details/fda-approves-symbyaxr-first-medication-treatment-resistant |title=FDA Approves Symbyax as First Medication for Treatment-Resistant Depression |publisher=Eli Lilly |access-date=17 March 2021}}</ref>

[[File:Fluoxetine 20mg with Packet.jpg|thumb|Fluoxetine [[blister pack]] 20 mg capsules]]

[[File:10mgBlueProzacPills.jpg|thumb|Fluoxetine 10 mg tablets]]

Fluoxetine is frequently used to treat [[major depressive disorder]], [[obsessive–compulsive disorder]] (OCD), [[post-traumatic stress disorder]] (PTSD), [[bulimia nervosa]], [[panic disorder]], [[premenstrual dysphoric disorder]], and [[trichotillomania]].<ref>{{Cite report |url=https://effectivehealthcare.ahrq.gov/topics/ptsd-adult-treatment-update/research-2018 |vauthors=Forman-Hoffman V, Middleton JC, Feltner C, Gaynes BN, Weber RP, Bann C, Viswanathan M, Lohr KN, Baker C, Green J |title=Psychological and Pharmacological Treatments for Adults With Posttraumatic Stress Disorder: A Systematic Review Update |date=17 May 2018 |location=Rockville (MD) |publisher=Agency for Healthcare Research and Quality (AHRQ) |series=Comparative Effectiveness Review |issue=235 |doi=10.23970/ahrqepccer207 |doi-broken-date=11 March 2024 |access-date=12 February 2024 |archive-date=10 July 2018 |archive-url=https://web.archive.org/web/20180710011511/https://effectivehealthcare.ahrq.gov/topics/ptsd-adult-treatment-update/research-2018 |url-status=dead }}</ref><ref name=Trichotillomania>{{cite book | vauthors = Hagerman RJ | chapter = Angelman Syndrome and Prader-Willi Syndrome |title=Neurodevelopmental Disorders: Diagnosis and Treatment|date=16 September 1999| chapter-url = https://books.google.com/books?id=9DvXxi_ugUUC&pg=PA273|publisher=[[Oxford University Press]]|isbn=978-0-19-512314-2|quote=Dech and Budow (1991) were among the first to report the anecdotal use of fluoxetine in a case of PWS to control behavior problems, appetite, and trichotillomania.}}</ref><ref name=DD>Truven Health Analytics, Inc. DrugPoint® System (Internet) [cited 2013 Oct 4]. Greenwood Village, CO: Thomsen Healthcare; 2013.</ref><ref>Australian Medicines Handbook 2013. The Australian Medicines Handbook Unit Trust; 2013.</ref><ref>British National Formulary (BNF) 65. Pharmaceutical Pr; 2013.</ref><ref>{{cite journal | vauthors = Husted DS, Shapira NA, Murphy TK, Mann GD, Ward HE, Goodman WK | title = Effect of comorbid tics on a clinically meaningful response to 8-week open-label trial of fluoxetine in obsessive compulsive disorder | journal = Journal of Psychiatric Research | volume = 41 | issue = 3–4 | pages = 332–337 | date = 2007 | pmid = 16860338 | doi = 10.1016/j.jpsychires.2006.05.007 }}</ref> It has also been used for [[cataplexy]], [[obesity]], and [[alcohol dependence]],<ref name=AHFS>{{cite web|title=Fluoxetine Hydrochloride|url=https://www.drugs.com/monograph/fluoxetine-hydrochloride.html|work=The American Society of Health-System Pharmacists|access-date=3 April 2011|url-status=live|archive-url=https://web.archive.org/web/20110411215533/http://www.drugs.com/monograph/fluoxetine-hydrochloride.html|archive-date=11 April 2011}}</ref> as well as [[binge eating disorder]].<ref>{{cite web|title=NIMH•Eating Disorders|work=The National Institute of Mental Health|publisher=National Institute of Health|year=2011|access-date=25 November 2013|url=http://www.nimh.nih.gov/health/publications/eating-disorders/binge-eating-disorder.shtml|url-status=live|archive-url=https://web.archive.org/web/20110819010403/http://www.nimh.nih.gov/health/publications/eating-disorders/binge-eating-disorder.shtml|archive-date=19 August 2011}}</ref> Fluoxetine seems to be ineffective for [[social anxiety disorder]].<ref>{{cite web|url=https://www.health.harvard.edu/newsletter_article/treating-social-anxiety-disorder|title=Treating social anxiety disorder|publisher=Harvard Health Publishing|access-date=15 May 2019|archive-date=23 September 2020|archive-url=https://web.archive.org/web/20200923013349/https://www.health.harvard.edu/newsletter_article/treating-social-anxiety-disorder|url-status=dead}}</ref> Studies do not support a benefit in children with [[autism]], though there is tentative evidence for its benefit in adult autism.<ref>{{cite journal | vauthors = Williams K, Brignell A, Randall M, Silove N, Hazell P | title = Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD) | journal = The Cochrane Database of Systematic Reviews | volume = 8 | issue = 8 | pages = CD004677 | date = August 2013 | pmid = 23959778 | doi = 10.1002/14651858.CD004677.pub3 }}</ref><ref>{{cite journal | vauthors = Myers SM | title = The status of pharmacotherapy for autism spectrum disorders | journal = Expert Opinion on Pharmacotherapy | volume = 8 | issue = 11 | pages = 1579–1603 | date = August 2007 | pmid = 17685878 | doi = 10.1517/14656566.8.11.1579 | s2cid = 24674542 }}</ref><ref>{{cite journal | vauthors = Doyle CA, McDougle CJ | title = Pharmacotherapy to control behavioral symptoms in children with autism | journal = Expert Opinion on Pharmacotherapy | volume = 13 | issue = 11 | pages = 1615–1629 | date = August 2012 | pmid = 22550944 | doi = 10.1517/14656566.2012.674110 | s2cid = 32144885 }}</ref><ref>{{cite journal | vauthors = Benvenuto A, Battan B, Porfirio MC, Curatolo P | title = Pharmacotherapy of autism spectrum disorders | journal = Brain & Development | volume = 35 | issue = 2 | pages = 119–127 | date = February 2013 | pmid = 22541665 | doi = 10.1016/j.braindev.2012.03.015 | s2cid = 19614718 }}</ref> Fluoxetine together with fluvoxamine has shown some initial promise as a potential treatment for reducing [[COVID-19]] severity if given early.<ref>{{cite journal | vauthors = Mahdi M, Hermán L, Réthelyi JM, Bálint BL | title = Potential Role of the Antidepressants Fluoxetine and Fluvoxamine in the Treatment of COVID-19 | journal = International Journal of Molecular Sciences | volume = 23 | issue = 7 | pages = 3812 | date = March 2022 | pmid = 35409171 | pmc = 8998734 | doi = 10.3390/ijms23073812 | doi-access = free }}</ref>

Fluoxetine is approved for the treatment of major depression in children and adults.<ref name="Prozac FDA label" /> Meta-analysis of trials in adults conclude that fluoxetine modestly outperforms placebo.<ref name="pmid29477251">{{cite journal |vauthors=Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, Leucht S, Ruhe HG, Turner EH, Higgins JP, Egger M, Takeshima N, Hayasaka Y, Imai H, Shinohara K, Tajika A, Ioannidis JP, Geddes JR |date=April 2018 |title=Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis |journal=Lancet |volume=391 |issue=10128 |pages=1357–1366 |doi=10.1016/S0140-6736(17)32802-7 |pmc=5889788 |pmid=29477251}}</ref> Fluoxetine may be less effective than other antidepressants, but has high acceptability.<ref name="Fluoxetine versus other types of pharmacotherapy for depression">{{cite journal | vauthors = Magni LR, Purgato M, Gastaldon C, Papola D, Furukawa TA, Cipriani A, Barbui C | title = Fluoxetine versus other types of pharmacotherapy for depression | journal = The Cochrane Database of Systematic Reviews | volume = 2013 | issue = 7 | pages = CD004185 | date = July 2013 | pmid = 24353997 | doi = 10.1002/14651858.CD004185.pub3 }}</ref>

For children and adolescents with moderate-to-severe depressive disorder, fluoxetine seems to be the best treatment (either with or without [[Cognitive behavioral therapy|cognitive behavioural therapy]], although fluoxetine alone does not appear to be superior to CBT alone) but more research is needed to be certain, as effect sizes are small and the existing evidence is of dubious quality.<ref name=":4">{{cite journal |date=12 October 2020 |title=Prozac may be the best treatment for young people with depression – but more research is needed |url=https://evidence.nihr.ac.uk/alert/prozac-may-be-the-best-treatment-for-young-people-with-depression-but-more-research-is-needed/ |journal=NIHR Evidence |type=Plain English summary |publisher=National Institute for Health and Care Research |doi=10.3310/alert_41917|s2cid=242952585 }}</ref><ref name=":5">{{cite journal | vauthors = Zhou X, Teng T, Zhang Y, Del Giovane C, Furukawa TA, Weisz JR, Li X, Cuijpers P, Coghill D, Xiang Y, Hetrick SE, Leucht S, Qin M, Barth J, Ravindran AV, Yang L, Curry J, Fan L, Silva SG, Cipriani A, Xie P | title = Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis | journal = The Lancet. Psychiatry | volume = 7 | issue = 7 | pages = 581–601 | date = July 2020 | pmid = 32563306 | pmc = 7303954 | doi = 10.1016/S2215-0366(20)30137-1 }}</ref><ref name=":42">{{cite journal | vauthors = Boaden K, Tomlinson A, Cortese S, Cipriani A | title = Antidepressants in Children and Adolescents: Meta-Review of Efficacy, Tolerability and Suicidality in Acute Treatment | journal = Frontiers in Psychiatry | volume = 11 | pages = 717 | date = 2 September 2020 | pmid = 32982805 | pmc = 7493620 | doi = 10.3389/fpsyt.2020.00717 | doi-access = free }}</ref><ref name=":6">{{cite journal | vauthors = Hetrick SE, McKenzie JE, Bailey AP, Sharma V, Moller CI, Badcock PB, Cox GR, Merry SN, Meader N | title = New generation antidepressants for depression in children and adolescents: a network meta-analysis | journal = The Cochrane Database of Systematic Reviews | volume = 2021 | issue = 5 | pages = CD013674 | date = May 2021 | pmid = 34029378 | pmc = 8143444 | doi = 10.1002/14651858.CD013674.pub2 | collaboration = Cochrane Common Mental Disorders Group }}</ref> A 2022 systematic review and trial restoration of the two original blinded-control trials used to approve the use of fluoxetine in children and adolescents with depression found that both of the trials were severely flawed, and therefore did not demonstrate the safety or efficacy of the medication.<ref name="Int J Risk Saf Med 33, 385–408">{{cite journal | vauthors = Gøtzsche PC, Healy D | title = Restoring the two pivotal fluoxetine trials in children and adolescents with depression | journal = The International Journal of Risk & Safety in Medicine | volume = 33 | pages = 385–408 | date = November 2022 | issue = 4 | pmid = 35786661 | doi = 10.3233/JRS-210034 | s2cid = 250241461 |type= Systematic review}}<!-- See article talk, not marked correctly in Pubmed --></ref>

===Obsessive–compulsive disorder===

Fluoxetine is effective in the treatment of [[obsessive–compulsive disorder]] (OCD) for adults.<ref>{{cite journal | vauthors = Etain B, Bonnet-Perrin E | title = [Value of fluoxetine in obsessive-compulsive disorder in the adult: review of the literature] | journal = L'Encephale | volume = 27 | issue = 3 | pages = 280–289 | date = May–Jun 2001 | pmid = 11488259 | url = https://pubmed.ncbi.nlm.nih.gov/11488259 }}</ref> It is also effective for treating OCD in children and adolescents.<ref name=":02">{{cite journal |date=3 November 2022 |title=Antidepressants for children and teenagers: what works for anxiety and depression? |url=https://evidence.nihr.ac.uk/collection/antidepressants-for-children-and-teenagers-what-works-anxiety-depression/ |journal=NIHR Evidence |type=Plain English summary |publisher=National Institute for Health and Care Research |doi=10.3310/nihrevidence_53342|s2cid=253347210 }}</ref><ref name=":42"/><ref name=":52">{{cite journal | vauthors = Correll CU, Cortese S, Croatto G, Monaco F, Krinitski D, Arrondo G, Ostinelli EG, Zangani C, Fornaro M, Estradé A, Fusar-Poli P, Carvalho AF, Solmi M | title = Efficacy and acceptability of pharmacological, psychosocial, and brain stimulation interventions in children and adolescents with mental disorders: an umbrella review | journal = World Psychiatry | volume = 20 | issue = 2 | pages = 244–275 | date = June 2021 | pmid = 34002501 | pmc = 8129843 | doi = 10.1002/wps.20881 }}</ref> The [[American Academy of Child and Adolescent Psychiatry]] state that [[SSRI]]s, including fluoxetine, should be used as first-line therapy in children, along with [[cognitive behavioral therapy]] (CBT), for the treatment of moderate to severe OCD.<ref>{{cite journal | vauthors = Geller DA, March J | collaboration = The AACAP Committee on Quality Issues (CQI) | title = Practice parameter for the assessment and treatment of children and adolescents with obsessive-compulsive disorder | journal = Journal of the American Academy of Child and Adolescent Psychiatry | volume = 51 | issue = 1 | pages = 98–113 | date = January 2012 | pmid = 22176943 | doi = 10.1016/j.jaac.2011.09.019 | doi-access = free }}</ref>

===Panic disorder===

The efficacy of fluoxetine in the treatment of [[panic disorder]] was demonstrated in two 12-week randomized multicenter [[Clinical trial#Phases|phase III clinical trials]] that enrolled patients diagnosed with panic disorder, with or without [[agoraphobia]]. In the first trial, 42% of subjects in the fluoxetine-treated arm were free of panic attacks at the end of the study, vs. 28% in the placebo arm. In the second trial, 62% of fluoxetine treated patients were free of panic attacks at the end of the study, vs. 44% in the placebo arm.<ref name="Prozac FDA label">{{cite web | title=Prozac- fluoxetine hydrochloride capsule | website=DailyMed | date=23 December 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c88f33ed-6dfb-4c5e-bc01-d8e36dd97299 | access-date=11 March 2023}}</ref>

===Bulimia nervosa===

A 2011 [[systematic review]] discussed seven trials which compared fluoxetine to a [[placebo]] in the treatment of [[bulimia nervosa]], six of which found a statistically significant reduction in symptoms such as vomiting and binge eating.<ref>{{cite journal | vauthors = Aigner M, Treasure J, Kaye W, Kasper S | title = World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of eating disorders | journal = The World Journal of Biological Psychiatry | volume = 12 | issue = 6 | pages = 400–43 | date = September 2011 | pmid = 21961502 | doi = 10.3109/15622975.2011.602720 | url = http://www.wfsbp.org/fileadmin/user_upload/Treatment_Guidelines/Aigner_WFSBP_guidelines_eating_disorder_World_J_Biol_Psychia_11.pdf | url-status = live | s2cid = 16733060 | archive-url = https://web.archive.org/web/20140801032832/http://www.wfsbp.org/fileadmin/user_upload/Treatment_Guidelines/Aigner_WFSBP_guidelines_eating_disorder_World_J_Biol_Psychia_11.pdf | archive-date = 1 August 2014 }}</ref> However, no difference was observed between treatment arms when fluoxetine and [[psychotherapy]] were compared to psychotherapy alone.

===Premenstrual dysphoric disorder===

Fluoxetine is used to treat [[premenstrual dysphoric disorder]], a condition where individuals have [[Affect (psychology)|affective]] and [[Somatic symptoms|somatic]] symptoms monthly during the [[luteal phase]] of menstruation.<ref name="Sarafem FDA label">{{cite web | title=Sarafem (fluoxetine hydrochloride tablets ) for oral use Initial U.S. Approval: 1987 | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=600145 | access-date=12 March 2023}}</ref><ref name=Rapkin>{{cite journal | vauthors = Rapkin AJ, Lewis EI | title = Treatment of premenstrual dysphoric disorder | journal = Women's Health | volume = 9 | issue = 6 | pages = 537–56 | date = November 2013 | pmid = 24161307 | doi = 10.2217/whe.13.62 | doi-access = free }}</ref> Taking fluoxetine 20&nbsp;mg/d can be effective in treating PMDD,<ref>{{cite journal | vauthors = Carr RR, Ensom MH | title = Fluoxetine in the treatment of premenstrual dysphoric disorder | journal = The Annals of Pharmacotherapy | volume = 36 | issue = 4 | pages = 713–7 | date = April 2002 | pmid = 11918525 | doi = 10.1345/aph.1A265 | s2cid = 37088388 }}</ref><ref>{{cite journal | vauthors = Romano S, Judge R, Dillon J, Shuler C, Sundell K | title = The role of fluoxetine in the treatment of premenstrual dysphoric disorder | journal = Clinical Therapeutics | volume = 21 | issue = 4 | pages = 615–33; discussion 613 | date = April 1999 | pmid = 10363729 | doi = 10.1016/S0149-2918(00)88315-0 }}</ref> though doses of 10&nbsp;mg/d have also been prescribed effectively.<ref>{{cite journal | vauthors = Pearlstein T, Yonkers KA | title = Review of fluoxetine and its clinical applications in premenstrual dysphoric disorder | journal = Expert Opinion on Pharmacotherapy | volume = 3 | issue = 7 | pages = 979–91 | date = July 2002 | pmid = 12083997 | doi = 10.1517/14656566.3.7.979 | s2cid = 9455962 }}</ref><ref>{{cite journal | vauthors = Cohen LS, Miner C, Brown EW, Freeman E, Halbreich U, Sundell K, McCray S | title = Premenstrual daily fluoxetine for premenstrual dysphoric disorder: a placebo-controlled, clinical trial using computerized diaries | journal = Obstetrics and Gynecology | volume = 100 | issue = 3 | pages = 435–44 | date = September 2002 | pmid = 12220761 | doi = 10.1016/S0029-7844(02)02166-X | s2cid = 753100 }}</ref>

===Impulsive aggression===

Fluoxetine is considered a first-line medication for the treatment of impulsive aggression of low intensity.<ref name="Felthous">{{cite book | vauthors = Felthous A, Stanford M |title=The Wiley International Handbook on Psychopathic Disorders and the Law |chapter=34.The Pharmacotherapy of Impulsive Aggression in Psychopathic Disorders |edition=2nd | veditors = Felthous A, Sass H |publisher=Wiley |year=2021 |pages=810–13 |isbn=978-1-119-15932-2 }}</ref> Fluoxetine reduced low intensity aggressive behavior in patients in intermittent aggressive disorder and [[borderline personality disorder]].<ref name="Felthous"/><ref>{{cite journal | vauthors = Coccaro EF, Lee RJ, Kavoussi RJ | title = A double-blind, randomized, placebo-controlled trial of fluoxetine in patients with intermittent explosive disorder | journal = The Journal of Clinical Psychiatry | volume = 70 | issue = 5 | pages = 653–62 | date = April 2009 | pmid = 19389333 | doi = 10.4088/JCP.08m04150 }}</ref><ref>{{cite journal | vauthors = Coccaro EF, Kavoussi RJ | title = Fluoxetine and impulsive aggressive behavior in personality-disordered subjects | journal = Archives of General Psychiatry | volume = 54 | issue = 12 | pages = 1081–8 | date = December 1997 | pmid = 9400343 | doi = 10.1001/archpsyc.1997.01830240035005 }}</ref> Fluoxetine also reduced acts of domestic violence in alcoholics with a history of such behavior.<ref>{{cite journal | vauthors = George DT, Phillips MJ, Lifshitz M, Lionetti TA, Spero DE, Ghassemzedeh N, Doty L, Umhau JC, Rawlings RR | title = Fluoxetine treatment of alcoholic perpetrators of domestic violence: a 12-week, double-blind, randomized, placebo-controlled intervention study | journal = The Journal of Clinical Psychiatry | volume = 72 | issue = 1 | pages = 60–5 | date = January 2011 | pmid = 20673556 | pmc = 3026856 | doi = 10.4088/JCP.09m05256gry }}</ref>

===Obesity and overweight adults===

In 2019 a [[systematic review]] compared the effects on weight of various doses of fluoxetine (60&nbsp;mg/d, 40&nbsp;mg/d, 20&nbsp;mg/d, 10&nbsp;mg/d) in obese and overweight adults.<ref name=":1">{{cite journal | vauthors = Serralde-Zúñiga AE, Gonzalez Garay AG, Rodríguez-Carmona Y, Melendez G | title = Fluoxetine for adults who are overweight or obese | journal = The Cochrane Database of Systematic Reviews | volume = 10 | issue = 10 | pages = CD011688 | date = October 2019 | pmid = 31613390 | pmc = 6792438 | doi = 10.1002/14651858.CD011688.pub2 | collaboration = Cochrane Metabolic and Endocrine Disorders Group }}</ref> When compared to placebo, all dosages of fluoxetine appeared to contribute to weight loss but lead to increased risk of experiencing side effects, such as dizziness, drowsiness, fatigue, insomnia and nausea, during period of treatment. However, these conclusions were from low certainty evidence.<ref name=":1" /> When comparing, in the same review, the effects of fluoxetine on weight of obese and overweight adults, to other anti-obesity agents, omega-3 [[gel capsule]] and not receiving a treatment, the authors could not reach conclusive results due to poor quality of evidence.<ref name=":1" />

===Special populations===

In children and adolescents, fluoxetine is the antidepressant of choice due to tentative evidence favoring its efficacy and tolerability.<ref>{{cite journal | vauthors = Taurines R, Gerlach M, Warnke A, Thome J, Wewetzer C | title = Pharmacotherapy in depressed children and adolescents | journal = The World Journal of Biological Psychiatry | volume = 12 | issue = Suppl 1 | pages = 11–5 | date = September 2011 | pmid = 21905988 | doi = 10.3109/15622975.2011.600295 | s2cid = 18186328 }}</ref><ref>{{cite journal | vauthors = Cohen D | title = Should the use of selective serotonin reuptake inhibitors in child and adolescent depression be banned? | journal = Psychotherapy and Psychosomatics | volume = 76 | issue = 1 | pages = 5–14 | year = 2007 | pmid = 17170559 | doi = 10.1159/000096360 | s2cid = 1112192 }}</ref> Evidence supporting an increased risk of major fetal malformations resulting from fluoxetine exposure is limited, although the [[Medicines and Healthcare products Regulatory Agency]] (MHRA) of the United Kingdom has warned prescribers and patients of the potential for fluoxetine exposure in the first trimester (during organogenesis, formation of the fetal organs) to cause a slight increase in the risk of congenital [[Heart|cardiac]] malformations in the newborn.<ref name=Preg>{{cite journal | vauthors = Morrison JL, Riggs KW, Rurak DW | title = Fluoxetine during pregnancy: impact on fetal development | journal = Reproduction, Fertility, and Development | volume = 17 | issue = 6 | pages = 641–50 | date = March 2005 | pmid = 16263070 | doi = 10.1071/RD05030 }}</ref><ref name= MD>{{cite book| chapter = Fluoxetine Hydrochloride| title = Martindale: The Complete Drug Reference|publisher=Pharmaceutical Press| veditors = Brayfield A |place=London, UK|date=13 August 2013|access-date=24 November 2013| chapter-url = http://www.medicinescomplete.com/mc/martindale/current/12763-x.htm}}{{subscription required}}</ref><ref name=MHRA>{{cite web|title=Fluoxetine in pregnancy: slight risk of heart defects in unborn child|work=MHRA|publisher=[[Medicines and Healthcare products Regulatory Agency]]|date=10 September 2011|access-date=23 November 2013|url=http://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con129100.pdf|url-status=dead|archive-url=https://web.archive.org/web/20131202231255/http://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con129100.pdf|archive-date=2 December 2013}}</ref> Furthermore, an association between fluoxetine use during the first trimester and an increased risk of minor fetal malformations was observed in one study.<ref name=MD/>

However, a systematic review and meta-analysis of 21 studies – published in the ''Journal of Obstetrics and Gynaecology Canada'' – concluded, "the apparent increased risk of fetal cardiac malformations associated with maternal use of fluoxetine has recently been shown also in depressed women who deferred SSRI therapy in pregnancy, and therefore most probably reflects an ascertainment bias. Overall, women who are treated with fluoxetine during the first trimester of pregnancy do not appear to have an increased risk of major fetal malformations."<ref name="pmid26334601">{{cite journal | vauthors = Rowe T | title = Drugs in Pregnancy | journal = Journal of Obstetrics and Gynaecology Canada | volume = 37 | issue = 6 | pages = 489–92 | date = June 2015 | pmid = 26334601 | doi = 10.1016/S1701-2163(15)30222-X | doi-access = free }}</ref>

Per the FDA, infants exposed to SSRIs in late pregnancy may have an increased risk for [[Persistent fetal circulation|persistent pulmonary hypertension of the newborn]]. Limited data support this risk, but the FDA recommends physicians consider tapering SSRIs such as fluoxetine during the third trimester.<ref name="Prozac FDA label" /> A 2009 review recommended against fluoxetine as a first-line SSRI during lactation, stating, "Fluoxetine should be viewed as a less-preferred SSRI for breastfeeding mothers, particularly with newborn infants, and in those mothers who consumed fluoxetine during gestation."<ref name="pmid19652194">{{cite journal | vauthors = Kendall-Tackett K, Hale TW | title = The use of antidepressants in pregnant and breastfeeding women: a review of recent studies | journal = Journal of Human Lactation | volume = 26 | issue = 2 | pages = 187–95 | date = May 2010 | pmid = 19652194 | doi = 10.1177/0890334409342071 | s2cid = 29112093 }}</ref> [[Sertraline]] is often the preferred SSRI during pregnancy due to the relatively minimal fetal exposure observed and its safety profile while breastfeeding.<ref name="Maudsley">{{cite book|isbn=978-0-470-97948-8|title=The Maudsley prescribing guidelines in psychiatry | vauthors = Taylor D, Paton C, Shitij K |year=2012|publisher=Wiley-Blackwell|location=West Sussex}}</ref>

==Adverse effects==

Side effects observed in fluoxetine-treated persons in clinical trials with an incidence >5% and at least twice as common in fluoxetine-treated persons compared to those who received a placebo pill include abnormal dreams, abnormal [[ejaculation]], anorexia, anxiety, [[asthenia]], [[diarrhea]], dizziness, dry mouth, [[dyspepsia]], fatigue, [[flu syndrome]], [[Erectile dysfunction|impotence]], [[insomnia]], decreased [[libido]], nausea, nervousness, [[pharyngitis]], rash, [[sinusitis]], [[somnolence]], sweating, [[tremor]], [[vasodilation]], and [[yawn]]ing.<ref name=":1" /><ref name = pkginsert>{{cite journal | vauthors = Bland RD, Clarke TL, Harden LB | title = Rapid infusion of sodium bicarbonate and albumin into high-risk premature infants soon after birth: a controlled, prospective trial | journal = American Journal of Obstetrics and Gynecology | volume = 124 | issue = 3 | pages = 263–7 | date = February 1976 | pmid = 2013 | doi = 10.1016/0002-9378(76)90154-x }}</ref> Fluoxetine is considered the most stimulating of the SSRIs (that is, it is most prone to causing insomnia and agitation).<ref name=Young>{{cite book | vauthors = Koda-Kimble MA, Alldredge BK |title=Applied therapeutics: the clinical use of drugs|year=2012|publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins|location=Baltimore|isbn=978-1-60913-713-7|edition=10th}}</ref> It also appears to be the most prone of the SSRIs for producing dermatologic reactions (e.g. [[Hives|urticaria]] (hives), rash, itchiness, etc.).<ref name = MD/>

===Sexual dysfunction===

{{See also|Selective serotonin reuptake inhibitor#Sexual dysfunction}}

Sexual dysfunction, including loss of libido, [[erectile dysfunction]], lack of vaginal lubrication, and [[anorgasmia]], are some of the most commonly encountered adverse effects of treatment with fluoxetine and other SSRIs. While early clinical trials suggested a relatively low rate of sexual dysfunction, more recent studies in which the investigator actively inquires about sexual problems suggest that the incidence is >70%.<ref>{{cite journal | vauthors = Clark MS, Jansen K, Bresnahan M | title = Clinical inquiry: How do antidepressants affect sexual function? | journal = The Journal of Family Practice | volume = 62 | issue = 11 | pages = 660–1 | date = November 2013 | pmid = 24288712 }}</ref>

In 2019, the [[European Medicines Agency#Pharmacovigilance Risk Assessment Committee|Pharmacovigilance Risk Assessment Committee]] of the [[European Medicines Agency]] recommended that packaging leaflets of selected SSRIs and [[SNRIs]] should be amended to include information regarding a possible risk of persistent sexual dysfunction.<ref>{{cite book |url= https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-13-16-may-2019-prac-meeting_en.pdf |publisher= [[European Medicines Agency]] |date = 11 June 2019 |title= PRAC recommendations on signals: Adopted at the 13-16 May 2019 PRAC meeting |page = 5 |access-date= 19 July 2023}}</ref> Following on the European assessment, a safety review by [[Health Canada]] "could neither confirm nor rule out a causal link{{spaces}}... which was long lasting in rare cases", but recommended that "healthcare professionals inform patients about the potential risk of long-lasting sexual dysfunction despite discontinuation of treatment".<ref name= HealthCanada>{{cite journal |title= SSRIs, SNRIs: risk of persistent sexual dysfunction |journal = Reactions Weekly |publisher= Springer |volume= 1838 |issue = 5 |date= 16 January 2021 |page = 5 |doi= 10.1007/s40278-021-89324-7|s2cid = 231669986 }}</ref>

===Antidepressant discontinuation syndrome===

Fluoxetine's longer [[half-life]] makes it less common to develop [[antidepressant discontinuation syndrome]] following cessation of therapy, especially when compared with antidepressants with shorter half-lives such as [[paroxetine]].<ref name=Bhat>{{cite journal | vauthors = Bhat V, Kennedy SH | title = Recognition and management of antidepressant discontinuation syndrome | journal = Journal of Psychiatry & Neuroscience | volume = 42 | issue = 4 | pages = E7–E8 | date = June 2017 | pmid = 28639936 | pmc = 5487275 | doi = 10.1503/jpn.170022 }}</ref><ref name=AFP>{{cite journal | vauthors = Warner CH, Bobo W, Warner C, Reid S, Rachal J | title = Antidepressant discontinuation syndrome | journal = American Family Physician | volume = 74 | issue = 3 | pages = 449–56 | date = August 2006 | pmid = 16913164 }}</ref> Although gradual dose reductions are recommended with antidepressants with shorter [[Half-life|half-lives]], tapering may not be necessary with fluoxetine.<ref name=CMAJ>{{cite journal | vauthors = Gabriel M, Sharma V | title = Antidepressant discontinuation syndrome | journal = CMAJ | volume = 189 | issue = 21 | pages = E747 | date = May 2017 | pmid = 28554948 | pmc = 5449237 | doi = 10.1503/cmaj.160991 }}</ref>

=== Pregnancy ===

Antidepressant exposure (including fluoxetine) is associated with shorter average duration of pregnancy (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75&nbsp;g), and lower [[Apgar score]]s (by <0.4 points).<ref>{{cite journal | vauthors = Ross LE, Grigoriadis S, Mamisashvili L, Vonderporten EH, Roerecke M, Rehm J, Dennis CL, Koren G, Steiner M, Mousmanis P, Cheung A | title = Selected pregnancy and delivery outcomes after exposure to antidepressant medication: a systematic review and meta-analysis | journal = JAMA Psychiatry | volume = 70 | issue = 4 | pages = 436–43 | date = April 2013 | pmid = 23446732 | doi = 10.1001/jamapsychiatry.2013.684 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Lattimore KA, Donn SM, Kaciroti N, Kemper AR, Neal CR, Vazquez DM | title = Selective serotonin reuptake inhibitor (SSRI) use during pregnancy and effects on the fetus and newborn: a meta-analysis | journal = Journal of Perinatology | volume = 25 | issue = 9 | pages = 595–604 | date = September 2005 | pmid = 16015372 | doi = 10.1038/sj.jp.7211352 | s2cid = 5558834 | doi-access = }}</ref> There is 30–36% increase in [[congenital heart defect]]s among children whose mothers were prescribed fluoxetine during pregnancy,<ref name="pmid30415641"/><ref name="pmid33354752">{{cite journal | vauthors = De Vries C, Gadzhanova S, Sykes MJ, Ward M, Roughead E | title = A Systematic Review and Meta-Analysis Considering the Risk for Congenital Heart Defects of Antidepressant Classes and Individual Antidepressants | journal = Drug Safety | volume = 44 | issue = 3 | pages = 291–312 | date = March 2021 | pmid = 33354752 | doi = 10.1007/s40264-020-01027-x | s2cid = 229357583 | url = https://unisa.alma.exlibrisgroup.com/view/delivery/61USOUTHAUS_INST/12212569530001831 }}</ref> with fluoxetine use in the first trimester associated with 38–65% increase in [[Heart septal defect|septal heart defect]]s.<ref name="pmid28513059">{{cite journal | vauthors = Gao SY, Wu QJ, Zhang TN, Shen ZQ, Liu CX, Xu X, Ji C, Zhao YH | title = Fluoxetine and congenital malformations: a systematic review and meta-analysis of cohort studies | journal = British Journal of Clinical Pharmacology | volume = 83 | issue = 10 | pages = 2134–2147 | date = October 2017 | pmid = 28513059 | pmc = 5595931 | doi = 10.1111/bcp.13321 }}</ref><ref name="pmid30415641">{{cite journal | vauthors = Gao SY, Wu QJ, Sun C, Zhang TN, Shen ZQ, Liu CX, Gong TT, Xu X, Ji C, Huang DH, Chang Q, Zhao YH | title = Selective serotonin reuptake inhibitor use during early pregnancy and congenital malformations: a systematic review and meta-analysis of cohort studies of more than 9 million births | journal = BMC Medicine | volume = 16 | issue = 1 | pages = 205 | date = November 2018 | pmid = 30415641 | pmc = 6231277 | doi = 10.1186/s12916-018-1193-5 | doi-access = free }}</ref>

{{Update section|date=March 2022}}

In October 2004, the FDA added a black box warning to all antidepressant drugs regarding use in children.<ref>{{cite journal | vauthors = Leslie LK, Newman TB, Chesney PJ, Perrin JM | title = The Food and Drug Administration's deliberations on antidepressant use in pediatric patients | journal = Pediatrics | volume = 116 | issue = 1 | pages = 195–204 | date = July 2005 | pmid = 15995053 | pmc = 1550709 | doi = 10.1542/peds.2005-0074 }}</ref> In 2006, the FDA included adults aged 25 or younger.<ref>{{cite journal | vauthors = Fornaro M, Anastasia A, Valchera A, Carano A, Orsolini L, Vellante F, Rapini G, Olivieri L, Di Natale S, Perna G, Martinotti G, Di Giannantonio M, De Berardis D | title = The FDA "Black Box" Warning on Antidepressant Suicide Risk in Young Adults: More Harm Than Benefits? | journal = Frontiers in Psychiatry | volume = 10 | pages = 294 | date = 3 May 2019 | pmid = 31130881 | pmc = 6510161 | doi = 10.3389/fpsyt.2019.00294 | doi-access = free }}</ref> Statistical analyses conducted by two independent groups of FDA experts found a 2-fold increase of the [[suicidal ideation]] and behavior in children and adolescents, and 1.5-fold increase of suicidality in the 18–24 age group. The suicidality was slightly decreased for those older than 24, and statistically significantly lower in the 65 and older group.<ref name=FDA>{{cite web| vauthors =Levenson M, Holland C| title =Antidepressants and Suicidality in Adults: Statistical Evaluation. (Presentation at Psychopharmacologic Drugs Advisory Committee; December 13, 2006)| website =[[Food and Drug Administration]]| access-date =13 May 2007| url =https://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4272s1-04-FDA.ppt| url-status =live| archive-url =https://web.archive.org/web/20070927214932/https://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4272s1-04-FDA.ppt| archive-date =27 September 2007| df =dmy-all}}</ref><ref name=FDA2>{{cite web | url =https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | title =Clinical Review: Relationship Between Antidepressant Drugs and Suicidality in Adults | access-date =22 September 2007 | vauthors =Stone MB, Jones ML | date =17 November 2006 | work =Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC) | publisher =U.S. [[Food and Drug Administration]] (FDA) | pages =11–74 | url-status =live | archive-url =https://web.archive.org/web/20070316092329/https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | archive-date =16 March 2007 | df =dmy-all }}</ref><ref name=FDA3>{{cite web | url = https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | title = Statistical Evaluation of Suicidality in Adults Treated with Antidepressants | access-date = 22 September 2007 | vauthors = Levenson M, Holland C | date = 17 November 2006 | work = Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC) | publisher = U.S. [[Food and Drug Administration]] (FDA) | pages = 75–140 | url-status = live | archive-url = https://web.archive.org/web/20070316092329/https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4272b1-01-FDA.pdf | archive-date = 16 March 2007}}</ref> This analysis was criticized by [[Donald F. Klein|Donald Klein]], who noted that suicidality, that is suicidal ideation and behavior, is not necessarily a good surrogate marker for suicide, and it is still possible, while unproven, that antidepressants may prevent actual suicide while increasing suicidality.<ref name="pmid16395296">{{cite journal | vauthors = Klein DF | title = The flawed basis for FDA post-marketing safety decisions: the example of anti-depressants and children | journal = Neuropsychopharmacology | volume = 31 | issue = 4 | pages = 689–699 | date = April 2006 | pmid = 16395296 | doi = 10.1038/sj.npp.1300996 | s2cid = 12599251 }}</ref> In February 2018, the [[Food and Drug Administration]] (FDA) ordered an update to the warnings based on statistical evidence from twenty four trials in which the risk of such events increased from two percent to four percent relative to the placebo trials.<ref>{{cite web |date=3 November 2018 |title=Suicidality in Children and Adolescents Being Treated With Antidepressant Medications |url=https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/suicidality-children-and-adolescents-being-treated-antidepressant-medications |publisher=U.S. [[Food and Drug Administration]] (FDA) }}</ref>

On 14 September 1989, [[Standard Gravure shooting|Joseph T. Wesbecker]] killed eight people and injured twelve before committing suicide.<ref>{{cite web | vauthors = Wolfson A |title=Prozac maker paid millions to secure favorable verdict in mass shooting lawsuit, victims say |url=https://www.usatoday.com/story/news/nation/2019/09/12/prozac-makers-secret-payment-mass-shooting-lawsuit-revealed/2302888001/ |access-date=20 March 2022 |website=[[USA Today]] }}</ref> His relatives and victims blamed his actions on the Prozac medication he had begun taking a month prior. The incident set off a chain of lawsuits and public outcries.<ref>{{cite web |title=Prozac Litigation - Link to Suicide, Birth Defects & Class Action |url=https://www.drugwatch.com/ssri/prozac/lawsuits/ |access-date=20 March 2022 |website=Drugwatch.com }}</ref> Lawyers began using Prozac to justify the abnormal behaviors of their clients.<ref>{{cite news | vauthors = Angier N |title=HEALTH; Eli Lilly Facing Million-Dollar Suits On Its Antidepressant Drug Prozac |url=https://www.nytimes.com/1990/08/16/us/health-eli-lilly-facing-million-dollar-suits-on-its-antidepressant-drug-prozac.html |work=The New York Times |date=16 August 1990 }}</ref> [[Eli Lilly and Company|Eli Lilly]] was accused of not doing enough to warn patients and doctors about the adverse effects, which it had described as [[Activation syndrome|"activation"]], years prior to the incident.<ref>{{cite news |date=30 December 2004 |title=Eli Lilly in storm over Prozac evidence |work=Financial Times |url=https://www.ft.com/content/903824a4-5a98-11d9-aa6e-00000e2511c8 |access-date=20 March 2022}}</ref>

There is less data on fluoxetine than on antidepressants as a whole. In 2004, the FDA had to combine the results of 295 trials of 11 antidepressants for psychiatric indications to obtain [[statistically significant]] results. Considered separately, fluoxetine use in children increased the odds of suicidality by 50%,<ref name=FDA4>{{cite web | url =https://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4065S1_08_FDA-Hammad.ppt | title =Results of the Analysis of Suicidality in Pediatric Trials of Newer Antidepressants | vauthors = Hammad TA | date =13 September 2004 | format =PDF | work =Presentation at the Meeting of Psychopharmacologic Drugs Advisory Committee and the Pediatric Advisory Committee on September 13, 2004 | publisher =U.S. [[Food and Drug Administration]] (FDA) | url-status =live | archive-url =https://web.archive.org/web/20080228024710/https://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4065S1_08_FDA-Hammad.ppt | archive-date =28 February 2008 | df =dmy-all }} pp. 25, 28. Retrieved 6 January 2008.</ref> and in adults decreased the odds of suicidality by approximately 30%.<ref name =FDA2/><ref name =FDA3/> A study published in May 2009 found that fluoxetine was more likely to increase overall suicidal behavior. 14.7% of the patients (n = 44) on fluoxetine had suicidal events, compared to 6.3% in the psychotherapy group and 8.4% from the combined treatment group.<ref>{{cite journal | vauthors = Vitiello B, Silva SG, Rohde P, Kratochvil CJ, Kennard BD, Reinecke MA, Mayes TL, Posner K, May DE, March JS | title = Suicidal events in the Treatment for Adolescents With Depression Study (TADS) | journal = The Journal of Clinical Psychiatry | volume = 70 | issue = 5 | pages = 741–747 | date = April 2009 | pmid = 19552869 | pmc = 2702701 | doi = 10.4088/JCP.08m04607 }}</ref> Similarly, the analysis conducted by the UK [[Medicines and Healthcare products Regulatory Agency|MHRA]] found a 50% increase in suicide-related events, not reaching statistical significance, in the children and adolescents on fluoxetine as compared to the ones on placebo. According to the MHRA data, fluoxetine did not change the rate of [[self-harm]] in adults and statistically significantly decreased suicidal ideation by 50%.<ref>{{cite web |author=[[Committee on Safety of Medicines]] Expert Working Group |title=Report on The Safety of Selective Serotonin Reuptake Inhibitor Antidepressants |url=http://www.mhra.gov.uk/home/groups/pl-p/documents/drugsafetymessage/con019472.pdf |access-date=25 September 2007 |date=December 2004 |publisher=[[Medicines and Healthcare products Regulatory Agency]] (MHRA) |url-status=live |archive-url=https://web.archive.org/web/20080228024705/http://www.mhra.gov.uk/home/groups/pl-p/documents/drugsafetymessage/con019472.pdf |archive-date=28 February 2008 }}</ref><ref name="pmid15718537">{{cite journal | vauthors = Gunnell D, Saperia J, Ashby D | title = Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults: meta-analysis of drug company data from placebo controlled, randomised controlled trials submitted to the MHRA's safety review | journal = BMJ | volume = 330 | issue = 7488 | pages = 385 | date = February 2005 | pmid = 15718537 | pmc = 549105 | doi = 10.1136/bmj.330.7488.385 }}</ref>

=== QT prolongation ===

Fluoxetine can affect the [[Ion channel|electrical currents]] that [[Cardiac muscle cell|heart muscle cells]] use to coordinate their contraction, specifically the [[potassium]] currents ''I''_to and ''I''_Ks that repolarise the [[cardiac action potential]].<ref>{{cite journal | vauthors = Cubeddu LX | title = Drug-induced Inhibition and Trafficking Disruption of ion Channels: Pathogenesis of QT Abnormalities and Drug-induced Fatal Arrhythmias | journal = Current Cardiology Reviews | volume = 12 | issue = 2 | pages = 141–54 | date = 2016 | pmid = 26926294 | pmc = 4861943 | doi = 10.2174/1573403X12666160301120217 }}</ref> Under certain circumstances, this can lead to prolongation of the [[QT interval]], a measurement made on an [[Electrocardiography|electrocardiogram]] reflecting how long it takes for the heart to electrically recharge after each heartbeat. When fluoxetine is taken alongside other drugs that prolong the QT interval, or by those with a susceptibility to [[long QT syndrome]], there is a small risk of potentially lethal [[Heart arrhythmia|abnormal heart rhythms]] such as [[torsades de pointes]].<ref>{{cite journal | vauthors = Tisdale JE | title = Drug-induced QT interval prolongation and torsades de pointes: Role of the pharmacist in risk assessment, prevention and management | journal = Canadian Pharmacists Journal | volume = 149 | issue = 3 | pages = 139–52 | date = May 2016 | pmid = 27212965 | pmc = 4860751 | doi = 10.1177/1715163516641136 }}</ref> A study completed in 2011 found that fluoxetine does not alter the QT interval and has no clinically meaningful effects on the cardiac action potential.<ref>{{cite journal | vauthors = Castro VM, Clements CC, Murphy SN, Gainer VS, Fava M, Weilburg JB, Erb JL, Churchill SE, Kohane IS, Iosifescu DV, Smoller JW, Perlis RH | title = QT interval and antidepressant use: a cross sectional study of electronic health records | journal = BMJ (Clinical Research Ed.) | volume = 346 | issue = | pages = f288 | date = January 2013 | pmid = 23360890 | pmc = 3558546 | doi = 10.1136/bmj.f288 | doi-access = free | title-link = doi }}</ref>

==Overdose==

{{See also|Serotonin syndrome}}

In overdose, most frequent adverse effects include:<ref name="Pubchem">{{cite web| title=Fluoxetine| url=https://pubchem.ncbi.nlm.nih.gov/compound/3386?from=summary#section=Toxicity | work = PubChem| publisher=U.S. National Library of Medicine | access-date=13 March 2015}}</ref>

{{Col-begin}}

{{Col-break}}

Nervous system effects

* [[anxiety]]

* [[wikt:nervousness|nervousness]]

* [[insomnia]]

* [[drowsiness]]

* fatigue or [[asthenia]]

* [[tremor]]

* [[dizziness]] or lightheadedness

{{Col-break}}

[[Gastrointestinal]] effects

* [[anorexia (symptom)]]

* [[nausea]]

* [[diarrhea]]

* [[vasodilation]]

* dry mouth

* abnormal vision

{{Col-break}}

Other effects

* abnormal ejaculation

* [[rash]]

* sweating

* decreased [[libido]]

{{col-end}}

== Interactions ==

Contraindications include prior treatment (within the past 5–6 weeks, depending on the dose)<ref>{{cite journal | vauthors = Gury C, Cousin F | title = [Pharmacokinetics of SSRI antidepressants: half-life and clinical applicability] | journal = L'Encéphale | volume = 25 | issue = 5 | pages = 470–6 | date = September 1999 | pmid = 10598311 }}</ref><ref>{{cite book|url=https://books.google.com/books?id=qaIBzKle4xEC&pg=PA250|title=Principles and Practice of Psychopharmacotherapy| vauthors = Janicak PG, Marder SR, Pavuluri MN |date=26 December 2011|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-7877-7|quote=A 2-week interval is adequate for all of these drugs, with the exception of fluoxetine. Because of the extended half-life of norfluoxetine, a minimum of 5 weeks should lapse between stopping fluoxetine (20mg/day) and starting an MAOI. With higher daily doses, the interval should be longer.}}</ref> with [[monoamine oxidase inhibitors|MAOI]]s such as [[phenelzine]] and [[tranylcypromine]], due to the potential for [[serotonin syndrome]].<ref name = TGA/> Its use should also be avoided in those with known hypersensitivities to fluoxetine or any of the other ingredients in the formulation used.<ref name = TGA/> Its use in those concurrently receiving [[pimozide]] or [[thioridazine]] is also advised against.<ref name = TGA/>

In case of short term administration of codeine for pain management, it is advised to monitor and adjust dosage. Codeine might not provide sufficient analgesia when fluoxetine is co-administered.<ref>{{cite book | vauthors = Dean L, Kane M | chapter = Codeine Therapy and CYP2D6 Genotype |date=2012 | chapter-url= http://www.ncbi.nlm.nih.gov/books/NBK100662/ |title = Medical Genetics Summaries | veditors = Pratt VM, Scott SA, Pirmohamed M, Esquivel B |place=Bethesda (MD) |publisher=National Center for Biotechnology Information (US) |pmid=28520350 |access-date=1 October 2022 }}</ref> If opioid treatment is required, oxycodone use should be monitored since [[oxycodone]] is metabolized by the cytochrome P450 (CYP) enzyme system and fluoxetine and paroxetine are potent inhibitors of CYP2D6 enzymes.<ref>{{cite journal | vauthors = Perananthan V, Buckley NA |title=Opioids and antidepressants: which combinations to avoid |journal=Australian Prescriber |year=2021 |volume=44 |issue=2 |pages=41–44 |url=https://www.nps.org.au/australian-prescriber/articles/opioids-and-antidepressants-which-combinations-to-avoid |doi=10.18773/austprescr.2021.004|s2cid=233579988 |doi-access=free }}</ref> This means combinations of codeine or oxycodone with fluoxetine antidepressant may lead to reduced analgesia.<ref>{{cite journal | vauthors = Hoffelt C, Gross T | title = A review of significant pharmacokinetic drug interactions with antidepressants and their management | journal = The Mental Health Clinician | volume = 6 | issue = 1 | pages = 35–41 | date = January 2016 | pmid = 29955445 | pmc = 6009245 | doi = 10.9740/mhc.2016.01.035 }}</ref>

In some cases, use of [[dextromethorphan]]-containing cold and cough medications with fluoxetine is advised against, due to fluoxetine increasing serotonin levels, as well as the fact that fluoxetine is a [[cytochrome P450 2D6]] inhibitor, which causes dextromethorphan to not be metabolized at a normal rate, thus increasing the risk of serotonin syndrome and other potential side effects of dextromethorphan.<ref name="Drugs.com 1">{{cite web |url=https://www.drugs.com/drug-interactions/dextromethorphan-with-fluoxetine-844-0-1115-0.html |title=Dextromethorphan and fluoxetine Drug Interactions |website=Drugs.com |access-date=3 March 2017 |url-status=live |archive-url=https://web.archive.org/web/20170814134442/https://www.drugs.com/drug-interactions/dextromethorphan-with-fluoxetine-844-0-1115-0.html |archive-date=14 August 2017 }}</ref>

Patients who are taking [[Nonsteroidal anti-inflammatory drug|NSAIDs]], [[antiplatelet drug]]s, [[anticoagulant]]s, [[omega-3 fatty acid]]s, [[vitamin E]], and garlic [[Dietary supplement|supplements]] must be careful when taking fluoxetine or other SSRIs, as they can sometimes increase the blood-thinning effects of these medications.<ref name="Drugs.com 2">{{cite web |url=https://www.drugs.com/drug-interactions/fluoxetine-with-ibuprofen-1115-0-1310-0.html |title=Fluoxetine and ibuprofen Drug Interactions |website=Drugs.com |access-date=3 March 2017 |url-status=live |archive-url=https://web.archive.org/web/20170831174108/https://www.drugs.com/drug-interactions/fluoxetine-with-ibuprofen-1115-0-1310-0.html |archive-date=31 August 2017 }}</ref><ref>{{cite web |title=UpToDate |url=https://www.uptodate.com/content-not-available |access-date=10 August 2022 |website=www.uptodate.com}}</ref>

Fluoxetine and [[norfluoxetine]] [[enzyme inhibitor|inhibit]] many [[isozyme]]s of the [[cytochrome P450]] system that are involved in [[drug metabolism]]. Both are potent inhibitors of [[CYP2D6]] (which is also the chief enzyme responsible for their metabolism) and [[CYP2C19]], and mild to moderate inhibitors of [[CYP2B6]] and [[CYP2C9]].<ref name=FAN>{{cite journal | vauthors = Sager JE, Lutz JD, Foti RS, Davis C, Kunze KL, Isoherranen N | title = Fluoxetine- and norfluoxetine-mediated complex drug-drug interactions: in vitro to in vivo correlation of effects on CYP2D6, CYP2C19, and CYP3A4 | journal = Clinical Pharmacology and Therapeutics | volume = 95 | issue = 6 | pages = 653–62 | date = June 2014 | pmid = 24569517 | pmc = 4029899 | doi = 10.1038/clpt.2014.50 }}</ref><ref>{{cite book | isbn = 978-1-60327-434-0 | title = Pharmacotherapy of Depression | edition = 2nd | year = 2011 | publisher = Humana Press | location = New York | doi = 10.1007/978-1-60327-435-7 | veditors = Ciraulo DA, Shader RI }}</ref> ''[[In vivo]]'', fluoxetine and norfluoxetine do not significantly affect the activity of [[CYP1A2]] and [[CYP3A4]].<ref name="FAN"/> They also inhibit the activity of [[P-glycoprotein]], a type of [[membrane transport protein]] that plays an important role in drug transport and metabolism and hence P-glycoprotein substrates, such as [[loperamide]], may have their central effects potentiated.<ref name=Sandson>{{cite journal | vauthors = Sandson NB, Armstrong SC, Cozza KL | title = An overview of psychotropic drug-drug interactions | journal = Psychosomatics | volume = 46 | issue = 5 | pages = 464–94 | year = 2005 | pmid = 16145193 | doi = 10.1176/appi.psy.46.5.464 | url = http://pdfs.semanticscholar.org/100b/e8a8a15ecfab66752d5a46df3a430c324b2b.pdf | url-status = dead | s2cid = 21838792 | archive-url = https://web.archive.org/web/20190218192242/http://pdfs.semanticscholar.org/100b/e8a8a15ecfab66752d5a46df3a430c324b2b.pdf | archive-date = 18 February 2019 }}</ref> This extensive effect on the body's pathways for drug metabolism creates the potential for [[drug interaction|interactions]] with many commonly used drugs.<ref name=Sandson/><ref>An extensive list of possible interactions is available in {{cite web |url=http://www.merck.com/mmpe/lexicomp/fluoxetine.html |title=Fluoxetine |date=September 2008 |author=Lexi-Comp |work=[[Merck Manual of Diagnosis and Therapy|The Merck Manual Professional]] |url-status=live |archive-url=https://web.archive.org/web/20070903050047/http://www.merck.com/mmpe/lexicomp/fluoxetine.html |archive-date=3 September 2007}}</ref>

Its use should also be avoided in those receiving other serotonergic drugs such as [[monoamine oxidase inhibitors]], [[tricyclic antidepressants]], [[methamphetamine]], [[amphetamine]], [[methylenedioxymethamphetamine|MDMA]], [[triptan]]s, [[buspirone]], [[ginseng]], [[Dextromethorphan|dextromethorphan (DXM)]], [[linezolid]], [[tramadol]], [[serotonin–norepinephrine reuptake inhibitors]], and other SSRIs due to the potential for [[serotonin syndrome]] to develop as a result.<ref name = TGA/><ref>{{cite journal | vauthors = Boyer EW, Shannon M | title = The serotonin syndrome | journal = The New England Journal of Medicine | volume = 352 | issue = 11 | pages = 1112–1120 | date = March 2005 | pmid = 15784664 | doi = 10.1056/NEJMra041867 }}</ref>

Fluoxetine may also increase the risk of opioid overdose in some instances, in part due to its inhibitory effect on cytochrome P-450.<ref name=Popsci>{{cite web|url=https://www.popsci.com/health/opioids-antidepressants-risk-overdose/|website=www.Popsci.com|title=Combining certain opioids and commonly prescribed prescribed antidepressants may increase the risk of overdose|date=30 July 2022 |access-date=30 July 2022}}</ref><ref>{{cite journal |doi=10.2174/1389200023338017 |title=Selective Serotonin Reuptake Inhibitors and Cytochrome P-450 Mediated Drug-Drug Interactions: An Update |date=2002 |journal=Current Drug Metabolism |volume=3 |issue=1 |pages=13–37 |pmid=11876575 | vauthors = Hemeryck A, Belpaire F }}</ref> Similar to how fluoxetine can effect the metabolization of dextromethorphan, it may cause medications like [[oxycodone]] to not be metabolized at a normal rate, thus increasing the risk of serotonin syndrome as well as resulting in an increased concentration of oxycodone in the blood, which may lead to [[accidental overdose]].

A 2022 study which examined the health insurance claims of over 2 million Americans who began taking oxycodone while using SSRIs between 2000 and 2020, found that patients taking [[paroxetine]] or fluoxetine had a 23% higher risk of overdosing on oxycodone than those using other SSRIs.<ref name=Popsci/>

There is also the potential for interaction with highly protein-bound drugs due to the potential for fluoxetine to displace said drugs from the plasma or vice versa hence increasing serum concentrations of either fluoxetine or the offending agent.<ref name = TGA/>

==Pharmacology==

{| class="wikitable sortable" style="float:right"

|+[[Binding affinities]] ([[Binding affinities|K_i]] in [[nanomole|nM]])<ref>{{cite web|title=PDSP K_i Database |work=Psychoactive Drug Screening Program (PDSP) | vauthors = Roth BL, Driscol J |url=http://pdsp.med.unc.edu/pdsp.php |publisher=University of North Carolina at Chapel Hill and the United States National Institute of Mental Health |access-date=24 June 2013 |date=12 January 2011 |url-status=dead |archive-url=https://web.archive.org/web/20131108013656/http://pdsp.med.unc.edu/pdsp.php |archive-date=8 November 2013 }}</ref><ref name="pmid11543737">{{cite journal | vauthors = Owens MJ, Knight DL, Nemeroff CB | title = Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine | journal = Biological Psychiatry | volume = 50 | issue = 5 | pages = 345–50 | date = September 2001 | pmid = 11543737 | doi = 10.1016/s0006-3223(01)01145-3 | s2cid = 11247427 }}</ref>

! scope="col" | Molecular<br />Target

! scope="col" | Fluoxetine

! scope="col" | [[Norfluoxetine]]

|-

| [[Serotonin transporter|SERT]] || 1 || 19

|-

| [[Norepinephrine transporter|NET]] || 660 || 2700

|-

| [[Dopamine transporter|DAT]] || 4180 || 420

|-

| [[5-HT2A receptor|5-HT_2A]] || 120 || 300<!--Based upon data from the PDSP database-->

|-

| [[5-HT2B receptor|5-HT_2B]] || 2514 || 5100 <!--Based upon data from the PDSP database-->

|-

| [[5-HT2C receptor|5-HT_2C]] || 120 || 91<!--Based upon data from the PDSP database-->

|-

| [[Alpha-1 adrenergic receptor|α₁]] || 3000 || 3900 <!--Based upon data from the PDSP database-->

|-

| [[Muscarinic acetylcholine receptor M1|M₁]] || 870 || 1200

|-

| [[Muscarinic acetylcholine receptor M2|M₂]] || 2700 || 4600

|-

| [[Muscarinic acetylcholine receptor M3|M₃]] || 1000 || 760

|-

| [[Muscarinic acetylcholine receptor M4|M₄]] || 2900 || 2600

|-

| [[Muscarinic acetylcholine receptor M5|M₅]] || 2700 || 2200

|-

| [[Histamine H1 receptor|H₁]] || 3250 || style="background:papayawhip" | 10000 <!--Based upon data from the PDSP database-->

|-

! scope="col" colspan="3" style="text-align:center; background:papayawhip" | <small>{{nobold|Entries with this color indicate a lower bound of the K_i value.}}</small>

|}

=== Pharmacodynamics ===

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and does not appreciably inhibit [[norepinephrine]] and [[dopamine]] reuptake at therapeutic doses. It does, however, delay the reuptake of serotonin, resulting in serotonin persisting longer when it is released. Large doses in rats have been shown to induce a significant increase in synaptic norepinephrine and dopamine.<ref>{{cite journal | vauthors = Perry KW, Fuller RW | title = Fluoxetine increases norepinephrine release in rat hypothalamus as measured by tissue levels of MHPG-SO4 and microdialysis in conscious rats | journal = Journal of Neural Transmission | volume = 104 | issue = 8–9 | pages = 953–66 | year = 1997 | pmid = 9451727 | doi = 10.1007/BF01285563 | s2cid = 2679296 }}</ref><ref name="pmid11919662">{{cite journal | vauthors = Bymaster FP, Zhang W, Carter PA, Shaw J, Chernet E, Phebus L, Wong DT, Perry KW | title = Fluoxetine, but not other selective serotonin uptake inhibitors, increases norepinephrine and dopamine extracellular levels in prefrontal cortex | journal = Psychopharmacology | volume = 160 | issue = 4 | pages = 353–61 | date = April 2002 | pmid = 11919662 | doi = 10.1007/s00213-001-0986-x | s2cid = 27296534 }}</ref><ref name="pmid12464452">{{cite journal | vauthors = Koch S, Perry KW, Nelson DL, Conway RG, Threlkeld PG, Bymaster FP | title = R-fluoxetine increases extracellular DA, NE, as well as 5-HT in rat prefrontal cortex and hypothalamus: an in vivo microdialysis and receptor binding study | journal = Neuropsychopharmacology | volume = 27 | issue = 6 | pages = 949–59 | date = December 2002 | pmid = 12464452 | doi = 10.1016/S0893-133X(02)00377-9 | doi-access = free }}</ref><ref name="Fluoxetine SBSS" /> Thus, dopamine and norepinephrine may contribute to the antidepressant action of fluoxetine in humans at supratherapeutic doses (60–80&nbsp;mg).<ref name="pmid12464452"/><ref name="pmid19298831">{{cite journal | vauthors = Miguelez C, Fernandez-Aedo I, Torrecilla M, Grandoso L, Ugedo L | title = alpha(2)-Adrenoceptors mediate the acute inhibitory effect of fluoxetine on locus coeruleus noradrenergic neurons | journal = Neuropharmacology | volume = 56 | issue = 6–7 | pages = 1068–73 | year = 2009 | pmid = 19298831 | doi = 10.1016/j.neuropharm.2009.03.004 | s2cid = 7485264 }}</ref> This effect may be mediated by 5HT_2C receptors, which are inhibited by higher concentrations of fluoxetine.<ref name="pmid8876023">{{cite journal|author2-link=Bryan Roth | vauthors = Pälvimäki EP, Roth BL, Majasuo H, Laakso A, Kuoppamäki M, Syvälahti E, Hietala J | title = Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor | journal = Psychopharmacology | volume = 126 | issue = 3 | pages = 234–40 | date = August 1996 | pmid = 8876023 | doi = 10.1007/BF02246453 | s2cid = 24889381 }}</ref>

Fluoxetine increases the concentration of circulating [[allopregnanolone]], a potent [[GABAA receptor positive allosteric modulator|GABA_A receptor positive allosteric modulator]], in the brain.<ref name="Fluoxetine SBSS">{{cite journal | vauthors = Pinna G, Costa E, Guidotti A | title = SSRIs act as selective brain steroidogenic stimulants (SBSSs) at low doses that are inactive on 5-HT reuptake | journal = Current Opinion in Pharmacology | volume = 9 | issue = 1 | pages = 24–30 | date = February 2009 | pmid = 19157982 | pmc = 2670606 | doi = 10.1016/j.coph.2008.12.006 }}</ref><ref>{{cite journal | vauthors = Brunton PJ | title = Neuroactive steroids and stress axis regulation: Pregnancy and beyond | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 160 | pages = 160–8 | date = June 2016 | pmid = 26259885 | doi = 10.1016/j.jsbmb.2015.08.003 | s2cid = 43499796 }}</ref> [[Norfluoxetine]], a primary [[active metabolite]] of fluoxetine, produces a similar effect on allopregnanolone levels in the brains of mice.<ref name="Fluoxetine SBSS" /> Additionally, both fluoxetine and norfluoxetine are such modulators themselves, actions which may be clinically relevant.<ref name="pmid12604672">{{cite journal | vauthors = Robinson RT, Drafts BC, Fisher JL | title = Fluoxetine increases GABA(A) receptor activity through a novel modulatory site | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 304 | issue = 3 | pages = 978–84 | date = March 2003 | pmid = 12604672 | doi = 10.1124/jpet.102.044834 | s2cid = 16061756 }}</ref>

In addition, fluoxetine has been found to act as an [[agonist]] of the [[sigma-1 receptor|σ₁-receptor]], with a [[Potency (pharmacology)|potency]] greater than that of [[citalopram]] but less than that of [[fluvoxamine]]. However, the significance of this property is not fully clear.<ref name="pmid8831113">{{cite journal | vauthors = Narita N, Hashimoto K, Tomitaka S, Minabe Y | title = Interactions of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brain | journal = European Journal of Pharmacology | volume = 307 | issue = 1 | pages = 117–9 | date = June 1996 | pmid = 8831113 | doi = 10.1016/0014-2999(96)00254-3 }}</ref><ref name="pmid20021354">{{cite journal | vauthors = Hashimoto K | title = Sigma-1 receptors and selective serotonin reuptake inhibitors: clinical implications of their relationship | journal = Central Nervous System Agents in Medicinal Chemistry | volume = 9 | issue = 3 | pages = 197–204 | date = September 2009 | pmid = 20021354 | doi = 10.2174/1871524910909030197 }}</ref> Fluoxetine also functions as a channel blocker of [[anoctamin 1]], a [[calcium-activated chloride channel]].<ref>{{cite web|title=Fluoxetine|url=http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=203|website=IUPHAR Guide to Pharmacology|publisher=IUPHAR|access-date=10 November 2014|url-status=live|archive-url=https://web.archive.org/web/20141110043923/http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=203|archive-date=10 November 2014}}</ref><ref>{{cite web|title=Calcium activated chloride channel|url=http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=130#show_object_708|website=IUPHAR Guide to Pharmacology|publisher=IUPHAR|access-date=10 November 2014|url-status=live|archive-url=https://web.archive.org/web/20141110041200/http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=130#show_object_708|archive-date=10 November 2014}}</ref> A number of other [[ion channel]]s, including [[nicotinic acetylcholine receptor]]s and [[5-HT3 receptor|5-HT₃ receptor]]s, are also known to be {{em|inhibited}} at similar concentrations.<ref name="pmid12604672" />

Fluoxetine has been shown to inhibit [[acid sphingomyelinase]], a key regulator of [[ceramide]] levels which derives ceramide from [[sphingomyelin]].<ref>{{cite journal | vauthors = Gulbins E, Palmada M, Reichel M, Lüth A, Böhmer C, Amato D, Müller CP, Tischbirek CH, Groemer TW, Tabatabai G, Becker KA, Tripal P, Staedtler S, Ackermann TF, van Brederode J, Alzheimer C, Weller M, Lang UE, Kleuser B, Grassmé H, Kornhuber J | title = Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs | journal = Nature Medicine | volume = 19 | issue = 7 | pages = 934–8 | date = July 2013 | pmid = 23770692 | doi = 10.1038/nm.3214 | s2cid = 205391407 | url = https://www.zora.uzh.ch/id/eprint/79905/1/Ms.pdf }}</ref><ref>{{cite journal | vauthors = Brunkhorst R, Friedlaender F, Ferreirós N, Schwalm S, Koch A, Grammatikos G, Toennes S, Foerch C, Pfeilschifter J, Pfeilschifter W | title = Alterations of the Ceramide Metabolism in the Peri-Infarct Cortex Are Independent of the Sphingomyelinase Pathway and Not Influenced by the Acid Sphingomyelinase Inhibitor Fluoxetine | journal = Neural Plasticity | volume = 2015 | pages = 503079 | date = October 2015 | pmid = 26605090 | pmc = 4641186 | doi = 10.1155/2015/503079 | doi-access = free }}</ref>

===Mechanism of action===

While it is unclear how fluoxetine exerts its effect on mood, it has been suggested that fluoxetine elicits antidepressant effect by inhibiting serotonin reuptake in the synapse by binding to the reuptake pump on the neuronal membrane<ref name=drugbank>{{cite web |title=Fluoxetine |url=https://www.drugbank.ca/drugs/DB00472 |website=www.drugbank.ca |access-date=28 January 2019}}</ref> to increase serotonin availability and enhance neurotransmission.<ref>{{cite book | vauthors = Hitchings A, Lonsdale D, Burrage D, Baker E |title=Top 100 drugs : clinical pharmacology and practical prescribing |date=2015 |publisher=Churchill Livingstone |isbn=978-0-7020-5516-4}}</ref> Over time, this leads to a downregulation of pre-synaptic [[5-HT1A receptor]]s, which is associated with an improvement in passive stress tolerance, and delayed downstream increase in expression of [[brain-derived neurotrophic factor]], which may contribute to a reduction in negative affective biases.<ref>{{cite journal | vauthors = Carhart-Harris RL, Nutt DJ | title = Serotonin and brain function: a tale of two receptors | journal = Journal of Psychopharmacology | volume = 31 | issue = 9 | pages = 1091–1120 | date = September 2017 | pmid = 28858536 | pmc = 5606297 | doi = 10.1177/0269881117725915 }}</ref><ref>{{cite journal | vauthors = Harmer CJ, Duman RS, Cowen PJ | title = How do antidepressants work? New perspectives for refining future treatment approaches | language = English | journal = The Lancet. Psychiatry | volume = 4 | issue = 5 | pages = 409–418 | date = May 2017 | pmid = 28153641 | pmc = 5410405 | doi = 10.1016/S2215-0366(17)30015-9 }}</ref> Norfluoxetine and desmethylfluoxetine are metabolites of fluoxetine and also act as serotonin reuptake inhibitors, increasing the duration of action of the drug.<ref>{{cite journal | vauthors = Benfield P, Heel RC, Lewis SP | title = Fluoxetine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness | journal = Drugs | volume = 32 | issue = 6 | pages = 481–508 | date = December 1986 | pmid = 2878798 | doi = 10.2165/00003495-198632060-00002 }}</ref><ref name=drugbank />

Prolonged exposure to fluoxetine changes the expression of genes involved in myelination, a process that shapes brain connectivity and contributes to symptoms of psychiatric disorders. The regulation of genes involved with myelination is partially responsible for the long-term therapeutic benefits of chronic SSRI exposure.<ref>{{cite journal |doi=10.1038/tp.2015.145 |title=Long-term consequences of chronic fluoxetine exposure on the expression of myelination-related genes in the rat hippocampus |date=2015 |journal=Translational Psychiatry |volume=5 |issue=9 |pages=e642 |pmid=26393488 |pmc=5068807 | vauthors = Kroeze Y, Peeters D, Boulle F, Van Den Hove DL, Van Bokhoven H, Zhou H, Homberg JR, Homberg JR }}</ref>

===Pharmacokinetics===

[[File:Seproxetine.svg|thumb|200px|The ''S'' [[enantiomer]] of [[norfluoxetine]], fluoxetine's chief active metabolite.]]

The [[bioavailability]] of fluoxetine is relatively high (72%), and peak plasma concentrations are reached in 6–8&nbsp;hours. It is highly [[plasma protein binding|bound]] to plasma proteins, mostly [[human serum albumin|albumin]] and α₁-glycoprotein.<ref name =TGA/> Fluoxetine is [[drug metabolism|metabolized]] in the [[liver]] by [[isoenzyme]]s of the [[cytochrome P450]] system, including [[CYP2D6]].<ref name="RxList">{{cite web | url = http://www.rxlist.com/cgi/generic/fluoxetine_cp.htm | title = Prozac Pharmacology, Pharmacokinetics, Studies, Metabolism | year = 2007 | access-date = 14 April 2007 | publisher = RxList.com | url-status = dead | archive-url = https://web.archive.org/web/20070410122720/http://www.rxlist.com/cgi/generic/fluoxetine_cp.htm | archive-date = 10 April 2007}}</ref> The role of CYP2D6 in the [[metabolism]] of fluoxetine may be clinically important, as there is great [[genetic variability]] in the function of this enzyme among people. CYP2D6 is responsible for converting fluoxetine to its only active metabolite, [[norfluoxetine]].<ref>{{cite journal | vauthors = Mandrioli R, Forti GC, Raggi MA | title = Fluoxetine metabolism and pharmacological interactions: the role of cytochrome p450 | journal = Current Drug Metabolism | volume = 7 | issue = 2 | pages = 127–33 | date = February 2006 | pmid = 16472103 | doi = 10.2174/138920006775541561 }}</ref> Both drugs are also potent [[enzyme inhibitor|inhibitors]] of CYP2D6.<ref>{{cite journal | vauthors = Hiemke C, Härtter S | title = Pharmacokinetics of selective serotonin reuptake inhibitors | journal = Pharmacology & Therapeutics | volume = 85 | issue = 1 | pages = 11–28 | date = January 2000 | pmid = 10674711 | doi = 10.1016/S0163-7258(99)00048-0 }}</ref>

The extremely slow elimination of fluoxetine and its active metabolite norfluoxetine from the body distinguishes it from other antidepressants. With time, fluoxetine and norfluoxetine inhibit their own metabolism, so fluoxetine [[elimination half-life]] increases from 1 to 3&nbsp;days, after a single dose, to 4 to 6&nbsp;days, after long-term use.<ref name = TGA/> Similarly, the half-life of norfluoxetine is longer (16&nbsp;days) after long-term use.<ref name="RxList"/><ref name="pmid10917403">{{cite journal | vauthors = Burke WJ, Hendricks SE, McArthur-Miller D, Jacques D, Bessette D, McKillup T, Stull T, Wilson J | title = Weekly dosing of fluoxetine for the continuation phase of treatment of major depression: results of a placebo-controlled, randomized clinical trial | journal = Journal of Clinical Psychopharmacology | volume = 20 | issue = 4 | pages = 423–7 | date = August 2000 | pmid = 10917403 | doi = 10.1097/00004714-200008000-00006 }}</ref><ref name="Newcastle">{{cite web |url = http://www.ncl.ac.uk/nnp/teaching/management/drugrx/antdep.html |title = Drug Treatments in Psychiatry: Antidepressants |year = 2005 |access-date = 14 April 2007 |publisher = [[Newcastle University]] School of Neurology, Neurobiology and Psychiatry |url-status = dead |archive-url = https://web.archive.org/web/20070417161229/http://www.ncl.ac.uk/nnp/teaching/management/drugrx/antdep.html |archive-date = 17 April 2007 |df = dmy-all }}</ref> Therefore, the concentration of the drug and its active metabolite in the blood continues to grow through the first few weeks of treatment, and their steady concentration in the blood is achieved only after four weeks.<ref name="pmid11199945">{{cite journal | vauthors = Pérez V, Puiigdemont D, Gilaberte I, Alvarez E, Artigas F | title = Augmentation of fluoxetine's antidepressant action by pindolol: analysis of clinical, pharmacokinetic, and methodologic factors | journal = Journal of Clinical Psychopharmacology | volume = 21 | issue = 1 | pages = 36–45 | date = February 2001 | pmid = 11199945 | doi = 10.1097/00004714-200102000-00008 | s2cid = 13542714 | collaboration = Grup de Recerca en Trastorns Afectius | hdl = 10261/34714 }}</ref><ref name="pmid12063152">{{cite journal | vauthors = Brunswick DJ, Amsterdam JD, Fawcett J, Quitkin FM, Reimherr FW, Rosenbaum JF, Beasley CM | title = Fluoxetine and norfluoxetine plasma concentrations during relapse-prevention treatment | journal = Journal of Affective Disorders | volume = 68 | issue = 2–3 | pages = 243–9 | date = April 2002 | pmid = 12063152 | doi = 10.1016/S0165-0327(00)00333-5 }}</ref> Moreover, the brain concentration of fluoxetine and its metabolites keeps increasing through at least the first five weeks of treatment.<ref name="pmid15886723">{{cite journal | vauthors = Henry ME, Schmidt ME, Hennen J, Villafuerte RA, Butman ML, Tran P, Kerner LT, Cohen B, Renshaw PF | title = A comparison of brain and serum pharmacokinetics of R-fluoxetine and racemic fluoxetine: A 19-F MRS study | journal = Neuropsychopharmacology | volume = 30 | issue = 8 | pages = 1576–83 | date = August 2005 | pmid = 15886723 | doi = 10.1038/sj.npp.1300749 | doi-access = free }}</ref> For major depressive disorder, while onset of antidepressant action may be felt as early as 1–2 weeks,<ref>{{cite journal | vauthors = Papakostas GI, Perlis RH, Scalia MJ, Petersen TJ, Fava M | title = A meta-analysis of early sustained response rates between antidepressants and placebo for the treatment of major depressive disorder | language = en-US | journal = Journal of Clinical Psychopharmacology | volume = 26 | issue = 1 | pages = 56–60 | date = February 2006 | pmid = 16415707 | doi = 10.1097/01.jcp.0000195042.62724.76 | s2cid = 42816815 }}</ref> the full benefit of the current dose a patient receives is not realized for at least a month following ingestion. For example, in one 6-week study, the median time to achieving consistent response was 29&nbsp;days.<ref name="pmid11199945"/> Likewise, complete excretion of the drug may take several weeks. During the first week after treatment discontinuation, the brain concentration of fluoxetine decreases by only 50%,<ref name="pmid15886723"/> The blood level of norfluoxetine four weeks after treatment discontinuation is about 80% of the level registered by the end of the first treatment week, and, seven weeks after discontinuation, norfluoxetine is still detectable in the blood.<ref name="pmid10917403"/>

===Measurement in body fluids===

Fluoxetine and norfluoxetine may be quantitated in blood, plasma or serum to monitor therapy, confirm a diagnosis of poisoning in hospitalized person or assist in a medicolegal death investigation. Blood or plasma fluoxetine concentrations are usually in a range of 50–500&nbsp;μg/L in persons taking the drug for its antidepressant effects, 900–3000 μg/L in survivors of acute overdosage and 1000–7000&nbsp;μg/L in victims of fatal overdosage. Norfluoxetine concentrations are approximately equal to those of the parent drug during chronic therapy, but may be substantially less following acute overdosage, since it requires at least 1–2 weeks for the metabolite to achieve equilibrium.<ref>{{cite journal | vauthors = Lemberger L, Bergstrom RF, Wolen RL, Farid NA, Enas GG, Aronoff GR | title = Fluoxetine: clinical pharmacology and physiologic disposition | journal = The Journal of Clinical Psychiatry | volume = 46 | issue = 3 Pt 2 | pages = 14–9 | date = March 1985 | pmid = 3871765 }}</ref><ref>{{cite journal | vauthors = Pato MT, Murphy DL, DeVane CL | title = Sustained plasma concentrations of fluoxetine and/or norfluoxetine four and eight weeks after fluoxetine discontinuation | journal = Journal of Clinical Psychopharmacology | volume = 11 | issue = 3 | pages = 224–5 | date = June 1991 | pmid = 1741813 | doi = 10.1097/00004714-199106000-00024 }}</ref><ref>{{cite book | vauthors = Baselt R | title = Disposition of Toxic Drugs and Chemicals in Man | edition = 8th | publisher = Biomedical Publications | location = Foster City, CA | date = 2008 | pages = 645–48 }}</ref>

The work which eventually led to the discovery of fluoxetine began at [[Eli Lilly and Company]] in 1970 as a collaboration between [[Bryan Molloy]] and Ray Fuller.<ref name=":2">{{cite web |title=Ray W. Fuller, David T. Wong, and Bryan B. Molloy |url=https://sciencehistory.org/education/scientific-biographies/ray-w-fuller-david-t-wong-and-bryan-b-molloy/ |access-date=24 June 2023 |website=Science History Institute |language=en-US}}</ref> It was known at that time that the [[antihistamine]] [[diphenhydramine]] showed some antidepressant-like properties. 3-Phenoxy-3-phenylpropylamine, a compound structurally similar to diphenhydramine, was taken as a starting point. Molloy and fellow Eli Lilly chemist [[Klaus Schmiegel]] synthesized a series of dozens of its derivatives.<ref name=Wong>{{cite journal | vauthors = Wong DT, Bymaster FP, Engleman EA | title = Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: twenty years since its first publication | journal = Life Sciences | volume = 57 | issue = 5 | pages = 411–41 | year = 1995 | pmid = 7623609 | doi = 10.1016/0024-3205(95)00209-O }}</ref><ref>{{cite web |title=Chemical & Engineering News: Top Pharmaceuticals: Prozac |url=https://pubsapp.acs.org/cen/coverstory/83/8325/8325prozac.html |access-date=24 June 2023 |website=pubsapp.acs.org}}</ref> Hoping to find a derivative inhibiting only [[serotonin]] reuptake, another Eli Lilly scientist, [[David T. Wong]], proposed to retest the series for the ''[[in vitro]]'' reuptake of serotonin, norepinephrine and [[dopamine]], using a technique developed by neuroscientist [[Solomon H. Snyder|Solomon Snyder]].<ref name=":2" /> This test showed the compound later named fluoxetine to be the most potent and selective inhibitor of serotonin reuptake of the series.<ref name="wong1974">{{cite journal | vauthors = Wong DT, Horng JS, Bymaster FP, Hauser KL, Molloy BB | title = A selective inhibitor of serotonin uptake: Lilly 110140, 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine | journal = Life Sciences | volume = 15 | issue = 3 | pages = 471–9 | date = August 1974 | pmid = 4549929 | doi = 10.1016/0024-3205(74)90345-2 }}</ref> The first article about fluoxetine was published in 1974.<ref name="wong1974"/> A year later, it was given the official chemical name fluoxetine and the Eli Lilly and Company gave it the brand name Prozac. In February 1977, Dista Products Company, a division of Eli Lilly & Company, filed an Investigational New Drug application to the [[U.S. Food and Drug Administration]] (FDA) for fluoxetine.<ref name="Bregginpp1-2">{{cite book | vauthors = Breggin PR, Breggin GR | title = Talking Back to Prozac | publisher = [[Macmillan Publishers]] | year = 1995 | pages = [https://archive.org/details/talkingbacktopro00pete/page/1 1–2] | isbn = 978-0-312-95606-6 | url = https://archive.org/details/talkingbacktopro00pete/page/1 }}</ref>

Fluoxetine appeared on the Belgian market in 1986.<ref>{{cite news | vauthors = Swiatek J |title = Prozac's profitable run coming to an end for Lilly |newspaper = The Indianapolis Star |date = 2 August 2001 |url = http://www2.indystar.com/library/factfiles/business/companies/lilly/stories/2001_0802.html |url-status = dead |archive-url = https://web.archive.org/web/20070818163109/http://www2.indystar.com/library/factfiles/business/companies/lilly/stories/2001_0802.html |archive-date = 18 August 2007 |df = dmy-all }}</ref> In the U.S., the FDA gave its final approval in December 1987,<ref>{{cite web |title=Electronic Orange Book |publisher=Food and Drug Administration |date=April 2007 |url=http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=018936&TABLE1=OB_Rx |access-date=24 May 2007 |archive-url=https://web.archive.org/web/20070820013552/http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=018936&TABLE1=OB_Rx |archive-date=20 August 2007 | url-status=dead}}</ref> and a month later Eli Lilly began marketing Prozac; annual sales in the U.S. reached $350 million within a year.<ref name="Bregginpp1-2"/> Worldwide sales eventually reached a peak of $2.6 billion a year.<ref>{{cite web | vauthors = Simons J | work = Fortune Magazine | date = 28 June 2004 | url = http://archive.fortune.com/magazines/fortune/fortune_archive/2004/06/28/374398/index.htm | title = Lilly Goes Off Prozac The drugmaker bounced back from the loss of its blockbuster, but the recovery had costs }}</ref>

Lilly tried several [[product line extension]] strategies, including extended release formulations and paying for clinical trials to test the efficacy and safety of fluoxetine in [[premenstrual dysphoric disorder]] and rebranding fluoxetine for that indication as "Sarafem" after it was approved by the FDA in 2000, following the recommendation of an advisory committee in 1999.<ref name=CEN2002/><ref>{{cite web |url=https://money.cnn.com/2000/07/06/companies/lilly/ |title=Lilly Menstrual drug OK'd – Jul. 6, 2000 |website=Money.cnn.com |date=6 July 2000 |access-date=3 March 2017 |url-status=live |archive-url=https://web.archive.org/web/20160505131906/https://money.cnn.com/2000/07/06/companies/lilly/ |archive-date=5 May 2016 }}</ref><ref name=SarafemRec>{{cite news| vauthors = Mechatie E |date=1 December 1999|title=FDA Panel Agrees Fluoxetine Effective For PMDD|newspaper=International Medical News Group|url=http://www.thefreelibrary.com/FDA+Panel+Agrees+Fluoxetine+Effective+For+PMDD.-a061621260}}</ref> The invention of using fluoxetine to treat PMDD was made by [[Richard Wurtman]] at MIT; the patent was licensed to his startup, Interneuron, which in turn sold it to Lilly.<ref>{{cite web | vauthors = Herper H | work = Forbes | date = 25 September 2002 | url = https://www.forbes.com/2002/09/25/0925indevus.html | title = A Biotech Phoenix Could Be Rising }}</ref>

To defend its Prozac revenue from generic competition, Lilly also fought a five-year, multimillion-dollar battle in court with the generic company [[Barr Pharmaceuticals]] to protect its patents on fluoxetine, and lost the cases for its line-extension patents, other than those for Sarafem, opening fluoxetine to generic manufacturers starting in 2001.<ref>{{cite web | vauthors = Petersen M | work = [[The New York Times]] | date = 2 August 2001 | url = https://www.nytimes.com/2001/08/02/business/02PLAC.html | title = Drug Maker Is Set to Ship Generic Prozac }}</ref> When Lilly's patent expired in August 2001,<ref>{{cite web|title=Patent Expiration Dates for Common Brand-Name Drugs|url=http://www.express-scripts.com/pharmacist/notifications/docs/genericdrugs.htm|access-date=20 July 2007|url-status=live|archive-url=https://web.archive.org/web/20070928201304/http://www.express-scripts.com/pharmacist/notifications/docs/genericdrugs.htm|archive-date=28 September 2007}}</ref> [[generic drug]] competition decreased Lilly's sales of fluoxetine by 70% within two months.<ref name=CEN2002>{{cite web | vauthors = Class S |title=Pharma Overview |url=http://pubs.acs.org/cen/coverstory/8048/8048pharmaceutical.html |date=2 December 2002 |access-date=15 June 2009}}</ref>

In 2000 an investment bank had projected that annual sales of Sarafem could reach $250M/year.<ref name=VV2000>{{cite web| vauthors = Spartos C |url=http://www.villagevoice.com/news/sarafem-nation-6416934 |title=Sarafem Nation |publisher=[[Village Voice]] |date=5 December 2000 |access-date=3 March 2017}}</ref> Sales of Sarafem reached about $85M/year in 2002, and in that year Lilly sold its assets connected with the drug for $295M to Galen Holdings, a small Irish pharmaceutical company specializing in dermatology and women's health that had a sales force tasked to gynecologists' offices; analysts found the deal sensible since the annual sales of Sarafem made a material financial difference to Galen, but not to Lilly.<ref>{{cite web | work = Dow Jones Newswires in [[The Wall Street Journal]] | date = 9 December 2002 | url = https://www.wsj.com/articles/SB1039435394136383873 | title = Galen to Pay $295 Million For U.S. Rights to Lilly Drug }}</ref><ref name=Telegraph2002>{{cite news | vauthors = Murray-West R | work = Telegraph | date = 10 December 2002 | url = https://www.telegraph.co.uk/finance/2836112/Galen-takes-Lillys-reinvented-Prozac.html | title = Galen takes Lilly's reinvented Prozac }}</ref>

Bringing Sarafem to market harmed Lilly's reputation in some quarters. The diagnostic category of PMDD was [[Premenstrual dysphoric disorder#History|controversial]] since it was first proposed in 1987, and Lilly's role in retaining it in the appendix of the [[DSM-IV-TR]], the discussions for which got under way in 1998, has been criticized.<ref name=VV2000/> Lilly was criticized for inventing a disease in order to make money,<ref name=VV2000/> and for not innovating but rather just seeking ways to continue making money from existing drugs.<ref>{{cite web | vauthors = Petersen M | work = [[The New York Times]] | date = 29 May 2002 | url = https://www.nytimes.com/2002/05/29/business/29DRUG.html | title = New Medicines Seldom Contain Anything New, Study Finds }}</ref> It was also criticized by the FDA and groups concerned with women's health for marketing Sarafem too aggressively when it was first launched; the campaign included a television commercial featuring a harried woman at the grocery store who asks herself if she has PMDD.<ref>{{cite news | vauthors = Vedantam S | newspaper = [[The Washington Post]] | date = 29 April 2001 | url = https://www.washingtonpost.com/archive/politics/2001/04/29/renamed-prozac-fuels-womens-health-debate/b05311b4-514a-4e65-aaa5-434cb2934271/ | title = Renamed Prozac Fuels Women's Health Debate }}</ref>

==Society and culture==

=== Prescription trends ===

In 2010, over 24.4 million prescriptions for generic fluoxetine were filled in the United States,<ref name="generic drugs 2010">{{cite web |date=June 2011 |title=Top 200 Generic Drugs by Units in 2010 |url=http://drugtopics.modernmedicine.com/drugtopics/data/articlestandard//drugtopics/252011/727243/article.pdf |url-status=dead |archive-url=https://web.archive.org/web/20121215070930/http://drugtopics.modernmedicine.com/drugtopics/data/articlestandard//drugtopics/252011/727243/article.pdf |archive-date=15 December 2012 |work=Drug Topics: Voice of the Pharmacist}}</ref> making it the third-most prescribed antidepressant after [[sertraline]] and [[citalopram]].<ref name="generic drugs 2010" />

In 2011, 6 million prescriptions for fluoxetine were filled in the United Kingdom.<ref>{{cite web |date=September 2012 |title=BBC – Health: Prozac |url=https://www.bbc.co.uk/health/emotional_health/addictions/prozac.shtml |url-status=dead |archive-url=https://web.archive.org/web/20121211084322/http://www.bbc.co.uk/health/emotional_health/addictions/prozac.shtml |archive-date=11 December 2012 |publisher=BBC |quote=In 2011 over 43 million prescriptions for antidepressants were handed out in the UK and about 14 per cent (or nearly 6 million prescriptions) of these were for a drug called fluoxetine, better known as Prozac. |vauthors=Macnair P}}</ref> Between 1998 and 2017, along with [[amitriptyline]], it was the most commonly prescribed first antidepressant for adolescents aged 12–17 years in England.<ref>{{cite journal | vauthors = Jack RH, Hollis C, Coupland C, Morriss R, Knaggs RD, Butler D, Cipriani A, Cortese S, Hippisley-Cox J | title = Incidence and prevalence of primary care antidepressant prescribing in children and young people in England, 1998-2017: A population-based cohort study | journal = PLOS Medicine | volume = 17 | issue = 7 | pages = e1003215 | date = July 2020 | pmid = 32697803 | pmc = 7375537 | doi = 10.1371/journal.pmed.1003215 | veditors = Hellner C | doi-access = free }}</ref>

===Environmental effects===

Fluoxetine has been detected in aquatic ecosystems, especially in North America.<ref>{{cite journal | vauthors = Hughes SR, Kay P, Brown LE | title = Global synthesis and critical evaluation of pharmaceutical data sets collected from river systems | journal = Environmental Science & Technology | volume = 47 | issue = 2 | pages = 661–77 | date = January 2013 | pmid = 23227929 | pmc = 3636779 | doi = 10.1021/es3030148 | bibcode = 2013EnST...47..661H }}</ref> There is a growing body of research addressing the effects of fluoxetine (among other SSRIs) exposure on non-target aquatic species.<ref>{{cite journal | vauthors = Stewart AM, Grossman L, Nguyen M, Maximino C, Rosemberg DB, Echevarria DJ, Kalueff AV | title = Aquatic toxicology of fluoxetine: understanding the knowns and the unknowns | journal = Aquatic Toxicology | volume = 156 | pages = 269–73 | date = November 2014 | pmid = 25245382 | doi = 10.1016/j.aquatox.2014.08.014 | bibcode = 2014AqTox.156..269S }}</ref><ref name=":0">{{cite journal | vauthors = Sumpter JP, Donnachie RL, Johnson AC | title = The apparently very variable potency of the anti-depressant fluoxetine | journal = Aquatic Toxicology | volume = 151 | pages = 57–60 | date = June 2014 | pmid = 24411166 | doi = 10.1016/j.aquatox.2013.12.010 | bibcode = 2014AqTox.151...57S | doi-access = free }}</ref><ref name="Brooks2003">{{cite journal | vauthors = Brooks BW, Foran CM, Richards SM, Weston J, Turner PK, Stanley JK, Solomon KR, Slattery M, La Point TW | title = Aquatic ecotoxicology of fluoxetine | journal = Toxicology Letters | volume = 142 | issue = 3 | pages = 169–83 | date = May 2003 | pmid = 12691711 | doi = 10.1016/S0378-4274(03)00066-3 | series = Hot Spot Pollutants: Pharmaceuticals in the Environment }}</ref><ref name="Menningen2011rev">{{cite journal | vauthors = Mennigen JA, Stroud P, Zamora JM, Moon TW, Trudeau VL | title = Pharmaceuticals as neuroendocrine disruptors: lessons learned from fish on Prozac | journal = Journal of Toxicology and Environmental Health Part B: Critical Reviews | volume = 14 | issue = 5–7 | pages = 387–412 | date = 1 July 2011 | pmid = 21790318 | doi = 10.1080/10937404.2011.578559 | bibcode = 2011JTEHB..14..387M | s2cid = 43341257 }}</ref>

In 2003, one of the first studies addressed in detail the potential effects of fluoxetine on aquatic wildlife; this research concluded that exposure at environmental concentrations was of little risk to [[Aquatic ecosystem|aquatic system]]s if a hazard quotient approach was applied to risk assessment.<ref name="Brooks2003" /> However, they also stated the need for further research addressing sub-lethal consequences of fluoxetine, specifically focusing on study species' sensitivity, behavioural responses, and endpoints modulated by the [[serotonin system]].<ref name="Brooks2003" />

Fluoxetine {{endash}} similar to several other SSRIs {{endash}} induces [[reproductive behavior]] in some [[shellfish]] at concentrations as low as 10{{sup|-10}} [[Molar concentration|M]], or 30 [[parts per trillion]].<ref name="Pharmaceuticals-and-Care-Products">{{cite book | title=Pharmaceuticals and Care Products in the Environment: Scientific and Regulatory Issues | year=2001 | pages=xvi+396 | publisher=[[American Chemical Society]] (ACS) | issn=0097-6156 | series=[[ACS Symposium Series]] | volume=791 | publication-place=[[Washington, DC]], US | isbn=978-0-8412-3739-1 | doi=10.1021/bk-2001-0791 | veditors = Daughton CG, Jones-Lepp TL }}</ref>{{rp|page=21}}

Since 2003, a number of studies have reported fluoxetine-induced impacts on a number of behavioural and physiological endpoints, inducing antipredator behaviour,<ref>{{cite journal | vauthors = Martin JM, Saaristo M, Bertram MG, Lewis PJ, Coggan TL, Clarke BO, Wong BB | title = The psychoactive pollutant fluoxetine compromises antipredator behaviour in fish | journal = Environmental Pollution | volume = 222 | pages = 592–599 | date = March 2017 | pmid = 28063712 | doi = 10.1016/j.envpol.2016.10.010 | bibcode = 2017EPoll.222..592M }}</ref><ref>{{cite journal| vauthors = Barry MJ |date=21 April 2014|title=Fluoxetine inhibits predator avoidance behavior in tadpoles |journal=Toxicological & Environmental Chemistry|volume=96|issue=4|pages=641–49|doi=10.1080/02772248.2014.966713 |bibcode=2014TxEC...96..641B |s2cid=85340761 }}</ref><ref>{{cite journal | vauthors = Painter MM, Buerkley MA, Julius ML, Vajda AM, Norris DO, Barber LB, Furlong ET, Schultz MM, Schoenfuss HL | title = Antidepressants at environmentally relevant concentrations affect predator avoidance behavior of larval fathead minnows (Pimephales promelas) | journal = Environmental Toxicology and Chemistry | volume = 28 | issue = 12 | pages = 2677–84 | date = December 2009 | pmid = 19405782 | doi = 10.1897/08-556.1 | url = http://pdfs.semanticscholar.org/17b6/072ddddfd0d997c304bacdaa67c6580ce43f.pdf | url-status = dead | s2cid = 25189716 | archive-url = https://web.archive.org/web/20190219084125/http://pdfs.semanticscholar.org/17b6/072ddddfd0d997c304bacdaa67c6580ce43f.pdf | archive-date = 19 February 2019 }}</ref> reproduction,<ref>{{cite journal | vauthors = Mennigen JA, Lado WE, Zamora JM, Duarte-Guterman P, Langlois VS, Metcalfe CD, Chang JP, Moon TW, Trudeau VL | title = Waterborne fluoxetine disrupts the reproductive axis in sexually mature male goldfish, Carassius auratus | journal = Aquatic Toxicology | volume = 100 | issue = 4 | pages = 354–64 | date = November 2010 | pmid = 20864192 | doi = 10.1016/j.aquatox.2010.08.016 | bibcode = 2010AqTox.100..354M }}</ref><ref name="Schultz 38–47">{{cite journal | vauthors = Schultz MM, Painter MM, Bartell SE, Logue A, Furlong ET, Werner SL, Schoenfuss HL | title = Selective uptake and biological consequences of environmentally relevant antidepressant pharmaceutical exposures on male fathead minnows | journal = Aquatic Toxicology | volume = 104 | issue = 1–2 | pages = 38–47 | date = July 2011 | pmid = 21536011 | doi = 10.1016/j.aquatox.2011.03.011 | bibcode = 2011AqTox.104...38S }}</ref> and foraging<ref>{{cite journal | vauthors = Mennigen JA, Sassine J, Trudeau VL, Moon TW | title = Waterborne fluoxetine disrupts feeding and energy metabolism in the goldfish Carassius auratus | journal = Aquatic Toxicology | volume = 100 | issue = 1 | pages = 128–37 | date = October 2010 | pmid = 20692053 | doi = 10.1016/j.aquatox.2010.07.022 | bibcode = 2010AqTox.100..128M }}</ref><ref>{{cite journal | vauthors = Gaworecki KM, Klaine SJ | title = Behavioral and biochemical responses of hybrid striped bass during and after fluoxetine exposure | journal = Aquatic Toxicology | volume = 88 | issue = 4 | pages = 207–13 | date = July 2008 | pmid = 18547660 | doi = 10.1016/j.aquatox.2008.04.011 | bibcode = 2008AqTox..88..207G }}</ref> at or below field-detected concentrations. However, a 2014 review on the [[ecotoxicology]] of fluoxetine concluded that, at that time, a consensus on the ability of environmentally realistic dosages to affect the behaviour of wildlife could not be reached.<ref name=":0" /> At environmentally realistic concentrations, fluoxetine alters [[insect emergence]] timing.<ref name="Richmond-et-al-2019-bundle">

{{Unbulleted list citebundle

|{{cite journal | vauthors = Richmond EK, Rosi EJ, Reisinger AJ, Hanrahan BR, Thompson RM, Grace MR | title=Influences of the antidepressant fluoxetine on stream ecosystem function and aquatic insect emergence at environmentally realistic concentrations | journal=Journal of Freshwater Ecology | volume=34 | issue=1 | date=1 January 2019 | issn=0270-5060 | doi=10.1080/02705060.2019.1629546 | pages=513–531| bibcode=2019JFEco..34..513R | s2cid=196679455 | doi-access=free }}

|{{cite journal | vauthors = Bundschuh M, Pietz S, Roodt AP, Kraus JM | title = Contaminant fluxes across ecosystems mediated by aquatic insects | journal = Current Opinion in Insect Science | volume = 50 | pages = 100885 | date = April 2022 | pmid = 35144033 | doi = 10.1016/j.cois.2022.100885 | s2cid = 246673478 | doi-access = free | bibcode = 2022COIS...5000885B }}

}}

</ref> Richmond ''et al.'', 2019 find that at low concentrations it accelerates emergence of [[Diptera]], while at unusually high concentrations it has no discernable effect.<ref name="Richmond-et-al-2019-bundle" />

Several common plants are known to absorb fluoxetine.<ref name="Wu-et-al-2010-bundle">

{{Unbulleted list citebundle

|{{cite journal | vauthors = Qin Q, Chen X, Zhuang J | title=The Fate and Impact of Pharmaceuticals and Personal Care Products in Agricultural Soils Irrigated With Reclaimed Water | journal=Critical Reviews in Environmental Science and Technology | volume=45 | issue=13 | date=9 September 2014 | issn=1064-3389 | doi=10.1080/10643389.2014.955628 | pages=1379–1408 | s2cid=94839032}}

|{{cite journal | vauthors = Carvalho PN, Basto MC, Almeida CM, Brix H | title = A review of plant-pharmaceutical interactions: from uptake and effects in crop plants to phytoremediation in constructed wetlands | journal = Environmental Science and Pollution Research International | volume = 21 | issue = 20 | pages = 11729–11763 | date = October 2014 | pmid = 24481515 | doi = 10.1007/s11356-014-2550-3 | publisher = [[Springer Science+Business Media|Springer]] | bibcode = 2014ESPR...2111729C | s2cid = 25786586 }}

|{{cite journal | vauthors = Christou A, Papadavid G, Dalias P, Fotopoulos V, Michael C, Bayona JM, Piña B, Fatta-Kassinos D | title = Ranking of crop plants according to their potential to uptake and accumulate contaminants of emerging concern | journal = Environmental Research | volume = 170 | pages = 422–432 | date = March 2019 | pmid = 30623890 | doi = 10.1016/j.envres.2018.12.048 | publisher = [[Elsevier]] | bibcode = 2019ER....170..422C | s2cid = 58564142 | hdl = 10261/202657 | hdl-access = free }}

|{{cite journal | vauthors = Wu C, Spongberg AL, Witter JD, Fang M, Czajkowski KP | title = Uptake of pharmaceutical and personal care products by soybean plants from soils applied with biosolids and irrigated with contaminated water | journal = Environmental Science & Technology | volume = 44 | issue = 16 | pages = 6157–6161 | date = August 2010 | pmid = 20704212 | doi = 10.1021/es1011115 | publisher = [[American Chemical Society]] (ACS) | bibcode = 2010EnST...44.6157W | s2cid = 20021866 }}

}}

</ref> Several crops have been tested, and Redshaw ''et al.'' 2008 find that [[cauliflower]] absorbs large amounts into the stem and leaf but not the head or root.<ref name="Wu-et-al-2010-bundle" /> Wu ''et al.'' 2012 find that [[lettuce]] and [[spinach]] also absorb detectable amounts, while Carter ''et al.'' 2014 find that [[radish]] (''Raphanus sativus''), ryegrass (''[[Lolium perenne]]'') – and Wu ''et al.'' 2010 find that [[soybean]] (''Glycine max'') – absorb little.<ref name="Wu-et-al-2010-bundle" /> Wu tested all tissues of soybean and all showed only low concentrations.<ref name="Wu-et-al-2010-bundle" /> By contrast various Reinhold ''et al.'' 2010 find [[duckweed]]s have a high uptake of fluoxetine and show promise for [[bioremediation]] of contaminated water, especially ''[[Lemna minor]]'' and ''[[Landoltia punctata]]''.<ref name="Wu-et-al-2010-bundle" /> Ecotoxicity for organisms involved in [[aquaculture]] is well documented.<ref name="Solsona-et-al-eds-2021">{{cite book | series=Handbook of Environmental Chemistry | title=Interaction and Fate of Pharmaceuticals in Soil-Crop Systems | publisher=[[Springer International Publishing]] | publication-place=[[Cham, Switzerland]] | year=2021 | volume=103 | isbn=978-3-030-61289-4 | issn=1867-979X | doi=10.1007/978-3-030-61290-0 | pages=x+530 | s2cid=231746862 | veditors = Solsona SP, Montemurro N, Chiron S, Barceló D }}</ref>{{rp|pages=275–276}} Fluoxetine affects both aquacultured [[invertebrate]]s and [[vertebrate]]s, and [[antimicrobial|inhibits soil microbes]] including a large [[antibacterial]] effect.<ref name="Solsona-et-al-eds-2021" /> For applications of this see {{section link||Other uses}}.

===Politics===

During the 1990 campaign for [[governor of Florida]], it was disclosed that one of the candidates, [[Lawton Chiles]], had depression and had resumed taking fluoxetine, leading his political opponents to question his fitness to serve as governor.<ref>{{cite news | vauthors = MacPherson M | date = 2 September 1990 | title = Prozac, Prejudice and the Politics of Depression | url = https://www.washingtonpost.com/archive/opinions/1990/09/02/prozac-prejudice-and-the-politics-of-depression/edfa16db-e941-4513-b208-cf13b86ff2b2/ | newspaper = The Washington Post | archive-url = https://archive.today/20210903191304/https://www.washingtonpost.com/archive/opinions/1990/09/02/prozac-prejudice-and-the-politics-of-depression/edfa16db-e941-4513-b208-cf13b86ff2b2/ | archive-date = 3 September 2021 | url-status = live | access-date = 23 April 2018 }}</ref>

===American aircraft pilots===

Beginning in April 2010, fluoxetine became one of four antidepressant drugs that the [[FAA]] permitted for [[Pilot in command|pilots]] with authorization from an [[aviation medical examiner]]. The other permitted antidepressants are [[sertraline]] (Zoloft), [[citalopram]] (Celexa), and [[escitalopram]] (Lexapro).<ref>{{cite press release |url=http://www.faa.gov/news/press_releases/news_story.cfm?newsId=11293 |title=FAA Proposes New Policy on Antidepressants for Pilots |vauthors=Duquette A, Dorr L |publisher=Federal Aviation Administration, U.S. Department of Transportation |location=Washington, DC |date=2 April 2010 |access-date=10 February 2012 |url-status=live |archive-url=https://web.archive.org/web/20120114140705/http://www.faa.gov/news/press_releases/news_story.cfm?newsId=11293 |archive-date=14 January 2012}}</ref> These four remain the only antidepressants permitted by FAA {{As of|2016|12|2|lc=y|url=https://www.faa.gov/about/office_org/headquarters_offices/avs/offices/aam/ame/guide/app_process/exam_tech/item47/amd/antidepressants/|post=.}}<ref>{{cite web |author1=Office of Aerospace Medicine |author2=Federal Aviation Administration |author2-link=Federal Aviation Administration |date=2 December 2016 |title=Decision Considerations – Aerospace Medical Dispositions: Item 47. Psychiatric Conditions – Use of Antidepressant Medications |url=https://www.faa.gov/about/office_org/headquarters_offices/avs/offices/aam/ame/guide/app_process/exam_tech/item47/amd/antidepressants/ |url-status=live |archive-url=https://web.archive.org/web/20170503112620/https://www.faa.gov/about/office_org/headquarters_offices/avs/offices/aam/ame/guide/app_process/exam_tech/item47/amd/antidepressants/ |archive-date=3 May 2017 |website=Guide for Aviation Medical Examiners |publisher=[[United States Department of Transportation]] |location=Washington, DC}}</ref>

Sertraline, citalopram, and escitalopram are the only antidepressants permitted for [[EASA]] medical certification, as of January 2019.<ref>{{cite web |title=Mental Health GM - Centrally Acting Medication |url=https://www.caa.co.uk/Aeromedical-Examiners/Medical-standards/Pilots-(EASA)/Conditions/Mental-health/Mental-health-GM/ |access-date=21 July 2021 |publisher=Civil Aviation Authority}}</ref><ref>{{cite web |title=Class 1/2 Certification – Depression |url=https://www.caa.co.uk/uploadedFiles/CAA/Content/Accordion/Standard_Content/Medical/AME/Depression%20FC%20v3.1.pdf |url-status=dead |archive-url=https://web.archive.org/web/20211010143156/https://www.caa.co.uk/uploadedFiles/CAA/Content/Accordion/Standard_Content/Medical/AME/Depression%20FC%20v3.1.pdf |archive-date=10 October 2021 |access-date=21 July 2021 |publisher=Civil Aviation Authority}}</ref>

==Research==

The antibacterial effect in described above ({{section link||Environmental effects}}) could be applied against [[Multiple drug resistance|multiresistant]] biotypes in [[crop bacterial disease]]s and bacterial [[aquaculture disease]]s.<ref name="Solsona-et-al-eds-2021" /> In a [[glucocorticoid receptor]]-defective [[genetically modified zebrafish|zebrafish mutant]] (''Danio rerio'') with reduced [[exploration|exploratory behavior]], fluoxetine rescued the normal exploratory behavior.<ref name="Affective-Disorder" /> This demonstrates relationships between glucocorticoids, fluoxetine, and exploration in this fish.<ref name="Affective-Disorder">

{{Unbulleted list citebundle

|{{*}} {{cite journal | vauthors = McCammon JM, Sive H | title = Addressing the Genetics of Human Mental Health Disorders in Model Organisms | journal = Annual Review of Genomics and Human Genetics | volume = 16 | issue = 1 | pages = 173–197 | year = 2015 | pmid = 26002061 | doi = 10.1146/annurev-genom-090314-050048 | publisher = [[Annual Reviews (publisher)|Annual Reviews]] | author2-link = Hazel Sive | s2cid = 19597664 }}

|{{*}} {{cite journal | vauthors = Ziv L, Muto A, Schoonheim PJ, Meijsing SH, Strasser D, Ingraham HA, Schaaf MJ, Yamamoto KR, Baier H | title = An affective disorder in zebrafish with mutation of the glucocorticoid receptor | journal = Molecular Psychiatry | volume = 18 | issue = 6 | pages = 681–691 | date = June 2013 | pmid = 22641177 | pmc = 4065652 | doi = 10.1038/mp.2012.64 | s2cid = 11962425 | id = NIHMSID: NIHMS368312 }}

}}

</ref>

Fluoxetine has an [[anti-nematode]] effect.<ref name="Repurposing" /> Choy ''et al.'', 1999 finds some of this effect is due to interference with certain [[transmembrane protein]]s.<ref name="Repurposing">

{{Unbulleted list citebundle

|{{*}} {{cite journal | vauthors = Mangoni AA, Tuccinardi T, Collina S, Vanden Eynde JJ, Muñoz-Torrero D, Karaman R, Siciliano C, de Sousa ME, Prokai-Tatrai K, Rautio J, Guillou C, Gütschow M, Galdiero S, Liu H, Agrofoglio LA, Sabatier JM, Hulme C, Kokotos G, You Q, Gomes PA | title = Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-3 | journal = [[Molecules (MDPI)|Molecules]] | volume = 23 | issue = 7 | page = 1596 | date = June 2018 | pmid = 29966350 | doi = 10.3390/molecules23071596 | pmc = 6099979 | s2cid = 49644934 | doi-access = free }}<!--- Published by MDPI but highly cited including by Jimenez-Lopez et al., 2020, Elmaaty et al., 2021, and Sridhar et al., 2020. --->

|{{*}} {{cite journal | vauthors = Weeks JC, Roberts WM, Leasure C, Suzuki BM, Robinson KJ, Currey H, Wangchuk P, Eichenberger RM, Saxton AD, Bird TD, Kraemer BC, Loukas A, Hawdon JM, Caffrey CR, Liachko NF | title = Sertraline, Paroxetine, and Chlorpromazine Are Rapidly Acting Anthelmintic Drugs Capable of Clinical Repurposing | journal = [[Scientific Reports]] | volume = 8 | issue = 1 | pages = 975 | date = January 2018 | pmid = 29343694 | doi = 10.1038/s41598-017-18457-w | pmc = 5772060 | bibcode = 2018NatSR...8..975W | s2cid = 205636792 }}

}}

</ref>

== Veterinary use ==

Fluoxetine is commonly used and effective in treating anxiety related behaviours and [[Separation anxiety in dogs|separation anxiety]] in dogs, especially when given as supplementation to [[Dog training|behaviour modification]].<ref>{{cite journal |vauthors=Echeverri N, Govendir M |date=23 November 2022 |title=Does the selective serotonin reuptake inhibitor (SSRI) fluoxetine modify canine anxiety related behaviour? |url=https://veterinaryevidence.org/index.php/ve/article/view/585 |journal=Veterinary Evidence |volume=7 |issue=4 |doi=10.18849/ve.v7i4.585 |issn=2396-9776 |s2cid=253873416 |doi-access=free}}</ref><ref>{{cite journal |vauthors=Sargisson RJ |date=30 October 2014 |title=Canine separation anxiety: strategies for treatment and management |journal= Veterinary Medicine: Research and Reports|volume=5 |pages=143–151 |doi=10.2147/VMRR.S60424 |pmc=7521022 |pmid=33062616 |doi-access=free}}</ref>

== See also ==

* [[List of antidepressants]]

== References ==

{{Reflist}}

== Further reading ==

{{refbegin}}

* {{cite journal | vauthors = Shorter E | title = The 25th anniversary of the launch of Prozac gives pause for thought: where did we go wrong? | journal = The British Journal of Psychiatry | volume = 204 | issue = 5 | pages = 331–2 | year = 2014 | pmid = 24785765 | doi = 10.1192/bjp.bp.113.129916 | doi-access = free }}

* {{cite news | title=Selling Prozac as the Life-Enhancing Cure for Mental Woes | website=[[The New York Times]] | date=21 September 2014 | vauthors = Haberman C | url= https://www.nytimes.com/2014/09/22/us/selling-prozac-as-the-life-enhancing-cure-for-mental-woes.html }}

{{refend}}

== External links ==

{{Spoken Wikipedia|date=13 March 2021|En-Fluoxetine-article.ogg}}

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{{GABAA receptor positive allosteric modulators}}

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