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Fluoxetine

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"Prozac" redirects here. For other uses, seeProzac (disambiguation).
Not to be confused withFluvoxamine.

Fluoxetine
Fluoxetine (top),
(R)-fluoxetine (left), (S)-fluoxetine (right)
Clinical data
Pronunciation/fluˈɒksətiːn/
floo-OKS-ə-teen
Trade namesProzac, Sarafem, others
AHFS/DrugsMonograph
MedlinePlusa689006
License data
Pregnancy
category
  • AU:C
Addiction
liability		None[1]
Routes of
administration		By mouth
Drug classSelective serotonin reuptake inhibitor(SSRI)[2]
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability60–80%[2]
Protein binding94–95%[7]
MetabolismLiver(mostlyCYP2D6-mediated)[9]
MetabolitesNorfluoxetine, desmethylfluoxetine
Eliminationhalf-life1–3 days (acute)
4–6 days (chronic)[9][10]
ExcretionUrine (80%), faeces (15%)[9][10]
Identifiers
  • N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.125.370Edit this at Wikidata
Chemical and physical data
FormulaC17H18F3NO
Molar mass309.332g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
Melting point179 to 182 °C (354 to 360 °F)
Boiling point395 °C (743 °F)
Solubility in water14
  • CNCCC(c1ccccc1)Oc2ccc(cc2)C(F)(F)F
  • InChI=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,11-12H2,1H3checkY
  • Key:RTHCYVBBDHJXIQ-UHFFFAOYSA-NcheckY
(verify)

Fluoxetine,sold under the brand nameProzac,among others, is anantidepressantof theselective serotonin reuptake inhibitor(SSRI) class.[2]It is used for the treatment ofmajor depressive disorder,obsessive–compulsive disorder(OCD),anxiety,bulimia nervosa,panic disorder,andpremenstrual dysphoric disorder.[2]It is also approved for treatment of major depressive disorder in adolescents and children 8 years of age and over.[11]It has also been used to treatpremature ejaculation.[2]Fluoxetine istaken by mouth.[2]

Common side effects include indigestion, trouble sleeping, sexual dysfunction, loss of appetite, nausea, diarrhea, dry mouth, and rash. Serious side effects includeserotonin syndrome,mania,seizures,an increased risk ofsuicidal behaviorin people under 25 years old, and an increased risk of bleeding.[2]Antidepressant discontinuation syndromeis 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 incongenital heart defectsin the newborns.[12][13]It has been suggested that fluoxetine therapy may be continued duringbreastfeedingif it was used during pregnancy or if other antidepressants were ineffective.[14]

Fluoxetine was invented byEli Lilly and Companyin 1972, and entered medical use in 1986.[15]It is on theWorld Health Organization's List of Essential Medicines.[16]It is available as ageneric medication.[2]In 2021, it was the 25th most commonly prescribed medication in the United States, with more than 22million prescriptions.[17][18]Lilly also markets fluoxetine in a fixed-dose combination witholanzapineasolanzapine/fluoxetine(Symbyax).[19][20]

Medical uses

[edit]
Fluoxetineblister pack20 mg capsules
Fluoxetine 10 mg tablets

Fluoxetine is frequently used to treatmajor depressive disorder,obsessive–compulsive disorder(OCD),post-traumatic stress disorder(PTSD),bulimia nervosa,panic disorder,premenstrual dysphoric disorder,andtrichotillomania.[21][22][23][24][25][26]It has also been used forcataplexy,obesity,andalcohol dependence,[27]as well asbinge eating disorder.[28]Fluoxetine seems to be ineffective forsocial anxiety disorder.[29]Studies do not support a benefit in children withautism,though there is tentative evidence for its benefit in adult autism.[30][31][32][33]Fluoxetine together with fluvoxamine has shown some initial promise as a potential treatment for reducingCOVID-19severity if given early.[34]

Depression

[edit]

Fluoxetine is approved for the treatment of major depression in children and adults.[7]Meta-analysis of trials in adults conclude that fluoxetine modestly outperforms placebo.[35]Fluoxetine may be less effective than other antidepressants, but has high acceptability.[36]

For children and adolescents with moderate-to-severe depressive disorder, fluoxetine seems to be the best treatment (either with or withoutcognitive 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.[37][38][39][40]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.[41]

Obsessive–compulsive disorder

[edit]

Fluoxetine is effective in the treatment ofobsessive–compulsive disorder(OCD) for adults.[42]It is also effective for treating OCD in children and adolescents.[43][39][44]TheAmerican Academy of Child and Adolescent Psychiatrystate thatSSRIs,including fluoxetine, should be used as first-line therapy in children, along withcognitive behavioral therapy(CBT), for the treatment of moderate to severe OCD.[45]

Panic disorder

[edit]

The efficacy of fluoxetine in the treatment ofpanic disorderwas demonstrated in two 12-week randomized multicenterphase III clinical trialsthat enrolled patients diagnosed with panic disorder, with or withoutagoraphobia.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.[7]

Bulimia nervosa

[edit]

A 2011systematic reviewdiscussed seven trials which compared fluoxetine to aplaceboin the treatment ofbulimia nervosa,six of which found a statistically significant reduction in symptoms such as vomiting and binge eating.[46]However, no difference was observed between treatment arms when fluoxetine andpsychotherapywere compared to psychotherapy alone.

Premenstrual dysphoric disorder

[edit]

Fluoxetine is used to treatpremenstrual dysphoric disorder,a condition where individuals haveaffectiveandsomaticsymptoms monthly during theluteal phaseof menstruation.[8][47]Taking fluoxetine 20 mg/d can be effective in treating PMDD,[48][49]though doses of 10 mg/d have also been prescribed effectively.[50][51]

Impulsive aggression

[edit]

Fluoxetine is considered a first-line medication for the treatment of impulsive aggression of low intensity.[52]Fluoxetine reduced low intensity aggressive behavior in patients in intermittent aggressive disorder andborderline personality disorder.[52][53][54]Fluoxetine also reduced acts of domestic violence in alcoholics with a history of such behavior.[55]

Obesity and overweight adults

[edit]

In 2019 asystematic reviewcompared the effects on weight of various doses of fluoxetine (60 mg/d, 40 mg/d, 20 mg/d, 10 mg/d) in obese and overweight adults.[56]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.[56]When comparing, in the same review, the effects of fluoxetine on weight of obese and overweight adults, to other anti-obesity agents, Omega -3gel capsuleand not receiving a treatment, the authors could not reach conclusive results due to poor quality of evidence.[56]

Special populations

[edit]

In children and adolescents, fluoxetine is the antidepressant of choice due to tentative evidence favoring its efficacy and tolerability.[57][58]Evidence supporting an increased risk of major fetal malformations resulting from fluoxetine exposure is limited, although theMedicines 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 congenitalcardiacmalformations in the newborn.[59][60][61]Furthermore, an association between fluoxetine use during the first trimester and an increased risk of minor fetal malformations was observed in one study.[60]

However, a systematic review and meta-analysis of 21 studies – published in theJournal 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."[62]

Per the FDA, infants exposed to SSRIs in late pregnancy may have an increased risk forpersistent 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.[7]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."[63]Sertralineis often the preferred SSRI during pregnancy due to the relatively minimal fetal exposure observed and its safety profile while breastfeeding.[64]

Adverse effects

[edit]

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, abnormalejaculation,anorexia, anxiety,asthenia,diarrhea,dizziness, dry mouth,dyspepsia,fatigue,flu syndrome,impotence,insomnia,decreasedlibido,nausea, nervousness,pharyngitis,rash,sinusitis,somnolence,sweating,tremor,vasodilation,andyawning.[56][65]Fluoxetine is considered the most stimulating of the SSRIs (that is, it is most prone to causing insomnia and agitation).[66]It also appears to be the most prone of the SSRIs for producing dermatologic reactions (e.g.urticaria(hives), rash, itchiness, etc.).[60]

Sexual dysfunction

[edit]
See also:Selective serotonin reuptake inhibitor § Sexual dysfunction

Sexual dysfunction, including loss of libido,erectile dysfunction,lack of vaginal lubrication, andanorgasmia,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%.[67]

In 2019, thePharmacovigilance Risk Assessment Committeeof theEuropean Medicines Agencyrecommended that packaging leaflets of selected SSRIs andSNRIsshould be amended to include information regarding a possible risk of persistent sexual dysfunction.[68]Following on the European assessment, a safety review byHealth Canada"could neither confirm nor rule out a causal link... 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 ".[69]

Antidepressant discontinuation syndrome

[edit]

Fluoxetine's longerhalf-lifemakes it less common to developantidepressant discontinuation syndromefollowing cessation of therapy, especially when compared with antidepressants with shorter half-lives such asparoxetine.[70][71]Although gradual dose reductions are recommended with antidepressants with shorterhalf-lives,tapering may not be necessary with fluoxetine.[72]

Pregnancy

[edit]

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 g), and lowerApgar scores(by <0.4 points).[73][74]There is 30–36% increase incongenital heart defectsamong children whose mothers were prescribed fluoxetine during pregnancy,[12][13]with fluoxetine use in the first trimester associated with 38–65% increase inseptal heart defects.[75][12]

Suicide

[edit]

In October 2004, the FDA added a black box warning to all antidepressant drugs regarding use in children.[76]In 2006, the FDA included adults aged 25 or younger.[77]Statistical analyses conducted by two independent groups of FDA experts found a 2-fold increase of thesuicidal ideationand 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.[78][79][80]This analysis was criticized byDonald 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.[81]In February 2018, theFood 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.[82]

On 14 September 1989,Joseph T. Wesbeckerkilled eight people and injured twelve before committing suicide.[83]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.[84]Lawyers began using Prozac to justify the abnormal behaviors of their clients.[85]Eli Lillywas accused of not doing enough to warn patients and doctors about the adverse effects, which it had described as"activation",years prior to the incident.[86]

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 obtainstatistically significantresults. Considered separately, fluoxetine use in children increased the odds of suicidality by 50%,[87]and in adults decreased the odds of suicidality by approximately 30%.[79][80]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.[88]Similarly, the analysis conducted by the UKMHRAfound 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 ofself-harmin adults and statistically significantly decreased suicidal ideation by 50%.[89][90]

QT prolongation

[edit]

Fluoxetine can affect theelectrical currentsthatheart muscle cellsuse to coordinate their contraction, specifically thepotassiumcurrentsItoandIKsthat repolarise thecardiac action potential.[91]Under certain circumstances, this can lead to prolongation of theQT interval,a measurement made on anelectrocardiogramreflecting 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 tolong QT syndrome,there is a small risk of potentially lethalabnormal heart rhythmssuch astorsades de pointes.[92]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.[93]

Overdose

[edit]
See also:Serotonin syndrome

In overdose, most frequent adverse effects include:[94]

Interactions

[edit]

Contraindications include prior treatment (within the past 5–6 weeks, depending on the dose)[95][96]withMAOIssuch asphenelzineandtranylcypromine,due to the potential forserotonin syndrome.[9]Its use should also be avoided in those with known hypersensitivities to fluoxetine or any of the other ingredients in the formulation used.[9]Its use in those concurrently receivingpimozideorthioridazineis also advised against.[9]

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.[97]If opioid treatment is required, oxycodone use should be monitored sinceoxycodoneis metabolized by the cytochrome P450 (CYP) enzyme system and fluoxetine and paroxetine are potent inhibitors of CYP2D6 enzymes.[98]This means combinations of codeine or oxycodone with fluoxetine antidepressant may lead to reduced analgesia.[99]

In some cases, use ofdextromethorphan-containing cold and cough medications with fluoxetine is advised against, due to fluoxetine increasing serotonin levels, as well as the fact that fluoxetine is acytochrome P450 2D6inhibitor, 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.[100]

Patients who are takingNSAIDs,antiplatelet drugs,anticoagulants,Omega -3 fatty acids,vitamin E,and garlicsupplementsmust be careful when taking fluoxetine or other SSRIs, as they can sometimes increase the blood-thinning effects of these medications.[101][102]

Fluoxetine andnorfluoxetineinhibitmanyisozymesof thecytochrome P450system that are involved indrug metabolism.Both are potent inhibitors ofCYP2D6(which is also the chief enzyme responsible for their metabolism) andCYP2C19,and mild to moderate inhibitors ofCYP2B6andCYP2C9.[103][104]In vivo,fluoxetine and norfluoxetine do not significantly affect the activity ofCYP1A2andCYP3A4.[103]They also inhibit the activity ofP-glycoprotein,a type ofmembrane transport proteinthat plays an important role in drug transport and metabolism and hence P-glycoprotein substrates, such asloperamide,may have their central effects potentiated.[105]This extensive effect on the body's pathways for drug metabolism creates the potential forinteractionswith many commonly used drugs.[105][106]

Its use should also be avoided in those receiving other serotonergic drugs such asmonoamine oxidase inhibitors,tricyclic antidepressants,methamphetamine,amphetamine,MDMA,triptans,buspirone,ginseng,dextromethorphan (DXM),linezolid,tramadol,serotonin–norepinephrine reuptake inhibitors,and other SSRIs due to the potential forserotonin syndrometo develop as a result.[9][107]

Fluoxetine may also increase the risk of opioid overdose in some instances, in part due to its inhibitory effect on cytochrome P-450.[108][109]Similar to how fluoxetine can effect the metabolization of dextromethorphan, it may cause medications likeoxycodoneto 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 toaccidental 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 takingparoxetineor fluoxetine had a 23% higher risk of overdosing on oxycodone than those using other SSRIs.[108]

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.[9]

Pharmacology

[edit]
Binding affinities(KiinnM)[110][111]
Molecular
Target 		Fluoxetine Norfluoxetine
SERT 1 19
NET 660 2'700
DAT 4'180 420
5-HT1A 14 NA
5-HT2A 120 300
5-HT2B 2'514 5'100
5-HT2C 120 91
α1 3'000 3'900
M1 870 1'200
M2 2'700 4'600
M3 1'000 760
M4 2'900 2'600
M5 2'700 2'200
H1 3'250 > 10'000

Pharmacodynamics

[edit]

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and does not appreciably inhibitnorepinephrineanddopaminereuptake 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.[112][113][114][115]Thus, dopamine and norepinephrine may contribute to the antidepressant action of fluoxetine in humans at supratherapeutic doses (60–80 mg).[114][116]This effect may be mediated by 5HT2Creceptors, which are inhibited by higher concentrations of fluoxetine.[117]

Fluoxetine increases the concentration of circulatingallopregnanolone,a potentGABAAreceptor positive allosteric modulator,in the brain.[115][118]Norfluoxetine,a primaryactive metaboliteof fluoxetine, produces a similar effect on allopregnanolone levels in the brains of mice.[115]Additionally, both fluoxetine and norfluoxetine are such modulators themselves, actions which may be clinically relevant.[119]

In addition, fluoxetine has been found to act as anagonistof theσ1-receptor,with apotencygreater than that ofcitaloprambut less than that offluvoxamine.However, the significance of this property is not fully clear.[120][121]Fluoxetine also functions as a channel blocker ofanoctamin 1,acalcium-activated chloride channel.[122][123]A number of otherion channels,includingnicotinic acetylcholine receptorsand5-HT3receptors,are also known to beinhibitedat similar concentrations.[119]

Fluoxetine has been shown to inhibitacid sphingomyelinase,a key regulator ofceramidelevels which derives ceramide fromsphingomyelin.[124][125]

Mechanism of action

[edit]

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[126]to increase serotonin availability and enhance neurotransmission.[127]Over time, this leads to a downregulation of pre-synaptic5-HT1A receptors,which is associated with an improvement in passive stress tolerance, and delayed downstream increase in expression ofbrain-derived neurotrophic factor,which may contribute to a reduction in negative affective biases.[128][129]Norfluoxetine and desmethylfluoxetine are metabolites of fluoxetine and also act as serotonin reuptake inhibitors, increasing the duration of action of the drug.[130][126]

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.[131]

Pharmacokinetics

[edit]
TheSenantiomerofnorfluoxetine,fluoxetine's chief active metabolite.

Thebioavailabilityof fluoxetine is relatively high (72%), and peak plasma concentrations are reached in 6–8 hours. It is highlyboundto plasma proteins, mostlyalbuminand α1-glycoprotein.[9]Fluoxetine ismetabolizedin theliverbyisoenzymesof thecytochrome P450system, includingCYP2D6.[132]The role of CYP2D6 in themetabolismof fluoxetine may be clinically important, as there is greatgenetic variabilityin the function of this enzyme among people. CYP2D6 is responsible for converting fluoxetine to its only active metabolite,norfluoxetine.[133]Both drugs are also potentinhibitorsof CYP2D6.[134]

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 fluoxetineelimination half-lifeincreases from 1 to 3 days, after a single dose, to 4 to 6 days, after long-term use.[9]Similarly, the half-life of norfluoxetine is longer (16 days) after long-term use.[132][135][136]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.[137][138]Moreover, the brain concentration of fluoxetine and its metabolites keeps increasing through at least the first five weeks of treatment.[139]For major depressive disorder, while onset of antidepressant action may be felt as early as 1–2 weeks,[140]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 days.[137]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%,[139]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.[135]

Measurement in body fluids

[edit]

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 μg/L in persons taking the drug for its antidepressant effects, 900–3000 μg/L in survivors of acute overdosage and 1000–7000 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.[141][142][143]

History

[edit]

The work which eventually led to the discovery of fluoxetine began atEli Lilly and Companyin 1970 as a collaboration betweenBryan Molloyand Ray Fuller.[144]It was known at that time that theantihistaminediphenhydramineshowed 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 chemistKlaus Schmiegelsynthesized a series of dozens of its derivatives.[145][146]Hoping to find a derivative inhibiting onlyserotoninreuptake, another Eli Lilly scientist,David T. Wong,proposed to retest the series for thein vitroreuptake of serotonin, norepinephrine anddopamine,using a technique developed by neuroscientistSolomon Snyder.[144]This test showed the compound later named fluoxetine to be the most potent and selective inhibitor of serotonin reuptake of the series.[147]The first article about fluoxetine was published in 1974,[147]following talks given atFASEBandASPET.[148]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 theU.S. Food and Drug Administration(FDA) for fluoxetine.[149]

Fluoxetine appeared on the Belgian market in 1986.[150]In the U.S., the FDA gave its final approval in December 1987,[151]and a month later Eli Lilly began marketing Prozac; annual sales in the U.S. reached $350 million within a year.[149]Worldwide sales eventually reached a peak of $2.6 billion a year.[152]

Lilly tried severalproduct line extensionstrategies, including extended release formulations and paying for clinical trials to test the efficacy and safety of fluoxetine inpremenstrual dysphoric disorderand 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.[153][154][155]The invention of using fluoxetine to treat PMDD was made byRichard Wurtmanat MIT; the patent was licensed to his startup, Interneuron, which in turn sold it to Lilly.[156]

To defend its Prozac revenue from generic competition, Lilly also fought a five-year, multimillion-dollar battle in court with the generic companyBarr Pharmaceuticalsto 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.[157]When Lilly's patent expired in August 2001,[158]generic drugcompetition decreased Lilly's sales of fluoxetine by 70% within two months.[153]

In 2000 an investment bank had projected that annual sales of Sarafem could reach $250M/year.[159]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.[160][161]

Bringing Sarafem to market harmed Lilly's reputation in some quarters. The diagnostic category of PMDD wascontroversialsince it was first proposed in 1987, and Lilly's role in retaining it in the appendix of theDSM-IV-TR,the discussions for which got under way in 1998, has been criticized.[159]Lilly was criticized for inventing a disease in order to make money,[159]and for not innovating but rather just seeking ways to continue making money from existing drugs.[162]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.[163]

Society and culture

[edit]
[edit]

In 2010, over 24.4 million prescriptions for generic fluoxetine were filled in the United States,[164]making it the third-most prescribed antidepressant aftersertralineandcitalopram.[164]

In 2011, 6 million prescriptions for fluoxetine were filled in the United Kingdom.[165]Between 1998 and 2017, along withamitriptyline,it was the most commonly prescribed first antidepressant for adolescents aged 12–17 years in England.[166]

Environmental effects

[edit]

Fluoxetine has been detected in aquatic ecosystems, especially in North America.[167]There is a growing body of research addressing the effects of fluoxetine (among other SSRIs) exposure on non-target aquatic species.[168][169][170][171]

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 toaquatic systemsif a hazard quotient approach was applied to risk assessment.[170]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 theserotonin system.[170]

Fluoxetine – similar to several other SSRIs – inducesreproductive behaviorin someshellfishat concentrations as low as 10-10M,or 30parts per trillion.[172]: 21 

Since 2003, a number of studies have reported fluoxetine-induced impacts on a number of behavioural and physiological endpoints, inducing antipredator behaviour,[173][174][175]reproduction,[176][177]and foraging[178][179]at or below field-detected concentrations. However, a 2014 review on theecotoxicologyof 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.[169]At environmentally realistic concentrations, fluoxetine altersinsect emergencetiming.[180]Richmondet al.,2019 find that at low concentrations it accelerates emergence ofDiptera,while at unusually high concentrations it has no discernable effect.[180]

Several common plants are known to absorb fluoxetine.[181]Several crops have been tested, and Redshawet al.2008 find thatcauliflowerabsorbs large amounts into the stem and leaf but not the head or root.[181]Wuet al.2012 find thatlettuceandspinachalso absorb detectable amounts, while Carteret al.2014 find thatradish(Raphanus sativus), ryegrass (Lolium perenne) – and Wuet al.2010 find thatsoybean(Glycine max) – absorb little.[181]Wu tested all tissues of soybean and all showed only low concentrations.[181]By contrast various Reinholdet al.2010 findduckweedshave a high uptake of fluoxetine and show promise forbioremediationof contaminated water, especiallyLemna minorandLandoltia punctata.[181]Ecotoxicity for organisms involved inaquacultureis well documented.[182]: 275–276 Fluoxetine affects both aquaculturedinvertebratesandvertebrates,andinhibits soil microbesincluding a largeantibacterialeffect.[182]For applications of this see§ Other uses.

Politics

[edit]

During the 1990 campaign forgovernor 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.[183]

American aircraft pilots

[edit]

Beginning in April 2010, fluoxetine became one of four antidepressant drugs that theFAApermitted forpilotswith authorization from anaviation medical examiner.The other permitted antidepressants aresertraline(Zoloft),citalopram(Celexa), andescitalopram(Lexapro).[184]These four remain the only antidepressants permitted by FAA as of 2 December 2016.[185]

Sertraline, citalopram, and escitalopram are the only antidepressants permitted forEASAmedical certification, as of January 2019.[186][187]

Research

[edit]

The antibacterial effect in described above (§ Environmental effects) could be applied againstmultiresistantbiotypes incrop bacterial diseasesand bacterialaquaculture diseases.[182]In aglucocorticoid receptor-defectivezebrafish mutant(Danio rerio) with reducedexploratory behavior,fluoxetine rescued the normal exploratory behavior.[188]This demonstrates relationships between glucocorticoids, fluoxetine, and exploration in this fish.[188]

Fluoxetine has ananti-nematodeeffect.[189]Choyet al.,1999 finds some of this effect is due to interference with certaintransmembrane proteins.[189]

Veterinary use

[edit]

Fluoxetine is commonly used and effective in treating anxiety related behaviours andseparation anxietyin dogs, especially when given as supplementation tobehaviour modification.[190][191]

See also

[edit]

References

[edit]
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