Fluoxetine, sold under the brand names Prozac and Sarafem among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class.[2] It is used for the treatment of major depressive disorder, obsessive–compulsive disorder (OCD), bulimia nervosa, panic disorder, and premenstrual dysphoric disorder.[2] It may decrease the risk of suicide in those over the age of 65.[2] It has also been used to treat premature ejaculation.[2] Fluoxetine is taken by mouth.[2] Common side effects include trouble sleeping, sexual dysfunction, loss of appetite, dry mouth, rash, and abnormal dreams.[2] 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.[2] If stopped suddenly, a withdrawal syndrome may occur with anxiety, dizziness, and changes in sensation.[2] It is unclear if it is safe in pregnancy.[6] If already on the medication, it may be reasonable to continue during breastfeeding.[6] Its mechanism of action is not entirely clear but believed to be related to increasing serotonin activity in the brain.[2] Fluoxetine was discovered by Eli Lilly and Company in 1972, and entered medical use in 1986.[7] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[8] It is available as a generic medication.[2] The wholesale cost in the developing world is between US$0.01 and US$0.04 per day as of 2014.[9] In the United States, it costs about US$0.85 per day.[2] In 2016 it was the 29th most prescribed medication in the United States with more than 23 million prescriptions.[10] 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.[11][12][13][14] It has also been used for cataplexy, obesity, and alcohol dependence,[15] as well as binge eating disorder.[16] Fluoxetine seems to be ineffective for social anxiety disorder.[17] Studies do support a benefit in children with autism, though there is but tentative evidence for its benefit in adult autism.[18][19][20][21] The effectiveness of fluoxetine and other antidepressants in the treatment of mild-to-moderate depression is controversial. A review of the comparative efficacy of 21 antidepressant drugs found that fluoxetine was effective for the treatment of depression, however other SSRI's were more effective.[22] A meta-analysis published by Kirsch in 2008 suggests, in those with mild or moderate symptoms, the efficacy of fluoxetine and other SSRIs is clinically insignificant.[23] A 2009 meta-analysis by Fournier which evaluated patient-level data from six trials of the SSRI paroxetine and the non-SSRI antidepressant imipramine has been further cited as evidence that antidepressants exhibit minimal efficacy in mild to moderate depression.[24] A 2012 meta-analysis using individual patient level-data of fluoxetine for the treatment of depression concluded statistically and clinically significant benefit was seen irrespective of baseline depression severity, and no significant effect was found on baseline severity on observed efficacy.[25] Overall there is no evidence from randomized controlled trials that fluoxetine or other SSRIs decrease the risk of suicide.[26] There is tentative evidence that suggests it may decrease the risk of suicide in those over the age of 65.[2] A 2009 systematic review by the National Institute of Care and Clinical Excellence (NICE) (which considered the Kirsch, but not the later meta-analyses) concluded strong evidence existed for the efficacy of SSRIs in the treatment of moderate and severe depression, with some evidence for their efficacy in the treatment of mild depression.[27] Both the NICE and the Fournier analyses concluded that greater evidence is seen for the efficacy of antidepressants in the treatment of chronic mild depression (dysthymia) than in recent-onset mild depression. NICE recommends antidepressant treatment with an SSRI in combination with psychosocial interventions as second-line treatment for short term mild depression, and as a first line treatment for severe and moderate depression, as well as mild depression that is recurrent or long-standing. The American Psychiatric Association includes antidepressant therapy among its first-line options for the treatment of depression, particularly when "a history of prior positive response to antidepressant medications, the presence of moderate to severe symptoms, significant sleep or appetite disturbances, agitation, patient preference, and anticipation of the need for maintenance therapy" exist.[28] The efficacy of fluoxetine in the treatment of obsessive–compulsive disorder (OCD) was demonstrated in two randomized multicenter phase III clinical trials. The pooled results of these trials demonstrated that 47% of completers treated with the highest dose were "much improved" or "very much improved" after 13 weeks of treatment, compared to 11% in the placebo arm of the trial.[4] The American Academy of Child and Adolescent Psychiatry state that SSRIs, 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.[29] The efficacy of fluoxetine in the treatment of panic disorder was demonstrated in two 12-week randomized multicenter 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.[4] A 2011 systematic review of 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.[30] However, no difference was observed between treatment arms when fluoxetine and psychotherapy were compared to psychotherapy alone. Fluoxetine is used to treat premenstrual dysphoric disorder.[31][32] In children and adolescents, fluoxetine is the antidepressant of choice due to tentative evidence favoring its efficacy and tolerability.[33][34] In pregnancy, fluoxetine is considered a category C drug by the USA FDA. 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 UK 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 cardiac malformations in the newborn.[35][36][37] Furthermore, an association between fluoxetine use during the first trimester and an increased risk of minor fetal malformations was observed in one study.[36] 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."[38] Per the FDA, infants exposed to SSRIs in late pregnancy may have an increased risk for 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.[4] 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."[39] Sertraline is often the preferred SSRI during pregnancy due to the relatively minimal fetal exposure observed and its safety profile while breastfeeding.[40] 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, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, decreased libido, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawning.[41] Fluoxetine is considered the most stimulating of the SSRIs (that is, it is most prone to causing insomnia and agitation).[42] It also appears to be the most prone of the SSRIs for producing dermatologic reactions (e.g. urticaria (hives), rash, itchiness, etc.).[36] Sexual dysfunction, including loss of libido, anorgasmia, lack of vaginal lubrication, and erectile dysfunction, 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%.[43] Symptoms of sexual dysfunction have been reported to persist after discontinuing SSRIs, although this is thought to be occasional.[4][44][45] Antidepressant discontinuation syndrome may occur within days or weeks of stopping an antidepressant. Symptoms may include dizziness, disturbance of balance, headache, nausea, insomnia, vivid dreams, sensations of tingling or numbness, irritability, hallucinations, fatigue, depression-like symptoms, and suicide. Antidepressant discontinuation syndrome is often mistaken for recurrent depression, prompting re-administration of the drug. Antidepressant discontinuation syndrome may be reduced or prevented by tapering the medication over several weeks or months.[46][47] Fluoxetine's longer half-life makes it less common to develop discontinuation syndrome following cessation of therapy, especially when compared to antidepressants with shorter half-lives such as paroxetine.[48][49] Although gradual dose reductions are recommended with antidepressants with shorter half-lives, tapering may not be necessary with fluoxetine.[50] Antidepressant exposure (including flouxetine) 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 lower Apgar scores (by <0.4 points).[51][52] It is uncertain whether there is an increased rate of septal heart defects among children whose mothers were prescribed an SSRI in early pregnancy.[53][54] In 2007 the FDA required all antidepressants to carry a black box warning stating that antidepressants may increase the risk of suicide in people younger than 25.[55] This warning is based on statistical analyses conducted by two independent groups of FDA experts that 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.[56][57][58] This analysis was criticized by Donald Klein, who noted that suicidality, that is suicidal ideation and behavior, is not necessarily a good surrogate marker for completed suicide, and it is still possible that antidepressants may prevent actual suicide while increasing suicidality.[59] There is less data on fluoxetine than on antidepressants as a whole. For the above analysis on the antidepressant level, 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%,[60] and in adults decreased the odds of suicidality by approximately 30%.[57][58] Similarly, the analysis conducted by the UK MHRA found a 50% increase of odds of 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, for adults fluoxetine did not change the rate of self-harm and statistically significantly decreased suicidal ideation by 50%.[61][62] Fluoxetine can affect the electrical currents that heart muscle cells use to coordinate their contraction, specifically the potassium currents Ito and IKs that repolarise the cardiac action potential. [63] Under certain circumstances, this can lead to prolongation of the QT interval, a measurement made on an 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 abnormal heart rhythms such as Torsades de Pointes.[64] As of 2019, the drug reference site CredibleMeds lists Fluoxetine as leading to a conditional risk of arrhythmias. [65] In overdose, most frequent adverse effects include:[66] Nervous system effects Gastrointestinal effects Other effects Contraindications include prior treatment (within the past two weeks) with MAOIs such as phenelzine and tranylcypromine, due to the potential for serotonin syndrome.[3] Its use should also be avoided in those with known hypersensitivities to fluoxetine or any of the other ingredients in the formulation used.[3] Its use in those concurrently receiving pimozide or thioridazine is also advised against.[3] 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.[67] Patients who are taking anticoagulants or NSAIDS must be careful when taking fluoxetine or other SSRIs, as they can sometimes increase the blood-thinning effects of these medications.[68] Fluoxetine and norfluoxetine inhibit many isozymes 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.[69][70] In vivo, fluoxetine and norfluoxetine do not significantly affect the activity of CYP1A2 and CYP3A4.[69] 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.[71] This extensive effect on the body's pathways for drug metabolism creates the potential for interactions with many commonly used drugs.[71][72] Its use should also be avoided in those receiving other serotonergic drugs such as monoamine oxidase inhibitors, tricyclic antidepressants, methamphetamine, amphetamine, MDMA, triptans, buspirone, serotonin–norepinephrine reuptake inhibitors and other SSRIs due to the potential for serotonin syndrome to develop as a result.[3] 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.[3] 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.[75][76][77][78] Thus, dopamine and norepinephrine may contribute to the antidepressant action of fluoxetine in humans at supratherapeutic doses (60–80 mg).[77][79] This effect may be mediated by 5HT2C receptors, which are inhibited by higher concentrations of fluoxetine.[80] Fluoxetine increases the concentration of circulating allopregnanolone, a potent GABAA receptor positive allosteric modulator, in the brain.[78][81] Norfluoxetine, a primary active metabolite of fluoxetine, produces a similar effect on allopregnanolone levels in the brains of mice.[78] Additionally, both fluoxetine and norfluoxetine are such modulators themselves, actions which may be clinically-relevant.[82] In addition, fluoxetine has been found to act as an agonist of the σ1-receptor, with a potency greater than that of citalopram but less than that of fluvoxamine. However, the significance of this property is not fully clear.[83][84] Fluoxetine also functions as a channel blocker of anoctamin 1, a calcium-activated chloride channel.[85][86] A number of other ion channels, including nicotinic acetylcholine receptors and 5-HT3 receptors, are also known to be inhibited at similar concentrations.[82] Fluoxetine has been shown to inhibit acid sphingomyelinase, a key regulator of ceramide levels which derives ceramide from sphingomyelin.[87][88] Fluoxetine elicits antidepressant effect by inhibiting serotonin re-uptake in the synapse by binding to the re-uptake pump on the neuronal membrane[89] to increase its availability and enhance neurotransmission.[90] Norfluoxetine and desmethylfluoxetine are metabolites of fluoxetine and also act as serotonin re-uptake inhibitors, so increase the duration of action of the drug.[91][89] The bioavailability of fluoxetine is relatively high (72%), and peak plasma concentrations are reached in 6–8 hours. It is highly bound to plasma proteins, mostly albumin and α1-glycoprotein.[3] Fluoxetine is metabolized in the liver by isoenzymes of the cytochrome P450 system, including CYP2D6.[92] 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.[93] Both drugs are also potent inhibitors of CYP2D6.[94] 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 changes from 1 to 3 days, after a single dose, to 4 to 6 days, after long-term use.[3] Similarly, the half-life of norfluoxetine is longer (16 days) after long-term use.[92][95][96] 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.[97][98] Moreover, the brain concentration of fluoxetine and its metabolites keeps increasing through at least the first five weeks of treatment.[99] That means that the full benefits of the current dose a patient receives are not realized for at least a month since its initiation. For example, in one 6-week study, the median time to achieving consistent response was 29 days.[97] Likewise, complete excretion of the drug may take several weeks. During the first week after the treatment discontinuation, the brain concentration of fluoxetine decreases only by 50%,[99] The blood level of norfluoxetine 4 weeks after the treatment discontinuation is about 80% of the level registered by the end of the first treatment week, and 7 weeks after the discontinuation norfluoxetine is still detectable in the blood.[95] 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.[100][101][102] In 2010, over 24.4 million prescriptions for generic fluoxetine were filled in the United States,[103] making it the third-most prescribed antidepressant after sertraline and citalopram.[103] In 2011, 6 million prescriptions for fluoxetine were filled in the United Kingdom.[104] 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 Robert Rathbun. It was known at that time that the antihistamine diphenhydramine shows some antidepressant-like properties. 3-Phenoxy-3-phenylpropylamine, a compound structurally similar to diphenhydramine, was taken as a starting point, and Molloy synthesized dozens of its derivatives.[105] Hoping to find a derivative inhibiting only serotonin reuptake, an Eli Lilly scientist, David T. Wong, proposed to retest the series for the in vitro reuptake of serotonin, norepinephrine and dopamine. This test, carried out by Jong-Sir Horng in May 1972,[105] showed the compound later named fluoxetine to be the most potent and selective inhibitor of serotonin reuptake of the series.[106] Wong published the first article about fluoxetine in 1974.[106] A year later, it was given the official chemical name fluoxetine and the Eli Lilly and Company gave it the trade 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.[107] Fluoxetine appeared on the Belgian market in 1986.[108] In the U.S., the FDA gave its final approval in December 1987,[109] and a month later Eli Lilly began marketing Prozac; annual sales in the U.S. reached $350 million within a year.[107] Worldwide sales eventually reached a peak of $2.6 billion a year.[110] 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 the drug in that indication as "Sarafem" after it was approved by the FDA in 2000, following the recommendation of an advisory committee in 1999.[111][112][113] The invention of using fluoxetine to treat PMDD was made by Richard Wurtman at MIT, and the patent was licensed to his startup, Interneuron, which in turn sold it to Lilly.[114] To defend its revenue from fluoxetine, 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.[115] When Lilly's patent expired in August 2001,[116] generic drug competition decreased Lilly's sales of fluoxetine by 70% within two months.[111] In 2000 an investment bank had projected that annual sales of Sarafem could reach $250M/year.[117] Sales of Sarafem reached about $85M/year in 2002, and in that year Lilly sold its assets around 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 difference to Galen, but not to Lilly.[118][119] Bringing Sarafem to market harmed Lilly's reputation in some quarters. The diagnostic category of PMDD was 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 underway in 1998, has been criticized.[117] Lilly was criticized for inventing a disease in order to make money,[117] and for not innovating but rather just seeking ways to continue making money from existing drugs.[120] 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.[121] Beginning April 5, 2010, fluoxetine became one of four antidepressant drugs that the FAA permitted for pilots with authorization from an aviation medical examiner. The other permitted antidepressants are sertraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro).[122] These four remain the only antidepressants permitted by FAA as of 2 December 2016.[ref][123] Fluoxetine has been detected in aquatic ecosystems, especially in North America.[124] There is a growing body of research addressing the effects of fluoxetine (among other SSRIs) exposure on non-target aquatic species.[125][126][127][128] 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 systems if a hazard quotient approach was applied to risk assessment.[127] 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 serotonin system.[127] Since this time, a number of studies have reported fluoxetine-induced impacts on a number of behavioural and physiological endpoints, inducing antipredator behaviour,[129][130][131] reproduction,[132][133][133] and foraging[134][135] 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 environmental realistic dosages to affect the behaviour of wildlife could not be reached.[126] 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.[136] Neither the American Psychiatric Association,[28] the National Institute for Health and Care Excellence (NICE),[137] nor the American College of Physicians[138] list violence among the potential side effects of treatment with serotonin selective reuptake inhibitors. Similarly, the World Health Organization and the European Psychiatric Association do not list violence among the potential side effects of SSRIs.[139][140] Serial case report studies of this type have been criticized as being subject to "confounding by indication", in which effects due to an underlying disease state are mistakenly attributed to the effects of treatment.[141] Other studies, including randomized clinical trials and observational studies, have suggested that fluoxetine and other SSRIs may reduce the propensity for violence. A randomized clinical trial performed by the US National Institutes for Mental Health found that fluoxetine reduced acts of domestic violence in alcoholics with a history of such behavior[142] A second clinical trial performed at the University of Chicago found that fluoxetine reduced aggressive behavior in patients in intermittent aggressive disorder.[143] A clinical trial found that fluoxetine reduced aggressive behavior in patients with borderline personality disorder.[144] These results are indirectly supported by studies demonstrating that other SSRIs can reduce violence and aggressive behavior.[145][146][147][148] A NBER study examining international trends in antidepressant use and crime rates in the 1990s found that increases in antidepressant drug prescriptions were associated with reductions in violent crime.[149] Despite the above cited evidence, psychiatrist David Healy and certain patient activist groups have compiled case reports of violent acts committed by individuals taking fluoxetine or other SSRIs,[150][151] and have argued that these drugs predispose susceptible individuals to commit violent acts.

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