Fluoxetine
Clinical data | |
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Pronunciation | /fluˈɒksətiːn/ floo-OKS-ə-teen |
Trade names | Prozac, Sarafem, others |
AHFS/Drugs.com | Monograph |
MedlinePlus | a689006 |
License data |
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Pregnancy category |
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Addiction liability | None[1] |
Routes of administration | By mouth |
Drug class | Selective serotonin reuptake inhibitor (SSRI)[2] |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | 60–80%[2] |
Protein binding | 94–95%[7] |
Metabolism | Liver (mostly CYP2D6-mediated)[9] |
Metabolites | Norfluoxetine, desmethylfluoxetine |
Elimination half-life | 1–3 days (acute) 4–6 days (chronic)[9][10] |
Excretion | Urine (80%), faeces (15%)[9][10] |
Identifiers | |
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JSmol) | |
Chirality | Racemic mixture |
Melting point | 179 to 182 °C (354 to 360 °F) |
Boiling point | 395 °C (743 °F) |
Solubility in water | 14 |
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Fluoxetine, sold under the brand name Prozac, 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), anxiety, bulimia nervosa, panic disorder, and premenstrual 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 treat premature ejaculation.[2] Fluoxetine is taken by mouth.[2]
Common side effects include indigestion, trouble sleeping, sexual dysfunction, loss of appetite, nausea, diarrhea, dry mouth, and rash. Serious side effects include
Fluoxetine was invented by
Medical uses
Fluoxetine is frequently used to treat
Depression
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 without 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.[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
Fluoxetine is effective in the treatment of
Panic disorder
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.[7]
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.[46] 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
Impulsive aggression
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 and borderline 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
In 2019 a
Special populations
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 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 cardiac malformations 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 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."[62]
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.[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] Sertraline is often the preferred SSRI during pregnancy due to the relatively minimal fetal exposure observed and its safety profile while breastfeeding.[64]
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
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%.[67]
In 2019, the
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.[70][71] Although gradual dose reductions are recommended with antidepressants with shorter half-lives, tapering may not be necessary with fluoxetine.[72]
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 g), and lower Apgar scores (by <0.4 points).[73][74] There is 30–36% increase in congenital heart defects among children whose mothers were prescribed fluoxetine during pregnancy,[12][13] with fluoxetine use in the first trimester associated with 38–65% increase in septal heart defects.[75][12]
Suicide
This section needs to be updated.(March 2022) |
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 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.[78][79][80] 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 suicide, and it is still possible, while unproven, that antidepressants may prevent actual suicide while increasing suicidality.[81] 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.[82]
On 14 September 1989, Joseph T. Wesbecker killed 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 Lilly was 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 obtain
QT prolongation
Fluoxetine can affect the
Overdose
In overdose, most frequent adverse effects include:[94]
Nervous system effects
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Gastrointestinal effects
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Other effects
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Interactions
Contraindications include prior treatment (within the past 5–6 weeks, depending on the dose)
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 since oxycodone is 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 of
Patients who are taking NSAIDs, antiplatelet drugs, anticoagulants, omega-3 fatty acids, vitamin E, and garlic supplements must be careful when taking fluoxetine or other SSRIs, as they can sometimes increase the blood-thinning effects of these medications.[101][102]
Fluoxetine and
Its use should also be avoided in those receiving other serotonergic drugs such as
Fluoxetine may also increase the risk of opioid overdose in some instances, in part due to its inhibitory effect on cytochrome P-450.
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
Molecular Target |
Fluoxetine | Norfluoxetine
|
---|---|---|
SERT | 1 | 19 |
NET | 660 | 2700 |
DAT | 4180 | 420 |
5-HT2A | 119 ± 10 | 300 |
5-HT2B | 2514 | 5100 |
5-HT2C | 118 ± 11 | 91.2 |
α1 | 3000 | 3900 |
M1 | 870 | 1200 |
M2 | 2700 | 4600 |
M3 | 1000 | 760 |
M4 | 2900 | 2600 |
M5 | 2700 | 2200 |
H1 | 3250 | 10000 |
Entries with this color indicate a lower bound of the Ki value. |
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.[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 5HT2C receptors, which are inhibited by higher concentrations of fluoxetine.[117]
Fluoxetine increases the concentration of circulating
In addition, fluoxetine has been found to act as an
Fluoxetine has been shown to inhibit acid sphingomyelinase, a key regulator of ceramide levels which derives ceramide from sphingomyelin.[124][125]
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[126] to increase serotonin availability and enhance neurotransmission.[127] Over time, this leads to a downregulation of pre-synaptic 5-HT1A receptors, 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.[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
The
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
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 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
The work which eventually led to the discovery of fluoxetine began at
Fluoxetine appeared on the Belgian market in 1986.[149] In the U.S., the FDA gave its final approval in December 1987,[150] and a month later Eli Lilly began marketing Prozac; annual sales in the U.S. reached $350 million within a year.[148] Worldwide sales eventually reached a peak of $2.6 billion a year.[151]
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.[152][153][154] 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.[155]
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.[156] When Lilly's patent expired in August 2001,[157] generic drug competition decreased Lilly's sales of fluoxetine by 70% within two months.[152]
In 2000 an investment bank had projected that annual sales of Sarafem could reach $250M/year.[158] 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.[159][160]
Bringing Sarafem to market harmed Lilly's reputation in some quarters. The diagnostic category of PMDD was
Society and culture
Prescription trends
In 2010, over 24.4 million prescriptions for generic fluoxetine were filled in the United States,[163] making it the third-most prescribed antidepressant after sertraline and citalopram.[163]
In 2011, 6 million prescriptions for fluoxetine were filled in the United Kingdom.[164] Between 1998 and 2017, along with amitriptyline, it was the most commonly prescribed first antidepressant for adolescents aged 12–17 years in England.[165]
Environmental effects
Fluoxetine has been detected in aquatic ecosystems, especially in North America.[166] There is a growing body of research addressing the effects of fluoxetine (among other SSRIs) exposure on non-target aquatic species.[167][168][169][170]
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
Fluoxetine – similar to several other SSRIs – induces
Since 2003, a number of studies have reported fluoxetine-induced impacts on a number of behavioural and physiological endpoints, inducing antipredator behaviour,
Several common plants are known to absorb fluoxetine.
Politics
During the 1990 campaign for
American aircraft pilots
Beginning in April 2010, fluoxetine became one of four antidepressant drugs that the
Sertraline, citalopram, and escitalopram are the only antidepressants permitted for
Research
The antibacterial effect in described above (
Fluoxetine has an
Veterinary use
Fluoxetine is commonly used and effective in treating anxiety related behaviours and separation anxiety in dogs, especially when given as supplementation to behaviour modification.[189][190]
See also
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Further reading
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- Haberman C (21 September 2014). "Selling Prozac as the Life-Enhancing Cure for Mental Woes". The New York Times.