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Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an
antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...
of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive disorder (OCD), bulimia nervosa, panic disorder, and
premenstrual dysphoric disorder Premenstrual dysphoric disorder (PMDD) is a mood disorder characterized by emotional, cognitive, and physical symptoms that cause significant distress or impairment in menstruating women during the luteal phase of the menstrual cycle. The symptoms ...
. It is also approved for treatment of major depressive disorder in adolescents and children 8 years of age and over. It has also been used to treat premature ejaculation. Fluoxetine is taken by mouth. Common side effects include indigestion, trouble sleeping, sexual dysfunction, loss of appetite, dry mouth, and rash. Serious side effects include serotonin syndrome,
mania Mania, also known as manic syndrome, is a mental and behavioral disorder defined as a state of abnormally elevated arousal, affect, and energy level, or "a state of heightened overall activation with enhanced affective expression together wit ...
, seizures, an increased risk of
suicidal behavior Suicide is the act of intentionally causing one's own death. Mental disorders (including depression, bipolar disorder, schizophrenia, personality disorders, anxiety disorders), physical disorders (such as chronic fatigue syndrome), and subs ...
in people under 25 years old, and an increased risk of bleeding. 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 defects in the newborns. It has been suggested that fluoxetine therapy may be continued during breastfeeding if it was used during pregnancy or if other antidepressants were ineffective. Fluoxetine was discovered by
Eli Lilly and Company Eli Lilly and Company is an American pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 countries. The company was founded in 1876 by, and named after, Colonel ...
in 1972, and entered medical use in 1986. It is on the World Health Organization's List of Essential Medicines. It is available as a
generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
. In 2020, it was the 25th most commonly prescribed medication in the United States, with more than 23million prescriptions. Lilly also markets fluoxetine in a fixed-dose combination with olanzapine as olanzapine/fluoxetine (Symbyax).


Medical uses

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 Premenstrual dysphoric disorder (PMDD) is a mood disorder characterized by emotional, cognitive, and physical symptoms that cause significant distress or impairment in menstruating women during the luteal phase of the menstrual cycle. The symptoms ...
, and
trichotillomania Trichotillomania (TTM), also known as hair-pulling disorder or compulsive hair pulling, is a mental disorder characterized by a long-term urge that results in the pulling out of one's own hair. A brief positive feeling may occur as hair is remov ...
.Truven Health Analytics, Inc. DrugPoint® System (Internet) ited 2013 Oct 4 Greenwood Village, CO: Thomsen Healthcare; 2013. It has also been used for cataplexy, obesity, and
alcohol dependence Alcohol dependence is a previous (DSM-IV and ICD-10) psychiatric diagnosis in which an individual is physically or psychologically dependent upon alcohol (also chemically known as ethanol). In 2013, it was reclassified as alcohol use disorde ...
, as well as binge eating disorder. Fluoxetine seems to be ineffective for social anxiety disorder. Studies do not support a benefit in children with
autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
, though there is tentative evidence for its benefit in adult autism. Fluoxetine together with fluvoxamine has shown some initial promise as a potential treatment for reducing COVID-19 severity if given early.


Depression

Efficacy of fluoxetine for short-term (acute) and maintenance treatment of major depressive disorder in adults as well as children and adolescents (8 to 18 years) was established in multiple clinical trials. In addition to being effective for depression in 6-week long double-blind controlled trials, fluoxetine was better than placebo for the prevention of depression recurrence, when the patients, who originally responded to fluoxetine, were treated for a further 38 weeks. Efficacy of fluoxetine for geriatric as well as pediatric depression was also demonstrated in placebo-controlled trials. For children and adolescents with moderate-to-severe depressive disorder, fluoxetine seems to be the best treatment (either with or without
cognitive behavioural therapy Cognitive behavioral therapy (CBT) is a psycho-social intervention that aims to reduce symptoms of various mental health conditions, primarily depression and anxiety disorders. CBT focuses on challenging and changing cognitive distortions (su ...
) but more research is needed to be certain. Fluoxetine is as effective as
tricyclic antidepressant Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and we ...
s but is better tolerated. Fluoxetine may belong to the group of less effective antidepressants; however, its acceptability is higher than any other antidepressant, except
agomelatine Agomelatine, sold under the brand names Valdoxan and Thymanax, among others, is an atypical antidepressant most commonly used to treat major depressive disorder and generalized anxiety disorder. One review found that it is as effective as other a ...
.


Obsessive–compulsive disorder

Fluoxetine is effective in the treatment of obsessive–compulsive disorder (OCD) for adults. It is also effective for treating OCD in children and adolescents. 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 Cognitive behavioral therapy (CBT) is a psycho-social intervention that aims to reduce symptoms of various mental health conditions, primarily depression and anxiety disorders. CBT focuses on challenging and changing cognitive distortions (suc ...
(CBT), for the treatment of moderate to severe OCD.


Panic disorder

The efficacy of fluoxetine in the treatment of panic disorder was demonstrated in two 12-week randomized multicenter
phase III clinical trials The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...
that enrolled patients diagnosed with panic disorder, with or without
agoraphobia Agoraphobia is a mental and behavioral disorder, specifically an anxiety disorder characterized by symptoms of anxiety in situations where the person perceives their environment to be unsafe with no easy way to escape. These situations can in ...
. 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.


Bulimia nervosa

A 2011
systematic review A systematic review is a Literature review, scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from publ ...
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. However, no difference was observed between treatment arms when fluoxetine and
psychotherapy Psychotherapy (also psychological therapy, talk therapy, or talking therapy) is the use of psychological methods, particularly when based on regular personal interaction, to help a person change behavior, increase happiness, and overcome pro ...
were compared to psychotherapy alone.


Premenstrual dysphoric disorder

Fluoxetine is used to treat
premenstrual dysphoric disorder Premenstrual dysphoric disorder (PMDD) is a mood disorder characterized by emotional, cognitive, and physical symptoms that cause significant distress or impairment in menstruating women during the luteal phase of the menstrual cycle. The symptoms ...
, a condition where individuals have affective and
somatic Somatic may refer to: * Somatic (biology), referring to the cells of the body in contrast to the germ line cells ** Somatic cell, a non-gametic cell in a multicellular organism * Somatic nervous system, the portion of the vertebrate nervous sys ...
symptoms monthly during the luteal phase of menstruation. Taking fluoxetine 20 mg/d can be effective in treating PMDD, though doses of 10 mg/d have also been prescribed effectively.


Impulsive aggression

Fluoxetine is considered a first-line medication for the treatment of impulsive aggression of low intensity. Fluoxetine reduced low intensity aggressive behavior in patients in intermittent aggressive disorder and
borderline personality disorder Borderline personality disorder (BPD), also known as emotionally unstable personality disorder (EUPD), is a personality disorder characterized by a long-term pattern of unstable interpersonal relationships, distorted sense of self, and strong ...
. Fluoxetine also reduced acts of domestic violence in alcoholics with a history of such behavior. Obesity and overweight adults In 2019 a
systematic review A systematic review is a Literature review, scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from publ ...
compared the effects on weight of various doses of fluoxetine (60mg/d, 40 mg/d, 20mg/d, 10mg/d) in obese and overweight adults. When compared to placebo, fluoxetine 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. 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 and not receiving a treatment, the authors could not reach conclusive results due to poor quality of evidence.


Special populations

In children and adolescents, fluoxetine is the antidepressant of choice due to tentative evidence favoring its efficacy and tolerability. In pregnancy, fluoxetine is considered a category C drug by the US Food and Drug Administration (FDA). Evidence supporting an increased risk of major fetal malformations resulting from fluoxetine exposure is limited, although the
Medicines and Healthcare products Regulatory Agency The Medicines and Healthcare products Regulatory Agency (MHRA) is an executive agency of the Department of Health and Social Care in the United Kingdom which is responsible for ensuring that medicines and medical devices work and are acceptably ...
(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. Furthermore, an association between fluoxetine use during the first trimester and an increased risk of minor fetal malformations was observed in one study. 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." 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. 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." Sertraline is often the preferred SSRI during pregnancy due to the relatively minimal fetal exposure observed and its safety profile while breastfeeding.


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 Influenza-like illness (ILI), also known as flu-like syndrome or flu-like symptoms, is a medical diagnosis of possible influenza or other illness causing a set of common symptoms. These include fever, shivering, chills, malaise, dry cough, loss o ...
, impotence, insomnia, decreased libido, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating,
tremor A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, fa ...
, vasodilation, and yawning. Fluoxetine is considered the most stimulating of the SSRIs (that is, it is most prone to causing insomnia and agitation). It also appears to be the most prone of the SSRIs for producing dermatologic reactions (e.g. urticaria (hives), rash, itchiness, etc.).


Sexual dysfunction

Sexual dysfunction, including loss of libido,
erectile dysfunction Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men.Cunningham GR, Rosen RC. Overview of male ...
, lack of vaginal lubrication, and
anorgasmia Anorgasmia is a type of sexual dysfunction in which a person cannot achieve orgasm despite adequate stimulation. Anorgasmia is far more common in females (4.6 percent) than in males and is especially rare in younger men. The problem is greater in ...
, 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%. On 11 June 2019, the Pharmacovigilance Risk Assessment Committee of the
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
concluded that there is a possible causal association between SSRI use and long-lasting sexual dysfunction that persists despite discontinuation of SSRI, including fluoxetine, and that the labels of these drugs should be updated to include a warning.


Antidepressant discontinuation syndrome

Fluoxetine's longer half-life makes it less common to develop antidepressant discontinuation syndrome following cessation of therapy, especially when compared to antidepressants with shorter half-lives such as paroxetine. Although gradual dose reductions are recommended with antidepressants with shorter
half-lives Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable at ...
, tapering may not be necessary with fluoxetine.


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 score The Apgar score is a quick way for doctors to evaluate the health of all newborns at 1 and 5 minutes after birth and in response to Neonatal resuscitation, resuscitation. It was originally developed in 1952 by an anesthesiologist at Columbia Univ ...
s (by <0.4 points). There is 30–36% increase in congenital heart defects among children whose mothers were prescribed fluoxetine during pregnancy, with fluoxetine use in the first trimester associated with 38–65% increase in
septal heart defect A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...
s.


Suicide

In October 2004, the FDA added a black box warning to all antidepressant drugs regarding use in children. In 2006, the FDA included adults aged 25 or younger. Statistical analyses conducted by two independent groups of FDA experts found a 2-fold increase of the
suicidal ideation Suicidal ideation, or suicidal thoughts, means having thoughts, ideas, or ruminations about the possibility of ending one's own life.World Health Organization, ''ICD-11 for Mortality and Morbidity Statistics'', ver. 09/2020MB26.A Suicidal ideatio ...
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. 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. In February 2018, the
FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
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. On 14 September 1989, Joseph T. Wesbecker killed eight people and injured twelve before committing suicide. 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. Lawyers began using Prozac to justify the abnormal behaviors of their clients. 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. 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 In statistical hypothesis testing, a result has statistical significance when it is very unlikely to have occurred given the null hypothesis (simply by chance alone). More precisely, a study's defined significance level, denoted by \alpha, is the p ...
results. Considered separately, fluoxetine use in children increased the odds of suicidality by 50%, pp. 25, 28. Retrieved 6 January 2008. and in adults decreased the odds of suicidality by approximately 30%. 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. Similarly, the analysis conducted by the UK
MHRA MHRA may refer to: Organisations * Medicines and Healthcare products Regulatory Agency, UK * Michigan Hot Rod Association, US * Modern Humanities Research Association, UK ** ''MHRA Style Guide'', an academic style guide Other uses * Men's human r ...
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 Self-harm is intentional behavior that is considered harmful to oneself. This is most commonly regarded as direct injury of one's own skin tissues usually without a suicidal intention. Other terms such as cutting, self-injury and self-mutilatio ...
in adults and statistically significantly decreased suicidal ideation by 50%.


QT prolongation

Fluoxetine can affect the electrical currents that
heart muscle cells Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle th ...
use to coordinate their contraction, specifically the potassium currents ''I''to and ''I''Ks that repolarise the cardiac action potential. Under certain circumstances, this can lead to prolongation of the
QT interval The QT interval is a measurement made on an electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the Q wave to the end of the T wave, and approximates to the time taken ...
, 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 Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, d ...
, there is a small risk of potentially lethal abnormal heart rhythms such as torsades de pointes. 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.


Overdose

In overdose, most frequent adverse effects include: Nervous system effects * anxiety * nervousness * insomnia * drowsiness * fatigue or asthenia *
tremor A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, fa ...
* dizziness or lightheadedness Gastrointestinal effects * anorexia (symptom) * nausea * diarrhea * vasodilation * dry mouth * abnormal vision Other effects * abnormal ejaculation * rash * sweating * decreased libido


Interactions

Contraindications include prior treatment (within the past 5–6 weeks, depending on the dose) with MAOIs such as phenelzine and
tranylcypromine Tranylcypromine, sold under the brand name Parnate among others,Drugs.co Page accessed April 17, 2016 is a monoamine oxidase inhibitor (MAOI). More specifically, tranylcypromine acts as nonselective and irreversible inhibitor of the enzyme mono ...
, due to the potential for serotonin syndrome. Its use should also be avoided in those with known hypersensitivities to fluoxetine or any of the other ingredients in the formulation used. Its use in those concurrently receiving pimozide or thioridazine is also advised against. 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. 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. This means combinations of codeine or oxycodone with fluoxetine antidepressant may lead to reduced analgesia. 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 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2D ...
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. Patients who are taking NSAIDs, antiplatelet drugs, anticoagulants, omega-3 fatty acids, vitamin E, and garlic
supplements Supplement or Supplemental may refer to: Health and medicine * Bodybuilding supplement * Dietary supplement * Herbal supplement Media * Supplement (publishing), a publication that has a role secondary to that of another preceding or concurre ...
must be careful when taking fluoxetine or other SSRIs, as they can sometimes increase the blood-thinning effects of these medications. Fluoxetine and
norfluoxetine Seproxetine, also known as (''S'')-norfluoxetine, is a selective serotonin reuptake inhibitor (SSRI). It is the ''S'' enantiomer of norfluoxetine, the main active metabolite of the widely used antidepressant fluoxetine; but little is known abo ...
inhibit many isozymes of the
cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
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 Cytochrome P450 2B6 is an enzyme that in humans is encoded by the ''CYP2B6'' gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances. Funct ...
and CYP2C9. '' In vivo'', fluoxetine and norfluoxetine do not significantly affect the activity of CYP1A2 and
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...
. They also inhibit the activity of
P-glycoprotein P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...
, 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. This extensive effect on the body's pathways for drug metabolism creates the potential for
interactions Interaction is action that occurs between two or more objects, with broad use in philosophy and the sciences. It may refer to: Science * Interaction hypothesis, a theory of second language acquisition * Interaction (statistics) * Interactions o ...
with many commonly used drugs. Its use should also be avoided in those receiving other serotonergic drugs such as monoamine oxidase inhibitors,
tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and wer ...
,
methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamph ...
,
amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
, MDMA, triptans, buspirone, ginseng, dextromethorphan (DXM), linezolid,
tramadol Tramadol, sold under the brand name Ultram among others, is an opioid pain medication used to treat moderate to moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an h ...
, serotonin–norepinephrine reuptake inhibitors, and other SSRIs due to the potential for serotonin syndrome to develop as a result. Fluoxetine may also increase the risk of opioid overdose in some instances, in part due to its inhibitory effect on cytochrome P-450. 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. 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.


Pharmacology


Pharmacodynamics

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and does not appreciably inhibit norepinephrine and
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
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. Thus, dopamine and norepinephrine may contribute to the antidepressant action of fluoxetine in humans at supratherapeutic doses (60–80 mg). This effect may be mediated by 5HT2C receptors, which are inhibited by higher concentrations of fluoxetine. Fluoxetine increases the concentration of circulating
allopregnanolone Allopregnanolone is a naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to treat postpartum d ...
, a potent GABAA receptor positive allosteric modulator, in the brain.
Norfluoxetine Seproxetine, also known as (''S'')-norfluoxetine, is a selective serotonin reuptake inhibitor (SSRI). It is the ''S'' enantiomer of norfluoxetine, the main active metabolite of the widely used antidepressant fluoxetine; but little is known abo ...
, a primary
active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...
of fluoxetine, produces a similar effect on allopregnanolone levels in the brains of mice. Additionally, both fluoxetine and norfluoxetine are such modulators themselves, actions which may be clinically-relevant. In addition, fluoxetine has been found to act as an
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
of the σ1-receptor, with a
potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of how ...
greater than that of citalopram but less than that of fluvoxamine. However, the significance of this property is not fully clear. Fluoxetine also functions as a channel blocker of
anoctamin 1 Anoctamin-1 (ANO1) also known as Transmembrane member 16A (TMEM16A) is a protein that, in humans, is encoded by the ''ANO1'' gene. Anoctamin-1 is a voltage-gated calcium-activated anion channel, which acts as a chloride channel and a bicarbonate ...
, a
calcium-activated chloride channel The Calcium-Dependent Chloride Channel (Ca-ClC) proteins (or calcium-activated chloride channels (CaCCs), are heterogeneous groups of ligand-gated ion channels for chloride that have been identified in many epithelial and endothelial cell types a ...
. A number of other
ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...
s, including nicotinic acetylcholine receptors and 5-HT3 receptors, are also known to be at similar concentrations. Fluoxetine has been shown to inhibit
acid sphingomyelinase Acid sphingomyelinase is one of the enzymes that make up the sphingomyelinase (SMase) family, responsible for catalyzing the breakdown of sphingomyelin to ceramide and phosphorylcholine. They are organized into alkaline, neutral, and acidic SMase de ...
, a key regulator of ceramide levels which derives ceramide from sphingomyelin.


Mechanism of action

Fluoxetine elicits antidepressant effect by inhibiting serotonin reuptake in the synapse by binding to the reuptake pump on the neuronal membrane to increase serotonin availability and enhance neurotransmission. 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. Norfluoxetine and desmethylfluoxetine are metabolites of fluoxetine and also act as serotonin reuptake inhibitors, increasing the duration of action of the drug.


Pharmacokinetics

The bioavailability of fluoxetine is relatively high (72%), and peak plasma concentrations are reached in 6–8 hours. It is highly
bound Bound or bounds may refer to: Mathematics * Bound variable * Upper and lower bounds, observed limits of mathematical functions Physics * Bound state, a particle that has a tendency to remain localized in one or more regions of space Geography *B ...
to plasma proteins, mostly albumin and α1-glycoprotein. Fluoxetine is
metabolized Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
in the liver by isoenzymes of the
cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
system, including CYP2D6. 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 Seproxetine, also known as (''S'')-norfluoxetine, is a selective serotonin reuptake inhibitor (SSRI). It is the ''S'' enantiomer of norfluoxetine, the main active metabolite of the widely used antidepressant fluoxetine; but little is known abo ...
. Both drugs are also potent inhibitors of CYP2D6. 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 days, after a single dose, to 4 to 6 days, after long-term use. Similarly, the half-life of norfluoxetine is longer (16 days) after long-term use. 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. Moreover, the brain concentration of fluoxetine and its metabolites keeps increasing through at least the first five weeks of treatment. For major depressive disorder, while onset of antidepressant action may be felt as early as 1-2 weeks, 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. 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%, 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.


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.


History

The work which eventually led to the discovery of fluoxetine began at
Eli Lilly and Company Eli Lilly and Company is an American pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 countries. The company was founded in 1876 by, and named after, Colonel ...
in 1970 as a collaboration between
Bryan Molloy Bryan Barnet Molloy (30 March 1939 – 20 May 2004) was a Scottish chemist, known notably for helping to invent the antidepressant ''Prozac'', a name for fluoxetine. ''Prozac'' was introduced in 1988, and has been the world's leading antidepressan ...
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 a series of dozens of its derivatives. Hoping to find a derivative inhibiting only
serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
reuptake, an Eli Lilly scientist,
David T. Wong David T. Wong (born circa 1936 in Hong Kong) is a Hong Kong-born American neuroscientist. He is a former researcher with Eli Lilly and Company and an adjunct professor at the Indiana University School of Medicine. Wong is known for the discovery of ...
, proposed to retest the series for the '' in vitro'' reuptake of serotonin, norepinephrine and
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
. This test, carried out by Jong-Sir Horng in May 1972, showed the compound later named fluoxetine to be the most potent and selective inhibitor of serotonin reuptake of the series. Wong published the first article about fluoxetine in 1974. 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. Fluoxetine appeared on the Belgian market in 1986. In the U.S., the FDA gave its final approval in December 1987, and a month later Eli Lilly began marketing Prozac; annual sales in the U.S. reached $350 million within a year. Worldwide sales eventually reached a peak of $2.6 billion a year. 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 Premenstrual dysphoric disorder (PMDD) is a mood disorder characterized by emotional, cognitive, and physical symptoms that cause significant distress or impairment in menstruating women during the luteal phase of the menstrual cycle. The symptoms ...
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. The invention of using fluoxetine to treat PMDD was made by
Richard Wurtman Richard Wurtman (March 9, 1936 – December 13, 2022) was an American neuroscientist who spent his career doing basic and translational neuroscience research at Massachusetts Institute of Technology. Early life and education Richard Wurtman earn ...
at MIT; the patent was licensed to his startup, Interneuron, which in turn sold it to Lilly. 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 Barr Pharmaceuticals was a global specialty and generic drug manufacturer with operations in 30 countries. Approximately 75% of the company's revenues were from the sale of generic drugs, including 18% of sales which were from the sale of oral co ...
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. When Lilly's patent expired in August 2001,
generic drug A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
competition decreased Lilly's sales of fluoxetine by 70% within two months. In 2000 an investment bank had projected that annual sales of Sarafem could reach $250M/year. 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. 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 under way in 1998, has been criticized. Lilly was criticized for inventing a disease in order to make money, and for not innovating but rather just seeking ways to continue making money from existing drugs. 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.


Society and culture


Prescription trends

In 2010, over 24.4 million prescriptions for generic fluoxetine were filled in the United States, making it the third-most prescribed antidepressant after sertraline and citalopram. In 2011, 6 million prescriptions for fluoxetine were filled in the United Kingdom. Between 1998 and 2017, along with amitriptyline, it was the most commonly prescribed first antidepressant for adolescents aged 12-17 years in England.


Environmental effects

Fluoxetine has been detected in aquatic ecosystems, especially in North America. There is a growing body of research addressing the effects of fluoxetine (among other SSRIs) exposure on non-target aquatic species. 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. 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. Fluoxetine similar to several other SSRIs induces reproductive behavior in some
shellfish Shellfish is a colloquial and fisheries term for exoskeleton-bearing aquatic invertebrates used as food, including various species of molluscs, crustaceans, and echinoderms. Although most kinds of shellfish are harvested from saltwater envir ...
at concentrations as low as 10 M, or 30 parts per trillion. Since 2003, a number of studies have reported fluoxetine-induced impacts on a number of behavioural and physiological endpoints, inducing antipredator behaviour, reproduction, and foraging 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. At environmentally realistic concentrations, fluoxetine alters
insect emergence A pupa ( la, pupa, "doll"; plural: ''pupae'') is the life stage of some insects undergoing transformation between immature and mature stages. Insects that go through a pupal stage are holometabolous: they go through four distinct stages in thei ...
timing. Richmond ''et al.'', 2019 find that at low concentrations it accelerates emergence of
Diptera Flies are insects of the order Diptera, the name being derived from the Greek δι- ''di-'' "two", and πτερόν ''pteron'' "wing". Insects of this order use only a single pair of wings to fly, the hindwings having evolved into advanced ...
, while at unusually high concentrations it has no discernable effect. Several common plants are known to absorb fluoxetine. Several crops have been tested, and Redshaw ''et al.'' 2008 find that
cauliflower Cauliflower is one of several vegetables in the species ''Brassica oleracea'' in the genus ''Brassica'', which is in the Brassicaceae (or mustard) family. It is an annual plant that reproduces by seed. Typically, only the head is eaten – the ...
absorbs large amounts into the stem and leaf but not the head or root. Wu ''et al.'' 2012 find that lettuce and
spinach Spinach (''Spinacia oleracea'') is a leafy green flowering plant native to central and western Asia. It is of the order Caryophyllales, family Amaranthaceae, subfamily Chenopodioideae. Its leaves are a common edible vegetable consumed either f ...
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. Wu tested all tissues of soybean and all showed only low concentrations. By contrast various Reinhold ''et al.'' 2010 find
duckweed Lemnoideae is a subfamily of flowering aquatic plants, known as duckweeds, water lentils, or water lenses. They float on or just beneath the surface of still or slow-moving bodies of fresh water and wetlands. Also known as bayroot, they arose ...
s have a high uptake of fluoxetine and show promise for bioremediation of contaminated water, especially '' Lemna minor'' and ''
Landoltia punctata ''Spirodela punctata'' (or ''Landoltia punctata'', common name dotted duckmeat) is a species of duckweed (Lemnoideae). The species is morphologically intermediate between ''Lemna'' and other species of ''Spirodela ''Spirodela'' is a genus of ...
''. Ecotoxicity for organisms involved in
aquaculture Aquaculture (less commonly spelled aquiculture), also known as aquafarming, is the controlled cultivation ("farming") of aquatic organisms such as fish, crustaceans, mollusks, algae and other organisms of value such as aquatic plants (e.g. lot ...
is well documented. Fluoxetine affects both aquacultured invertebrates and vertebrates, and inhibits soil microbes including a large antibacterial effect. For applications of this see .


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.


American aircraft pilots

Beginning 5 April 2010, fluoxetine became one of four antidepressant drugs that the FAA permitted for
pilots An aircraft pilot or aviator is a person who controls the flight of an aircraft by operating its directional flight controls. Some other aircrew members, such as navigators or flight engineers, are also considered aviators, because they a ...
with authorization from an
aviation medical examiner In Europe, the United States, and other countries, an Aviation Medical Examiner or Aero-medical Examiner (AME) is a physician designated by the local aviation authority and given the authority to perform flight physical examinations and issue aviat ...
. The other permitted antidepressants are sertraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro). These four remain the only antidepressants permitted by FAA Sertraline, citalopram and escitalopram are the only antidepressants permitted for EASA medical certification, as of January 2019.


Other uses

The antibacterial effect in described above () could be applied against multiresistant biotypes in
crop bacterial disease Plant pathology (also phytopathology) is the scientific study of diseases in plants caused by pathogens (infectious organisms) and environmental conditions (physiological factors). Organisms that cause infectious disease include fungus, fung ...
s and bacterial
aquaculture disease Aquaculture (less commonly spelled aquiculture), also known as aquafarming, is the controlled cultivation ("farming") of aquatic organisms such as fish, crustaceans, mollusks, algae and other organisms of value such as aquatic plants (e.g. lotus) ...
s. In a glucocorticoid receptor-defective zebrafish mutant (''Danio rerio'') with reduced exploratory behavior, fluoxetine rescued the normal exploratory behavior. This demonstrates relationships between glucocorticoids, fluoxetine, and exploration in this fish. Fluoxetine has an
anti-nematode A nematicide is a type of chemical pesticide used to kill plant- parasitic nematodes. Nematicides have tended to be broad-spectrum toxicants possessing high volatility or other properties promoting migration through the soil. Aldicarb (Temik), a c ...
effect. Choy ''et al.'', 1999 finds some of this effect is due to interference with certain transmembrane proteins.


References


Further reading

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External links

* * {{Portal bar , Medicine 5-HT2C antagonists 5-HT3 antagonists Anorectics Anticonvulsants Antidepressants AbbVie brands CYP2D6 inhibitors Eli Lilly and Company brands GABAA receptor positive allosteric modulators Nicotinic antagonists Phenol ethers Secondary amines Selective serotonin reuptake inhibitors Sigma agonists Trifluoromethyl compounds World Health Organization essential medicines Wikipedia medicine articles ready to translate