Fluoxetine
Encyclopedia
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
of the selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
(SSRI) class. It is manufactured and marketed by Eli Lilly and Company
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
. In combination with olanzapine
Olanzapine
Olanzapine is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder...
it is known as Symbyax.
Fluoxetine is approved for the treatment of major depression (including pediatric depression), obsessive-compulsive disorder
Obsessive-compulsive disorder
Obsessive–compulsive disorder is an anxiety disorder characterized by intrusive thoughts that produce uneasiness, apprehension, fear, or worry, by repetitive behaviors aimed at reducing the associated anxiety, or by a combination of such obsessions and compulsions...
(in both adult and pediatric populations), bulimia nervosa
Bulimia nervosa
Bulimia nervosa is an eating disorder characterized by binge eating and purging or consuming a large amount of food in a short amount of time, followed by an attempt to rid oneself of the food consumed, usually by purging and/or by laxative, diuretics or excessive exercise. Bulimia nervosa is...
, panic disorder
Panic disorder
Panic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
and premenstrual dysphoric disorder
Premenstrual dysphoric disorder
Premenstrual dysphoric disorder is a severe form of premenstrual syndrome, afflicting 3% to 8% of women. It is a diagnosis associated primarily with the luteal phase of the menstrual cycle...
.
Despite the availability of newer agents, fluoxetine remains extremely popular. In 2010, over 24.4 million prescriptions for generic formulations of fluoxetine were filled in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
alone, making it the third most prescribed antidepressant after sertraline
Sertraline
Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...
(SSRI; became generic in 2006) and citalopram
Citalopram
Citalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...
(SSRI; became generic in 2003) in that country.
Medical uses
Fluoxetine is frequently used to treat major depression, bipolar disorderBipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
, obsessive compulsive disorder, bulimia nervosa
Bulimia nervosa
Bulimia nervosa is an eating disorder characterized by binge eating and purging or consuming a large amount of food in a short amount of time, followed by an attempt to rid oneself of the food consumed, usually by purging and/or by laxative, diuretics or excessive exercise. Bulimia nervosa is...
, panic disorder
Panic disorder
Panic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
and premenstrual dysphoric disorder
Premenstrual dysphoric disorder
Premenstrual dysphoric disorder is a severe form of premenstrual syndrome, afflicting 3% to 8% of women. It is a diagnosis associated primarily with the luteal phase of the menstrual cycle...
. It has also been used for cataplexy
Cataplexy
Cataplexy is a sudden and transient episode of loss of muscle tone, often triggered by emotions. It is a rare disease , but affects roughly 70% of people who have narcolepsy...
, obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
, and alcohol dependence
Alcohol dependence
Alcohol dependence, as described in the DSM-IV, is a psychiatric diagnosis describing an entity in which an individual uses alcohol despite significant areas of dysfunction, evidence of physical dependence, and/or related hardship.-Definition and diagnosis:According to the DSM-IV criteria for...
, as well as binge eating disorder
Binge eating disorder
Binge eating disorder is the most common eating disorder in the United States affecting 3.5% of females and 2% of males and is prevalent in up to 30% of those seeking weight loss treatment...
.
Depression
Fluoxetine was shown to be effective for depression in 6-week long double-blind controlled trials, where it also alleviated anxiety and improved sleep. 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.The recent research suggests that a significant part of the resistance to the SSRIs paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
(Paxil) and citalopram
Citalopram
Citalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...
(Celexa) can be explained by the genetic variation
Genetic variation
Genetic variation, variation in alleles of genes, occurs both within and among populations. Genetic variation is important because it provides the “raw material” for natural selection. Genetic variation is brought about by mutation, a change in a chemical structure of a gene. Polyploidy is an...
of Pgp
P-glycoprotein
P-glycoprotein 1 also known as multidrug resistance protein 1 or ATP-binding cassette sub-family B member 1 or cluster of differentiation 243 is a glycoprotein that in humans is encoded by the ABCB1 gene...
transporter. Paroxetine and citalopram, which are Pgp substrates, are actively transported from the brain by this protein. Fluoxetine is not a substrate of Pgp, and thus a switch from paroxetine or citalopram to fluoxetine may be beneficial to the nonresponders.
Obsessive-compulsive disorder
OCDObsessive-compulsive disorder
Obsessive–compulsive disorder is an anxiety disorder characterized by intrusive thoughts that produce uneasiness, apprehension, fear, or worry, by repetitive behaviors aimed at reducing the associated anxiety, or by a combination of such obsessions and compulsions...
was successfully treated by fluoxetine in two adult and one pediatric placebo-controlled 13-week trials. The higher doses of fluoxetine appeared to result in better response, while the reverse relationship was observed in the treatment of depression. Fluoxetine dramatically, by 40-50%, decreased the frequency of panic attacks in two controlled trials of panic disorder patients. In three double-blind trials, fluoxetine significantly decreased the number of binge-eating
Binge eating
Binge eating is a pattern of disordered eating which consists of episodes of uncontrollable eating. It is sometimes as a symptom of binge eating disorder. During such binges, a person rapidly consumes an excessive amount of food...
and purging episodes of bulimia nervosa
Bulimia nervosa
Bulimia nervosa is an eating disorder characterized by binge eating and purging or consuming a large amount of food in a short amount of time, followed by an attempt to rid oneself of the food consumed, usually by purging and/or by laxative, diuretics or excessive exercise. Bulimia nervosa is...
. Continued year-long treatment of the patients, who originally responded to fluoxetine, was more effective than placebo for the prevention of bulimia nervosa episodes.
Adverse effects
Sexual dysfunction
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
is a common side effect with SSRIs
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
. Specifically, side effects often include difficulty becoming aroused, erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
, lack of interest in sex, and anorgasmia
Anorgasmia
Anorgasmia, or Coughlan's syndrome, is a type of sexual dysfunction in which a person cannot achieve orgasm, even with adequate stimulation. In males the condition is often related to delayed ejaculation . Anorgasmia can often cause sexual frustration...
(inability to achieve orgasm). Genital anesthesia, loss of or decreased response to sexual stimuli, and ejaculatory anhedonia are also possible. Although usually reversible, these sexual side effects can last for months, years, or permanence after the drug has been completely withdrawn. This is known as Post SSRI Sexual Dysfunction
Post SSRI Sexual Dysfunction
Post-SSRI sexual dysfunction is a name given to a reported iatrogenic sexual dysfunction caused by the previous use of selective serotonin reuptake inhibitor antidepressants. While apparently uncommon, it can last for months, years, or sometimes indefinitely after the discontinuation of SSRIs. ...
.
According to the manufacturer of Prozac brand of fluoxetine, Eli Lilly
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
, fluoxetine is contraindicated in individuals taking monoamine oxidase inhibitor
Monoamine oxidase inhibitor
Monoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
s, pimozide
Pimozide
Pimozide is an antipsychotic drug of the diphenylbutylpiperidine class. It was discovered at Janssen Pharmaceutica in 1963. It has a high potency compared to chlorpromazine . On a weight basis it is even more potent than haloperidol. It also has special neurologic indications for Tourette syndrome...
(Orap) or thioridazine
Thioridazine
Thioridazine is a piperidine typical antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis...
(Mellaril). The prescribing information recommends that the treatment of the patients with liver impairment "must be approached with caution". The elimination of fluoxetine and its metabolite norfluoxetine is about half as fast in these patients, resulting in the proportionate increase of exposure to the drug. Ibuprofen used in combination with fluoxetine can cause significant intestinal bleeding after a period of use.
Among the common adverse effects
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
associated with fluoxetine and listed in the prescribing information, the effects with the greatest difference from placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
are nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
(22% vs 9% for placebo), insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
(19% vs 10% for placebo), somnolence
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
(12% vs 5% for placebo), anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
(10% vs 3% for placebo), anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
(12% vs 6% for placebo), nervousness (13% vs 8% for placebo), asthenia (11% vs 6% for placebo) and tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
(9% vs 2% for placebo). Those that most often resulted in interruption of the treatment were anxiety, insomnia, and nervousness (1-2% each), and in pediatric trials—mania (2%).
Similarly to other SSRIs, sexual side effects
Sexual dysfunction
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
are common with fluoxetine; they include anorgasmia
Anorgasmia
Anorgasmia, or Coughlan's syndrome, is a type of sexual dysfunction in which a person cannot achieve orgasm, even with adequate stimulation. In males the condition is often related to delayed ejaculation . Anorgasmia can often cause sexual frustration...
and reduced libido
Libido
Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
.
In addition, rash or urticaria, sometimes serious, was observed in 7% patients in clinical trials; one-third of these cases resulted in discontinuation of the treatment. Postmarketing reports note several cases of complications developed in patients with rash. The symptoms included vasculitis
Vasculitis
Vasculitis refers to a heterogeneous group of disorders that are characterized by inflammatory destruction of blood vessels. Both arteries and veins are affected. Lymphangitis is sometimes considered a type of vasculitis...
and lupus-like syndrome
Lupus erythematosus
Lupus erythematosus is a category for a collection of diseases with similar underlying problems with immunity . Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs...
. Death has been reported to occur in association with these systemic events.
Akathisia
Akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
, that is inner tension, restlessness, and the inability to stay still, often accompanied by "constant pacing, purposeless movements of the feet and legs, and marked anxiety", is a common side effect of fluoxetine. Akathisia usually begins after the initiation of the treatment or increase of the dose and disappears after fluoxetine is stopped or its dose is decreased, or after treatment with propranolol. There are case reports directly linking akathisia with suicidal attempts, with patients feeling better after the withdrawal of fluoxetine, and again developing severe akathisia on repeated exposure to fluoxetine. These patients described "that the development of the akathisia made them feel suicidal and that it had precipitated their prior suicide attempts". The experts note that because of the link of akathisia with suicide and the distress it causes to the patient, "it is of vital importance to increase awareness amongst staff and patients of the symptoms of this relatively common condition". More rarely, fluoxetine has been associated with related movement disorders acute dystonia
Dystonia
Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...
and tardive dyskinesia
Tardive dyskinesia
Tardive dyskinesia is a difficult-to-treat form of dyskinesia that can be tardive...
.
Fluoxetine taken during pregnancy also increases rate of poor neonatal adaptation. Because fluoxetine is excreted in human milk
Breast milk
Breast milk, more specifically human milk, is the milk produced by the breasts of a human female for her infant offspring...
, nursing while on fluoxetine is not recommended. A study of fluoxetine administered to newborn mice found that early postnatal exposure of the drug later caused the adult mice to exhibit depressive and anxious behavior similar to those of induced depression, which could be relieved by fluoxetine. The American Association of Pediatrics classifies fluoxetine as a drug for which the effect on the nursing infant is unknown but may be of concern.
Discontinuation syndrome
Several case reports in the literature describe severe withdrawal or discontinuation symptoms following an abrupt interruption of fluoxetine treatment. However, various studies have shown that the side effects of the fluoxetine discontinuation are uncommon and mild, especially compared to paroxetine, venlafaxine and fluvoxamine, probably due to the relatively long pharmacological half-life of fluoxetine. One of the recommended strategies for the management of discontinuation syndrome with other SSRIs is to substitute fluoxetine for the original agent, in cases where tapering off the dose of the original SSRI is ineffective. The double-blindDouble-blind
A blind or blinded experiment is a scientific experiment where some of the people involved are prevented from knowing certain information that might lead to conscious or subconscious bias on their part, invalidating the results....
controlled studies support this opinion. No increase in side effects was observed in several studies when the treatment with fluoxetine was blindly interrupted for a short time (4–8 days) and then reinstated, this result being consistent with its slow elimination from the body. More side effects occurred during the interruption of sertraline
Sertraline
Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...
(Zoloft) in these studies, and significantly more during the interruption of paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
. In a longer, 6 week-long, blind discontinuation study, an insignificantly higher (32% vs 27%) overall rate of new or worsened side effects was observed in the group that discontinued fluoxetine than in the group that continued treatment. However, a significantly higher 4.2% rate of somnolence
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
at week 2 and 5-7% rate of dizziness at weeks 4-6 were reported by the patients in the discontinuation group. This prolonged course of the discontinuation symptoms, with dizziness persisting to the end of the study, is also consistent with the long half-life of fluoxetine in the body. According to a 2007 summary report of available evidence, fluoxetine has the lowest incidence of discontinuation syndrome among several antidepressants including paroxetine and venlafaxine.
See also SSRI discontinuation syndrome
SSRI discontinuation syndrome
SSRI discontinuation syndrome, also known as SSRI withdrawal syndrome or SSRI cessation syndrome, is a syndrome that can occur following the interruption, dose reduction, or discontinuation of SSRI or SNRI antidepressant medications...
.
Suicide
The FDA requires all antidepressants to carry a black box warningBlack box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
stating that antidepressants may increase the risk of suicide
Suicide
Suicide is the act of intentionally causing one's own death. Suicide is often committed out of despair or attributed to some underlying mental disorder, such as depression, bipolar disorder, schizophrenia, alcoholism, or drug abuse...
in persons younger than 25. This warning is based on statistical analyses conducted by two independent groups of the 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. 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. This opinion goes against the general consensus that "suicidal ideation has been associated with suicide attempt
Parasuicide
Parasuicide refers to suicide attempts or gestures and self-harm where there is no result in death. It is a non-fatal act in which a person deliberately causes injury to himself or ingests any prescribed or generally recognised therapeutic dose in excess...
in retrospective studies and with suicide in prospective studies".
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% (not statistically significant due to the low number of cases), and in adults decreased the odds of suicidality by approximately 30% (statistically significant). Similarly, the analysis conducted by the UK MHRA
Medicines and Healthcare products Regulatory Agency
The Medicines and Healthcare products Regulatory Agency is the UK government agency which is responsible for ensuring that medicines and medical devices work and are acceptably safe....
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
Self-harm
Self-harm or deliberate self-harm includes self-injury and self-poisoning and is defined as the intentional, direct injuring of body tissue most often done without suicidal intentions. These terms are used in the more recent literature in an attempt to reach a more neutral terminology...
and statistically significantly decreased suicidal ideation by 50%.
Interactions
Fluoxetine and norfluoxetine inhibitEnzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
many isozyme
Isozyme
Isozymes are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes usually display different kinetic parameters Isozymes (also known as isoenzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes...
s of the cytochrome P450 system that make drug metabolism
Drug metabolism
Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...
possible. Both are potent inhibitors of CYP2D6
CYP2D6
Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
(the main enzyme responsible for their metabolism) and mild to moderate inhibitors of CYP1A2
CYP1A2
Cytochrome P450 1A2 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body...
, CYP2B6
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.- Function :...
, CYP2C9
CYP2C9
Cytochrome P450 2C9 is a protein that in humans is encoded by the CYP2C9 gene.- Function :CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes...
/2C19
CYP2C19
Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...
, and CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
; furthermore, they inhibit the activity of P-glycoprotein
P-glycoprotein
P-glycoprotein 1 also known as multidrug resistance protein 1 or ATP-binding cassette sub-family B member 1 or cluster of differentiation 243 is a glycoprotein that in humans is encoded by the ABCB1 gene...
, a type of membrane transport protein that plays an important role in drug transport and metabolism. This extensive effect on the body's pathways for drug metabolism creates the potential for interactions
Drug interaction
A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...
with many commonly used drugs.
The simultaneous use of fluoxetine with triptans, tramadol
Tramadol
Tramadol hydrochloride is a centrally acting synthetic opioid analgesic used in treating moderate pain. The drug has a wide range of applications, including treatment for restless legs syndrome and fibromyalgia...
or other serotonergic
Serotonergic
Serotonergic or serotoninergic means "related to the neurotransmitter serotonin". A synapse is serotonergic if it uses serotonin as its neurotransmitter...
agents can result in a rare, but potentially life-threatening adverse drug reaction called serotonin syndrome
Serotonin syndrome
Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...
.
Fluoxetine has been shown to have antimicrobial activity against several groups of microorganisms. This is mainly against Gram positive microorganisms. It also shows synergistic activity when combined with some antibiotics against several bacteria.
Pharmacokinetics
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
of fluoxetine is relatively high (72%), and peak plasma concentrations are reached in 6 to 8 hours. It is highly bound
Plasma protein binding
A drug's efficiency may be affected by the degree to which it binds to the proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Common blood proteins that drugs bind to are human serum albumin, lipoprotein, glycoprotein, α, β‚ and γ...
to plasma proteins, mostly albumin
Human serum albumin
Human serum albumin is the most abundant protein in human blood plasma. It is produced in the liver. Albumin constitutes about half of the blood serum protein...
.
Fluoxetine is metabolized
Drug metabolism
Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...
in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
by isoenzymes of the cytochrome P450 system, including CYP2D6
CYP2D6
Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
. The role of CYP2D6 in the metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
of fluoxetine may be clinically important, as there is great genetic variability
Genetic variability
Genetic variability is a measure of the tendency of individual genotypes in a population to vary from one another. Variability is different from genetic diversity, which is the amount of variation seen in a particular population. The variability of a trait describes how much that trait tends to...
in the function of this enzyme among people. Only one metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
of fluoxetine, norfluoxetine
Norfluoxetine
Seproxetine, also known as -norfluoxetine, is a selective serotonin reuptake inhibitor . It is an active metabolite of fluoxetine. Seproxetine was being investigated by Eli Lilly and Company as an antidepressant but development was never completed and the drug was never marketed.-Synthesis:Fuller,...
(N-demethylated
Demethylation
Demethylation is the chemical process resulting in the removal a of methyl group from a molecule.A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen atoms....
fluoxetine), is biologically active.
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. 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. 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. 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%, 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.
A PET study compared the action of a single dose of fluoxetine on exclusively heterosexual and exclusively homosexual
Homosexuality
Homosexuality is romantic or sexual attraction or behavior between members of the same sex or gender. As a sexual orientation, homosexuality refers to "an enduring pattern of or disposition to experience sexual, affectional, or romantic attractions" primarily or exclusively to people of the same...
men who attested that their past and present sexual behavior
Human sexual behavior
Human sexual activities or human sexual practices or human sexual behavior refers to the manner in which humans experience and express their sexuality. People engage in a variety of sexual acts from time to time, and for a wide variety of reasons...
, desires, and fantasies were directed entirely toward women or men, respectively. The study found that in some areas of the brain the metabolic response in these two groups was different. "Both groups, however, did exhibit similar widespread lateralized metabolic responses to fluoxetine (relative to placebo), with most areas of the brain responding in the same direction." They "did not differ on behavioral measures or blood levels of fluoxetine".
Fluoxetine is a selective serotonin reuptake inhibitor and does not appreciably inhibit norepinephrine and dopamine reuptake. Nevertheless, Eli Lilly researchers found that a single injection of a rat with a large dose of fluoxetine also results in a significant increase of brain concentrations of norepinephrine and dopamine. This effect may be mediated by 5HT2a and, in particular, 5HT2c receptors, which are inhibited by higher concentrations of fluoxetine. The Ely Lilly scientists also suggested that the effects on dopamine and norepinephrine may contribute to the antidepressant action of fluoxetine. In the opinion of other researchers, however, the magnitude of this effect is unclear. The dopamine and norepinephrine increase was not observed at a smaller, more clinically relevant dose of fluoxetine. Similarly, in electrophysiological studies only larger and not smaller doses of fluoxetine changed the activity of rat's norepinephrinergic neurons. Some authors, however, argue that these findings may still have clinical relevance for the treatment of severe illness with supratherapeutic doses (60–80 mg) of fluoxetine. Among SSRIs, 'fluoxetine is the least "selective" of all the SSRIs, with a 10-fold difference in binding affinity between its first and second neural targets (i.e., the serotonin and norepinephrine uptake pumps, respectively).' Anything greater than a 10-fold difference results in insignificant activation of the secondary neuronal targets.
Besides its well-known effects on serotonin, fluoxetine also increases density of endogenous opioid receptors in the brains of rats. It is unclear if this occurs in humans, but if so it might account for some of fluoxetine's antidepressant and/or side effect profile.
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 patients 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.Mechanism of action
Fluoxetine's mechanism of action is primarily that of an SSRI although it may produce some of its effects through 5-HT2C antagonism in a manner similar to the novel antidepressant agomelatine. Other psychopharmacological substances that exhibit 5-HT2C antagonism are mirtazapineMirtazapine
Mirtazapine is a tetracyclic antidepressant used primarily in the treatment of depression. It is also sometimes used as a hypnotic, antiemetic, and appetite stimulant, and for the treatment of anxiety, among other indications...
, agomelatine, trazodone
Trazodone
Trazodone is an antidepressant of the serotonin antagonist and reuptake inhibitor class. It is a phenylpiperazine compound...
, some tricyclic antidepressants
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
and various (mainly atypical) antipsychotics
Atypical antipsychotic
The atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
.
Fluoxetine acts as an agonist at the σ1-receptor
Sigma-1 receptor
The sigma-1 receptor is a chaperone protein at the endoplasmatic reticulum that modulates calcium signaling through the IP3 receptor. In humans, the sigma-1 receptor is encoded by the SIGMAR1 gene....
, with a potency greater than that of Citalopram, but less than that of Fluvoxamine.
History
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 antihistamineAntihistamine
An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...
diphenhydramine
Diphenhydramine
Diphenhydramine hydrochloride is a first-generation antihistamine possessing anticholinergic, antitussive, antiemetic, and sedative properties which is mainly used to treat allergies. Like most other first-generation antihistamines, the drug also has a powerful hypnotic effect, and for this reason...
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. Testing the physiological effects of these compounds in mice resulted in nisoxetine
Nisoxetine
Nisoxetine is a drug which inhibits the reuptake of norepinephrine . It is a racemic compound with two isomers...
, a selective norepinephrine reuptake inhibitor
Norepinephrine reuptake inhibitor
A norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...
currently widely used in biochemical experiments.
Later, hoping to find a derivative inhibiting only serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
reuptake, another Eli Lilly scientist, David Wong
David Wong
David Wong may refer to:* David Wong Louie, American writer of novels and short stories * Dave Wong , Chinese singer* David Wong , philosophy professor at Duke University...
, proposed to retest the series for the in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
reuptake of serotonin, norepinephrine and dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
. 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, presented a new drug request to the U.S. Food and Drug Administration (FDA) for fluoxetine.
A controversy ensued after Lilly researchers published a paper titled "Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug" claiming fluoxetine to be the first selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
(SSRI). Two years later they had to issue a correction, admitting that the first SSRI was zimelidine
Zimelidine
Zimelidine was the first selective serotonin reuptake inhibitor antidepressant to be marketed. It is a pyridylallylamine, and is structurally different from other antidepressants....
developed by Arvid Carlsson
Arvid Carlsson
Arvid Carlsson is a Swedish scientist who is best known for his work with the neurotransmitter dopamine and its effects in Parkinson's disease...
and colleagues. Fluoxetine made its appearance on the Belgian market in 1986 and was approved for use by the FDA in December 1987. Fluoxetine was the fourth SSRI to make it to market, after zimelidine
Zimelidine
Zimelidine was the first selective serotonin reuptake inhibitor antidepressant to be marketed. It is a pyridylallylamine, and is structurally different from other antidepressants....
, indalpine
Indalpine
Indalpine is an SSRI class drug that was discovered in 1977 by the pharmacologists Le Fur and Uzan at Pharmuka, a small Paris based pharmaceutical firm, who credit Baron Shopsin and the innovative body of basic and clinical research carried out with colleagues at NYU-Bellevue/NYU School of...
and fluvoxamine
Fluvoxamine
Fluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
. However, the first two were withdrawn due to the side effects, and a vigorous marketing campaign by Eli Lilly made sure that in the popular culture fluoxetine has been perceived as a scientific breakthrough and associated with the title of the first SSRI.
Eli Lilly
Eli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
's patent on Prozac (fluoxetine) expired in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
in August 2001, prompting an influx of generic drugs onto the market. Prozac was rebranded "Sarafem" for the treatment of PMDD in an attempt to stem the post-patent decrease in Eli Lilly's sales of fluoxetine.
Controversy
In 1989, Joseph WesbeckerStandard Gravure shooting
The Standard Gravure shooting occurred on September 14, 1989 when 47-year old Joseph T. Wesbecker, a pressman on disability for mental illness entered Standard Gravure, his former workplace, and killed eight people and injured twelve before committing suicide after a history of suicidal ideation...
shot and killed eight people and injured 12 others before killing himself at his place of work in Kentucky. Wesbecker had been taking the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine for four weeks before these homicides, and this led to a legal action against the makers of fluoxetine, Eli Lilly. The case was tried and settled in 1994, and as part of the settlement a number of pharmaceutical company documents about drug-induced activation were released into the public domain. Subsequent legal cases have further raised the possibility of a link between antidepressant use and violence.
The Prozac Survivors Support Group created a report on 288 individuals who had suffered adverse effects from Fluoxetine during 1991 and 1992. It showed that most of the cases led to violence against self or other individuals. There were 164 cases in the suicide and suicide ideation category, including 34 complete suicides. There were also 133 cases of crime and violence, which featured 14 murders, nine attempted murders, 39 violent actions, 54 violent preoccupations and 17 crimes. The report also showed that 13 individuals had become addicted to Fluoxetine and 14 cases of alcoholism forming or worsening. However, Mayo Clinic psychiatrist Daniel K. Hall-Flavin has stated that people cannot get addicted to antidepressants.
A meta-analysis
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
published in February 2008 combined 35 clinical trials of four newer antidepressants (fluoxetine, paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
(Paxil), nefazodone
Nefazodone
Nefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...
(Serzone) and venlafaxine
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
(Effexor)). These antidepressants belonging to three different pharmacological groups were considered together, and the authors did not analyze them separately. The authors concluded that "although the difference [between the placebo and antidepressants] easily attained statistical significance
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
", it did not meet the criterion for clinical significance, as used by National Institute for Health and Clinical Excellence
National Institute for Health and Clinical Excellence
The National Institute for Health and Clinical Excellence is a special health authority of the English National Health Service , serving both English NHS and the Welsh NHS...
(UK), "for any but the most severely depressed patients". Some articles in the press using the titles "The creation of the Prozac myth" and "Prozac does not work in majority of depressed patients" presented these general findings about the relative efficacy of antidepressants and placebo as the findings about ineffectiveness of fluoxetine. In a follow-up article, the authors of the meta-analysis noted that "unfortunately, during its initial coverage, the media often portrayed the results as “antidepressants do not work”, which misrepresented our more nuanced pattern of findings".
As of April 2, 2010, Fluoxetine (Prozac) is one of four antidepressant drugs that the FAA will allow pilots to take without automatically prohibiting them from piloting an aircraft. The others are Sertraline
Sertraline
Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...
(Zoloft), Citalopram
Citalopram
Citalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...
(Celexa), and Escitalopram
Escitalopram
Escitalopram is an antidepressant of the selective serotonin reuptake inhibitor class. It is approved by the U.S...
(Lexapro).
In popular culture
Because of its wide appeal as a popular antidepressant, Prozac has had numerous references to it in popular culture, including many books, movies, and songs. The book Listening to Prozac was written in 1993 by psychiatrist Peter D. KramerPeter D. Kramer
Peter D. Kramer, M.D., is an American psychiatrist, former Marshall Scholar and faculty member of Brown Medical School specializing in the area of depression. He considers depression to be a serious illness with tangible physiological effects such as disorganizing the brain and disrupting the...
. The memoir Prozac Nation
Prozac Nation (book)
Prozac Nation , an autobiography published in 1994 and written by Elizabeth Wurtzel, describes the author's experiences with major depression, her own character failings and how she managed to live through particularly difficult periods while completing college and working as a writer...
was written in 1994 by Elizabeth Wurtzel
Elizabeth Wurtzel
Elizabeth Lee Wurtzel is an American corporate attorney, writer and journalist, known for her work in the confessional memoir genre. She is a graduate of Harvard College and Yale Law School.-Early life:...
; it was made into a movie of the same name in 2001, starring Christina Ricci
Christina Ricci
Christina Ricci is an American actress. Ricci received initial recognition and praise as a child star for her performance as Wednesday Addams in The Addams Family and Addams Family Values , and her role as Kat Harvey in Casper...
. Yet another book, Talking Back to Prozac, was authored in 1994 by psychiatrist Peter Breggin
Peter Breggin
Peter Roger Breggin is an American psychiatrist and critic of biological psychiatry and psychiatric medication. In his books, he advocates replacing psychiatry's use of drugs and electroconvulsive therapy with humanistic approaches, such as psychotherapy, education, and broader human...
.
Other brand names
- Zactin (Australia)
- Lovan (Australia)
- Fluohexal (Australia)
- Auscap (Australia)
- Depreks (Turkey)
- Floxet (Hungary; Egis Pharmaceuticals Ltd.)
- Flunil (India) Intas BiopharmaceuticalsIntas BiopharmaceuticalsIntas Biopharmaceuticals Ltd. is an Indian biotechnology company headquartered in Ahmedabad, India. Located in the Moraiya,Ahmedabad,it is one of the leading biosimilar product manufacturer in Asia....
- Prodep (India)
- Fluox (NZ)
- Fluzac (Ireland)
- Fluxen - Флуксен (Ukraine)
- Philozac - (Egypt)