Open Access Articles- Top Results for Fluoxetine
Journal of Bioequivalence & BioavailabilitySimultaneous Estimation of Fluoxetine and Norfluoxetine in Plasma by RP-HPLC Employing Pre-Column Derivatization for UV-Sensitivity Enhancement
|Systematic (IUPAC) name|
|Trade names||Listed below|
|Licence data||US FDA:|
|Metabolism||Hepatic (mostly CYP2D6-mediated)|
|Onset of action||~2–4 weeks|
1–3 days (acute)|
4–6 days (chronic)
|Excretion||Urine (80%), faeces (15%)|
|Melting point||Script error: No such module "convert".|
|Boiling point||Script error: No such module "convert".|
|14 mg/mL (20 °C)|
|14px (what is this?)|
Fluoxetine (also known by the trade names Prozac, and Sarafem, among others) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Fluoxetine was discovered and developed by scientists from Eli Lilly and Company. It was approved by the U.S. Food and Drug Administration for the treatment of major depressive disorder in December 1987. The U.S. fluoxetine patent expired in August 2001, so generic formulations are now available in the U.S.
Fluoxetine is used for the treatment of major depressive disorder (including pediatric depression), obsessive–compulsive disorder (in both adults and children), bulimia nervosa, panic disorder, and premenstrual dysphoric disorder. In addition, it is used to treat trichotillomania if cognitive behaviour therapy has been unsuccessful.
In 2010, over 24.4 million prescriptions for generic formulations of 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. It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.
- 1 Medical uses
- 2 Contraindications
- 3 Adverse effects
- 4 Overdose
- 5 Interactions
- 6 Pharmacology
- 7 History
- 8 Society and culture
- 9 See also
- 10 References
- 11 External links
Fluoxetine is frequently used to treat major depressive disorder, obsessive-compulsive disorder, post-traumatic stress disorder, bulimia nervosa, panic disorder, premenstrual dysphoric disorder, and trichotillomania. It has also been used for cataplexy, obesity, and alcohol dependence, as well as binge eating disorder. It has also been tried as a treatment for autism spectrum disorders with moderate success in adults.
The effectiveness of fluoxetine and other antidepressants in the treatment of mild-to-moderate depression is controversial. A meta-analysis published by Kirsch in 2008 suggests, in those with mild or moderate symptoms, the efficacy of fluoxetine and other SSRIs is clinically insignificant. A 2009 meta-analysis by Fournier et al., which evaluated patient-level data from six trials of the SSRI paroxetine and the non-SSRI antidepressant imipramine has been further cited as evidence that antidepressants exhibit minimal efficacy in mild to moderate depression. A 2012 meta-analysis using individual patient level-data from 18 randomized controlled clinical trials of fluoxetine for the treatment of depression concluded statistically and clinically significant benefit was seen irrespective of baseline depression severity, and no significant effect was found on baseline severity on observed efficacy.
A 2009 systematic review by the National Institute of Care and Clinical Excellence (NICE) (which considered the Kirsch, but not the later meta-analyses) concluded strong evidence existed for the efficacy of SSRIs in the treatment of moderate and severe depression, with some evidence for their efficacy in the treatment of mild depression. Both the NICE and the Fournier analyses concluded greater evidence is seen for the efficacy of antidepressants in the treatment of chronic mild depression (dysthymia) than in recent-onset mild depression.
NICE recommends antidepressant treatment with an SSRI in combination with psychosocial interventions as second-line treatment for short term mild depression, and as a first line treatment for severe and moderate depression, as well as mild depression that is recurrent or long-standing. The American Psychiatric Association includes antidepressant therapy among it first-line options for the treatment of depression, particularly when "a history of prior positive response to antidepressant medications, the presence of moderate to severe symptoms, significant sleep or appetite disturbances, agitation, patient preference, and anticipation of the need for maintenance therapy" exist.
The efficacy of fluoxetine in the treatment of obsessive-compulsive disorder was demonstrated in two randomized multicenter phase III clinical trials. The pooled results of these trials demonstrated that 47% of completers treated with the highest dose were "much improved" or "very much improved" after 13 weeks of treatment, compared to 11% in the placebo arm of the trial. SSRIs including fluoxetine should be used as first-line therapy, along with CBT, for the treatment of moderate to severe OCD.
The efficacy of fluoxetine in the treatment of panic disorder was demonstrated in two 12-week randomized multicenter phase III trials that enrolled patients diagnosed with panic disorder, with or without agoraphobia. In the first trial, 42% of subjects in the fluoxetine-treated arm were free of panic attacks at the end of the study, vs. 28% in the placebo arm. In the second trial, 62% of fluoxetine treated patients were free of panic attacks at the end of the study, vs. 44% in the placebo arm.
A 2011 systematic review of seven trials which compared fluoxetine to a placebo in the treatment of bulimia nervosa; six of which found a statistically significant reduction in symptoms such as vomiting and binge eating. However, no difference was observed between treatment arms when fluoxetine and psychotherapy were compared to psychotherapy alone.
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. Evidence supporting an increased risk of major fetal malformations resulting from fluoxetine exposure is limited, although the Medicines and Healthcare Products Regulatory Agency 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 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." But the study found also 15 cohort studies that evaluated cardiac malformations and yielded an overall odds ratio of 1.6 (95% confidence interval: 1.31 to 1.95).
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 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.
Contraindications include prior treatment (within the past two weeks) with MAOIs such as phenelzine and tranylcypromine, 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.
Side effects observed in fluoxetine-treated persons in clinical trial with an incidence >5% and at least twice as common in fluoxetine-treated persons compared to those who received a sugar pill include abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, decreased libido, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawning. 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, including loss of libido, anorgasmia, lack of vaginal lubrication, and erectile dysfunction, is one 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 enquires about sexual problems suggest that the incidence is >70%. Symptoms of sexual dysfunction have been reported to occasionally persist after discontinuing SSRIs.
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-blind 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 (Zoloft) in these studies, and significantly more during the interruption of paroxetine. According to a 2007 summary report of available evidence, fluoxetine has the lowest incidence of discontinuation syndrome among several antidepressants including paroxetine and venlafaxine.
The FDA now requires all antidepressants to carry a black box warning stating that antidepressants may increase the risk of suicide in people 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.
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%, and in adults decreased the odds of suicidality by approximately 30%. Similarly, the analysis conducted by the UK MHRA found a 50% increase of odds of suicide-related events, not reaching statistical significance, in the children and adolescents on fluoxetine as compared to the ones on placebo. According to the MHRA data, for adults fluoxetine did not change the rate of self-harm and statistically significantly decreased suicidal ideation by 50%.
In overdose, most frequent adverse effects include:
Nervous system effects
Fluoxetine and norfluoxetine inhibit many isozymes of the cytochrome P450 system that are involved in drug metabolism. Both are potent inhibitors of CYP2D6 (which is also the chief enzyme responsible for their metabolism) and CYP2C19, and mild to moderate inhibitors of CYP2B6 and CYP2C9. In vivo, fluoxetine and norfluoxetine do not significantly affect the activity of CYP1A2 and CYP3A4. They also inhibit the activity of P-glycoprotein, a type of membrane transport protein that plays an important role in drug transport and metabolism and hence P-glycoprotein substrates such as loperamide may have their central effects potentiated. This extensive effect on the body's pathways for drug metabolism creates the potential for interactions with many commonly used drugs.
Its use should also be avoided in those receiving other serotonergic drugs such as monoamine oxidase inhibitors, tricyclic antidepressants, methamphetamine, MDMA, triptans, buspirone, serotonin-norepinephrine reuptake inhibitors and other SSRIs due to the potential for serotonin syndrome to develop as a result.
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.
|†Values for both drugs represents a lower bound|
Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and selective brain steroidogenic stimulant (SBSS) and does not appreciably inhibit norepinephrine and dopamine reuptake at therapeutic doses. It does, however, delay the reuptake of serotonin, resulting in serotonin persisting longer when it is released. Large doses in rats has been shown to induce in 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's effect on neurosteroids is primarily related to an increase in allopregnanolone, a potent GABAA receptor positive allosteric modulator; a reduction in circulating brain (primarily mesocorticolimbic) allopregnanolone has been associated with both depression and anxiety disorders. Improvement in depressive symptoms in medicated individuals is correlated with fluoxetine-induced increases in allopregnanolone levels. Norfluoxetine, a primary active metabolite of fluoxetine, produces a similar effect on allopregnanolone levels in the brain, and has therefore also been characterized as a selective brain steroidogenic stimulant.
In addition, fluoxetine has been found to act as an agonist of the σ1-receptor, with a potency greater than that of citalopram but less than that of fluvoxamine. However, the significance of this property is not fully clear. Fluoxetine also functions as a channel blocker of anoctamin 1, a calcium-activated chloride channel. In addition, it acts as a positive allosteric modulator of the GABAA receptor at high concentrations, and norfluoxetine does the same but more potently, actions which may be clinically-relevant. A number of other ion channels, including nicotinic acetylcholine receptors and 5-HT3 receptors, are also known to be inhibited at similar concentrations.
The bioavailability of fluoxetine is relatively high (72%), and peak plasma concentrations are reached in 6 to 8 hours. It is highly bound to plasma proteins, mostly albumin and α1-glycoprotein. Fluoxetine is metabolized in the liver by isoenzymes of the cytochrome P450 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. 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 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.
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.
Hoping to find a derivative inhibiting only serotonin reuptake, an Eli Lilly scientist, David T. Wong, proposed to retest the series for the in vitro reuptake of serotonin, norepinephrine and dopamine. This test, carried out by Jong-Sir Horng in May 1972, 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, file 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.
Eli Lilly's U.S. patent on Prozac (fluoxetine) expired 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.
There has been research on possible effects of fluoxetine on marine life.
Society and culture
Neither the American Psychiatric Association, the National Institute for Health and Care Excellence (NICE), nor the American College of Physicians list violence among the potential side effects of treatment with serotonin selective reuptake inhibitors. Similarly, the World Health Organization and the European Psychiatric Association do not list violence among the potential side effects of SSRIs.
Psychiatrist David Healy and certain patient activist groups have compiled case reports of violent acts committed by individuals taking fluoxetine or other SSRIs, and have argued that these drugs predispose susceptible individuals to commit violent acts.
Serial case report studies of this type have been criticized as being subject to "confounding by indication", in which effects due to an underlying disease state are mistakenly attributed to the effects of treatment. Other studies, including randomized clinical trials and observational studies, have suggested that fluoxetine and other SSRIs may reduce the propensity for violence. A randomized clinical trial performed by the US National Institutes for Mental Health found that fluoxetine reduced acts of domestic violence in alcoholics with a history of such behavior A second clinical trial performed at the University of Chicago found that fluoxetine reduced aggressive behavior in patients in intermittent aggressive disorder. A clinical trial found that fluoxetine reduced aggressive behavior in patients with borderline personality disorder. These results are indirectly supported by studies demonstrating that other SSRIs can reduce violence and aggressive behavior. A NBER study examining international trends in antidepressant use and crime rates in the 1990s found that increases in antidepressant drug prescriptions were associated with reductions in violent crime.
Fluoxetine is available under many brand names internationally. The table below provides a listing of these and the countries they are marketed in.
|Table of brand names for fluoxetine pills|
† indicates discontinued brands|
|Table of brand names for fluoxetine/olanzapine combination pill|
† indicates discontinued brands|
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