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Prozac

"Prozac" redirects here. For other uses, see Prozac (disambiguation).
Not to be confused with Fluvoxamine.

Template:Drugbox

Fluoxetine (also known by the tradenames Prozac, Sarafem, Ladose and Fontex, among others) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Fluoxetine was first documented in 1974 by scientists from Eli Lilly and Company.[1] It was presented to the U.S. Food and Drug Administration in February 1977, with Eli Lilly receiving final approval to market the drug in December 1987. Fluoxetine went off-patent in August 2001.[2]

Fluoxetine is approved for the treatment of major depression (including pediatric depression), obsessive-compulsive disorder (in both adult and pediatric populations), bulimia nervosa, panic disorder and premenstrual dysphoric disorder.[3] In addition, fluoxetine is used to treat trichotillomania if cognitive behaviour therapy is unsuccessful.[4] In combination with olanzapine it is known as Symbyax, which is approved for Bipolar I disorder and Treatment-resistant depression.

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 alone,[5] making it the third most prescribed antidepressant after sertraline (SSRI; became generic in 2006) and citalopram (SSRI; became generic in 2003).[5] In 2011, 6 million prescriptions for fluoxetine were handed out in the UK.[6]

Medical uses

Fluoxetine is frequently used to treat major depression, obsessive compulsive disorder, post-traumatic stress disorder, bulimia nervosa, panic disorder, body dysmorphic disorder,[7] premenstrual dysphoric disorder, and trichotillomania.[4][8][9][10] A recent clinical trial found that in bipolar II disorder fluoxetine was equally effective as lithium in preventing future mood episodes.[11] It has also been used for cataplexy, obesity, and alcohol dependence,[12] as well as binge eating disorder.[13]

Depression

Fluoxetine was shown to be effective for depression in six-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.[14] However two meta-analyses of randomized placebo-controlled trials suggested that in patients with mild or moderate symptoms, the efficacy is clinically insignificant.[15][16] It has also been argued that any improvements in mood found in trials for fluoxetine (and other SSRIs) are simply a product of an exaggerated placebo effect, regardless of the severity of depression.[17]

Research suggests that a significant part of the resistance to the SSRIs paroxetine (Paxil) and citalopram (Celexa) can be explained by the genetic variation of Pgp 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.[18][19]

Fluoxetine is considered the most stimulating of the SSRIs (that is it is most prone to causing insomnia and agitation).[20][20]

Obsessive-compulsive disorder

OCD 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.[14] 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 and purging episodes of bulimia nervosa. Continued year-long treatment of the patients, who originally responded to fluoxetine, was more effective than placebo for the prevention of bulimia nervosa episodes.[14]

Antiviral

In 2012 researchers at UCLA discovered that fluoxetine and various other SSRIs have the potential to act as antivirals in the treatment against enteroviruses such as polio.[21] The discovery was hailed by the American Society for Microbiology as a major breakthrough as there currently exists no drugs used in the treatment of enteroviruses.[22]

Adverse effects

Sexual dysfunction is a common side effect with SSRIs. Specifically, side effects often include difficulty becoming aroused, erectile dysfunction, lack of interest in sex, and anorgasmia (inability to achieve orgasm). Genital anesthesia,[23] 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 permanently after the drug has been completely withdrawn.[24] This is known as Post SSRI Sexual Dysfunction.

According to the manufacturer of Prozac brand of fluoxetine, Eli Lilly, fluoxetine is contraindicated in individuals taking monoamine oxidase inhibitors, pimozide (Orap) or thioridazine (Mellaril).[14] 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.[14] Ibuprofen used in combination with fluoxetine can cause significant intestinal bleeding after a period of use.


Among the common adverse effects associated with fluoxetine and listed in the prescribing information, the effects with the greatest difference from placebo are nausea (22% vs 9% for placebo), insomnia (19% vs 10% for placebo), somnolence (12% vs 5% for placebo), anorexia (10% vs 3% for placebo), anxiety (12% vs 6% for placebo), nervousness (13% vs 8% for placebo), asthenia (11% vs 6% for placebo) and tremor (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%).[14][25][26][27][28]

Similarly to other SSRIs, sexual side effects are common with fluoxetine; they include anorgasmia and reduced libido.

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 and lupus-like syndrome. Death has been reported to occur in association with these systemic events.[14]

Akathisia, 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.[29][30] 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.[29][31][32] 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".[32] 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".[33][34] More rarely, fluoxetine has been associated with related movement disorders acute dystonia and tardive dyskinesia.[30][35][36]

Fluoxetine taken during pregnancy also increases rate of poor neonatal adaptation.[37] Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended.[38] 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.[39] 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.[40]


Discontinuation syndrome

Several case reports in the literature describe severe withdrawal or discontinuation symptoms following an abrupt interruption of fluoxetine treatment.[41] 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.[41] 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.[42][43] 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.[44] 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 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.[45] According to a 2007 summary report of available evidence, fluoxetine has the lowest incidence of discontinuation syndrome among several antidepressants including paroxetine and venlafaxine.[46]

Suicide

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.[47][48][49] 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.[50]

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%,[51] and in adults decreased the odds of suicidality by approximately 30%.[48][49] 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%.[52][53]

Violence

Psychiatrist David Healy and certain patient activist groups have compiled case reports of violent acts committed by individuals taking fluoxetine or other SSRIs,[54][55] 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.[56] 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[57] A second clinical trial performed at the University of Chicago found that fluoxetine reduced aggressive behavior in patients in intermittent aggressive disorder.[58] A clinical trial found that fluoxetine reduced aggressive behavior in patients with borderline personality disorder.[59] These results are indirectly supported by studies demonstrating that other SSRIs can reduce violence and aggressive behavior.[60][61][62][63] 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[64]

Interactions

Fluoxetine and norfluoxetine inhibit many isozymes of the cytochrome P450 system that make drug metabolism possible. Both are potent inhibitors of CYP2D6 (the main enzyme responsible for their metabolism) and mild to moderate inhibitors of CYP1A2, CYP2B6, CYP2C9/2C19, and CYP3A4; furthermore, they inhibit the activity of P-glycoprotein, a type of membrane transport protein that plays an important role in drug transport and metabolism.[65] This extensive effect on the body's pathways for drug metabolism creates the potential for interactions with many commonly used drugs.[65][66]

The simultaneous use of fluoxetine with triptans, tramadol or other serotonergic agents can result in a rare, but potentially life-threatening adverse drug reaction called serotonin syndrome.

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.[67]

Pharmacokinetics


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.

Fluoxetine is metabolized in the liver by isoenzymes of the cytochrome P450 system, including CYP2D6.[3] 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. Only one metabolite of fluoxetine, norfluoxetine (N-demethylated 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.[3][70][71] 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.[72][73] Moreover, the brain concentration of fluoxetine and its metabolites keeps increasing through at least the first five weeks of treatment.[74] 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.[72] 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%,[74] 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.[70]

A PET study compared the action of a single dose of fluoxetine on exclusively heterosexual and exclusively homosexual men who attested that their past and present sexual behavior, 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".[75]

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 large dose of fluoxetine given to a rat also resulted in a significant increase of brain concentrations of norepinephrine and dopamine.[76][77][78] This effect may be mediated by 5HT2a and, in particular, 5HT2c receptors, which are inhibited by higher concentrations of fluoxetine. The Eli Lilly scientists also suggested that the effects on dopamine and norepinephrine may contribute to the antidepressant action of fluoxetine.[78] In the opinion of other researchers, however, the magnitude of this effect is unclear.[74] The dopamine and norepinephrine increase was not observed at a smaller, more clinically relevant dose of fluoxetine.[79] 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.[80] 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.[81]

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.[82]

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.[83][84][85]

Mechanism of action

Fluoxetine's mechanism of action is predominantly that of a serotonin reuptake inhibitor.[86][87] Fluoxetine delays the reuptake of serotonin, resulting in serotonin persisting longer when it is released. Fluoxetine may also produce some of its effects via its weak 5-HT2C receptor antagonist effects.[88] 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.[89][90]

Table 1: Binding affinity (Ki) of fluoxetine and norfluoxetine towards their molecular targets[91]

Molecular Target Fluoxetine Norfluoxetine
SERT 1.0 19
NET 660 2700
DAT 4180 420
5-HT2A 200 300
5-HT2B ≥5000 ≥5100
5-HT2C 260 91
M1 870 1200
M2 2700 4600
M3 1000 760
M4 2900 2600
M5 2700 2200

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 antihistamine diphenhydramine shows some antidepressant-like properties. 3-Phenoxy-3-phenylpropylamine, a compound structurally similar to diphenhydramine, was taken as a starting point, and Molloy synthesized dozens of its derivatives. Testing the physiological effects of these compounds in mice resulted in nisoxetine, a selective norepinephrine reuptake inhibitor currently widely used in biochemical experiments.[92][93]

Later, hoping to find a derivative inhibiting only serotonin reuptake, another 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,[93] showed the compound later named fluoxetine to be the most potent and selective inhibitor of serotonin reuptake of the series.[1] Wong published the first article about fluoxetine in 1974.[1] 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.[94]

In May 1984, Germany’s regulatory agency (BGA) rejected Prozac as "totally unsuitable for treating depression".[95] In May 1985, FDA’s (then) chief safety investigator, Dr. Richard Kapit, wrote: “Unlike traditional tricyclic antidepressants fluoxetine’s profile of adverse side effects more closely resembles that of a stimulant drug than one that causes sedation". He said "It is fluoxetine’s particular profile of adverse side-effects which may perhaps, in the future give rise to the greatest clinical liabilities in the use of this medication to treat depression".[96]

Fluoxetine appeared on the Belgian market in 1986.[97] After over a decade, the FDA gave its final approval in December 1987,[98] and a month later Eli Lilly began marketing Prozac; annual sales in the U.S. reached $350 million within a year.[94]

A controversy ensued after Lilly researchers published a paper titled "Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug"[93] claiming fluoxetine to be the first selective serotonin reuptake inhibitor (SSRI). Two years later they had to issue a correction, admitting that the first SSRI was zimelidine developed by Arvid Carlsson and colleagues.[99]

Eli Lilly's U.S. patent on Prozac (fluoxetine) expired in August 2001,[100] 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.[101]

A meta-analysis published in February 2008 combined 35 clinical trials of four newer antidepressants (fluoxetine, paroxetine (Paxil), nefazodone (Serzone) and venlafaxine (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", it did not meet the criterion for clinical significance, as used by the UK's National Institute for Health and Clinical Excellence, "for any but the most severely depressed patients".[102] Some articles in the press using the titles "The creation of the Prozac myth"[103] and "Prozac does not work in majority of depressed patients"[104][105] 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".[106]

As of April 2, 2010, fluoxetine is one of four antidepressant drugs that the FAA allows pilots to take. The others are sertraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro).[107]

There has been research on possible effects of fluoxetine on marine life.[108]

Other brand names

  • Zactin (Australia)[109]
  • Lovan (Australia)[110]
  • Fluohexal (Australia)
  • Auscap (Australia)[111]
  • Depreks (Turkey)[112]
  • Deprozan (South Africa; Meridian Pharmaceuticals, div. of Elttab)
  • Floxet (Hungary; Egis Pharmaceuticals Ltd.)[113]
  • Flunil (India; Intas Biopharmaceuticals)
  • Prodep (India)
  • Fludac (India)
  • Flutine (Israel)
  • Fluox (New Zealand; Mylan NZ)
  • Fluoxetina (Colombia, Brazil, Portugal)
  • Fluzac (Ireland)
  • Fluxen – Флуксен (Ukraine)
  • Fluoxin (Romania)
  • Fontex (Denmark, Norway, Sweden)
  • Foxetin, Eburnate, Alental, Neupax, Saurat, Lapsus (Argentina)
  • Ladose (Greece)
  • Flusetin (Bosnia and Herzegovina)
  • Philozac (Egypt)[114]
  • Biozac, Deprexetin, Fluval, Biflox, Deprexit, Sofluxen, Floxet, Ranflutin – (Bulgaria)[115]
  • Flunisan, Orthon, Refloksetin, Fluoksetin – (Macedonia)[116]
  • Motivest (Philippines)
  • Seronil (Finland)
  • Lorien (South Africa; Aspen Pharmacare)
  • Affectine (Israel)
  • Proxetin (Thailand)
  • Flux (Pakistan)
  • Fluxil (Singapore)
  • Magrilan (Slovakia)

Prozac in popular culture

Prozac has had numerous references to it in popular culture, including many books, movies, and songs.

References

External links

  • Trouble in Prozac, from Fortune magazine
  • United States National Library of Medicine's Drug Information Portal
  • Biographies of inventors:
    • David T. Wong, from Nature
    • Bryan B. Molloy, from Invent Now
he:SSRI#תרופות ממשפחת SSRI
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