Fluoxetine hydrochloride (Prozac, Fontex, Ladose, Sarafem) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Fluoxetine is approved for the treatment of major depression (including pediatric depression), obsessive-compulsive disorder (in both adult and pediatric populations), bulimia nervosa, anorexia nervosa, panic disorder and premenstrual dysphoric disorder. Despite the availability of newer agents, it remains extremely popular. Over 22.2 million prescriptions for generic formulations of fluoxetine were filled in the United States in 2007, making it the third most prescribed antidepressant. Fluoxetine was developed by Eli Lilly and Company.
Later, hoping to find a derivative inhibiting only serotonin reuptake, Wong proposed to re-test 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.
A controversy ensued after Lilly researchers published a paper entitled "Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug" implicitly 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. Fluoxetine made its appearance on the Belgian market in 1986 and was approved for use by the FDA in the United States in December 1987. Fluoxetine was the fourth SSRI to make it to market, after zimelidine, indalpine and fluvoxamine. However, the first two were withdrawn due to the side effects, and a vigorous marketing campaign by Eli Lilly made sure that in the popular culture fluoxetine has been perceived as a scientific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's patent on Prozac (fluoxetine) expired in August, 2001, prompting an influx of generic drugs onto the market.
The peculiar pharmacokinetics of fluoxetine with its brain levels rising extremely slowly over at least first 5 weeks of treatment (see #Pharmacokinetics) makes it unclear whether the 20-mg/day optimal dose established in the short term (6-8 weeks) trials is applicable for the longer term supportive treatment. One 60-mg dose of fluoxetine per week was found to be equivalent to 20 mg/day for the continuation treatment of responders to 20 mg/day of fluoxetine. Furthermore, 5 mg/day fluoxetine was shown to be better than placebo and similar to 20 mg/day, and one weekly dose of 80 mg fluoxetine was equivalent to 60 mg/day fluoxetine or 150 mg/day amitriptyline. On the other hand, increase of the dose to 60 mg/day in non-responders from 20 mg/day brought no additional benefits as compared to continuing the 20 mg/day treatment.
The recent 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 non-responders.
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. 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.
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%).
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. 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. 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 and tardive dyskinesia.
Fluoxetine taken during pregnancy also increases rate of poor neonatal adaptation. Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended. 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.
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. Only one metabolite of fluoxetine, norfluoxetine (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. 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 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".
"In 1989, Joseph Wesbecker shot dead 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.
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 National Institute for Health and Clinical Excellence (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.
Third Eye Blind references Prozac in the song "losing a whole year" in the lines "...when you start talking I hear the Prozac."
Vanilla Ice has a song called "Prozac." After having the drug prescribed for her, Cheryl Wheeler wrote and recorded a song called, "Is It Peace, Or Is It Prozac?" The British band Killing Joke has a song called "Prozac People." Rap artist Jay-Z makes reference to Prozac in his song "Nigga What, Nigga Who."
The song "The Sound of Muzak" by Porcupine Tree refers to it as "Elevator Prozac".
Bowling For Soup refer to Prozac in the line "one Prozac a day" in the song "1985".
The Offspring refer to Prozac in the line "Prozac will make it better" in the song "Original Prankster".
In the musical Rent, Angel insists Benny needs a Prozac during the song "You'll See."
Main character of the popular TV show "Sopranos", mobster Tony Soprano, uses Prozac in treatment of psychological issues caused by his work and family problems.
Cleveland Hardcore band, 9 Shocks Terror have a song titled 'Prozac Logic', appearing on the 'Zen and the Art of Beating your Ass' LP.