Fluoxetine

  Fluoxetine hydrochloride (Prozac) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Fluoxetine is approved for the treatment of clinical depression (including pediatric depression), obsessive-compulsive disorder (in both adult and pediatric populations), bulimia nervosa, panic disorder and premenstrual dysphoric disorder.^[1] Other indications include hypochondriasis and body dysmorphic disorder. Despite the availability of newer agents, it remains extremely popular. Over 23.1 million prescriptions for generic formulations of fluoxetine were filled in the United States in 2006, making it the third most prescribed antidepressant.^[2]

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History

According to David Wong,^[3] the work which eventually led to the discovery of fluoxetine began at Eli Lilly in 1970 as a collaboration between Bryan Molloy and Robert Rathburn. It was known at that time that 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.^[3]

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,^[3] showed the compound later named fluoxetine to be the most potent and selective inhibitor of serotonin reuptake of the series.^[4]

A controversy ensued after Lilly researchers published a paper entitled "Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug"^[3] 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.^[5] Fluoxetine made its appearance on the Belgian market in 1986^[6] and was approved for use by the FDA in the United States in December 1987.^[7] Fluoxetine was the fourth SSRI to make it to market, after indalpine, zimelidine 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 However, the first two were withdrawn due to the side effects, and a vigorous marketing campaign by Eli Lilly made sure that in the popular culture fluoxetine has been perceived as a scientific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,^[8] prompting an influx of generic drugs onto the market.

Adverse effects

Fluoxetine is generally well-tolerated. Possible side effects for patients taking fluoxetine are as follows:

• Akathisia
• Anxiety
• Asthenia
• Headache
• Flu syndrome
• Fever
• Vasodilation
• Nausea
• Diarrhea
• Loss of appetite
• Dry mouth
• Dyspepsia
• Drowsiness
• Insomnia
• Nervousness
• Somnolence
• Dizziness
• Tremor
• Sweating
• Dilated pupils
• Heartburn
• Seizures
• Hives
• Rash
• Suicide

Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, hypomania, and mania, have been reported in adult and pediatric patients being treated with Prozac for major depressive disorder as well as for other indications, both psychiatric and non-psychiatric. If these symptoms occur the medication should be reduced or cautiously withdrawn.

Since the introduction of fluoxetine, systemic events, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these events are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic events.

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.

SSRIs such as fluoxetine have been associated with tardive dyskinesia and akathisia, among other extrapyramidal symptoms more commonly associated with antipsychotics.^[9][10]

Reproductive and developmental toxicity

Other side effects may occur, including sexual dysfunction. Possible sexual side effects can include anorgasmia, reduced libido and impotence.

A U.S. NTP-CERHR expert panel concluded that the SSRI fluoxetine (Prozac) produces reproductive toxicity by causing reversible impaired sexual function and exhibits developmental toxicity characterized by an increased rate of poor neonatal adaptation.^[11]

Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended.^[12] 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.^[13]

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 men or women, 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".^[14]

Discontinuation syndrome

Main article: SSRI discontinuation syndrome

Several case reports in the literature describe severe withdrawal or discontinuation symptoms following an abrupt interruption of fluoxetine treatment.^[15] Considering the number of fluoxetine prescriptions dispensed over the years, this is exceedingly rare. It is generally believed that the side effects of the fluoxetine discontinuation are mild,^[15] and one of the recommended strategies for the management of discontinuation syndrome with other SSRIs is to substitute fluoxetine for the original agent.^[16][17] 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 re-instated, which is consistent with its slow elimination from the body. More side effects occurred during the interruption of sertraline in these studies, and significantly more—during the interruption of paroxetine.^[18] In a longer, 6 week-long, blind discontinuation study, 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, significantly higher 4% 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.^[19]

Suicidality

Whether or not fluoxetine decreases or increases suicidal ideation and incidence of suicide is currently controversial. Different results from studies could be a result of: using case studies rather than large-scale studies, manufacturer bias, and crude methodologies employed in meta-analyses, eg. searching trial literature for keywords to construct analyses. It is difficult to obtain objective data on this subject primarily because there is little financial incentive to pursue unbiased, balanced studies. Manufacturers like Eli Lilly have withheld data with negative findings on Prozac^{[citation needed]} that have endangered consumers taking fluoxetine (see below), and it is not unexpected that studies endorsed or directly funded by Eli Lilly have supported the purported safety of fluoxetine due to experimental or analytical bias.^{[citation needed]} On the other side of this controversy, research on the dangers of fluoxetine suffer from a similar lack of cohesive data due to lack of large funding for broader studies (see below).^{[citation needed]}

The FDA requires all antidepressants, including fluoxetine, to carry a black box warning stating that antidepressants may increase the risk of suicide 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.^[20][21][22] Suicidal ideation and behavior in clinical trials are rare. For the above analysis, the FDA combined the results of 295 trials of 11 antidepressants for psychiatric indications in order to obtain statistically significant results. Considered separately, fluoxetine use in adults statistically significantly decreased the odds of suicidality by approximately 30%.^[21][22]

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%.^[23][24]

These presentations [to the U.S. Food and Drug Administration from parents claiming Prozac caused homicidal and suicidal behavior] deeply concerned the Committee. However, its members recognized that self-selected clinical anecdotes cannot establish causality because of the post hoc ergo propter hoc^[25] fallacy. Their central dilemma was that, in the clinical trials that might allow a causal inference, there had been no completed suicides. [...] Did the clinical trial data actually support the families' outrage about deaths due to suicide-provoking drugs (which might also induce homicide)?

—Donald Klein, New York State Psychiatric Institute, Columbia University, Neuropsychopharmacology (2006) 31, 689–699.^[26]

Other studies have found that fluoxetine can increase suicide and self-destructive tendencies in some patients.^[27] One study notes that "Reanalyses of placebo-controlled trials reveal an increased risk of suicidal ideations or parasuicidal acts in children and adolescents under treatment with selective serotonin reuptake inhibitors (SSRI) or other antidepressants."^[28]

Another study draws attention to neglected data in earlier studies, which also call into question subsequent meta-analyses that used early trial data: "Recent announcement by the Food and Drug Administration (FDA) requiring pharmaceutical companies to warn patients about the increased likelihood of suicidal thoughts when taking antidepressants was largely due to the recent availability of data that had gone unreported in the original research reports. The current article is a summary of the comparison between the published literature and the recently released data available on the FDA web site, with a focus on Prozac, Paxil, and Zoloft."^[29]

The signs of violence and suicidality have existed since Prozac was tested in premarketing trials. In May 1984, Germany’s regulatory agency (Bundesgesundheitsamt, BGA) rejected Prozac as “totally unsuitable for treating depression.” In July 1985, Eli Lilly’s own data analysis—from a pool of 1,427 patients—showed high incidence of adverse drug effects and evidence of drug-induced violence in some patients. (Eli Lilly internal analysis submitted to the Joachim Wernicke (July 2, 1985), PZ 2441 2000. Document uncovered during Fentress litigation.)^{[citation needed]} In May 1985, FDA’s (then) chief safety investigator, 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 warned: “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.”^[30]

A lay article, like the New York Times article cited above for statistics supporting that fluoxetine does not increase suicidal ideation, addresses data on the opposite viewpoint: "since its launch in January 1988 in the US, and in the UK shortly after, when Prozac was let loose on whole populations rather than on selected patients in clinical trials, there has been a spate of disturbing accounts of violence and suicide committed by people prescribed the drug by their doctors. Some 200 cases have come to court in the US. Victims and families of killers have sued the multi-national Eli Lilly, manufacturers of the world's most commercially successful drug. Until recently, not one case reached a verdict. Either it was dropped, or Lilly settled out of court, sometimes for millions of dollars - Lilly's defence has always been the same: blame the disease, not the drug."^[31]

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.^[1] 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.

Fluoxetine is cleared slowly from the body; its elimination half-life ranges from 1 to 3 days—after a single dose—to 4 to 6 days (after long-term use) in healthy adults, and is prolonged in those with liver disease. The half-life of norfluoxetine is longer (16 days after long-term use).^[1] Complete excretion of the drug may take several weeks.^[32]

Fluoxetine and violence

"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 ^[33]. 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." ^[34]

References