Definition

Fluoxetine is an antidepressant of the type known as selective serotonin reuptake inhibitors (SSRI). It is sold in the United States under the brand names Prozac and Sarafem.

Purpose

Fluoxetine is used to treat depression, premenstrual syndrome, bulimia, and obsessive-compulsive disorder.

Description

Serotonin is a neurotransmitter—a brain chemical that carries nerve impulses from one nerve cell to another. Researchers think that depression and certain other mental disorders may be caused, in part, because there is not enough serotonin being released and transmitted in the brain. Like the other SSRI antidepressants, fluvoxamine (Luvox), sertraline (Zoloft), and paroxetine (Paxil), fluoxetine increases the level of brain serotonin (also known as 5-HT). Increased serotonin levels in the brain may be beneficial in patients with obsessive-compulsive dirder, alcoholism, certain types of headaches, post-traumatic stress disorder (PTSD), pre-menstrual tension and mood swings, and panic disorder.

Fluoxetine was the first of the class of antidepressants called selective serotonin reuptake inhibitors (SSRIs) to be approved for use in the United States. In 2000, fluoxetine was approved by the FDA for use in treating premenstrual dysphoric disorder.

The benefits of fluoxetine develop slowly over a period of several weeks. Patients should be aware of this and continue to take the drug as directed, even if they feel no immediate improvement.

Fluoxetine (marketed as Prozac) is available in 10-, 20-, and 40-mg capsules, 10-mg tablets, and in a liquid solution with 20 mg of active drug per 5 ml. Prozac Weekly capsules are a time-release formula containing 90 mg of active drug. Sarafem is available in 10- and 20-mg capsules.

Recommended dosage

Fluoxetine therapy in adults is started as a single 20-mg dose, initially taken in the morning. Depending on the patient's response after four to six weeks of therapy, this dose can be increased up to a total of 80 mg per day. Doses over 20 mg per day can be given as equally divided morning and afternoon doses.

Precautions

Patients taking fluoxetine should be monitored closely for insomnia, anxiety, mania, significant weight loss, seizures, and thoughts of suicide.

Caution should also be exercised when prescribing fluoxetine to patients with impaired liver or kidney function, the elderly (over age 60) children, individuals with known manic-depressive disorder or a history of seizures, people with diabetes, and individuals expressing ideas of committing suicide.

Individuals should not take MAO inhibitors during fluoxetine therapy, for two weeks prior to beginning fluoxetine therapy, and for five weeks after stopping fluoxetine therapy.

Care should be taken to weigh the risks and benefit of this drug in women who are, or wish to become, pregnant, as well as in breast-feeding mothers.

People with diabetes should monitor their blood or urine sugar more carefully, since fluoxetine can affect blood sugar.

Until an individual understands the effects that fluoxetine may have, he or she should avoid driving, operating dangerous machinery, or participating in hazardous activities. Alcohol should not be used while taking fluoxetine.

Side effects

More common side effects include decrease sexual drive, restlessness, difficulty sitting still, skin rash, hives, and itching.

Less common side effects include fever and/or chills, and pain in joints or muscles.

Rare side effects include pain or enlargement of breasts and/or abnormal milk production in women, seizures, fast heart rate, irregular heartbeats, red or purple spots on the skin, low blood sugar and its symptoms (anxiety, chills, cold sweats, confusion, difficulty concentrating, drowsiness, excess hunger, rapid heart rate, headache, shakiness or unsteadiness, severe fatigue), low blood sodium and its symptoms (including confusion, seizures, drowsiness, dry mouth, severe thirst, decreased energy), serotonin syndrome (usually at least three of the following: diarrhea, fever, sweatiness, mood or behavior changes, overactive reflexes, fast heart rate, restlessness, shivering or shaking), excitability, agitation, irritability, pressured talking, difficulty breathing, and odd body or facial movements.

Interactions

Fluoxetine interacts with a long list of other medications. People starting this drug should review the other medications they are taking with their physician and pharmacist for possible interactions. Patients should always inform all of their health care providers, including dentists, that they are taking fluoxetine.

When taken with fluoxetine, blood levels of the following drugs may increase: benzodiazepines, beta blockers, carbamazepine, dextromethorphan, haloperidol, atorvastatin, lovastatin, simvastatin, phenytoin, and tricyclic antidepressants.

The following drugs may increase the risk of serotonin syndrome: dexfenfluramine, fenfluramine, and tryptophan.

When buspirone is taken with fluoxetine, the therapeutic effect of buspirone may be impaired.

Low blood sodium may occur when fluoxetine is taken along with diuretics.

Increased risk of mania and high blood pressure occurs when selegiline is taken along with fluoxetine.

Severe, fatal reactions have occurred when fluoxetine is given along with MAO inhibitors.

Resources

BOOKS

Ellsworth, Allan J. Mosby's Medical Drug Reference. St. Louis, MO: Mosby Inc., 1999.

Mosby's Drug Consult. St. Louis, MO: Mosby, Inc., 2002.

Rosalyn Carson-DeWitt, M.D.

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. 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.

History

According to David Wong, 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 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.

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 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, prompting an influx of generic drugs onto the market.

Indications

Fluoxetine has been approved by the FDA for the treatment of clinical depression, obsessive compulsive disorder, bulimia nervosa and panic disorder. 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 peculiar pharmacokinetics of fluoxetine with its brain levels rising extremely slowly over at least first 5 weeks of treatment (see Fluoxetine#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 to 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.

Adverse effects

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). 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 twice slower in these patients, resulting in the proportionate increase of exposure to the drug.

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.

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

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.

Discontinuation syndrome

Several case reports in the literature describe severe withdrawal or discontinuation symptoms following an abrupt interruption of fluoxetine treatment. 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, and one of the recommended strategies for the management of discontinuation syndrome with other SSRIs is to substitute fluoxetine for the original agent. 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, this result being 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. 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.

Suicidality in antidepressant trials

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. The suicidality was slightly decreased for those older than 24, and statistically significantly lower in the 65 and older group. This analysis was critiqued 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 in retrospective studies and with suicide in prospective studies."

Suicidality and fluoxetine

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 children increased the odds of suicidality by 50% (not statistically significant), and in adults decreased the odds of suicidality by approximately 30% (statistically significant). 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%.

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.)

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. 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".

Interactions

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.

Controversy

"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, nefazodone and venlafaxine). 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 NICE, "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.

References

External links

• Lilly's Reconcile website, a version of Prozac for veterinary use treating dogs for separation anxiety
• Biography of Dr. David T. Wong, one of the inventors of Prozac
• Biography of Dr. Bryan B. Molloy, one of the inventors of Prozac
• Trouble in Prozac - Fortune Magazine