Fluoxetine hydrochloride (Prozac) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class.
Fluoxetine is approved for the treatment of 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 21.7 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[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.
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. (However, unlike its successful cousin, zimelidine was banned worldwide because of serious side effects.) Fluoxetine was the third SSRI on the market. Fluvoxamine (Luvox) had been marketed in Europe since 1983. Fluoxetine made its appearance on the Belgian market in 1986 and was approved for use by the Food and Drug Administration (FDA) in the United States in December 1987.
Eli Lilly's patent on Prozac (fluoxetine) expired in August, 2001, prompting an influx of generic drugs onto the market.
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). Complete excretion of the drug may take several weeks.
Dosing and administration
Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in major depressive disorder in most cases. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose.
At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with fluoxetine. In addition, at least 5 weeks, perhaps longer, should be allowed after stopping Prozac before starting an MAOI.
Fluoxetine comes in 10, 20, 40 and 60 mg capsules. Prozac Weekly comes in 90 mg capsules.
It may take 4 to 5 weeks or longer before the patient feels the full benefit of fluoxetine for most indications and even longer - up to 3 months, for obsessive compulsive disorder.
Side effects
The most common side effects for patients taking Fluoxetine are as follows:
Akathisia
Anxiety
Asthenia
Headache
Flu syndrome
Fever
Vasodilatation
Nausea
Diarrhea
Dry mouth
Dyspepsia
Insomnia
Nervousness
Somnolence
Dizziness
Tremor
Sweating
Dilated pupils
Heartburn
Seizures
Hives
Rash
Other side effects may occur, including sexual dysfunction. Possible sexual side effects can include anorgasmia, reduced libido and impotence.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), 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 nonpsychiatric have been documented. 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.
Serotonin syndrome - Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of fluoxetine and triptans, tramadol or other serotonergic agents.
Nursing mothers
Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended.
Discontinuation of treatment
Main article: SSRI discontinuation syndrome
During marketing of fluoxetine and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with fluoxetine.
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