Fluoxetine detailed information

# Overview
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 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 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. 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 daysafter a single doseto 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 (and perhaps in high doses - 60 mg or more), for obsessive compulsive disorder.

# Side effects
Fluoxetine is generally well tolerated. The most common side effects for patients taking Fluoxetine are as follows:
- Akathisia
- Anxiety
- Asthenia
- Headache
- Flu syndrome
- Fever
- Vasodilation
- Nausea
- Diarrhea
- Dry mouth
- Dyspepsia
- Insomnia
- Nervousness
- Somnolence
- Dizziness
- Tremor
- Sweating
- Dilated pupils
- Heartburn
- Seizures
- Hives
- Rash
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.

## 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.
Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended. The AAP classifies fluoxetine as a drug for which the effect on the nursing infant is unknown but may be of concern.

# Discontinuation of treatment
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.

# Suicide Rate
On September 6, 2007, the Centers for Disease Control and Prevention reported suicide rate in American adolescents (especially girls, 10 to 24 years old) increased 8% (2003 to 2004), the largest jump in 15 years. Specifically, in 2004 - 4,599 suicides in Americans ages 10 to 24, up from 4,232 in 2003, for a rate of 7.32  per 100,000 people that age. Before, the rate dropped to 6.78  per 100,000 in 2003 from 9.48 per 100,000 in 1990. The findings also reinforced the fact that antidepressant drugs reduce suicide risk. Psychiatrists found that the increase is due to the decline in prescriptions of antidepressant drugs like Prozac to young people since 2003, leaving more cases of serious depression untreated. In a December 2006 study, The American Journal of Psychiatry said that a decrease in antidepressant prescriptions to minors of just a few percentage points coincided with a 14 percent increase in suicides in the United States; in the Netherlands, the suicide rate was 50% up, upon prescription drop.