Prozac

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]

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 However, the first two were withdrawn due to the side effects, and a vigorous marketing campaign by Eli Lilly made sure that in the popular culture fluoxetine has been perceived as a scientific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.

Indications

Fluoxetine has been approved by the FDA for the treatment of clinical depression, obsessive compulsive disorder, bulimia nervosa and panic disorder.[9] 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 placebo-controlled trials.[9] 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.[9] 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.[9]

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).[9] 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.[9]

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%).[9]

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.[9] 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.[10][11] 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.[12][13][10] 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."[13] 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 this relatively common condition".[14][15] More rarely, fluoxetine has been associated with related movement disorders acute dystonia and tardive dyskinesia.[11][16][17] Other side effects may occur, including sexual dysfunction. Possible sexual side effects can include anorgasmia, reduced libido and impotence.[18]

Fluoxetine taken during pregnancy also increases rate of poor neonatal adaptation.[18] Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended.[19] 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.[20]

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.[26][27][28] 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.[29] Nevertheless, the general consensus is that "suicidal ideation has been associated with suicide attempt in retrospective studies and with suicide in prospective studies."[30]

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. The extremely slow elimination of fluoxetine and its active metabolite norfluoxetine from the body distinguishes it from 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).[1] For that reason, the concentration of the drug and its active metabolite in the blood continues to grow through the first three weeks of treatment, and their steady concentration is achieved only after 3-4 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 more than a month since its initiation. For example, in a 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%. [34] 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".[35]

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.

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