fluoxetine

Fluoxetine hydrochloride is an antidepressant drug used medically in the treatment of depression, obsessive-compulsive disorder, bulimia nervosa, premenstrual dysphoric disorder and panic disorder. Fluoxetine is also used (off-label) to treat many other conditions, such as ADHD. Fluoxetine was derived from diphenhydramine, an antihistamine found to inhibit reuptake of the neurotransmitter serotonin.

Compared to other popular selective serotonin reuptake inhibitors (SSRIs), fluoxetine has a strong energizing effect. This makes fluoxetine highly effective in treatment of clinical depression cases where symptoms like depressed mood and lack of energy prevail. Although stimulating, it is also approved for a variety of anxiety disorders, including panic disorder and obsessive compulsive disorder.

Trade Names

Fluoxetine is sold under the brand names Prozac, Symbyax (compounded with olanzapine), Sarafem, FLUX (Pakistan), Fontex (Sweden, Norway), Foxetin (Argentina), Ladose (Greece), Fluctin (Austria, Germany), Prodep (India), Fludac* (India) Oxetin (Bosnalijek,Bosnia and Herzegovina), Seronil (Finland), Lovan (Australia) and Prizma (Israel).

It is also available under many generic names "fluoxetine XXX", xxx being the name of the laboratory

History

Prozac was invented at Eli Lilly by a team headed by Dr. Ray W. Fuller, with Drs. Bryan B. Molloy and David T. Wong. They were later awarded the Pharmaceutical Discoverer's Award from NARSAD (National Alliance for Research on Schizophrenia and Depression) for this. ^{[1] [2]} The molecule of Prozac has its origins in Diphenhydramine. In the 1960s it was found that diphenhydramine inhibits reuptake of the neurotransmitter serotonin. This discovery led to a search for viable antidepressants with similar structures and fewer side effects, culminating in the invention of fluoxetine (Prozac), a selective serotonin reuptake inhibitor (SSRI). A similar search had previously led to the synthesis of the first SSRI zimelidine from chlorpheniramine, also an antihistamine.

FDA approval and marketing campaign

Eli Lilly's Prozac was approved by the FDA on December 29, 1987 and introduced in the US at the beginning of 1988. The drug became very popular, with millions around the world having taken the medication. In the fall of 2001, Eli Lilly lost a patent dispute with Barr Laboratories and now fluoxetine hydrochloride is manufactured by many companies. Prozac's popularity and selling success has been aided greatly by Lilly's extensive marketing campaign for the drug, considered one of the most successful in the history of American pharmaceuticals.

Indications

Approved

Fluoxetine hydrochloride is approved in the United States to treat depression, obsessive-compulsive disorder, bulimia nervosa, premenstrual dysphoric disorder and panic disorder.^[3] In the United Kingdom, it is approved to treat depression with or without anxiety, bulimia nervosa, and obsessive-compulsive disorder.^[4]

In December 2003 the Food and Drug Administration (FDA) approved Symbyax to treat bipolar depression. Symbyax is a combination of fluoxetine and olanzapine. (However, the pure form of fluoxetine can cause mania, mixed-states, rapid cycling and psychosis in bipolar patients, particularly if the patient is not also taking a mood stabilizer.)

Unapproved/Off-label/Investigational

In 2003, Michel Harper, Fukodome Takayasu, and Andrew G. Engel reported that fluoxetine given over a period of three years at doses of up to 80-120 mg/day to two patients with slow-channel congenital myasthenic syndrome who were allergic to quinidine resulted in substantial subjective and objective improvement in muscle strength.^[5]

Fluoxetine is also often prescribed in the therapy of anorexia nervosa, mainly due to comorbidities between this disorder and other psychiatric disorders, such as clinical depression. The efficacy of fluoxetine administration to patients with anorexia nervosa has come into question in a recent publication of a randomized controlled trial. ^[6]

Mechanism of action

Per the prescribing label, the mechanism of action of fluoxetine is unknown. Recent research indicates that fluoxetine may increase the production of new neurons (brain cells) in adult brain (adult neurogenesis)^[7][8] and that it interacts with the system of "clock genes"^[9], the transcription factors involved in drug abuse and possibly obesity ^[10][11].

Atypical SSRI

In a study comparing the effects of fluoxetine, paroxetine, sertraline, citalopram, and fluvoxamine on extracellular concentrations of serotonin, dopamine, and norepinepherine in the prefrontal cortex, only fluoxetine showed robust and sustained increases in extracellular concentrations of norepinephrine and dopamine after acute systemic administration^[12], suggesting that fluoxetine is an atypical SSRI.

Interactions

Fluoxetine has a wide range of published interactions, notably with monoamine oxidase inhibitors (serotonin syndrome).

Side effects

Common adverse effects include akathisia, rage, and anxiety, which is possibly associated with an interaction of fluoxetine with the pineal gland,^[13] in addition to restlessness and insomnia. Weight loss, trembling, weakness, skin rash, anorgasmia, itching, and a decrease in sexual drive, have also been reported. It has been reported to cause subsequent weight gain [1].

Like other SSRIs, an overdose of fluoxetine or combining it with other antidepressants can lead to serotonin syndrome.

Metabolism

Fluoxetine is eliminated very slowly by the human body. The half-life of fluoxetine after a single dose is two days and, after multiple dosing, four days. The liver then metabolizes fluoxetine into norfluoxetine, a desmethyl metabolite, which is also a serotonin reuptake inhibitor; norfluoxetine has an even longer half-life, i.e. 8.6 and 9.3 days for single and repeated dosage respectively. These long half-lives may be helpful in those patients with compliance issues, but fluoxetine is most effective when taken daily. Other SSRIs have, by comparison, a very short half-life.

Some professionals feel that it is fluoxetine's long half-life that gives it much of its therapeutic utility, however this has never been proven under rigorous scientific study. Nevertheless, its long half life is also relevant because suddenly discontinuing SSRIs is known to produce both somatic and psychological withdrawal symptoms, a phenomenon known as "SSRI discontinuation syndrome".^[14] It is generally accepted that fluoxetine´s withdrawal symptoms are much smoother than with other SSRIs, as the substance takes several days to completely leave the system. Fluoxetine is a potent CYP2D6 inhibitor, which can decrease metabolism of other medications.

Formulations

Fluoxetine is sold in capsules containing 10, 15, 20, 40, 60 or 90 mg of active ingredient, in tablets containing 10 mg, or 20 mg or in an oral suspension with concentration of 20 mg/5 ml.

Prozac Weekly is 90 mg of regular enteric-coated fluoxetine, taken every 7 days. These capsules resist dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. The enteric coating delays the onset of absorption of fluoxetine 1 to 2 hours relative to the immediate-release formulations.

Controversy

In the late 1990s, backlash grew against Prozac. Prozac's manufacturer, Eli Lilly and Company, which had earned billions from the drug's success became the target of numerous accusations (see David Healy affair). Lawsuits amounting to millions were instigated, contending that the drug made users feel suicidal and/or caused other serious side effects. The accusations and lawsuits have been unsuccessful in stemming the prescription and use of the medication. Recently, the US FDA considered similar controversial issues regarding Prozac and its use in children and adolescents; it issued a "black box warning" (its most serious warning) for Prozac and other antidepressants (SSRI's and antidepressants of related classes) due to findings of increased suicidal tendency in some children and adolescents on the drugs.

A more recent controversy embroiled Lilly, and a class action lawsuit has been filed after several people received in the mail free samples of Prozac Weekly™. The suit alleges that the samples' recipients' right to privacy was mishandled.

In August 2004 a report by the Environment Agency found trace amounts of fluoxetine in UK drinking water, although the Drinking Water Inspectorate said that it was unlikely to pose a health risk.^[15] However, the effects from ingestion of fluoxetine in drinking water have not been investigated.

In January, 2005, the British Medical Journal leaked official Eli Lilly documents from the 1980s suggesting there was a link between fluoxetine and suicide and psychosis. It was originally claimed that the documents had not been previously disclosed, and they were subsequently provided to the FDA for further investigation. However, Eli Lilly insisted that the documents had been released in earlier litigation.^[16] The British Medical Journal ultimately retracted its claim that the documents had not been previously disclosed, and apologized to Eli Lilly.^[17]

Advertisements for Prozac have claimed for years that the medication works by correcting a chemical imbalance in the brain, a claim that is not supported by the product label and has been confirmed as false by the head of the FDA psychopharmacological drugs committee. Yet these claims are likely to have led to the drug's popularity. (http://medicine.plosjournals.org/archive/1549-1676/2/12/pdf/10.1371_journal.pmed.0020392-S.pdf)

Prozac for children

On 7th June 2006, the European Medicines Agency had announced that Prozac could be prescribed for children as young as 8 years old. They had concluded that the benefits of Prozac outweighed the risks in children with moderate to severe depression who had failed to respond to psychological therapy. However, they have warned that the drug should only be used in combination with on-going therapy and not as a stand alone treament ^[18].

References

1. ^ NARSAD (National Alliance for Research on Schizophrenia and Depression)
2. ^ Innovation's story on the invention of Prozac
3. ^ Eli Lilly and Company (2005). PROZAC Product/Prescribing Information (PDF). Official Prozac Website. Eli Lilly and Company. Retrieved on 8 February 2006.
4. ^ Discovery Pharmaceuticals (2004). Oxactin Capsules 20mg. electronic Medicines Compendium. Association of the British Pharmaceutical Industry. Retrieved on 8 February 2006.
5. ^ Harper, Michel, Takayasu Fukodome and Andrew G. Engel (27 May 2003). "Treatment of slow-channel congenital myasthenic syndrome with fluoxetine". Neurology 60 (10): 1710-3. PubMed.
6. ^ Walsh, Timothy, Allan Kaplan, Evelyn Attia, Marion Olmsted, Michael Parides, Jacqueline Carter, Kathleen Pike, Michael Devlin, Blake Woodside, Christina Roberto, and Wendi Rockert (14 June 2006). "Fluoxetine After Weight Restoration in Anorexia Nervosa: A Randomized Controlled Trial". Journal of the American Medical Association 295 (22): 2605-12.
7. ^ Malberg, Jessica E., Amelia J. Eisch, Eric J. Nestler, and Ronald S. Duman (December 15, 2000). "Chronic Antidepressant Treatment Increases Neurogenesis in Adult Rat Hippocampus". The Journal of Neuroscience 20 (24): 9104-10. PubMed.
8. ^ Manev, Hari, Tolga Uz, Neil R. Smalheiser and Radmila Manev (January 5, 2001). "Antidepressants alter cell proliferation in the adult brain in vivo and in neural cultures in vitro". European Journal of Pharmacology 411 (1-2): 67-70. DOI:10.1016/S0014-2999(00)00904-3.
9. ^ Uz, Tolga, Rehan Ahmed, Mustafa Akhisaroglu, Murat Kurtuncu, Marta Imbesi, Ahmet Dirim Arslan and Hari Manev (2005). "Effect of fluoxetine and cocaine on the expression of clock genes in the mouse hippocampus and striatum". Neuroscience 134 (4): 1309-16. DOI:10.1016/j.neuroscience.2005.05.003.
10. ^ Yuferov, Vadim, Eduardo R Butelman and Mary J Kreek (October 2005). "Biological clock: Biological clocks may modulate drug addiction". European Journal of Human Genetics 13 (10): 1101-3. DOI:10.1038/sj.ejhg.5201483.
11. ^ Manev, Hari, Tolga Uz (January 2006). "Clock genes as a link between addiction and obesity". European Journal of Human Genetics 14 (1): 5. DOI:10.1038/sj.ejhg.5201524.
12. ^ Zhang, Bymaster, Carter PA, Shaw J, Chernet E, Phebus L, Wong DT, Perry KW (April, 2002). "Fluoxetine, but not other selective serotonin uptake inhibitors, increases norepinephrine and dopamine extracellular levels in prefrontal cortex.".
13. ^ Uz, Tolga, Nikola Dimitrijevic, Mustafa Akhisaroglu, Marta Imbesi, Murat Kurtuncu, and Hari Manev (March 22, 2004). "The pineal gland and anxiogenic-like action of fluoxetine in mice". Neuroreport 15 (4): 691-4. PubMed.
14. ^ Tamam, Lut, Nurgul Ozpoyraz (January/February 2002). "Selective Serotonin Reuptake Inhibitor Discontinuation Syndrome: A Review". Advances in Therapy 19 (1): 17-26. PubMed.
15. ^ BBC NEWS (2004). Prozac 'found in drinking water'. British Broadcasting Corporation. Retrieved on 9 February 2006.
16. ^ Eli Lilly and Company (2004). Lilly Affirms: No 'Missing' Prozac Documents and No New Scientific Information. Official Eli Lilly and Company Website. Retrieved on 9 February 2006.
17. ^ (29 January 2005)"Eli Lilly: Correction and apology". British Medical Journal 330 (7485): 211. DOI:10.1136/bmj.330.7485.211-a.
18. ^ BBC NEWS (2006). Eight-year-olds 'can use Prozac'. British Broadcasting Corporation. Retrieved on 7 June 2006.

See also

• Antidepressants
• Clinical depression
• Eli Lilly and Company
• Selective serotonin reuptake inhibitors
• Serotonin
• SSRI discontinuation syndrome

External links

• NIH Expert Panel Report on the reproductive and developmental toxicology of Prozac (Fluoxetine)
• NIH Monograph on the potential human reproductive and developmental effects of Prozac (Fluoxetine)
• Producer of Prozac, Eli Lilly and Company, Inc.
• Lilly's Prozac advertising website
  
• Open Directory Fluoxetine
• Biography of Dr. Ray W. Fuller, one of the inventors of Prozac
• Biography of Dr. David T. Wong, one of the inventors of Prozac
• Biography of Dr. Bryan B. Molloy, one of the inventors of Prozac
• Link page to external chemical sources.