Fluoxetine , also known by the trade names Prozac and Sarafem , among others, are antidepressants of the selective serotonin reuptake inhibitor class (SSRI). It is used for the treatment of major depressive disorder, obsessive-compulsive disorder (OCD), bulimia nervosa, panic disorder and premenstrual dysphoric disorder. This can reduce the risk of suicide in those aged over 65. It has also been used to treat premature ejaculation. Fluoxetine is taken.
Common side effects include difficulty sleeping, sexual dysfunction, loss of appetite, dry mouth, rashes and abnormal dreams. Serious side effects include serotonin syndrome, mania, seizures, increased risk of suicidal behavior in people under 25 years and an increased risk of bleeding. If it stops suddenly, withdrawal syndrome can occur with anxiety, dizziness and sensation changes. It is unclear if it is safe in pregnancy. If you are already on medication, it may make sense to continue during breastfeeding. The mechanism of action is not entirely clear but is believed to be associated with increased serotonin activity in the brain.
Fluoxetine was invented by Eli Lilly and Company in 1972 and entered into medical use in 1986. It is a List of Essential Medicines of the World Health Organization, the most effective and safe medicines needed in the health system. It is available as a generic drug. Wholesale costs in developing countries are between 0.01 and 0.04 USD per day in 2014. In the United States, it costs around 0.85 USD per day.
Video Fluoxetine
Medical use
Fluoxetine is often used to treat major depressive disorders, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), bulimia nervosa, panic disorder, premenstrual dysphoric disorder, and trichotillomania. It has also been used for cataplexy, obesity, and alcohol dependence, as well as eating disorders of the party. It has also been tried as a treatment for autism spectrum disorders with moderate success in adults.
Depression
The effectiveness of fluoxetine and other antidepressants in the treatment of mild to moderate depression is controversial. A meta-analysis published by Kirsch in 2008 showed, in those with mild or moderate symptoms, the effectiveness of fluoxetine and other SSRIs was clinically insignificant. A 2009 meta-analysis by Fournier that evaluated patient-level data from six trials of SSRI paroxetine and non-SSRI imipramine antidepressants has been cited further as evidence that antidepressants exhibit minimal efficacy in mild to moderate depression. A 2012 meta-analysis using individual patient-level fluoxetine data for the treatment of depression concluded statistical and clinical benefits were significantly seen regardless of the severity of early depression, and no significant effects were found at the severity level at the initial observed efficacy.
A systematic review of 2009 by the National Institute of Care and Clinical Excellence (NICE) (which considers Kirsch, but not a later meta-analysis) concluded strong evidence exists for SSRI efficacy in the treatment of moderate and severe depression, with some evidence for their efficacy in treatment mild depression. Both NICE and Fournier's analysis concluded that greater evidence was seen for the efficacy of antidepressants in the treatment of mild chronic depression (dysthymia) rather than recent mild depression.
NICE recommends antidepressant treatment with SSRIs in combination with psychosocial interventions as second-line treatment for mild short-term depression, and as first-line treatment for severe and moderate depression, as well as mild or recurrent mild depression. The American Psychiatric Association covers antidepressant therapy among first-line options for the treatment of depression, especially when "a history of previous positive responses to antidepressant drugs, moderate to severe symptoms, significant sleep or appetite disorders, agitation, patient preferences, and anticipated needs for maintenance therapy "exists.
Obsessive-compulsive disorder
The efficacy of fluoxetine in the treatment of obsessive-compulsive disorder (OCD) was demonstrated in two randomized, phase III multicenter clinical trials. The results collected from this trial showed that 47% of the supplement treated with the highest dose were "much better" or "greatly improved" after 13 weeks of treatment, compared with 11% in the placebo group from the trial. The American Academy of Child and Adolescent Psychiatry states that SSRIs, including fluoxetine, should be used as first-line therapy in children, along with cognitive behavioral therapy (CBT), for the treatment of moderate to severe OCD.
Panic disorder
The efficacy of fluoxetine in the treatment of panic disorder is demonstrated in two clinical trials of 12 week Physicenter phase III phases that register patients diagnosed with panic disorder, with or without agoraphobia. In the first trial, 42% of subjects in the group treated with fluoxetine were free of panic attacks at the end of the study, vs 28% in the placebo group. In the second trial, 62% of patients treated with fluoxetine were free of panic attacks at the end of the study, vs 44% in the placebo group.
Bulimia nervosa
A systematic review of seven trials comparing fluoxetine with placebo in the treatment of bulimia nervosa; six of whom found statistically significant decrease in symptoms such as vomiting and binge eating. However, no differences were observed between treatment groups when fluoxetine and psychotherapy were compared with psychotherapy alone.
Premenstrual dysphoric disorder
Fluoxetine is used to treat premenstrual dysphoric disorder.
Custom population
In children and adolescents, fluoxetine is the antidepressant of choice because the evidence while supporting its efficacy and tolerability. In pregnancy, fluoxetine is considered a category C drug. Evidence that supports increased risk of major fetal malformations due to limited fluoxetine exposure, although the UK's Drug and Health Products Regulatory Agency (MHRA) has alerted prescribers and patients about the potential for exposure to fluoxetine in the first trimester organogenesis, formation). fetal organs) leads to a slightly increased risk of congenital heart malformation in newborns. Furthermore, the relationship between fluoxetine use during the first trimester and an increased risk of minor fetal malformations was observed in one study.
However, a systematic review and meta-analysis of 21 studies - published in the Journal of Obstetrics and Gynecology Canada - concluded, "an increased risk of fetal heart malformation associated with recent fluoxetine use in mothers has been done , is also shown in depressed women who delay SSRI therapy in pregnancy, and therefore most likely reflect a determinant bias Overall, women treated with fluoxetine during the first trimester of pregnancy do not appear to have an increased risk of major fetal malformations. "
As per FDA, babies exposed to SSRIs at the end of pregnancy may have an increased risk for persistent pulmonary hypertension in newborns. Limited data support this risk, but the FDA recommends doctors consider SSRI reduction as fluoxetine during the third trimester. A 2009 review recommended against fluoxetine as a first-line SSRI during breast-feeding, states, "[fluoxetine] should be seen as a less favorable SSRI for breastfeeding mothers, especially with newborns, and in mothers who consume fluoxetine during pregnancy." Sertraline is often the preferred SSRI during pregnancy because of relatively minimal exposure to the fetus and its safety profile when breastfeeding.
Maps Fluoxetine
Adverse effects
Side effects observed in people treated with fluoxetine in clinical trials with incidence & gt; 5% and at least twice as common in people treated with fluoxetine as compared to those receiving placebo pills including abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, decreased libido , nausea, nervousness, pharyngitis, rash, sinusitis, somnolen, sweating, tremor, vasodilation, and yawning. Fluoxetine is considered the most stimulating of SSRIs (the most vulnerable to causing insomnia and agitation). It also appears to be the most susceptible of SSRIs to produce dermatological reactions (eg urticaria (itching), rashes, itching, etc.).
Sex Sexual dysfunction
Sexual dysfunction, including loss of libido, anorgasmia, lack of vaginal lubrication, and erectile dysfunction, are some of the most common adverse effects of treatment with fluoxetine and other SSRIs. While preliminary clinical trials show relatively low levels of sexual dysfunction, a more recent study in which investigators â € <â € <â €
The antidepressant termination syndrome is a detrimental effect of second generation anti-depressants, including fluoxetine. Symptoms come with the rapid termination of any of these drugs, and can include dizziness, balance disorders, headache, nausea, insomnia, and lively dreams. Others may include tingling or numbing sensations, sensations such as electric shock, and irritability, with some cases of hallucinations. They can generally be prevented by reducing the drug over a four-week period, although the evidence is weak to taper off optimally and there is disagreement among experts over the schedule. If a person is informed about the risk of termination syndrome before starting the drug and again before starting any reduction, the symptoms of cessation appear to be less and less severe, but again evidence is weak. Slow-acting drugs, such as fluoxetine, may be less likely to cause symptoms of discontinuation, but evidence for this is also weak. The mechanism by which the termination syndrome occurs in some people is not well understood.
Suicide
In 2007 the FDA required all antidepressants to carry black box warnings stating that antidepressants could increase the risk of suicide in people younger than 25. This warning is based on statistical analysis conducted by two independent groups of FDA experts who found a 2-fold increase. of suicidal ideation and behavior in children and adolescents, and a 1.5-fold increase of suicide in the 18-24 age group. Suicidality declined slightly for those over the age of 24, and was statistically significantly lower in the 65 and older groups. This analysis was criticized by Donald Klein, who notes that suicide, ie suicidal and behavioral desires, is not always a good surrogate marker for suicide, and it is still possible that antidepressants can prevent actual suicides while increasing suicide.
There is little data about fluoxetine than antidepressants as a whole. For the above analysis at the antidepressant level, the FDA should combine the results of 295 trials of 11 antidepressants for psychiatric indications to obtain statistically significant results. Considered separately, the use of fluoxetine in children increases the likelihood of suicide by 50%, and in adults reduces the likelihood of suicide by about 30%. Similarly, the analysis by the UK MHRA found a 50% increase in the likelihood of suicide-related events, not reaching statistical significance, in children and adolescents in fluoxetine compared with those on placebo. According to MHRA data, for adults fluoxetine does not alter self-harm levels and statistically significantly reduces the idea of ​​suicide by 50%.
Overdose
In overdose, the most common side effects include:
Interactions
Contraindications include previous treatments (within the past two weeks) with MAOIs such as phenelzine and tranylcypromine, due to the potential of serotonin syndrome. Its use should also be avoided in those known as hypersensitivity to fluoxetine or any of the other ingredients in the formulation used. Its use in those who simultaneously receive pimozide or thioridazine is also advised against.
In some cases, the use of dextromethorphan containing cold & amp; cough with fluoxetine is recommended against, because fluoxetine increases serotonin levels, as well as the fact that fluoxetine is a cytochrome P450 2D6 inhibitor, which causes dextromethorphan not metabolized at normal levels, thus increasing the risk of serotonin and other syndromes. potential side effects of dextromethorphan.
Patients who use anticoagulants or NSAIDS should be careful when using fluoxetine or other SSRIs, as it can sometimes increase the blood-thinning effect of these drugs.
Fluoxetine and norfluoxetine inhibit many of the cytochrome P450 isozymes involved in drug metabolism. Both are potent CYP2D6 inhibitors (which are also the major enzymes responsible for their metabolism) and CYP2C19, and mild to moderate CYP2B6 and CYP2C9 inhibitors. in vivo , fluoxetine and norfluoxetine did not significantly affect CYP1A2 and CYP3A4 activity. They also inhibit the activity of P-glycoprotein, a type of membrane transport protein that plays an important role in drug transport and metabolism and hence P-glycoprotein substrate such as loperamide may have a reinforced central effect. Broad effects on the body pathways for drug metabolism create the potential for interaction with many commonly used drugs.
Use should also be avoided in those receiving other serotonergic drugs such as monoamine oxidase inhibitors, tricyclic antidepressants, methamphetamine, MDMA, triptans, buspirone, serotonin-norepinephrine reuptake inhibitors and other SSRIs because of the potential for serotonin syndrome to develop as a result.
There is also the potential for interactions with high protein-bound drugs because of the potential of fluoxetine to replace these drugs from plasma or vice versa thereby increasing serum concentrations of either fluoxetine or offending agents.
Pharmacology
Pharmacodynamics
Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) and inadequately inhibits norepinephrine and dopamine reuptake in therapeutic doses. However, delaying the reuptake of serotonin, so serotonin lasts longer when released. Large doses in mice have been shown to induce a significant increase in norepinephrine and synaptic dopamine. Thus, dopamine and norepinephrine may contribute to the action of fluoxetine antidepressants in humans at supratherapeutic doses (60-80 mg). This effect can be mediated by the 5HT 2C receptor, which is inhibited by higher fluoxetine concentrations.
Fluoxetine increases the circulating concentration of allopregnanolone, strong GABA A positive allosteric modulator receptor, in the brain. Norfluoxetine, the main active metabolite of fluoxetine, produces the same effect at allopregnanolone levels in the rat brain. In addition, both fluoxetine and norfluoxetine are modulators themselves, actions that may be clinically relevant.
In addition, fluoxetine has been found to act as a receptor agonist? 1 , with potency greater than citalopram but less than fluvoxamine. However, the meaning of this property is not entirely clear. Fluoxetine also acts as an anoctamin channel blocker, a calcium-activated chloride channel. A number of other ion channels, including nicotinic acetylcholine receptors and 5-HT receptors 3 , are also known to be inhibited at the same concentration.
Fluoxetine has been shown to inhibit acid sphingomyelinase, a key regulator of ceramide levels derived from ceramide from sphingomyelin.
Pharmacokinetics
Bioavailability of fluoxetine is relatively high (72%), and peak plasma concentrations are achieved in 6-8 hours. It's so tied up with plasma proteins, mostly albumin and? 1 -glycoprotein. Fluoxetine is metabolized in the liver by cytochrome P450 isoenzymes, including CYP2D6. The role of CYP2D6 in fluoxetine metabolism may be clinically important, as there is great genetic variability in the function of this enzyme among people. CYP2D6 is responsible for converting fluoxetine into its only active metabolite, norfluoxetine. Both of these drugs are also potent CYP2D6 inhibitors.
The very slow removal of fluoxetine and norfluoxetine active metabolites from the body differentiate it from other antidepressants. With time, fluoxetine and norfluoxetine inhibit their own metabolism, resulting in a half-life elimination of fluoxetine from 1 to 3 days, after a single dose, up to 4 to 6 days, after prolonged use. Similarly, the longer half of the norfluoxetine (16 days) after long-term use. Therefore, the concentration of the drug and its active metabolites in the blood continue to grow during the first few weeks of treatment, and their stable blood concentration is achieved only after four weeks. In addition, brain concentrations of fluoxetine and metabolites continue to increase until at least the first five weeks of treatment. That means that the full benefits of the current dose the patient receives are not realized at least one month since initiation. For example, in one 6-week study, the average time to achieve a consistent response was 29 days. Likewise, complete drug excretion may take several weeks. During the first week after discontinuation, fluoxetine brain concentrations decreased by only 50%, norfluoxetine 4 weeks after treatment interruption was approximately 80% of the levels enrolled at the end of the first treatment week, and 7 weeks after discontinuation of norfluoxetine was detectable in the blood.
Measurements in body fluids
Fluoxetine and norfluoxetine can be quantized in blood, plasma or serum to monitor therapy, confirm the diagnosis of poisoning in hospitalized patients or assist in investigation of medicolegal death. The concentration of blood or plasma fluoxetine is usually in the 50-500 range? G/L in people taking the drug for its antidepressant effect, 900-3000? G/L in the victims of acute overdose and 1000-7000? G/L on victims of fatal overdose. The concentration of Norfluoxetine is approximately equal to the concentration of the parent drug during chronic therapy, but may be substantially less after an acute overdose, since it takes at least 1-2 weeks for the metabolite to reach equilibrium.
Usage
In 2010, more than 24.4 million recipes for generic fluoxetine were filled in the United States, making it the most widely prescribed antidepressant after sertraline and citalopram. In 2011, 6 million recipes for fluoxetine were filled in the UK.
History
The work that eventually led to the discovery of fluoxetine began at Eli Lilly and Company in 1970 as a collaboration between Bryan Molloy and Robert Rathbun. At that time it was known that diphenhydramine antihistamines showed some properties such as antidepressants. 3-Phenoxy-3-phenylpropylamine, a compound structurally similar to diphenhydramine, is taken as a starting point, and Molloy synthesizes dozens of its derivatives. Hoping to find a derivative inhibitor only serotonin reuptake, an Eli Lilly scientist, David T. Wong, proposed to retest the series for in vitro serotonin reuptake, norepinephrine and dopamine. This test, conducted by Jong-Sir Horng in May 1972, showed the compound was then called fluoxetine as the most powerful and selective serotonin reuptake inhibitor of this series. Wong published the first article on fluoxetine in 1974. A year later, the official chemical name of fluoxetine and Eli Lilly and Company gave it the Prozac trade name. In February 1977, Dista Products Company, Eli Lilly & amp; The Company, filed an Investigational New Drug application to the US Food and Drug Administration (FDA) for fluoxetine.
Fluoxetine appeared in the Belgian market in 1986. In the US, the FDA granted final approval in December 1987, and a month later Eli Lilly began marketing Prozac; annual sales in the US reach $ 350 million in a year. Worldwide sales eventually peaked at $ 2.6 billion per year.
Lilly attempted several expansion strategies for the product line, including extended release formulations and pay for clinical trials to test the efficacy and safety of fluoxetine in premenstrual dysphoric disorder and drug rebranding in indication as "Sarafem" after being approved by the FDA in 2000, following recommendations from the advisory committee on 1999. The discovery using fluoxetine to treat PMDD was made by Richard Wurtman at MIT, and the patent was licensed to his startup, Interneuron, which was then sold to Lilly.
To keep his income from fluoxetine, Lilly also fought for five years, a multimillion-dollar war in court with generic company Barr Pharmaceuticals to protect his patent on fluoxetine, and lost the case for his line-extension patent in addition to Sarafem, opening fluoxetine to generic manufacturers starting in 2001. When Lilly's patent expired in August 2001, generic drug competition lowered Lily's fluoxetine sales by 70% within two months.
In 2000, an investment bank projected that Sarafem's annual sales could reach $ 250 million/year. Sarafem's sales amounted to approximately $ 85M/year in 2002, and that year Lilly sold his assets around the drug for $ 295 million to Galen Holdings, a small Irish pharmaceutical company specializing in the field of dermatology and women's health that has an assigned sales force to an obstetrician. office; analysts find the deal reasonable because Sarafem's annual sales make a difference to Galen, but not to Lilly.
Bringing Sarafem to market damaged Lilly's reputation in some circles. The controversial category of PMDD diagnostic since it was first proposed in 1987, and Lilly's role in defending it in the DSM-IV-TR appendix, a discussion that took place in 1998, has been criticized. Lilly was criticized for creating illness to make money, and not to innovate but to find ways to continue making money from existing medicines. It was also criticized by the FDA and the group concerned with women's health for Sarafem's marketing was too aggressive when it was first launched; the campaign included a television commercial featuring a rushed woman in a grocery store who asked herself whether she had PMDD.
Society and culture
airline pilots
Beginning April 5, 2010, fluoxetine became one of four antidepressant drugs that the FAA allowed for pilots with authorization from aviation medical examiners. Other antidepressants that are allowed are sertraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro). The four remain the only antidepressants allowed by the FAA on 2 December 2016.
Environmental effects
Fluoxetine has been detected in aquatic ecosystems, especially in North America. There is a growing body of research that addresses the effects of fluoxetine exposure (eg SSRIs) in non-target aquatic species. In 2003, one of the first studies to discuss in detail the potential effects of fluoxetine on aquatic wildlife, the study concluded that exposure to environmental concentrations is a small risk for aquatic systems if a hazard risk approach is applied to risk assessment. However, they also stated the need for further research that discusses the sub-lethal consequences of fluoxetine, in particular focusing on the sensitivity of species studies, behavioral responses, and endpoints modulated by the serotonin system. Since now, a number of studies have reported the effects of fluoxetine on a number of behavioral and physiological endpoints, encouraging antipredator, reproductive and foraging behavior at or below detectable concentrations in the field. Although, the 2014 review on fluoxetine ecotoxicology concluded that at that time consensus on the ability of realistic environmental doses to influence wildlife behavior could not be achieved.
Politics
During the 1990 campaign for the Florida governor, it was revealed that one of the candidates, Lawton Chiles, was depressed and had again taken fluoxetine, leading his political opponents to question his fitness to serve as Governor.
Research
Violence
Both the American Psychiatric Association, the National Institute for Health and Care Excellence (NICE), and the American College of Physicians note the violence between potential side effects of treatment with serotonin selective reuptake inhibitors. Similarly, the World Health Organization and the European Psychiatric Association do not include violence among potential SSRI side effects.
The study of case reports of this type of series has been criticized as the subject of "confounding by indication", in which effects due to underlying illness conditions are erroneously attributed to the effects of treatment. Other studies, including randomized clinical trials and observational studies, have suggested that fluoxetine and other SSRIs can reduce violent tendencies. A randomized clinical trial conducted by the US National Institutes of Health for Mental Health found that fluoxetine reduced domestic violence to alcoholics with a history of such behavior. A second clinical trial conducted at the University of Chicago found that fluoxetine reduced aggressive behavior in patients with aggressive intermittent. chaos. A clinical trial found that fluoxetine reduces aggressive behavior in patients with impaired personality thresholds. These results are indirectly supported by research showing that other SSRIs can reduce violence and aggressive behavior. A NBER study examining international trends in the use of antidepressants and crime rates in the 1990s found that an increase in antidepressant drug prescriptions was associated with a reduction in violent crime.
Despite the above-mentioned evidence, psychiatrist David Healy and certain patient activist groups have compiled reports of violent cases committed by individuals using fluoxetine or other SSRIs, and argue that these drugs affect vulnerable individuals to commit acts of violence.
See also
- Atomoxetine (basic modification and termination of the same molecule) it is a variant of the same structure
References
External links
- Fluoxetine, from the Drug Information Portal of the National Library of the United States
- Shorter, E (2014). "The 25th anniversary of the launch of Prozac provides a pause to think: where are we wrong?". British journal of psychiatry: the journal of mental sciences . 204 : 331-2. doi: 10.1192/bjp.bp.113.129916. PMIDÃ, 24785765. < span>
Source of the article : Wikipedia
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