Fluoxetine, sold under the brand name Prozac, among others, is an Antidepressant of the selective serotonin reuptake inhibitor (SSRI) class used for the treatment of major depressive disorder, Anxiety disorder, obsessive–compulsive disorder (OCD), panic disorder, premenstrual dysphoric disorder, and bulimia nervosa. It is also approved for treatment of major depressive disorder in adolescents and children 8 years of age and over. It has also been used to treat premature ejaculation. Fluoxetine is taken by mouth.
Common side effects include loss of appetite, nausea, diarrhea, headache, insomnia, xerostomia, and sexual dysfunction. Serious side effects include serotonin syndrome, mania, , an increased risk of suicide, and an increased risk of bleeding. Antidepressant discontinuation syndrome is less likely to occur with fluoxetine than with other antidepressants. Fluoxetine taken during pregnancy is associated with a significant increase in congenital heart defects in newborns. It has been suggested that fluoxetine therapy may be continued during breastfeeding if it was used during pregnancy or if other antidepressants were ineffective.
Fluoxetine was invented by Eli Lilly and Company in 1972 and entered medical use in 1986.
It is on the World Health Organization's List of Essential Medicines and is available as a generic medication. In 2022, it was the 22nd most commonly prescribed medication in the United States, with more than 24million prescriptions.Eli Lilly also markets fluoxetine in a fixed-dose combination with olanzapine as olanzapine/fluoxetine (Symbyax), which was approved by the US Food and Drug Administration (FDA) for the treatment of depressive episodes of bipolar I disorder in 2003 and for treatment-resistant depression in 2009.
For children and adolescents with moderate-to-severe depressive disorder, fluoxetine seems to be the best treatment (either with or without cognitive behavioural therapy, although fluoxetine alone does not appear to be superior to CBT alone) but more research is needed to be certain, as effect sizes are small and the existing evidence is of dubious quality. A 2022 systematic review and trial restoration of the two original blinded-control trials used to approve the use of fluoxetine in children and adolescents with depression found that both of the trials were severely flawed, and therefore did not demonstrate the safety or efficacy of the medication. In 2025, a trial restoration of the influential TADS study found that fluoxetine had not been superior to placebo in the treatment of depressed adolescents, contradicting previously reported results used in meta-analyses and guidelines.
However, a systematic review and meta-analysis of 21 studies – published in the Journal of Obstetrics and Gynaecology Canada – concluded, "the apparent increased risk of fetal cardiac malformations associated with maternal use of fluoxetine has recently been shown also in depressed women who deferred SSRI therapy in pregnancy, and therefore most probably reflects an ascertainment bias. Overall, women who are treated with fluoxetine during the first trimester of pregnancy do not appear to have an increased risk of major fetal malformations."
Per the US Food and Drug Administration (FDA), infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn. Limited data support this risk, but the FDA recommends physicians consider tapering SSRIs such as fluoxetine during the third trimester. A 2009 review recommended against fluoxetine as a first-line SSRI during lactation, stating, "Fluoxetine should be viewed as a less-preferred SSRI for breastfeeding mothers, particularly with newborn infants, and in those mothers who consumed fluoxetine during gestation." Sertraline is often the preferred SSRI during pregnancy due to the relatively minimal fetal exposure observed and its safety profile while breastfeeding.
In 2019, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency recommended that packaging leaflets of selected SSRIs and SNRIs should be amended to include information regarding a possible risk of persistent sexual dysfunction. Following on the European assessment, a safety review by Health Canada "could neither confirm nor rule out a causal link... which was long lasting in rare cases", but recommended that "healthcare professionals inform patients about the potential risk of long-lasting sexual dysfunction despite discontinuation of treatment".
In October 2004, the FDA added its most serious warning, a black box warning, to all antidepressant drugs regarding use in children. In 2006, the FDA included adults aged 25 or younger. Statistical analyses conducted by two independent groups of FDA experts 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. In February 2018, the FDA ordered an update to the warnings based on statistical evidence from twenty-four trials in which the risk of such events increased from two percent to four percent relative to the placebo trials.
A study published in May 2009 found that fluoxetine was more likely to increase overall suicidal behavior. 14.7% of the patients (n=44) on Fluoxetine had suicidal events, compared to 6.3% in the psychotherapy group and 8.4% from the combined treatment group. Similarly, the analysis conducted by the UK MHRA found a 50% increase in suicide-related events, not reaching statistical significance, in the children and adolescents on fluoxetine as compared to the ones on placebo. According to the MHRA data, fluoxetine did not change the rate of self-harm in adults and statistically significantly decreased suicidal ideation by 50%.
Nervous system effects
Gastrointestinal effects
Other effects
In case of short-term administration of codeine for pain management, it is advised to monitor and adjust dosage. Codeine might not provide sufficient analgesia when fluoxetine is co-administered. If opioid treatment is required, oxycodone use should be monitored since oxycodone is metabolized by the cytochrome P450 (CYP) enzyme system and fluoxetine and paroxetine are potent inhibitors of CYP2D6 enzymes. This means combinations of codeine or oxycodone with fluoxetine antidepressant may lead to reduced analgesia.
In some cases, use of dextromethorphan-containing cold and cough medications with fluoxetine is advised against, due to fluoxetine increasing serotonin levels, as well as the fact that fluoxetine is a cytochrome P450 2D6 inhibitor, which causes dextromethorphan to not be metabolized at a normal rate, thus increasing the risk of serotonin syndrome and other potential side effects of dextromethorphan.
Patients who are taking NSAIDs, antiplatelet drugs, , omega-3 fatty acids, vitamin E, and garlic supplements must be careful when taking fluoxetine or other SSRIs, as they can sometimes increase the blood-thinning effects of these medications.
Fluoxetine and norfluoxetine enzyme inhibitor many of the cytochrome P450 system that are involved in drug metabolism. Both are potent inhibitors of CYP2D6 (which is also the chief enzyme responsible for their metabolism) and CYP2C19, and mild to moderate inhibitors of CYP2B6 and CYP2C9.
Its use should also be avoided in those receiving other serotonergic drugs such as monoamine oxidase inhibitors, tricyclic antidepressants, methamphetamine, amphetamine, MDMA, , buspirone, ginseng, Dextromethorphan, linezolid, tramadol, serotonin–norepinephrine reuptake inhibitors (SNRIs), and other SSRIs due to the potential for serotonin syndrome to develop as a result.
Fluoxetine may also increase the risk of opioid overdose in some instances, in part due to its inhibitory effect on cytochrome P-450. Similar to how fluoxetine can effect the metabolization of dextromethorphan, it may cause medications like oxycodone to not be metabolized at a normal rate, thus increasing the risk of serotonin syndrome as well as resulting in an increased concentration of oxycodone in the blood, which may lead to accidental overdose. A 2022 study that examined the health insurance claims of over 2 million Americans who began taking oxycodone while using SSRIs between 2000 and 2020, found that patients taking paroxetine or fluoxetine had a 23% higher risk of overdosing on oxycodone than those using other SSRIs.
There is also the potential for interaction with highly protein-bound drugs due to the potential for fluoxetine to displace said drugs from the plasma or vice versa hence increasing serum concentrations of either fluoxetine or the offending agent.
+Binding affinities (Ki in nanomole) ! scope="col" | Molecular Target ! scope="col" | Fluoxetine |
19 | ||
2700 | ||
420 | ||
13700 | ||
295 | ||
91 | ||
3900 | ||
1200 | ||
4600 | ||
760 | ||
2600 | ||
2200 | ||
H1 | 3250 | 10000+ |
Fluoxetine increases the concentration of circulating allopregnanolone, a potent GABAA receptor positive allosteric modulator, at concentrations that are inactive on serotonin reuptake. Norfluoxetine, a primary active metabolite of fluoxetine, produces a similar effect on allopregnanolone levels in the brains of mice. Additionally, both fluoxetine and norfluoxetine are such modulators themselves, actions which may be clinically relevant.
In addition, fluoxetine has been found to act as an agonist of the σ1-receptor, with a potency greater than that of citalopram but less than that of fluvoxamine. However, the significance of this property is not fully clear. Fluoxetine also functions as a channel blocker of anoctamin 1, a calcium-activated chloride channel. A number of other , including nicotinic acetylcholine receptors and 5-HT3 receptors, are also known to be at similar concentrations.
Fluoxetine has been shown to inhibit acid sphingomyelinase, a key regulator of ceramide levels which derives ceramide from sphingomyelin.
Prolonged exposure to fluoxetine changes the expression of genes involved in myelination, a process that shapes brain connectivity and contributes to symptoms of psychiatric disorders. The regulation of genes involved with myelination is partially responsible for the long-term therapeutic benefits of chronic SSRI exposure.
The extremely slow elimination of fluoxetine and its active metabolite norfluoxetine from the body distinguishes it from other antidepressants. With time, fluoxetine and norfluoxetine inhibit their own metabolism, so fluoxetine elimination half-life increases 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. Therefore, the concentration of the drug and its active metabolite in the blood continues to grow through the first few weeks of treatment, and their steady concentration in the blood is achieved only after four weeks. Moreover, the brain concentration of fluoxetine and its metabolites keeps increasing through at least the first five weeks of treatment. For major depressive disorder, while onset of antidepressant action may be felt as early as 1–2 weeks, the full benefit of the current dose a patient receives is not realized for at least a month following ingestion. For example, in one 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 treatment discontinuation, the brain concentration of fluoxetine decreases by only 50%, The blood level of norfluoxetine four weeks after treatment discontinuation is about 80% of the level registered by the end of the first treatment week, and, seven weeks after discontinuation, norfluoxetine is still detectable in the blood.
Fluoxetine appeared on the Belgian market in 1986. In the U.S., the FDA gave its final approval in December 1987, and a month later Eli Lilly began marketing Prozac; annual sales in the U.S. reached $350 million within a year. Worldwide sales eventually reached a peak of $2.6 billion a year.
Lilly tried several product line extension strategies, including extended-release formulations and paying for clinical trials to test the efficacy and safety of fluoxetine in premenstrual dysphoric disorder and rebranding fluoxetine for that indication as "Sarafem" after it was approved by the FDA in 2000, following the recommendation of an advisory committee in 1999. The invention of using fluoxetine to treat PMDD was made by Richard Wurtman at MIT; the patent was licensed to his startup, Interneuron, which in turn sold it to Lilly.
To defend its Prozac revenue from generic competition, Lilly also fought a five-year, multimillion-dollar battle in court with the generic company Barr Pharmaceuticals to protect its patents on fluoxetine, and lost the cases for its line-extension patents, other than those for Sarafem, opening fluoxetine to generic manufacturers starting in 2001. When Lilly's patent expired in August 2001, generic drug competition decreased Lilly's sales of fluoxetine by 70% within two months.
In 2000 an investment bank had projected that annual sales of Sarafem could reach $250M/year. Sales of Sarafem reached about $85M/year in 2002, and in that year Lilly sold its assets connected with the drug for $295M to Galen Holdings, a small Irish pharmaceutical company specializing in dermatology and women's health that had a sales force tasked to gynecologists' offices; analysts found the deal sensible since the annual sales of Sarafem made a material financial difference to Galen, but not to Lilly.
Bringing Sarafem to market harmed Lilly's reputation in some quarters. The diagnostic category of PMDD was controversial since it was first proposed in 1987, and Lilly's role in retaining it in the appendix of the DSM-IV-TR, the discussions for which got underway in 1998, has been criticized. Lilly was criticized for inventing a disease to make money, and for not innovating but rather just seeking ways to continue making money from existing drugs. It was also criticized by the FDA and groups concerned with women's health for marketing Sarafem too aggressively when it was first launched; the campaign included a television commercial featuring a harried woman at the grocery store who asks herself if she has PMDD.
In 2011, 6 million prescriptions for fluoxetine were filled in the United Kingdom. Between 1998 and 2017, along with amitriptyline, it was the most commonly prescribed first antidepressant for adolescents aged 12–17 years in England.
In 2003, one of the first studies addressed in detail the potential effects of fluoxetine on aquatic wildlife; this research concluded that exposure at environmental concentrations was of little risk to aquatic systems if a hazard quotient approach was applied to risk assessment. However, they also stated the need for further research addressing sub-lethal consequences of fluoxetine, specifically focusing on study species' sensitivity, behavioural responses, and endpoints modulated by the serotonin system.
Fluoxetine similar to several other SSRIs induces reproductive behavior in some shellfish at concentrations as low as 10 M, or 30 parts per trillion.
Since 2003, several studies have reported fluoxetine-induced impacts on many behavioural and physiological endpoints, inducing antipredator behaviour, reproduction, and foraging at or below field-detected concentrations. However, a 2014 review on the ecotoxicology of fluoxetine concluded that, at that time, a consensus on the ability of environmentally realistic dosages to affect the behaviour of wildlife could not be reached. At environmentally realistic concentrations, fluoxetine alters insect emergence timing.
Richmond et al., 2019 find that at low concentrations it accelerates emergence of Diptera, while at unusually high concentrations it has no discernable effect.
Several common plants are known to absorb fluoxetine.
Several crops have been tested, and Redshaw et al. 2008 find that cauliflower absorbs large amounts into the stem and leaf but not the head or root. Wu et al. 2012 find that lettuce and spinach also absorb detectable amounts, while Carter et al. 2014 find that radish ( Raphanus sativus), ryegrass ( Lolium perenne) – and Wu et al. 2010 find that soybean ( Glycine max) – absorb little. Wu tested all tissues of soybean and all showed only low concentrations. By contrast various Reinhold et al. 2010 find have a high uptake of fluoxetine and show promise for bioremediation of contaminated water, especially Lemna minor and Landoltia punctata. Ecotoxicity for organisms involved in aquaculture is well documented.
Sertraline, citalopram, and escitalopram are the only antidepressants permitted for EASA medical certification, as of January 2019.
Fluoxetine has an anti-nematode effect. Choy et al., 1999 found some of this effect is due to interference with certain transmembrane proteins.
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