Fluoxetine 20 mg capsules.
Fluoxetine (also known by the tradenames Prozac, Sarafem, Fontex, among others) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Fluoxetine was first documented in 1974 by scientists from Eli Lilly and Company.[1] It was presented to the U.S. Food and Drug Administration in February 1977, with Eli Lilly receiving final approval to market the drug in December 1987. Fluoxetine went off-patent in August 2001.
Fluoxetine is approved for the treatment of major depression (including pediatric depression), obsessive-compulsive disorder (in both adult and pediatric populations), bulimia nervosa, panic disorder and premenstrual dysphoric disorder.[2] In combination with olanzapine it is known as Symbyax.
Despite the availability of newer agents, fluoxetine remains extremely popular. In 2010, over 24.4 million prescriptions for generic formulations of fluoxetine were filled in the United States alone,[3] making it the third most prescribed antidepressant after sertraline (SSRI; became generic in 2006) and citalopram (SSRI; became generic in 2003).[3]
Fluoxetine is frequently used to treat major depression, obsessive compulsive disorder, bulimia nervosa, panic disorder, body dysmorphic disorder and premenstrual dysphoric disorder. Caution should be taken when using any SSRI for bipolar disorder as this can increase the likelihood of mania; however, fluoxetine can be used with an antipsychotic (such as Quetiapine) for bipolar[4] It has also been used for cataplexy, obesity, and alcohol dependence,[4] as well as binge eating disorder.[5]
Fluoxetine was shown to be effective for depression in six-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 in placebo-controlled trials.[6]
Research suggests that a significant part of the resistance to the SSRIs paroxetine (Paxil) and citalopram (Celexa) can be explained by the genetic variation of Pgp transporter. Paroxetine and citalopram, which are Pgp substrates, are actively transported from the brain by this protein. Fluoxetine is not a substrate of Pgp, and thus a switch from paroxetine or citalopram to fluoxetine may be beneficial to the nonresponders.[7][8]
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.[6] 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.[6]
Fluoxetine capsules (20 mg), as prescribed in the United Kingdom.
Sexual dysfunction is a common side effect with SSRIs. Specifically, side effects often include difficulty becoming aroused, erectile dysfunction, lack of interest in sex, and anorgasmia (inability to achieve orgasm). Genital anesthesia,[9] loss of or decreased response to sexual stimuli, and ejaculatory anhedonia are also possible. Although usually reversible, these sexual side effects can last for months, years, or permanence after the drug has been completely withdrawn.[10] This is known as Post SSRI Sexual Dysfunction.
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).[6] 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 half as fast in these patients, resulting in the proportionate increase of exposure to the drug.[6] Ibuprofen used in combination with fluoxetine can cause significant intestinal bleeding after a period of use.
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%).[6][11][12][13][14]
Similarly to other SSRIs, sexual side effects are common with fluoxetine; they include anorgasmia and reduced libido.[15]
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.[6]
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.[16][17] 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.[16][18][19] 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".[19] 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 of this relatively common condition".[20][21] More rarely, fluoxetine has been associated with related movement disorders acute dystonia and tardive dyskinesia.[17][22][23]
Fluoxetine taken during pregnancy also increases rate of poor neonatal adaptation.[15] Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended.[24] A study of fluoxetine administered to newborn mice found that early postnatal exposure of the drug later caused the adult mice to exhibit depressive and anxious behavior similar to those of induced depression, which could be relieved by fluoxetine.[25] 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.[26]
Several case reports in the literature describe severe withdrawal or discontinuation symptoms following an abrupt interruption of fluoxetine treatment.[27] However, various studies have shown that the side effects of the fluoxetine discontinuation are uncommon and mild, especially compared to paroxetine, venlafaxine and fluvoxamine, probably due to the relatively long pharmacological half-life of fluoxetine.[27] One of the recommended strategies for the management of discontinuation syndrome with other SSRIs is to substitute fluoxetine for the original agent, in cases where tapering off the dose of the original SSRI is ineffective.[28][29] The double-blind controlled studies support this opinion. No increase in side effects was observed in several studies when the treatment with fluoxetine was blindly interrupted for a short time (4–8 days) and then reinstated, this result being consistent with its slow elimination from the body. More side effects occurred during the interruption of sertraline (Zoloft) in these studies, and significantly more during the interruption of paroxetine.[30] In a longer, 6‑week-long, blind discontinuation study, an insignificantly higher (32% vs 27%) overall rate of new or worsened side effects was observed in the group that discontinued fluoxetine than in the group that continued treatment. However, a significantly higher 4.2% rate of somnolence at week 2 and 5–7% rate of dizziness at weeks 4–6 were reported by the patients in the discontinuation group. This prolonged course of the discontinuation symptoms, with dizziness persisting to the end of the study, is also consistent with the long half-life of fluoxetine in the body.[31] According to a 2007 summary report of available evidence, fluoxetine has the lowest incidence of discontinuation syndrome among several antidepressants including paroxetine and venlafaxine.[32] See also SSRI discontinuation syndrome.
The FDA requires all antidepressants 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.[33][34][35] This analysis was criticized 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.[36] This opinion goes against the general consensus that "suicidal ideation has been associated with suicide attempt in retrospective studies and with suicide in prospective studies".[37]
There is less data on fluoxetine than on antidepressants as a whole. For the above analysis on the antidepressant level, the FDA had to combine the results of 295 trials of 11 antidepressants for psychiatric indications to obtain statistically significant results. Considered separately, fluoxetine use in children increased the odds of suicidality by 50% (not statistically significant due to the low number of cases),[38] and in adults decreased the odds of suicidality by approximately 30% (statistically significant).[34][35] Similarly, the analysis conducted by the UK MHRA found a 50% increase of odds of 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, for adults fluoxetine did not change the rate of self-harm and statistically significantly decreased suicidal ideation by 50%.[39][40]
Fluoxetine and norfluoxetine inhibit many isozymes of the cytochrome P450 system that make drug metabolism possible. Both are potent inhibitors of CYP2D6 (the main enzyme responsible for their metabolism) and mild to moderate inhibitors of CYP1A2, CYP2B6, CYP2C9/2C19, and CYP3A4; furthermore, they inhibit the activity of P-glycoprotein, a type of membrane transport protein that plays an important role in drug transport and metabolism.[41] This extensive effect on the body's pathways for drug metabolism creates the potential for interactions with many commonly used drugs.[41][42]
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.
Fluoxetine has been shown to have antimicrobial activity against several groups of microorganisms. This is mainly against Gram positive microorganisms. It also shows synergistic activity when combined with some antibiotics against several bacteria.[43]
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.[2] 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 (N-demethylated fluoxetine), is biologically active.
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 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.[2][46][47] 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.[48][49] Moreover, the brain concentration of fluoxetine and its metabolites keeps increasing through at least the first five weeks of treatment.[50] That means that the full benefits of the current dose a patient receives are not realized for at least a month since its initiation. For example, in one 6-week study, the median time to achieving consistent response was 29 days.[48] 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%,[50] The blood level of norfluoxetine 4 weeks after the treatment discontinuation is about 80% of the level registered by the end of the first treatment week, and 7 weeks after the discontinuation norfluoxetine is still detectable in the blood.[46]
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 women or men, 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".[51]
Fluoxetine is a selective serotonin reuptake inhibitor and does not appreciably inhibit norepinephrine and dopamine reuptake. Nevertheless, Eli Lilly researchers found that a single injection of a large dose of fluoxetine given to a rat also resulted in a significant increase of brain concentrations of norepinephrine and dopamine.[52][53][54] This effect may be mediated by 5HT2a and, in particular, 5HT2c receptors, which are inhibited by higher concentrations of fluoxetine. The Ely Lilly scientists also suggested that the effects on dopamine and norepinephrine may contribute to the antidepressant action of fluoxetine.[54] In the opinion of other researchers, however, the magnitude of this effect is unclear.[50] The dopamine and norepinephrine increase was not observed at a smaller, more clinically relevant dose of fluoxetine.[55] Similarly, in electrophysiological studies only larger and not smaller doses of fluoxetine changed the activity of rat's norepinephrinergic neurons. Some authors, however, argue that these findings may still have clinical relevance for the treatment of severe illness with supratherapeutic doses (60–80 mg) of fluoxetine.[56] Among SSRIs, 'fluoxetine is the least "selective" of all the SSRIs, with a 10-fold difference in binding affinity between its first and second neural targets (i.e., the serotonin and norepinephrine uptake pumps, respectively)'. Anything greater than a 10-fold difference results in insignificant activation of the secondary neuronal targets.[57]
Besides its well-known effects on serotonin, fluoxetine also increases density of endogenous opioid receptors in the brains of rats. It is unclear if this occurs in humans, but if so it might account for some of fluoxetine's antidepressant and/or side effect profile.[58]
Fluoxetine and norfluoxetine may be quantitated in blood, plasma or serum to monitor therapy, confirm a diagnosis of poisoning in hospitalized patients or assist in a medicolegal death investigation. Blood or plasma fluoxetine concentrations are usually in a range of 50–500 μg/L in persons taking the drug for its antidepressant effects, 900–3000 μg/L in survivors of acute overdosage and 1000–7000 μg/L in victims of fatal overdosage. Norfluoxetine concentrations are approximately equal to those of the parent drug during chronic therapy, but may be substantially less following acute overdosage, since it requires at least 1–2 weeks for the metabolite to achieve equilibrium.[59][60][61]
Fluoxetine's mechanism of action is predominantly that of a serotonin reuptake inhibitor.[62][63] However, it may also produce some of its effects via its potent 5-HT2C receptor antagonist effects.[64] 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, though the significance of this property is not fully clear either.[65][66]
The work which eventually led to the discovery of fluoxetine began at Eli Lilly and Company in 1970 as a collaboration between Bryan Molloy and Robert Rathbun.[citation needed] It was known at that time that the 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.[67][68]
Later, hoping to find a derivative inhibiting only serotonin reuptake, another Eli Lilly scientist, David Wong, proposed to retest the series for the in vitro reuptake of serotonin, norepinephrine and dopamine. This test, carried out by Jong-Sir Horng in May 1972,[68] showed the compound later named fluoxetine to be the most potent and selective inhibitor of serotonin reuptake of the series.[1] Wong published the first article about fluoxetine in 1974.[1] A year later, it was given the official chemical name fluoxetine and the Eli Lilly and Company gave it the trade name Prozac. In February 1977, Dista Products Company, a division of Eli Lilly & Company, presented a new drug request to the U.S. Food and Drug Administration (FDA) for fluoxetine.[69]
Fluoxetine appeared on the Belgian market in 1986[70] After over a decade, the FDA gave its final approval in December 1987,[71] and a month later Eli Lilly began marketing Prozac; annual sales in the U.S. reached $350 million within a year.[69]
In 1989, Joseph Wesbecker shot and killed eight people and injured 12 others before killing himself at his place of work in Kentucky. Wesbecker had been taking fluoxetine for four weeks before these homicides, and this led to a legal action against Eli Lilly.[72] The case was tried and settled in 1994, and as part of the settlement a number of pharmaceutical company documents about drug-induced activation were released into the public domain. Subsequent legal cases have further raised the possibility of a link between antidepressant use and violence.[73] The Prozac Survivors Support Group created a report on 288 individuals who had suffered adverse effects from Fluoxetine during 1991 and 1992. It showed that most of the cases led to violence against self or other individuals. There were 164 cases in the suicide and suicide ideation category, including 34 complete suicides. There were also 133 cases of crime and violence, which featured 14 murders, nine attempted murders, 39 violent actions, 54 violent preoccupations and 17 crimes. The report also showed that 13 individuals had become addicted to Fluoxetine and 14 cases of alcoholism forming or worsening.[74] However, Mayo Clinic psychiatrist Daniel K. Hall-Flavin is of the opinion that people cannot get addicted to antidepressants, stating "Addiction represents harmful, long-term chemical changes in the brain. It's characterized by intense cravings and the inability to control your use of a substance.".[75]
"...the efficacy of Prozac could not be distinguished from placebo in 6 out of 10 clinical trials (Moore, 1999)..."[76]
A controversy ensued after Lilly researchers published a paper titled "Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug"[68] 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.[77]
Eli Lilly's U.S. patent on Prozac (fluoxetine) expired in August 2001,[78] prompting an influx of generic drugs onto the market. Prozac was rebranded "Sarafem" for the treatment of PMDD in an attempt to stem the post-patent decrease in Eli Lilly's sales of fluoxetine.[79]
A meta-analysis published in February 2008 combined 35 clinical trials of four newer antidepressants (fluoxetine, paroxetine (Paxil), nefazodone (Serzone) and venlafaxine (Effexor)). These antidepressants belonging to three different pharmacological groups were considered together, and the authors did not analyze them separately. The authors concluded that "although the difference [between the placebo and antidepressants] easily attained statistical significance", it did not meet the criterion for clinical significance, as used by the UK's National Institute for Health and Clinical Excellence, "for any but the most severely depressed patients".[80] Some articles in the press using the titles "The creation of the Prozac myth"[81] and "Prozac does not work in majority of depressed patients"[82][83] presented these general findings about the relative efficacy of antidepressants and placebo as the findings about ineffectiveness of fluoxetine. In a follow-up article, the authors of the meta-analysis noted that "unfortunately, during its initial coverage, the media often portrayed the results as “antidepressants do not work”, which misrepresented our more nuanced pattern of findings".[84]
As of April 2, 2010, fluoxetine is one of four antidepressant drugs that the FAA allows pilots to take. The others are sertraline (Zoloft), citalopram (Celexa), and escitalopram (Lexapro).[85]
- Zactin (Australia)[86]
- Lovan (Australia)[87]
- Fluohexal (Australia)
- Auscap (Australia)[88]
- Depreks (Turkey)[89]
- Floxet (Hungary; Egis Pharmaceuticals Ltd.)[90]
- Flunil (India) Intas_Biopharmaceuticals
- Prodep (India)
- Fludac (India)
- Flutine (Israel)
- Fluox (New Zealand)
- Fluoxetina (Colombia)
- Fluzac (Ireland)
- Fluxen – Флуксен (Ukraine)
- Fontex (Denmark, Norway, Sweden)
- Ladose (Greece)
- Philozac – (Egypt)[91]
- Biozac, Deprexetin, Fluval, Biflox, Deprexit, Sofluxen, Floxet, Ranflutin – (Bulgaria)[92]
- Flunisan, Orthon, Refloksetin, Fluoksetin – (Macedonia)[93]
- Seronil (Finland)
Because of its wide appeal as a popular antidepressant, Prozac has had numerous references to it in popular culture, including many books, movies, and songs. The book Listening to Prozac was written in 1993 by psychiatrist Peter D. Kramer. The memoir Prozac Nation was written in 1994 by Elizabeth Wurtzel; it was made into a film of the same name in 2001, starring Christina Ricci as Wurtzel. A well-known book critical of the drug, Talking Back to Prozac, was written by psychiatrist Peter Breggin and published in 1994 (ISBN 0312114869) It is also mention in the Superman graphic novel Red Son, where Brainiac uses it to control people's mood in the Superman's Empire.[69]
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- ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 645–648.
- ^ Fuller RW, Perry KW, Molloy BB (September 1974). "Effect of an uptake inhibitor on serotonin metabolism in rat brain: studies with 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine (Lilly 110140)". Life Sciences 15 (6): 1161–71. PMID 4550008.
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- ^ Pälvimäki EP, Roth BL, Majasuo H, et al. (August 1996). "Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor". Psychopharmacology 126 (3): 234–40. PMID 8876023. http://link.springer.de/link/service/journals/00213/bibs/6126003/61260234.htm.
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- ^ Owens, Joanna (2005). "Can making a correlation be patented?". Nature Reviews Drug Discovery 4 (12): 950. DOI:10.1038/nrd1921.
- ^ a b c Wong, David T.; Bymaster, Frank P.; Engleman, Eric A. (1995). "Prozac (fluoxetine, lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: Twenty years since its first publication". Life Sciences 57 (5): 411–41. DOI:10.1016/0024-3205(95)00209-O. PMID 7623609.
- ^ a b c Breggin, Peter R.; Ginger Ross Breggin (1995). Talking Back to Prozac. Macmillan Publishers. pp. 1–2. ISBN 978-0-312-95606-6.
- ^ Swiatek, Jeff (August 2, 2001). "Prozac's profitable run coming to an end for Lilly". The Indianapolis Star. http://www2.indystar.com/library/factfiles/business/companies/lilly/stories/2001_0802.html.
- ^ "Electronic Orange Book". Food and Drug Administration. April 2007. http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=018936&TABLE1=OB_Rx. Retrieved May 24, 2007.
- ^ Healy D (2004) Let them eat Prozac. New York: New York University Press. pp 124–148.
- ^ Healy, David; Herxheimer, Andrew; Menkes, David B. (2006). "Antidepressants and Violence: Problems at the Interface of Medicine and Law". PLoS Medicine 3 (9): e372. DOI:10.1371/journal.pmed.0030372. PMC 1564177. PMID 16968128. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1564177.
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- ^ "Antidepressant withdrawal: Is there such a thing?". MayoClinic.com. September 10, 2010. http://www.mayoclinic.com/health/antidepressant-withdrawal/AN01425. Retrieved February 10, 2012.
- ^ "Antidepressant-Placebo Debate". Srmhp.org. February 1, 2003. http://www.srmhp.org/0201/media-watch.html. Retrieved February 10, 2012.
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- ^ "Patent Expiration Dates for Common Brand-Name Drugs". http://www.express-scripts.com/pharmacist/notifications/docs/genericdrugs.htm. Retrieved July 20, 2007.
- ^ Class, Selena (December 2, 2002). "Pharma Overview". http://pubs.acs.org/cen/coverstory/8048/8048pharmaceutical.html. Retrieved June 15, 2009.
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- ^ "The creation of the Prozac myth". The Guardian (London). February 27, 2008. http://www.guardian.co.uk/society/2008/feb/27/mentalhealth.health1. Retrieved March 1, 2008.
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- ^ Blue, Laura (February 26, 2008). "Antidepressants Hardly Help". Time. http://www.time.com/time/health/article/0,8599,1717306,00.html. Retrieved March 1, 2008.
- ^ Johnson, Blair T.; Kirsch, Irving (2008). "Do antidepressants work? Statistical significance versus clinical benefits". Significance 5 (2): 54. DOI:10.1111/j.1740-9713.2008.00286.x.
- ^ "Press Release – FAA Proposes New Policy on Antidepressants for Pilots". Faa.gov. April 2, 2010. http://www.faa.gov/news/press_releases/news_story.cfm?newsId=11293. Retrieved February 10, 2012.
- ^ http://www.alphapharm.com.au/media/39940/zactin%20cmi.pdf
- ^ http://www.alphapharm.com.au/media/39670/lovan%20cmi.pdf
- ^ http://www.mydr.com.au/cmis/PDFs/CMI6561.pdf
- ^ [2][dead link]
- ^ "Floxet (Fluoxetine Hydrochloride) Egis". Drugs-about.com. http://drugs-about.com/drugs-f/floxet.html. Retrieved February 10, 2012.
- ^ [3][dead link]
- ^ medicine.bg. "Флуоксетин (Fluoxetine) | Aктивни съставки | Лекарства". Medicine.bg. http://www.medicine.bg/lekarstva/fluoxetine/. Retrieved February 10, 2012.
- ^ "Регистар на лекови – листа по генеричко име". Reglek.com.mk. http://reglek.com.mk/lekpogenime.php?gen=303. Retrieved February 10, 2012.
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Serotonin modulators and stimulators (SMSs)
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Others
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Nonselective
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MAOA-Selective
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MAOB-Selective
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- Agonists: Azapirones: Alnespirone
- Binospirone
- Buspirone
- Enilospirone
- Eptapirone
- Gepirone
- Ipsapirone
- Perospirone
- Revospirone
- Tandospirone
- Tiospirone
- Umespirone
- Zalospirone; Antidepressants: Etoperidone
- Nefazodone
- Trazodone
- Vortioxetine; Antipsychotics: Aripiprazole
- Asenapine
- Clozapine
- Quetiapine
- Ziprasidone; Ergolines: Dihydroergotamine
- Ergotamine
- Lisuride
- Methysergide
- LSD; Tryptamines: 5-CT
- 5-MeO-DMT
- 5-MT
- Bufotenin
- DMT
- Indorenate
- Psilocin
- Psilocybin; Others: 8-OH-DPAT
- Adatanserin
- Bay R 1531
- Befiradol
- BMY-14802
- Cannabidiol
- Dimemebfe
- Ebalzotan
- Eltoprazine
- F-11,461
- F-12,826
- F-13,714
- F-14,679
- F-15,063
- F-15,599
- Flesinoxan
- Flibanserin
- Lesopitron
- LY-293,284
- LY-301,317
- MKC-242
- Naluzotan
- NBUMP
- Osemozotan
- Oxaflozane
- Pardoprunox
- Piclozotan
- Rauwolscine
- Repinotan
- Roxindole
- RU-24,969
- S 14,506
- S-14,671
- S-15,535
- Sarizotan
- SSR-181,507
- Sunepitron
- U-92,016-A
- Urapidil
- Vilazodone
- Xaliproden
- Yohimbine
Antagonists: Antipsychotics: Iloperidone
- Risperidone
- Sertindole; Beta blockers: Alprenolol
- Cyanopindolol
- Iodocyanopindolol
- Oxprenolol
- Pindobind
- Pindolol
- Propranolol
- Tertatolol; Others: AV965
- BMY-7,378
- CSP-2503
- Dotarizine
- Flopropione
- GR-46611
- Isamoltane
- Lecozotan
- Mefway
- Metitepine/Methiothepin
- MPPF
- NAN-190
- Robalzotan
- S-15535
- SB-649,915
- SDZ 216-525
- Spiperone
- Spiramide
- Spiroxatrine
- UH-301
- WAY-100,135
- WAY-100,635
- Xylamidine
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- Agonists: Lysergamides: Dihydroergotamine
- Methysergide; Triptans: Almotriptan
- Avitriptan
- Eletriptan
- Frovatriptan
- Naratriptan
- Rizatriptan
- Sumatriptan
- Zolmitriptan; Tryptamines: 5-CT
- 5-Ethyl-DMT
- 5-MT
- 5-(Nonyloxy)tryptamine; Others: CP-135,807
- CP-286,601
- GR-46611
- L-694,247
- L-772,405
- PNU-109,291
- PNU-142,633
Antagonists: Lysergamides: Metergoline; Others: Alniditan
- BRL-15,572
- Elzasonan
- GR-127,935
- Ketanserin
- LY-310,762
- LY-367,642
- LY-456,219
- LY-456,220
- Metitepine/Methiothepin
- Ritanserin
- Yohimbine
- Ziprasidone
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- Agonists: Phenethylamines: 2C-B
- 2C-E
- 2C-I
- 2C-T-2
- 2C-T-7
- 2C-T-21
- DOB
- DOC
- DOI
- DOM
- MDA
- MDMA
- Mescaline; Piperazines: Aripiprazole
- mCPP
- TFMPP; Tryptamines: 5-CT
- 5-MeO-α-ET
- 5-MeO-α-MT
- 5-MeO-DET
- 5-MeO-DiPT
- 5-MeO-DMT
- 5-MeO-DPT
- 5-MT
- α-ET
- α-Methyl-5-HT
- α-MT
- Bufotenin
- DET
- DiPT
- DMT
- DPT
- Psilocin
- Psilocybin; Others: A-372,159
- AL-38022A
- CP-809,101
- Dimemebfe
- Lorcaserin
- Medifoxamine
- MK-212
- Org 12,962
- ORG-37,684
- Oxaflozane
- PNU-22394
- Ro60-0175
- Ro60-0213
- Vabicaserin
- WAY-629
- WAY-161,503
- YM-348
Antagonists: Atypical antipsychotics: Clorotepine
- Clozapine
- Iloperidone
- Melperone
- Olanzapine
- Paliperidone
- Pimozide
- Quetiapine
- Risperidone
- Sertindole
- Ziprasidone
- Zotepine; Typical antipsychotics: Chlorpromazine
- Loxapine
- Pipamperone; Antidepressants: Agomelatine
- Amitriptyline
- Amoxapine
- Aptazapine
- Etoperidone
- Fluoxetine
- Mianserin
- Mirtazapine
- Nefazodone
- Nortriptyline
- Tedatioxetine
- Trazodone; Others: Adatanserin
- CEPC
- Cinanserin
- Cyproheptadine
- Deramciclane
- Dotarizine
- Eltoprazine
- Esmirtazapine
- FR-260,010
- Ketanserin
- Ketotifen
- Latrepirdine
- Metitepine/Methiothepin
- Methysergide
- Pizotifen
- Ritanserin
- RS-102,221
- S-14,671
- SB-200,646
- SB-206,553
- SB-221,284
- SB-228,357
- SB-242,084
- SB-243,213
- SDZ SER-082
- Xylamidine
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- Agonists: Lysergamides: Dihydroergotamine
- Ergotamine
- Lisuride
- LSD
- Mesulergine
- Metergoline
- Methysergide; Tryptamines: 2-Methyl-5-HT
- 5-BT
- 5-CT
- 5-MT
- Bufotenin
- E-6801
- E-6837
- EMD-386,088
- EMDT
- LY-586,713
- N-Methyl-5-HT
- Tryptamine; Others: WAY-181,187
- WAY-208,466
Antagonists: Antidepressants: Amitriptyline
- Amoxapine
- Clomipramine
- Doxepin
- Mianserin
- Nortriptyline; Atypical antipsychotics: Aripiprazole
- Asenapine
- Clorotepine
- Clozapine
- Fluperlapine
- Iloperidone
- Olanzapine
- Tiospirone; Typical antipsychotics: Chlorpromazine
- Loxapine; Others: BGC20-760
- BVT-5182
- BVT-74316
- Cerlapirdine
- EGIS-12,233
- GW-742,457
- Ketanserin
- Latrepirdine
- Lu AE58054
- Metitepine/Methiothepin
- MS-245
- PRX-07034
- Ritanserin
- Ro04-6790
- Ro 63-0563
- SB-258,585
- SB-271,046
- SB-357,134
- SB-399,885
- SB-742,457
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- Agonists: Lysergamides: LSD; Tryptamines: 5-CT
- 5-MT
- Bufotenin; Others: 8-OH-DPAT
- AS-19
- Bifeprunox
- E-55888
- LP-12
- LP-44
- RU-24,969
- Sarizotan
Antagonists: Lysergamides: 2-Bromo-LSD
- Bromocriptine
- Dihydroergotamine
- Ergotamine
- Mesulergine
- Metergoline
- Methysergide; Antidepressants: Amitriptyline
- Amoxapine
- Clomipramine
- Imipramine
- Maprotiline
- Mianserin; Atypical antipsychotics: Amisulpride
- Aripiprazole
- Clorotepine
- Clozapine
- Olanzapine
- Risperidone
- Sertindole
- Tiospirone
- Ziprasidone
- Zotepine; Typical antipsychotics: Chlorpromazine
- Loxapine; Others: Butaclamol
- EGIS-12,233
- Ketanserin
- LY-215,840
- Metitepine/Methiothepin
- Pimozide
- Ritanserin
- SB-258,719
- SB-258,741
- SB-269,970
- SB-656,104
- SB-656,104-A
- SB-691,673
- SLV-313
- SLV-314
- Spiperone
- SSR-181,507
- Vortioxetine
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