Fluoxetine (Prozac)

Fluoxetine in Brief
  • Generic name : Fluoxetine hydrochloride
  • Brand names: Prozac, Sarafem, Fontex, Foxetin, Ladose, Fluctin, Prodep, Fludac, Lovan
  • Therapeutic class: Antidepressant
  • Pharmacologic class: Selective serotonin reuptake inhibitor (SSRI)
  • FDA Approved: December 29, 1987
  • Patent expiration date: August, 2001
  • Chemical Formula: C17H18F3NO
  • Pregnancy Category: C
  • Habit forming? No
  • Originally discovered: 1970s; Eli Lilly, USA USA

Based on "Essential Psychopharmacology"
written by Stephen M. Stahl, MD, PhD


In the early 1970s, evidence of the role of serotonin (5-hydroxytryptamine or 5-HT) in depression began to emerge and the hypothesis that enhancing 5-HT neurotransmission would be a viable mechanism to mediate antidepressant response was put forward.

On the basis of this hypothesis, efforts to develop agents that inhibit the uptake of 5-HT from the synaptic cleft were initiated. These studies led to the discovery and development of the selective serotonin-reuptake inhibitor fluoxetine hydrochloride (Prozac; Eli Lilly), which was approved for the treatment of depression by the US FDA in 1987.


In late 1971 Bryan Molloy in Lilly synthesized a range of new compounds, a group of phenoxyphenyl-propylamines from diphenhydramine, an antihistamine found to inhibit reuptake of the neurotransmitter "serotonin". One of these compounds, Lilly-110140 (later in 1975 called fluoxetine), was found to be highly selective, affecting only the neurotransmitter serotonin. As the chemist who synthesized the new series of compounds, Molloy was in this literal sense Prozac’s creator. Years of development and testing finally led to approval of fluoxetine for marketing.

In 1976 Eli Lilly begins clinical trials of fluoxetine. In 1983 Lilly applied to U.S. FDA for approval to sell Prozac for treatment of depression. Fluoxetine was initially approved for treatment of depression in Belgium in 1986, and then Eli Lilly's Prozac was approved by the FDA on December 29, 1987 and introduced in the United States at the beginning of 1988. It was the first of a new class of drugs, called selective serotonin reuptake inhibitors (SSRIs), to be approved for use in the United States.

FDA approved indications

  • Major depressive disorder
  • Obsessive-compulsive disorder
  • Bulimia nervosa (binge-eating and vomiting behaviors in patients with moderate to severe bulimia nervosa)
  • Panic disorder
  • Premenstrual dysphoric disorder.

Off-label & Investigational uses

  • Migraine headaches 10, 11
  • Chronic daily headache 16
  • Fibromyalgia 12
  • Alcoholism 14
  • Attention-deficit hyperactivity disorder (ADHD/ADD) 15
  • Tourette's Syndrome 17
  • Premature ejaculation 18
  • Discontinuation of other SSRIs and SNRIs
  • Smoking cessation 20
  • Irritable Bowel Syndrome (IBS) 21
  • Chronic pain syndromes 22
  • Anxiety disorders in children and adolescents 23
  • Hot flashes 24
  • Anorexia nervosa31

Fluoxetine for Migraine headaches
Fluoxetine may be useful for patients who cannot use standard prophylactic agents or if other agents fail. It is also a good choice for persons with concomitant depression or other illness treatable with SSRI. Three randomized, double-blind, placebo-controlled studies showed a decrease in the frequency and severity of migraine headaches with fluoxetine therapy. Daily dosages of fluoxetine ranged from 20 to 40 mg in these studies 10, 11.

Fluoxetine for Fibromyalgia
Fibromyalgia is the most common rheumatic cause of chronic pain.

In randomized placebo-controlled study women who received fluoxetine had significant improvement in pain, fatigue and depression compared with those who received placebo. In this study fluoxetine was generally well tolerated.

Crossover, placebo-controlled trial comparing fluoxetine (20 mg daily) and amitriptyline (25 mg daily) demonstrated significant improvement in global well-being, pain, and sleep for each medication alone. Further improvement in efficacy and in fatigue and feeling refreshed upon awakening occurred when two medications were used in combination 12.

Premature ejaculation
Fluoxetine has been found to increase the latent period of intravaginal ejaculation and therefore to be beneficial in patients who prematurely ejaculate.


Fluoxetine "pros" and "cons"

Fluoxetine may be an appropriate antidepressant choice in persons with hypersomnia, psychomotor retardation, or low energy, who are poorly compliant with medications.

Fluoxetine has activating properties and should probably be avoided in persons with concomitant anxiety, agitation, and panic. This antidepressant is more likely to increase nervousness, insomnia, and anxiety than other SSRIs, especially at higher dosages.


  • Fluoxetine has advantages over other SSRIs in patients who are poorly compliant 3. Fluoxetine has a long half-life, so missing the dose unlikely to cause problems.
  • Safety in overdose, relatively mild toxic effects even in children 25, 26
  • Mild withdrawal symptoms 8
  • Low potential for weight gain 9.
  • The only SSRI approved by FDA for use in children 8 years of age and older
  • Associated with the lowest risk of suicide 28
  • Fluoxetine improves peripheral and hepatic insulin action in type 2 diabetes patients 29


  • Delayed onset of action. Fluoxetine is not suitable for patients in whom a rapid antidepressant effect is important or for those who are agitated 3
  • Less effective than sertraline, mirtazapine, and venlafaxine for depression 4
  • Activating (insomnia, agitation, tremor and anxiety) and gastrointestinal (nausea, vomiting, diarrhoea) adverse effects are higher than with other antidepressants 5
  • May alter blood glucose control in patients with diabetes.
  • Potential for drug interactions -- fluoxetine is a strong inhibitor of CYP 2D6 and a moderate inhibitor of 2C9, 2C19, and 3A4.
  • Long wash out period is required when switching to another antidepressant.
  • Long half-life and non-linear pharmacokinetics make dose titration more difficult.
  • Decreases sleep quality.
  • Sexual dysfunction, according to the prospective multicenter study the incidence of fluoxetine-induced SD is about 58% 19.

Mechanism of action

The antidepressant, antiobsessional, and antibulimic effects of fluoxetine are thought to be related to its effects on serotonergic neurotransmission. It is a potent and selective inhibitor of serotonin (5-HT) uptake, but not of norepinephrine or dopamine uptake, in the central nervous system (CNS). In depressed patients who had received 40 to 60 mg per day of fluoxetine for 6 weeks, the cerebrospinal fluid concentrations of the metabolites of 5-HT (5-HIAA), dopamine (HVA), and norepinephrine (HMPG) were reduced by 46%, 14%, and 18%, respectively. Because uptake inactivates serotonin by removing it from the synaptic cleft, uptake inhibition by fluoxetine enhances serotonergic function. As a consequence, the 5-HT 1 receptors are desensitized or downregulated after long-term fluoxetine administration. Fluoxetine does not interact directly with postsynaptic serotonin receptors, muscarinic-cholinergic receptors, histaminergic receptors, or alpha-adrenergic receptors. It does not appear to cause downregulation of postsynaptic beta-adrenergic receptors or a decrease in beta-adrenergic–stimulated cyclic adenosine monophosphate (cAMP) generation as do older antidepressants.

Fluoxetine is an atypical SSRI. Studies have shown that plasma norepinephrine, epinephrine and dopamine levels are significantly increased after acute and chronic treatment with fluoxetine 7.

Time to clear out of the system

The body eliminates fluoxetine very slowly. The half-life of fluoxetine after a single dose is 2 days and after multiple dosing 4 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.

Because of the long half-lives of fluoxetine and norfluoxetine, it may take up to 1 to 2 months for the active substance to disappear from the body. There are no effective methods known to enhance the elimination of fluoxetine.

Onset of action

Because of the long time it takes for fluoxetine to reach a steady state (4-5 weeks), full therapeutic effect may be delayed until 4 or 6 weeks of treatment. The lack of onset of response at 4-6 weeks is associated with about a 73%-88% chance that patient would not have an onset of response by 8 weeks 27.

Weaning off Fluoxetine (Prozac)

After treatment with fluoxetine, abrupt cessation may produce discontinuation (withdrawal) reactions. Fluoxetine discontinuation symptoms include:

  • dysphoric mood
  • irritability
  • fatigue
  • weakness
  • agitation
  • dizziness
  • sensory disturbances (paresthesias such as electric shock sensations)
  • anxiety
  • confusion
  • headache
  • lethargy
  • emotional lability
  • insomnia
  • hypomania
  • nausea and vomiting

Fluoxetine (Prozac) and Alcohol

Although fluoxetine has not been shown to alter alcohol metabolism and does not appear to potentiate cognitive or psychomotor effects of alcohol in healthy subjects, concomitant use is not recommended.Further reading


  • 1. U.S. FDA Fluoxetine Prescribing Information.
  • 2. Wong DT, Bymaster FP, Engleman EA. Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: twenty years since its first publication. Life Sci. 1995;57(5):411-41. PubMed
  • 3. Edwards JG, Anderson I. Systematic review and guide to selection of selective serotonin reuptake inhibitors. Drugs. 1999 Apr;57(4):507-33. PubMed
  • 4. Magni LR, Purgato M, Gastaldon C, Papola D, Furukawa TA, Cipriani A, Barbui C. Fluoxetine versus other types of pharmacotherapy for depression. Cochrane Database Syst Rev. 2013 Jul 17. PubMed
  • 5. Brambilla P, Cipriani A, Hotopf M, Barbui C. Side-effect profile of fluoxetine in comparison with other SSRIs, tricyclic and newer antidepressants: a meta-analysis of clinical trial data. Pharmacopsychiatry. 2005 Mar;38(2):69-77. PubMed
  • 6. Anjaneyulu M, Chopra K. Possible involvement of cholinergic and opioid receptor mechanisms in fluoxetine mediated antinociception response in streptozotocin-induced diabetic mice. Eur J Pharmacol. 2006 May 24;538(1-3):80-4. PubMed
  • 7. Blardi P, de Lalla A, Auteri A, Iapichino S, Dell'Erba A, Castrogiovanni P. Plasma catecholamine levels after fluoxetine treatment in depressive patients. Neuropsychobiology. 2005;51(2):72-6. PubMed
  • 8. Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry. 1998 Jul 15;44(2):77-87. PubMed
  • 9. Fava M, Judge R, Hoog SL, Nilsson ME, Koke SC. J Clin Psychiatry. 2000 Nov;61(11):863-7. PubMed
  • 10. d'Amato CC, Pizza V, Marmolo T, Giordano E, Alfano V, Nasta A. Fluoxetine for migraine prophylaxis: a double-blind trial. Headache. 1999 Nov-Dec;39(10):716-9.
  • 11. Adly C, Straumanis J, Chesson A. Fluoxetine prophylaxis of migraine. Headache. 1992 Feb;32(2):101-4. PubMed
  • 12. Goldenberg D, Mayskiy M, Mossey C, Ruthazer R, Schmid C. A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis Rheum. 1996 Nov;39(11):1852-9. PubMed
  • 13. Riggin L, Frankel Z, Moretti M, Pupco A, Koren G. The fetal safety of fluoxetine: a systematic review and meta-analysis. J Obstet Gynaecol Can. 2013 Apr;35(4):362-9.
  • 14. Naranjo CA, Poulos CX, Bremner KE, Lanctot KL. Fluoxetine attenuates alcohol intake and desire to drink. Int Clin Psychopharmacol. 1994 Sep;9(3):163-72. PubMed
  • 15. Quintana H, Butterbaugh GJ, Purnell W, Layman AK. Fluoxetine monotherapy in attention-deficit/hyperactivity disorder and comorbid non-bipolar mood disorders in children and adolescents. Child Psychiatry Hum Dev. 2007 Feb;37(3):241-53. PubMed
  • 16. Saper JR, Silberstein SD, Lake AE 3rd, Winters ME. Double-blind trial of fluoxetine: chronic daily headache and migraine. Headache. 1994 Oct;34(9):497-502. PubMed
  • 17. Scahill L, Riddle MA, King RA, Hardin MT, Rasmusson A, Makuch RW, Leckman JF. Fluoxetine has no marked effect on tic symptoms in patients with Tourette's syndrome: a double-blind placebo-controlled study. J Child Adolesc Psychopharmacol. 1997 Summer;7(2):75-85. PubMed
  • 18. Haensel SM, Klem TM, Hop WC, Slob AK. Fluoxetine and premature ejaculation: a double-blind, crossover, placebo-controlled study. J Clin Psychopharmacol. 1998 Feb;18(1):72-7. PubMed
  • 19. Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the Study of Psychotropic-Related Sexual Dysfunction. J Clin Psychiatry. 2001;62 Suppl 3:10-21. Pubmed
  • 20. Saules KK, Schuh LM, Arfken CL, Reed K, Kilbey MM, Schuster CR. Double-blind placebo-controlled trial of fluoxetine in smoking cessation treatment including nicotine patch and cognitive-behavioral group therapy. Am J Addict. 2004 Oct-Dec;13(5):438-46. PubMed
  • 21. Vahedi H, Merat S, Rashidioon A, Ghoddoosi A, Malekzadeh R. The effect of fluoxetine in patients with pain and constipation-predominant irritable bowel syndrome: a double-blind randomized-controlled study. Aliment Pharmacol Ther. 2005 Sep 1;22(5):381-5. PubMed
  • 22. Xia D, Wang P, Chen J, Wang S, Jiang H. Fluoxetine and fluvoxamine for treatment of chronic pain. Minerva Anestesiol. 2000 Jan-Feb;66(1-2):55-61.
  • 23. Birmaher B, Axelson DA, Monk K, Kalas C, Clark DB, Ehmann M, Bridge J, Heo J, Brent DA. Fluoxetine for the treatment of childhood anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2003 Apr;42(4):415-23 PubMed
  • 24. Sicat BL, Brokaw DK. Nonhormonal alternatives for the treatment of hot flashes. Pharmacotherapy. 2004 Jan;24(1):79-93. PubMed
  • 25. Borys DJ, Setzer SC, Ling LJ, Reisdorf JJ, Day LC, Krenzelok EP. The effects of fluoxetine in the overdose patient. J Toxicol Clin Toxicol. 1990;28(3):331-40. PubMed
  • 26. Feierabend RH Jr. Benign course in a child with a massive fluoxetine overdose. J Fam Pract. 1995 Sep;41(3):289-91.
  • 27. Nierenberg AA, Farabaugh AH, Alpert JE, Gordon J, Worthington JJ, Rosenbaum JF, Fava M. Timing of onset of antidepressant response with fluoxetine treatment. Am J Psychiatry. 2000 Sep;157(9):1423-8.
  • 28. Tiihonen J, Lonnqvist J, Wahlbeck K, Klaukka T, Tanskanen A, Haukka J. Antidepressants and the risk of suicide, attempted suicide, and overall mortality in a nationwide cohort. Arch Gen Psychiatry. 2006 Dec;63(12):1358-67.
  • 29. Potter van Loon BJ, Radder JK, Frölich M, Krans HM, Zwinderman AH, Meinders AE. Fluoxetine increases insulin action in obese type II (non-insulin dependent) diabetic patients. Int J Obes Relat Metab Disord. 1992 Dec
  • 30. Waiskopf N, Ofek K, Gilboa-Geffen A, Bekenstein U, Bahat A, Bennett ER, Podoly E, Livnah O, Hartmann G, Soreq H. AChE and RACK1 Promote the Anti-Inflammatory Properties of Fluoxetine. J Mol Neurosci. 2013 Nov 21.
  • 31. Sebaaly JC, Cox S, Hughes CM, Kennedy ML, Garris SS. Use of fluoxetine in anorexia nervosa before and after weight restoration. Ann Pharmacother. 2013 Sep;47(9):1201-5. PubMed

Published: November 27, 2008
Last updated: January 30, 2017

Interesting facts

Fluoxetine facts
  • Several recent studies have revealed that fluoxetine possesses anti-inflammatory properties 30.
  • Fluoxetine exists as a racemic mixture, and a single-enantiomer version, R-fluoxetine, was in development. R-fluoxetine is a potent inhibitor of the serotonin transporter, but due to cardiotoxicity resulting from prolongation of QTc intervals, its development was stopped in favor of continuing use of the racemate.
  • Prozac is the best studied of the SSRIs in pregnancy. While it has not been proven to be entirely safe, its use during pregnancy may be appropriate under certain conditions 13.
  • Fluoxetine produces antinociceptive effect, which involves central opioid, muscarinic and the serotoninergic pathways 6.

More Facts
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