Fluoxetine (Prozac) vs Paroxetine (Paxil)

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

Fluoxetine advantages over Paroxetine

  • Fluoxetine is a unique SSRI because of its own long half-life and extremely long half-life of its active metabolite norfluoxetine. This feature grants several important advantages as well as certain inconveniences.
  • Due to its very long half-life and relatively weak potency as a serotonin inhibitor, fluoxetine has less prominent discontinuation symptoms than paroxetine and many other antidepressants.
  • Fluoxetine unique features cause Prozac® to be the only SSRI approved by the FDA for use in children 8 years of age and older.
  • Fluoxetine is a better choice than paroxetine for patients with fatigue or low energy.

Paroxetine advantages over Fluoxetine

  • Paroxetine is a more potent SSRI whereas fluoxetine appears to be the weakest of the SSRIs.
  • Paroxetine can be taken at bedtime due to lack of stimulating effects.
  • Paroxetine may work better than fluoxetine for depression accompanied by insomnia and hyperarousal symptoms.
Fluoxetine Paroxetine
Brand names
Paxil CR®
Initial approval date
• December, 1987 • December, 1992
Drug class
Selective serotonin reuptake inhibitor (SSRI), Antidepressant
Dose formulations
• Capsules
• Tablets
• Capsules, delayed-release
• Solution, oral
• Capsules
• Tablets
• Tablets, extended-release
• Oral suspension
Legal status
• Rx only
• Not a controlled drug
Labeled indications
• Depression
• Obsessive-compulsive disorder
• Panic disorder
• Premenstrual dysphoric disorder
• Bulimia nervosa
• Social anxiety disorder
• Generalized anxiety disorder
• Posttraumatic stress disorder
• Hot flashes
"Off-label" uses
• Premature ejaculation. Paroxetine produces the greatest ejaculatory delay among all the SSRIs.
• Social anxiety
• Anorexia
• Irritable Bowel Syndrome
Mechanism of action
Selectively inhibit reabsorption (reuptake) of neurotransmitter serotonin in the brain.
Paroxetine is a more potent inhibitor of serotonin reuptake than fluoxetine. However, differences in potency do not affect antidepressant efficacy.
• 1-3 days (after a single dose)
• 4-6 days (long-term use)
• Half-life of active metabolite norfluoxetine is 96–364 hours
• 21 hours
• 33.2 hours for Pexeva®
Oral bioavailability
• 60–80% • 50%
Time to steady-state concentration
• ~4 weeks •7-14 days
Metabolism, Elimination
• Main active metabolite of fluoxetine is norfluoxetine.
• Fluoxetine is metabolized in the liver by hepatic enzyme CYP2D6 to its active metabolite.
• Eliminated in urine (18%), small amounts in feces.
• Complete elimination of fluoxetine takes 4 to 6 weeks after its discontinuation.
• Paroxetine does not have active metabolites.
• Paroxetine undergoes extensive hepatic metabolism by CYP2D6 isoenzymes.
• Excreted in the urine (64%), and in feces (36%).
• Concurrent use with a monoamine oxidase (MAO) inhibitors or within 14 days of stopping an MAOI
Side effects
• The most troubling side effects with long-term SSRI therapy are sexual dysfunction, weight gain, and sleep disturbances.
• Constipation, indigestion, tremor, sweating and ejaculation problems are more common with paroxetine.
• Nausea and nervousness are more frequent with fluoxetine. Weight loss is more common with fluoxetine 4.
• Both antidepressants are associated with tooth grinding during sleep9.
Weight gain
Paroxetine has a greater tendency to cause weight gain2. Fluoxetine is usually associated with weight loss during initial period of treatment. When fluoxetine is used for long period the drug may lead to weight gain.
Sexual side effects
Both paroxetine and fluoxetine produce adverse effects on sexual function, including:
• decreased libido
• ejaculatory delay
• orgasm difficulties
• inability to obtain or maintain an erection
However, sexual problems occur more frequently with paroxetine as compared with fluoxetine.
  • Paroxetine carries a higher risk for inducing suicidal behavior.
• Animal studies show that paroxetine may make a person more sensitive and vulnerable to environmental stress 3.
Withdrawal symptoms
Discontinuation of paroxetine more often results in somatic and psychological symptoms than discontinuation of fluoxetine. Patients treated with fluoxetine appear to be protected by its longer half-life 1.
Drug interactions
• Monoamine oxidase inhibitors - concomitant use is strictly contraindicated
• Drugs metabolized by CYP2D6 - both paroxetine and fluoxetine inhibit the activity of CYP2D6 enzyme and may increase blood levels of concurrently administered drugs that also are metabolized by this enzyme.
• Serotonergic agents
• Additive effects with CNS depressants


Fluoxetine vs Paroxetine for depression

Paroxetine and fluoxetine have comparable efficacy in the treatment of depression. However, paroxetine has a significantly higher response rate than fluoxetine. Paroxetine appears to produce earlier antidepressant effect, improvement in agitation and anxiety symptoms 5, 4.

Fluoxetine vs Paroxetine for anxiety disorders

Paroxetine is approved by the U.S. FDA for the treatment of social anxiety and generalized anxiety disorders.

Fluoxetine is prescribed "off-label" for social phobia6, generalized anxiety disorder7 , and childhood anxiety disorders8.

Currently fluoxetine is not considered to be a reliable first-line anti-anxiety medication.

Further reading


  • 1. Judge R, Parry MG, Quail D, Jacobson JG. Comparison of brief interruption of fluoxetine and paroxetine. Int Clin Psychopharmacol. 2002 Sep;17(5):217-25. PubMed
  • 2. Serretti A, Mandelli L. Antidepressants and body weight. J Clin Psychiatry. 2010 Oct;71(10):1259-72.
  • Amodeo LR, Greenfield VY, Humphrey DE, et al. Effects of acute or repeated paroxetine and fluoxetine treatment on affective behavior in male and female adolescent rats. Psychopharmacology (Berl). 2015 Oct;232(19):3515-28.
  • 4. Chouinard G, Saxena B, Be'langer MC, Ravindran A, Bakish D, Beauclair L, Morris P, Vasavan Nair NP, Manchanda R, Reesal R, Remick R, O'Neill MC. A Canadian multicenter, double-blind study of paroxetine and fluoxetine in major depressive disorder. J Affect Disord. 1999 Jul;54(1-2):39-48. PubMed
  • 5. Geretsegger C, Bohmer F, Ludwig M. Paroxetine in the elderly depressed patient: randomized comparison with fluoxetine of efficacy, cognitive and behavioural effects. Int Clin Psychopharmacol. 1994 Spring;9(1):25-9. PubMed
  • 6. Van Ameringen M, Mancini C, Streiner DL. Fluoxetine efficacy in social phobia. J Clin Psychiatry. 1993 Jan;54(1):27-32.
  • 7. Zou C, Ding X, Flaherty JH, Dong B. Clinical efficacy and safety of fluoxetine in generalized anxiety disorder in Chinese patients. Neuropsychiatr Dis Treat. 2013;9:1661-70
  • 8. Birmaher B, Axelson DA, Monk K, et al. Fluoxetine for the treatment of childhood anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2003 Apr;42(4):415-23.
  • 9. Isa Kara M, Ertaş ET, Ozen E, Atıcı M, Aksoy S, Erdogan MS, Kelebek S. BiteStrip analysis of the effect of fluoxetine and paroxetine on sleep bruxism. Arch Oral Biol. 2017 Aug;80:69-74.

Published: March 31, 2008
Last updated: August 14, 2018


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