Paroxetine (Paxil)

Paroxetine in Brief
  • Generic names: Paroxetine hydrochloride; Paroxetine mesylate
  • Brand names: Paxil®, Paxil® CR, Seroxat®, Brisdelle®, Aropax, Pondera, Deroxat, Paroxat, Cebrilin; Pexeva® (paroxetine mesylate)
  • Therapeutic class: Antidepressant
  • Pharmacologic class: Selective serotonin reuptake inhibitor (SSRI)
  • FDA Approved: December 29, 1992
  • Chemical Formula: C19H20FNO3
  • Pregnancy Category: D
  • Habit forming? No
  • Originally discovered: 1975, Ferrosan, Denmark Denmark

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


Paroxetine, a phenylpiperidine derivative, was originally developed in 1975 by Jorgen Buus-Lassen and associates working in a small Danish company Ferrosan. Paroxetine was the second SSRI synthesized by Buus-Lassen In 1975, Danish scientists had produced femoxetine, which had a disadvantage compared to paroxetine - femoxetine needed very high doses, between 300 and 600 mg. However, in clinical trials femoxetine turned out to be more effective than paroxetine.

Ferrosan patented paroxetine formula in February 8th, 1977 under U.S. Patent #4,007,196. The patent claims paroxetine and its salts and discloses their antidepressant properties. Ferrosan eventually developed a process to produce the crystalline hydrochloride salt of paroxetine, or paroxetine hydrochloride.


Ferrosan sold paroxetine to Beecham pharmaceuticals in 1980. Beecham later merged with SmithKline & French to become SmithKline Beecham (SB) and later at the turn of the millennium with Glaxo to become GlaxoSmithKline (GSK), at that point the world’s largest pharmaceutical corporation. Ferrosan had meanwhile been acquired by Novo-Nordisk, which had little interest in psychiatry, and femoxetine died from neglect.

Paroxetine ended up being licensed as Paxil® in 1993 in the United States and Seroxat® in 1992 in the United Kingdom. To try to catch up with the competition, marketers within SmithKline Beecham came up with the acronym SSRI. Compared to the other serotonin reuptake inhibitors, paroxetine was supposedly the selective serotonin reuptake inhibitor - in other words the SSRI. The name worked - too well. It was adopted for the entire group of compounds. In this way, Paxil® made Prozac® and Zoloft® into SSRIs.

FDA approved indications

  • Major depressive disorder
  • Obsessive compulsive disorder
  • Panic disorder
  • Social anxiety disorder
  • Generalized anxiety disorder
  • Posttraumatic stress disorder
  • Premenstrual dysphoric disorder (controlled release formulation)
  • Hot flashes (vasomotor symptoms) associated with menopause14 (Brisdelle®, low-dose paroxetine 7.5 mg), FDA approved in 2013

Off-label & Investigational uses

  • chronic headaches 12, 13
  • fibromyalgia 19
  • premature ejaculation 15, 16
  • bipolar disorder 17
  • diabetic neuropathy 18
  • compulsive gambling 20
  • irritable bowel syndrome (IBS) 21, 22
  • social anxiety disorder in children and adolescents 7
  • kleptomania
  • trichotillomania
  • vasovagal syncope 24

Premature ejaculation
Paroxetine is an effective therapy for premature ejaculation. Paroxetine 20 mg daily and scheme on-demand (20 mg 4-6 hours before the intercourse) appears similar like effective options 15, 16. Paroxetine can be used for treatment of premature ejaculation in combination with tadalafil (Cialis®) 22.

Irritable Bowel Syndrome (IBS)
Antidepressants are recommended for severe or refractory symptoms of pain, and may be helpful for other IBS symptoms like constipation. Paroxetine has neuromodulatory and analgesic properties independent of its psychotropic effect, which may set in relatively fast.

The clinical study found that patients taking 10 to 40 mg of paroxetine per day were more likely than those taking placebo to have a clinically significant improvement in overall well-being (63% versus 26%). This benefit was present in both depressed and non-depressed patients 22.

A pilot open-label study suggested that paroxetine 20 to 40 mg is effective in reducing pain, constipation, and diarrhea associated with IBS 21.


Paroxetine "pros" and "cons"

Paroxetine (Paxil) may be useful antidepressant in patients with anxiety disorder or insomnia. It should probably be avoided in persons for whom the mild anticholinergic effects would be undesirable, such as those with Alzheimer's disease or other cognitive disorders.


  • Broad abtidepressant and antianxiety efficacy.
  • Inhibits fewer CYP enzymes than fluoxetine.
  • The only SSRI indicated for all five anxiety disorders in addition to major depressive disorder.
  • Long-term treatment efficacy and tolerability 8.
  • Good choice for patients with a strong anxiety component or poor sleep.


  • Highest incidence and severity of SSRI withdrawal syndrome 2, 4.
  • High risk for weight gain 3 (weight gain related to paroxetine occurs mainly during the first 12 months of treatment).
  • High rate of sexual side effects (up to 75%), produces a significant delay in male ejaculation, significantly decreases libido, arousal, and duration of orgasm.
  • High rate of drowsiness and sedation, higher than with fluoxetine, sertraline and venlafaxine.
  • May impair cognition and vigilance 26
  • Drug interactions -- paroxetine is a potent inhibitor of CYP2D6.
  • Paroxetine was reclassified as Pregnancy Category D by the FDA after the demonstration of an increased risk for congenital heart defects in newborns 25.

Mechanism of action

Paroxetine, a phenylpiperidine derivative, is the most potent inhibitor of the reuptake of serotonin of all currently available antidepressants including the class of SSRIs. It is a very weak inhibitor of norepinephrine (NE) uptake but it is still more potent at this site than the other SSRIs. In vitro, paroxetine is approximately 3- to 5-fold more potent at inhibiting serotonin than noradrenaline reuptake.

Paroxetine has little affinity for muscarinic cholinergic, histamine H1, dopaminergic and adrenergic receptors and by comparison with tricyclic antidepressants (TCAs) has, therefore, reduced propensity to cause central and autonomic side effects. Paroxetine is also a nitric oxide synthase (NOS) inhibitor, hence serum nitrite and nitrate levels are reduced in paroxetine users.

Paroxetine potently and selectively inhibits neuronal serotonin reuptake through antagonism of the serotonin transporter. Its antidepressant, antiobsessional, and antipanic activities are presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS). Paroxetine inhibits the active membrane transport mechanism for reuptake of serotonin, which increases concentration of the neurotransmitter at the synaptic cleft and prolongs its activity at synaptic receptor sites. Inhibition of serotonin reuptake also enhances serotonergic neurotransmission by reducing turnover of the neurotransmitter via a negative feedback mechanism. Paroxetine inhibits serotonin reuptake in vitro more selectively and more potently than do fluoxetine, sertraline, fluvoxamine, zimeldine, or clomipramine.

Time to clear out of the system

The elimination half-life is variable but is generally about 21 hours (3-65 hours). Paroxetine has no active metabolites. Half-life is prolonged in patients with severe hepatic or renal function impairment. Generally, paroxetine is more rapidly cleared in youths than adults.

It may take 5 to 12 days for paroxetine to clear out of the system.

Onset of action

Depression: Studies have shown, that depressive and anxiety symptoms may improve after 1 week with paroxetine 9. However, it may take up to 6 weeks for the full therapeutic effect to be realized.

Generalized anxiety disorder: In generalized anxiety disorder (GAD) improvement of core symptoms occurs early after 1 week and significant reduction in disability occurs after only 8 weeks of treatment 10.

Posttraumatic stress disorder: It may take up to 12 weeks to achieve significant reduction of PTSD symptoms 11.

Paroxetine withdrawal

Withdrawal symptoms occur frequently upon paroxetine discontinuation and sometimes are very severe. The risk of withdrawal symptoms depends on several factors, including the duration of therapy, dose, and the rate of dose reduction.

Discontinuation symptoms include:

  • dizziness
  • sensory disturbances (including paraesthesia, electric shock sensations and tinnitus)
  • sleep disturbances (including intense dreams)
  • agitation
  • anxiety
  • nausea
  • tremor
  • confusion
  • sweating
  • headache
  • diarrhoea
  • palpitations
  • emotional instability
  • irritability
  • visual disturbances

In order to minimize the chance of withdrawal syndrome, paroxetine should be withdrawn very gradually by reducing the dose very slowly over a period of weeks, or months in cases where the symptoms are severe.

By reducing the dosage in small increments, your serotonergic system can gradually restore it's own natural serotonin producing activity and slowly adapt to living without the drug. The tapering process may consist of gradual dose reduction of 5% per week.

The taper phase regimen used in clinical trials involved decreasing the daily dose by 10 mg at weekly intervals. However, such regimen may be too fast. If intolerable symptoms occur following a decrease in the dose, then resuming the previous dose may be considered. When symptoms have settled, resume tapering process at a more gradual rate.

Paroxetine & alcohol

Paroxetine does not impair psychomotor function and does not potentiate the depressant effects of ethanol. Paroxetine may slightly inhibit the sedation caused by alcohol27.Further reading


  • 1. U.S. FDA. Paroxetine Prescribing Information.
  • 2. Hindmarch I, Kimber S, Cockle SM. Abrupt and brief discontinuation of antidepressant treatment: effects on cognitive function and psychomotor performance. Int Clin Psychopharmacol. 2000 Nov;15(6):305-18. PubMed
  • 3. Fava M, Judge R, Hoog SL, Nilsson ME, Koke SC. Fluoxetine versus sertraline and paroxetine in major depressive disorder: changes in weight with long-term treatment. J Clin Psychiatry. 2000 Nov;61(11):863-7. PubMed
  • 4. Alison Tonks. Withdrawal from paroxetine can be severe, warns FDA. BMJ. 2002 February 2; 324(7332): 260.
  • 5. Montejo-Gonzalez AL, Llorca G, Izquierdo JA, Ledesma A, Bousono M, Calcedo A, Carrasco JL, Ciudad J, Daniel E, De la Gandara J, Derecho J, Franco M, Gomez MJ, Macias JA, Martin T, Perez V, Sanchez JM, Sanchez S, Vicens E. SSRI-induced sexual dysfunction. J Sex Marital Ther. 1997 Fall;23(3):176-94. PubMed
  • 6. Gilmor ML, Owens MJ, Nemeroff CB. Inhibition of norepinephrine uptake in patients with major depression treated with paroxetine. Am J Psychiatry. 2002 Oct;159(10):1702-10.
  • 7. Wagner KD, Berard R, Stein MB, Wetherhold E, Carpenter DJ, Perera P, Gee M, Davy K, Machin A. A multicenter, randomized, double-blind, placebo-controlled trial of paroxetine in children and adolescents with social anxiety disorder. Arch Gen Psychiatry. 2004 Nov;61(11):1153-62.
  • 8. Rickels K, Rynn M, Iyengar M, Duff D. Remission of generalized anxiety disorder: a review of the paroxetine clinical trials database. J Clin Psychiatry. 2006 Jan;67(1):41-7.
  • 9. Golden RN, Nemeroff CB, McSorley P, Pitts CD, Dube' EM. Efficacy and tolerability of controlled-release and immediate-release paroxetine in the treatment of depression. J Clin Psychiatry. 2002 Jul;63(7):577-84. PubMed
  • 10. Pollack MH, Zaninelli R, Goddard A, McCafferty JP, Bellew KM, Burnham DB, Iyengar MK. Paroxetine in the treatment of generalized anxiety disorder: results of a placebo-controlled trial. J Clin Psychiatry. 2001 May;62(5):350-7. PubMed
  • 11. Tucker P, Zaninelli R, Yehuda R, Ruggiero L, Dillingham K, Pitts CD. Paroxetine in the treatment of chronic posttraumatic stress disorder: results of a placebo-controlled trial. J Clin Psychiatry. 2001 Nov;62(11):860-8. PubMed
  • 12. Holroyd KA, Labus JS, O'Donnell FJ, Cordingley GE. Treating chronic tension-type headache not responding to amitriptyline hydrochloride with paroxetine hydrochloride: a pilot evaluation. Headache. 2003 Oct;43(9):999-1004. PubMed
  • 13. Foster CA, Bafaloukos J. Paroxetine in the treatment of chronic daily headache. Headache. 1994 Nov-Dec;34(10):587-9. PubMed
  • 14. Simon JA, Portman DJ, Kaunitz AM, Mekonnen H, Kazempour K, Bhaskar S, Lippman J. Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: two randomized controlled trials. Menopause. 2013 Oct;20(10):1027-35. PubMed
  • 15. Ludovico GM, Corvasce A, Pagliarulo G, Cirillo-Marucco E, Marano A, Pagliarulo A. Paroxetine in the treatment of premature ejaculation. Br J Urol. 1996 Jun;77(6):881-2. PubMed
  • 16. Rivera P, Gonzalez R, Gonzalez F, Storme O. Use of paroxetine on-demand in premature ejaculation. Actas Urol Esp. 2005 Apr;29(4):387-91. PubMed
  • 17. McElroy SL, Weisler RH, Chang W, et al. A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). J Clin Psychiatry. 2010 Feb;71(2):163-74. PubMed
  • 18. Sindrup SH, Gram LF, Brosen K, Eshoj O, Mogensen EF. The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain. 1990 Aug;42(2):135-44. PubMed
  • 19. Patkar AA, Masand PS, Krulewicz S, Mannelli P, Peindl K, Beebe KL, Jiang W. A randomized, controlled, trial of controlled release paroxetine in fibromyalgia. Am J Med. 2007 May;120(5):448-54. PubMed
  • 20. Grant JE, Kim SW, Potenza MN, Blanco C, Ibanez A, Stevens L, Hektner JM, Zaninelli R. Paroxetine treatment of pathological gambling: a multi-centre randomized controlled trial. Int Clin Psychopharmacol. 2003 Jul;18(4):243-9. PubMed
  • 21. Masand PS, Gupta S, Schwartz TL, Virk S, Lockwood K, Hameed A, King M, Kaplan DS. Paroxetine in Patients With Irritable Bowel Syndrome: A Pilot Open-Label Study. Prim Care Companion J Clin Psychiatry. 2002 Feb;4(1):12-16. PubMed
  • 22. Tabas G, Beaves M, Wang J, Friday P, Mardini H, Arnold G. Paroxetine to treat irritable bowel syndrome not responding to high-fiber diet: a double-blind, placebo-controlled trial. Am J Gastroenterol. 2004 May;99(5):914-20.
  • 23. Lepkifker E, Dannon PN, Ziv R, Iancu I, Horesh N, Kotler M. The treatment of kleptomania with serotonin reuptake inhibitors. Clin Neuropharmacol. 1999 Jan-Feb;22(1):40-3.
  • 24. Di Girolamo E, Di Iorio C, Sabatini P, Leonzio L, Barbone C, Barsotti A. Effects of paroxetine hydrochloride on refractory vasovagal syncope: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol. 1999 Apr;33(5):1227-30. PubMed
  • 25. Bérard A, Ramos E, Rey E, Blais L, St-André M, Oraichi D. First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage. Birth Defects Res B Dev Reprod Toxicol. 2007;80:18. PubMed
  • 26. Schmitt JA, Ramaekers JG, Kruizinga MJ, van Boxtel MP, Vuurman EF, Riedel WJ. Additional dopamine reuptake inhibition attenuates vigilance impairment induced by serotonin reuptake inhibition in man. J Psychopharmacol. 2002 Sep;16(3):207-14. PubMed
  • 27. Kerr JS, Fairweather DB, Mahendran R, Hindmarch I. The effects of paroxetine, alone and in combination with alcohol on psychomotor performance and cognitive function in the elderly. Int Clin Psychopharmacol. 1992 Nov;7(2):101-8.
  • 28. Moudi E, Kasaeeyan AA. Comparison Between Tadalafil Plus Paroxetine and Paroxetine Alone in the Treatment of Premature Ejaculation. Nephrourol Mon. 2016 Jan 27;8(1):e32286. PubMed

Published: March 31, 2008
Last updated: January 26, 2017

Interesting facts

Paroxetine facts
  • Paroxetine inhibits its own metabolism.
    The starting dose of paroxetine has an elimination half-life of approximately 24 h. However, the half-life becomes longer at higher doses due to paroxetine's inhibition of its own clearance.
  • Paroxetine is the most potent inhibitor of the reuptake of serotonin among the available SSRIs.
  • Paroxetine, currently classified as a SSRI, can act as a serotonin and norepinephrine uptake inhibitor in vivo 6.

More Facts
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