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Paroxetine (Paxil)

Paroxetine in Brief
  • Active ingredient: Paroxetine hydrochloride
  • Common brand names: Paxil, Paxil CR, Seroxat, Aropax, Pondera, Deroxat, Paroxat, Cebrilin
  • Drug class: Antidepressant, 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


Paroxetine was first developed in 1975 by Jorgen Buus-Lassen and colleagues working in a small Danish company called Ferrosan. Paroxetine was Buus-Lassen’s the second SSRI. In 1975, this group had produced femoxetine, which was in clinical trials by the time paroxetine came along. Femoxetine had a disadvantage compared to paroxetine - it needed high doses, between 300 and 600 mg. It was not going to be a simple once-a-day pill. But in clinical trials femoxetine appeared more effective than paroxetine.

Ferrosan patented the formula for the paroxetine 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. As part of the effort to make up ground on the others, marketers within SmithKline Beecham coined the acronym SSRI. Compared to the other serotonin reuptake inhibitors, paroxetine was supposedly the selective serotonin reuptake inhibitor - 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)

Off-label & Investigational uses
  • chronic tension-type headache 12
  • chronic daily headache 13
  • fibromyalgia 19
  • hot flashes 14
  • premature ejaculation 15, 16
  • bipolar disorder 17
  • diabetic neuropathy 18
  • compulsive gambling 20
  • irritable bowel syndrome (IBS) 21, 22
  • social anxiety disorder in in children and adolescents 7
  • kleptomania
  • trichotillomania

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.

Irritable Bowel Syndrome (IBS)
Antidepressants are recommended for severe or refractory symptoms of pain, and may be helpful for other 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 and other IBS symptoms (constipation and diarrhea) 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 therapeutic 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


  • highest incidence rate 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

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, it 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 (Paxil) withdrawal

Withdrawal problems occur more commonly and are more severe with paroxetine than with the other SSRIs. The risk of withdrawal symptoms depends on several factors including the duration and dose of therapy 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 minimise the chance of withdrawal problems, it is suggested that 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 take over 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.

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. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA. 2003 Jun 4;289(21):2827-34.
  • 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. Shelton RC, Stahl SM. Risperidone and paroxetine given singly and in combination for bipolar depression. J Clin Psychiatry. 2004 Dec;65(12):1715-9. 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.

Published: March 31, 2008
Last updated: April 12, 2012

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 selective serotonin reuptake inhibitor, can act as a serotonin and norepinephrine uptake inhibitor in vivo 6.