Chemistry:Paroxetine

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Short description: SSRI antidepressant medication
Paroxetine
Paroxetine-2D-skeletal.svg
Paroxetine-from-HCl-xtal-3D-balls.png
Clinical data
Trade namesPaxil, Seroxat, Loxamine
AHFS/Drugs.comMonograph
MedlinePlusa698032
License data
Pregnancy
category
  • AU: D
Routes of
administration		Oral (By mouth)
Drug classSelective serotonin reuptake inhibitor (SSRI)
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • BR: Class C1 (Other controlled substances)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding93–95%[1][2][3]
MetabolismExtensive, hepatic (mostly CYP2D6-mediated)[1][2][3]
Elimination half-life21 hours[1][2][3]
ExcretionRenal (64%; 2% unchanged and 62% as metabolites), faecal (36%; <1% unchanged)[1][2][3]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC19H20FNO3
Molar mass329.371 g·mol−1
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

Paroxetine, sold under the brand names Paxil and Seroxat among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class.[4] It is used to treat major depressive disorder, obsessive-compulsive disorder, panic disorder, social anxiety disorder, post-traumatic stress disorder, generalized anxiety disorder, and premenstrual dysphoric disorder.[4] It has also been used in the treatment of premature ejaculation and hot flashes due to menopause.[4][5] It is taken orally (by mouth).[4]

Common side effects include drowsiness, dry mouth, loss of appetite, sweating, trouble sleeping, and sexual dysfunction.[4] Serious side effects may include suicidal thoughts in those under the age of 25, serotonin syndrome, and mania.[4] While the rate of side effects appears similar compared to other SSRIs and SNRIs, antidepressant discontinuation syndromes may occur more often.[6][7] Use in pregnancy is not recommended, while use during breastfeeding is relatively safe.[8] It is believed to work by blocking the reuptake of the chemical serotonin by neurons in the brain.[4]

Paroxetine was approved for medical use in the United States in 1992 and initially sold by GlaxoSmithKline.[4][9] It is on the World Health Organization's List of Essential Medicines.[10] It is available as a generic medication.[11] In 2020, it was the 82nd most commonly prescribed medication in the United States, with more than 9 million prescriptions.[12][13] In 2018, it was in the top 10 of most prescribed antidepressants in the United States.[14] In 2012, the United States Department of Justice fined GlaxoSmithKline $3 billion for withholding data, unlawfully promoting use in those under 18, and preparing an article that misleadingly reported the effects of paroxetine in adolescents with depression following its clinical trial study 329.[15][16][17]

Medical uses

Paroxetine is primarily used to treat major depressive disorder, obsessive-compulsive disorder, post-traumatic stress disorder, social anxiety disorder, and panic disorder. It is also occasionally used for agoraphobia, generalized anxiety disorder, premenstrual dysphoric disorder, and menopausal hot flashes.[18][19][20][21][22]

Depression

A variety of meta-analyses have been conducted to evaluate the efficacy of paroxetine in depression. They have variously concluded that paroxetine is superior or equivalent to placebo and that it is equivalent to other antidepressants.[23][24][25] Despite this, there was no clear evidence that paroxetine was better or worse compared with other antidepressants at increasing response to treatment at any point in time.[26]

Anxiety disorders

Paroxetine was the first antidepressant approved in the United States for the treatment of panic disorder.[27][page needed] Several studies have concluded that paroxetine is superior to placebo in the treatment of panic disorder.[25][28]

Paroxetine has demonstrated efficacy for the treatment of social anxiety disorder in adults and children.[29][30] It is also beneficial for people with co-occurring social anxiety disorder and alcohol use disorder.[31] It appears to be similar to a number of other SSRIs.[32]

Paroxetine is used in the treatment of obsessive-compulsive disorder.[33] Comparative efficacy of paroxetine is equivalent to that of clomipramine and venlafaxine.[34][35] Paroxetine is also effective for children with obsessive-compulsive disorder.[36]

Paroxetine is approved for treatment of PTSD in the United States, Japan, and Europe.[37][38][39] In the United States, it is approved for short-term use.[38]

Paroxetine is also FDA-approved for generalized anxiety disorder.[40]

Menopausal hot flashes

In 2013, low-dose paroxetine was approved in the US for the treatment of moderate-to-severe vasomotor symptoms such as hot flashes and night sweats associated with menopause.[5] At the low dose used for menopausal hot flashes, side effects are similar to placebo and dose tapering is not required for discontinuation.[41]

Fibromyalgia

Studies have also shown paroxetine "appears to be well-tolerated and improve the overall symptomatology in patients with fibromyalgia", but is less robust in helping with the pain involved.[42][43]

Adverse effects

Common side effects include drowsiness, dry mouth, loss of appetite, sweating, insomnia, and sexual dysfunction.[4] Serious side effects may include suicide in those under the age of 25, serotonin syndrome, and mania.[4] While the rate of side effects appears similar compared to other SSRIs and SNRIs, antidepressant discontinuation syndromes may occur more often.[6][7] Use in pregnancy is not recommended, while use during breastfeeding is relatively safe.[8]

Paroxetine shares many of the common adverse effects of SSRIs, including (with the corresponding rates seen in people treated with placebo in parentheses):

  • nausea 26% (9%)
  • diarrhea 12% (8%)
  • constipation 14% (9%)
  • dry mouth 18% (12%)
  • somnolence 23% (9%)
  • insomnia 13% (6%)
  • headache 18% (17%)
  • hypomania 1% (0.3%)
  • blurred vision 4% (1%)
  • loss of appetite 6% (2%)
  • nervousness 5% (3%)
  • paraesthesia 4% (2%)
  • dizziness 13% (6%)
  • asthenia (weakness; 15% (6%))
  • tremor 8% (2%)
  • sweating 11% (2%)
  • sexual dysfunction (≥10% incidence).[44]

Most of these adverse effects are transient and go away with continued treatment. Central and peripheral 5-HT3 receptor stimulation is believed to result in the gastrointestinal effects observed with SSRI treatment.[45] Compared to other SSRIs, it has a lower incidence of diarrhea, but a higher incidence of anticholinergic effects (e.g., dry mouth, constipation, blurred vision, etc.), sedation/somnolence/drowsiness, sexual side effects, and weight gain.[46]

Due to reports of adverse withdrawal reactions upon terminating treatment, the Committee for Medicinal Products for Human Use at the European Medicines Agency recommends gradually reducing over several weeks or months if the decision to withdraw is made.[47] See also Discontinuation syndrome (withdrawal).

Mania or hypomania may occur in 1% of patients with depression and up to 12% of patients with bipolar disorder.[48] This side effect can occur in individuals with no history of mania, but it may be more likely to occur in those with bipolar disorder or with a family history of mania.[49]

Suicide

Like other antidepressants, paroxetine may increase the risk of suicidal thinking and behaviour in people under the age of 25.[50][51] The FDA conducted a statistical analysis of paroxetine clinical trials in children and adolescents in 2004 and found an increase in suicidality and ideation as compared to placebo, which was observed in trials for both depression and anxiety disorders.[52] In 2015 a paper published in The BMJ that reanalysed the original case notes argued that in Study 329,[53] assessing paroxetine and imipramine against placebo in adolescents with depression, the incidence of suicidal behavior had been under-reported and the efficacy exaggerated for paroxetine.[54][55][56][57][58]

Sexual dysfunction

Sexual dysfunction, including loss of libido, anorgasmia, lack of vaginal lubrication, and erectile dysfunction, is one of the most commonly encountered adverse effects of treatment with paroxetine and other SSRIs. While early clinical trials suggested a relatively low rate of sexual dysfunction, more recent studies in which the investigator actively inquires about sexual problems suggest that the incidence is higher than 70%.[59] Symptoms of sexual dysfunction have been reported to persist after discontinuing SSRIs, although this is thought to be occasional.[60][61][62]

Pregnancy

Antidepressant exposure (including paroxetine) is associated with shorter duration of pregnancy (by three days), increased risk of preterm delivery (by 55%), lower birth weight (by 75 g or 2.6 oz), and lower Apgar scores (by <0.4 points).[63][64] The American College of Obstetricians and Gynecologists recommends that for pregnant women and women planning to become pregnant, paroxetine "be avoided, if possible", as it may be associated with increased risk of birth defects.[65][66]

Babies born to women who used paroxetine during the first trimester have an increased risk of cardiovascular malformations, primarily ventricular and atrial septal defects. Unless the benefits of paroxetine justify continuing treatment, consideration should be given to stopping or switching to another antidepressant.[67] Paroxetine use during pregnancy is associated with about 1.5– to 1.7-fold increase in congenital birth defects, in particular, heart defects, cleft lip and palate, clubbed feet, or any birth defects.[68][69][70][71][72]

Discontinuation syndrome

Many psychoactive medications can cause withdrawal symptoms upon discontinuation from administration. Paroxetine has among the highest incidence rates and severity of withdrawal syndrome of any medication of its class.[73] Common withdrawal symptoms for paroxetine include nausea, dizziness, lightheadedness and vertigo; insomnia, nightmares and vivid dreams; feelings of electricity in the body, as well as rebound depression and anxiety. Liquid formulation of paroxetine is available and allows a very gradual decrease of the dose, which may prevent discontinuation syndrome. Another recommendation is to temporarily switch to fluoxetine, which has a longer half-life and thus decreases the severity of discontinuation syndrome.[74][75][76]

In 2002, the U.S. FDA published a warning regarding "severe" discontinuation symptoms among those terminating paroxetine treatment, including paraesthesia, nightmares, and dizziness. The agency also warned of case reports describing agitation, sweating, and nausea. In connection with a Glaxo spokesperson's statement that withdrawal reactions occur only in 0.2% of patients and are "mild and short-lived", the International Federation of Pharmaceutical Manufacturers Associations said GSK had breached two of the federation's codes of practice.[77]

Paroxetine prescribing information posted at GlaxoSmithKline has been updated related to the occurrence of a discontinuation syndrome, including serious discontinuation symptoms.[67]

Overdose

Acute overdosage is often manifested by emesis, lethargy, ataxia, tachycardia, and seizures. Plasma, serum, or blood concentrations of paroxetine may be measured to monitor therapeutic administration, confirm a diagnosis of poisoning in hospitalized patients or to aid in the medicolegal investigation of fatalities. Plasma paroxetine concentrations are generally in a range of 40–400 μg/L in persons receiving daily therapeutic doses and 200–2,000 μg/L in poisoned patients. Postmortem blood levels have ranged from 1–4 mg/L in acute lethal overdose situations.[78][79] Along with the other SSRIs, sertraline and fluoxetine, paroxetine is considered a low-risk drug in cases of overdose.[80]

Interactions

Interactions with other drugs acting on the serotonin system or impairing the metabolism of serotonin may increase the risk of serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reaction. Such reactions have been observed with SNRIs and SSRIs alone, but particularly with concurrent use of triptans, MAO inhibitors, antipsychotics, or other dopamine antagonists.

The prescribing information states that paroxetine should "not be used in combination with an MAOI (including linezolid, an antibiotic which is a reversible non-selective MAOI), or within 14 days of discontinuing treatment with an MAOI", and should not be used in combination with pimozide, thioridazine, tryptophan, or warfarin.[67]

Paroxetine interacts with the following cytochrome P450 enzymes:[46][81]

Paroxetine has been shown to be an inhibitor of G protein-coupled receptor kinase 2 (GRK2).[82][83]

Pharmacology

Mechanism of paroxetine inhibition of CYP2D6[84]

Pharmacodynamics

Paroxetine is the most potent and one of the most specific selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs).[85] It also binds to the allosteric site of the serotonin transporter, similarly to escitalopram, though less potently so.[86] Paroxetine also inhibits the reuptake of norepinephrine to a lesser extent (<50 nmol/L).[87] Based on evidence from four weeks of administration in rats, the equivalent of 20 mg paroxetine taken once daily occupies approximately 88% of serotonin transporters in the prefrontal cortex.[81]

Receptor Ki (nM)
SERT 0.07 – 0.2
NET 40 – 85
DAT 490
D2 7,700
5-HT1A 21,200
5-HT2A 6,300
5-HT2C 9,000
α1 1,000 – 2,700
α2 3,900
M1 72
H1 13,700 – 23,700

Pharmacokinetics

Paroxetine is well-absorbed following oral administration.[81] It has an absolute bioavailability of about 50%, with evidence of a saturable first pass effect.[88] When taken orally, it achieves maximum concentration in about 6–10 hours[81] and reaches steady-state in 7–14 days.[88] Paroxetine exhibits significant interindividual variations in volume of distribution and clearance.[88] Less than 2% of an oral dose is excreted in urine unchanged.[88]

Paroxetine is a mechanism-based inhibitor of CYP2D6.[84][89]

Metabolism of paroxetine in humans[89]

Society and culture

Paroxetine was approved for medical use in the United States in 1992 and initially sold by GlaxoSmithKline.[4][90] It is currently available as a generic medication.[11] In 2017, it was the 68th most commonly prescribed medication in the United States, with more than eleven million prescriptions.[12][13]

GlaxoSmithKline has paid substantial fines, paid settlements in class-action lawsuits, and become the subject of several highly critical books about its marketing of paroxetine, in particular the off-label marketing of paroxetine for children, the suppression of negative research results relating to its use in children, and allegations that it failed to warn consumers of substantial withdrawal effects associated with use of the drug.[15][16]

Marketing

In early 2004, GSK agreed to settle charges of consumer fraud for $2.5 million.[91] The legal discovery process also uncovered evidence of deliberate, systematic suppression of unfavorable Paxil research results. One of GSK's internal documents read, "It would be commercially unacceptable to include a statement that efficacy [in children] had not been demonstrated, as this would undermine the profile of paroxetine".[92]

The United States Department of Justice fined GlaxoSmithKline $3 billion in 2012, for withholding data, unlawfully promoting use in those under 18, and preparing an article that misleadingly reported the effects of paroxetine in adolescents with depression following its clinical trial study 329.[15][16][17]

On 12 February 2016, the UK Competition and Markets Authority imposed record fines of £45 million on companies which were found to have infringed European Union and UK Competition law by entering into agreements to delay the market entry of generic versions of the drug in the UK. GlaxoSmithKline received the bulk of the fines, being fined £37,600,757. Other companies, which produce generics, were issued fines which collectively total £7,384,146. UK public health services are likely to claim damages for being overcharged in the period where the generic versions of the drug were illegally blocked from the market, as the generics are over 70% less expensive. GlaxoSmithKline may also face actions from other generics manufacturers who incurred loss as a result of the anticompetitive conduct.[93] On 18 April 2016, appeals were lodged with the Competition Appeal Tribunal by the companies which were fined.[94][95][96][97][98]

GSK marketed paroxetine through television advertisements throughout the late 1990s and early 2000s. Commercials also aired for the CR version of the drug beginning in 2003.[99]

Sales

In 2007, paroxetine was ranked 94th on the list of bestselling drugs, with over $1 billion in sales. In 2006, paroxetine was the fifth-most prescribed antidepressant in the U.S. retail market, with more than 19.7 million prescriptions.[100] In 2007, sales had dropped slightly to 18.1 million but paroxetine remained the fifth-most prescribed antidepressant in the U.S.[101][102]

Trade names

Trade names include Aropax, Paretin, Brisdelle, Deroxat, Paxil,[103][104] Pexeva, Paxtine, Paxetin, Paroxat, Paraxyl,[105] Sereupin, Daparox and Seroxat.

Research

Several studies have suggested that paroxetine can be used in the treatment of premature ejaculation. In particular, intravaginal ejaculation latency time (IELT) was found to increase with 6- to 13-fold, which was somewhat longer than the delay achieved by the treatment with other SSRIs (fluvoxamine, fluoxetine, sertraline, and citalopram).[106][107][108] However, paroxetine taken acutely ("on demand") 3–10 hours before coitus resulted only in a "clinically irrelevant and sexually unsatisfactory" 1.5-fold delay of ejaculation and was inferior to clomipramine, which induced a fourfold delay.[108]

There is also evidence that paroxetine may be effective in the treatment of compulsive gambling[109] and hot flashes.[110]

Benefits of paroxetine prescription for diabetic neuropathy[111] or chronic tension headache[112] are uncertain.

Although the evidence is conflicting, paroxetine may be effective for the treatment of dysthymia, a chronic disorder involving depressive symptoms for most days of the year.[113]

There is evidence to support that paroxetine selectively binds to and inhibits G protein-coupled receptor kinase 2 (GRK2) in mice with heart failure. Since GRK2 regulates the activity of the beta adrenergic receptor, which becomes desensitized in cases of heart failure, paroxetine (or a paroxetine derivative) could be used as a heart failure treatment in the future.[82][83][114]

Paroxetine has been identified as a potential disease-modifying osteoarthritis drug.[115]

Other organisms

Paroxetine is a common finding in waste water.[116] It is highly toxic to the alga Pseudokirchneriella subcapitata (syn. Raphidocelis subcapitata).[116]

It also is toxic to the soil nematode Caenorhabditis elegans.[117]

Alberca et al., 2016 finds paroxetine acts as a trypanocide against T. cruzi.[118]

Alberca et al., 2016 finds a leishmanicide effect.[119] Alberca finds that paroxetine produces cell death of the promastigotes of L. infantum.[119] The mechanism of action remains unknown.[119]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Cite error: Invalid <ref> tag; no text was provided for refs named TGA
  2. ↑ 2.0 2.1 2.2 2.3 Cite error: Invalid <ref> tag; no text was provided for refs named DM
  3. ↑ 3.0 3.1 3.2 3.3 Cite error: Invalid <ref> tag; no text was provided for refs named EMC
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 "Paroxetine Hydrochloride Monograph for Professionals". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/paroxetine-hydrochloride.html. 
  5. ↑ 5.0 5.1 Fischer A (28 June 2013). "FDA approves the first non-hormonal treatment for hot flashes associated with menopause" (Press release). Food and Drug Administration. Archived from the original on 18 January 2017.
  6. ↑ 6.0 6.1 "SSRIs and SNRIs: A review of the Discontinuation Syndrome in Children and Adolescents". Journal of the Canadian Academy of Child and Adolescent Psychiatry 20 (1): 60–67. February 2011. PMID 21286371. 
  7. ↑ 7.0 7.1 "Paroxetine: current status in psychiatry". Expert Review of Neurotherapeutics 7 (2): 107–120. February 2007. doi:10.1586/14737175.7.2.107. PMID 17286545. 
  8. ↑ 8.0 8.1 "Paroxetine Pregnancy and Breastfeeding Warnings". Drugs.com. https://www.drugs.com/pregnancy/paroxetine.html. 
  9. ↑ Food and Drug Administration (2011). Approved Drug Products with Therapeutic Equivalence Evaluations – FDA Orange Book 31st Edition (2011): FDA Orange Book 31st Edition (2011). DrugPatentWatch.com. p. 344. ISBN 9781934899816. https://books.google.com/books?id=JDZ4DAAAQBAJ&pg=PR344. Retrieved 4 March 2019. 
  10. ↑ World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. WHO/MHP/HPS/EML/2021.02. 
  11. ↑ 11.0 11.1 British national formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 363. ISBN 9780857113382. 
  12. ↑ 12.0 12.1 "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  13. ↑ 13.0 13.1 "Paroxetine - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Paroxetine. 
  14. ↑ "Top 25 Psychiatric Medications for 2018". 15 December 2019. https://psychcentral.com/blog/top-25-psychiatric-medications-for-2018/. 
  15. ↑ 15.0 15.1 15.2 "GlaxoSmithKline to Plead Guilty and Pay $3 Billion to Resolve Fraud Allegations and Failure to Report Safety Data" (Press release). United States Department of Justice, Office of Public Affairs. 2 July 2012. Archived from the original on 9 September 2014. Retrieved 6 October 2015. The United States alleges that, among other things, GSK participated in preparing, publishing and distributing a misleading medical journal article that misreported that a clinical trial of Paxil demonstrated efficacy in the treatment of depression in patients under age 18, when the study failed to demonstrate efficacy.
  16. ↑ 16.0 16.1 16.2 United States ex rel. Greg Thorpe, et al. v. GlaxoSmithKline PLC, and GlaxoSmithKline LLC, pp. 3–19 (D. Mass. 26 October 2011). Text
  17. ↑ 17.0 17.1 "Glaxo Agrees to Pay $3 Billion in Fraud Settlement". The New York Times. 2 July 2012. https://www.nytimes.com/2012/07/03/business/glaxosmithkline-agrees-to-pay-3-billion-in-fraud-settlement.html. 
  18. ↑ "Paroxetine: an update of its use in psychiatric disorders in adults". Drugs 62 (4): 655–703. March 2002. doi:10.2165/00003495-200262040-00010. PMID 11893234. 
  19. ↑ "Paroxetine controlled release was effective and tolerable for treating menopausal hot flash symptoms in women". Evidence Based Medicine 9 (1): 23. 1 January 2004. doi:10.1136/ebm.9.1.23. ISSN 1473-6810. http://ebm.bmj.com/content/9/1/23.full. Retrieved 20 January 2017. 
  20. ↑ "Paroxetine: an antidepressant". 29 August 2018. https://www.nhs.uk/medicines/paroxetine/. 
  21. ↑ "Paroxetine 20 mg Tablets - Summary of Product Characteristics (SmPC) - (emc)". https://www.medicines.org.uk/emc/product/4168/smpc. 
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  25. ↑ 25.0 25.1 "The efficacy of paroxetine and placebo in treating anxiety and depression: a meta-analysis of change on the Hamilton Rating Scales". PLOS ONE 9 (8): e106337. 27 August 2014. doi:10.1371/journal.pone.0106337. PMID 25162656. Bibcode: 2014PLoSO...9j6337S. 
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  34. ↑ "Paroxetine versus clomipramine in the treatment of obsessive-compulsive disorder. OCD Paroxetine Study Investigators". The British Journal of Psychiatry 169 (4): 468–474. October 1996. doi:10.1192/bjp.169.4.468. PMID 8894198. 
  35. ↑ "A double blind comparison of venlafaxine and paroxetine in obsessive-compulsive disorder". Journal of Clinical Psychopharmacology 23 (6): 568–575. December 2003. doi:10.1097/01.jcp.0000095342.32154.54. PMID 14624187. 
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  39. ↑ "Search results detail| Kusurino-Shiori (Drug information Sheet)". http://www.rad-ar.or.jp/siori/english/kekka.cgi?n=34488. 
  40. ↑ "FDA Approves Antidepressant For Generalized Anxiety Disorder". Psychiatric News 36 (10): 14. 18 May 2001. doi:10.1176/pn.36.10.0014b. 
  41. ↑ "FDA approval of paroxetine for menopausal hot flushes". The New England Journal of Medicine 370 (19): 1777–1779. May 2014. doi:10.1056/NEJMp1402080. PMID 24806158. 
  42. ↑ "A randomized, controlled, trial of controlled release paroxetine in fibromyalgia". The American Journal of Medicine 120 (5): 448–454. May 2007. doi:10.1016/j.amjmed.2006.06.006. PMID 17466657. 
  43. ↑ "Efficacy and tolerability of paroxetine in patients with fibromyalgia syndrome: a single-blind study". Current Therapeutic Research 60 (12): 696–702. December 1999. doi:10.1016/S0011-393X(99)90008-5. 
  44. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named MSR
  45. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named GG
  46. ↑ 46.0 46.1 46.2 Pharmacotherapy of Depression (2nd ed.). New York, NY: Humana Press. 2011. doi:10.1007/978-1-60327-435-7. ISBN 978-1-60327-434-0. 
  47. ↑ "Press release, CHMP meeting on Paroxetine and other SSRIs". European Medicines Agency. 9 December 2004. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2009/11/WC500015202.pdf. 
  48. ↑ "Prescribing Information Paxil (paroxetine hydrochloride) Tablets and Oral Suspension". http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020031s067,020710s031.pdf. 
  49. ↑ "Induction of mania in depression by paroxetine". Human Psychopharmacology 18 (7): 565–568. October 2003. doi:10.1002/hup.531. PMID 14533140. 
  50. ↑ "Medication Guide About Using Antidepressants in Children and Teenagers". FDA. https://www.fda.gov/downloads/drugs/drugsafety/informationbydrugclass/UCM161646.pdf. 
  51. ↑ "FDA Launches a Multi-Pronged Strategy to Strengthen Safeguards for Children Treated With Antidepressant Medications". https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2004/ucm108363.htm. 
  52. ↑ "Review and evaluation of clinical data: relationship between psychotropic drugs and pediatric suicidality". FDA. 16 August 2004. p. 30. https://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4065b1-10-TAB08-Hammads-Review.pdf. 
  53. ↑ "Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial". Journal of the American Academy of Child and Adolescent Psychiatry 40 (7): 762–772. July 2001. doi:10.1097/00004583-200107000-00010. PMID 11437014. 
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  72. ↑ "Paroxetine and congenital malformations: meta-Analysis and consideration of potential confounding factors". Clinical Therapeutics 29 (5): 918–926. May 2007. doi:10.1016/j.clinthera.2007.05.003. PMID 17697910. 
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  76. ↑ "Dependence on Antidepressants & Halting SSRIs". http://www.benzo.org.uk/healy.htm. 
  77. ↑ "Withdrawal from paroxetine can be severe, warns FDA". BMJ 324 (7332): 260. February 2002. doi:10.1136/bmj.324.7332.260. PMID 11823353. 
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  100. ↑ The paroxetine prescriptions were calculated as a total of prescriptions for Paxil CR and generic paroxetine using data from the charts for generic and brand-name drugs."Top 200 generic drugs by units in 2006. Top 200 brand-name drugs by units". http://www.drugtopics.com/drugtopics/article/articleDetail.jsp?id=407652. 
  101. ↑ The paroxetine prescriptions were calculated as a total of prescriptions for Paxil CR and generic paroxetine using data from the charts for generic and brand-name drugs."Top 200 generic drugs by units in 2007". 18 February 2008. http://drugtopics.modernmedicine.com/drugtopics/Top200Drugs/ArticleStandard/article/detail/491194. 
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  103. ↑ "Paroxetine-The Antidepressant from Hell? Probably Not, But Caution Required". Psychopharmacology Bulletin 46 (1): 77–104. March 2016. PMID 27738376. 
  104. ↑ Dictionary of Psychology (Second ed.). Oxford University Press. 2006. pp. 552. 
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  111. ↑ "The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms". Pain 42 (2): 135–144. August 1990. doi:10.1016/0304-3959(90)91157-E. PMID 2147235. 
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  115. ↑ "Paroxetine-mediated GRK2 inhibition is a disease-modifying treatment for osteoarthritis". Science Translational Medicine 13 (580): eaau8491. February 2021. doi:10.1126/scitranslmed.aau8491. PMID 33568523. 
  116. ↑ 116.0 116.1
  117. ↑
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