Paroxetine

Paroxetine-2D-skeletal.svg
Paroxetine-3D-balls.png
Paroxetine
Systematic (IUPAC) name
(3S,4R)-3-(1,3-benzodioxol-5-yloxymethyl)-4-(4-fluorophenyl)piper​idine
Identifiers
CAS number 61869-08-7
ATC code N06AB05
PubChem 43815
DrugBank APRD00364
ChemSpider 39888
Chemical data
Formula C19H20FNO3 
Mol. mass 329.3
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability Completely absorbed from GI, but extensive first-pass metabolism in the liver; Tmax 4.9 (with meals) to 6.4 hours (fasting)
Protein binding 93–95%
Metabolism Extensive, hepatic (mostly CYP2D6-mediated)
Half life 24 hours (range 3–65 hours)
Excretion 64% in urine, 36% in bile
Therapeutic considerations
Licence data

US
Pregnancy cat.

D(US)
Legal status

℞ Prescription only
Routes Oral

Paroxetine (trade names Seroxat, Paxil, Parotin, Aropax, Xetanor, ParoMerck, Rexetin) is a selective serotonin reuptake inhibitor (SSRI) antidepressant. It was released in 1992 by the pharmaceutical company GlaxoSmithKline. In 2006 it was the fifth-most prescribed antidepressant in the United States retail market, with more than 19.7 million prescriptions.[1] The prescription of this drug is controversial because of side effects such as suicidal ideation (thoughts of suicide) and withdrawal syndrome which have resulted in legal proceedings against the manufacturer.

Contents

Indications

Approved

Paroxetine is primarily used to treat the symptoms of major depression, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), panic disorder, generalized anxiety disorder (GAD),[2] social phobia/social anxiety disorder,[3] and premenstrual dysphoric disorder (PMDD).[4]

It was the first antidepressant formally approved in the United States for the treatment of panic attacks.[5]

According to the prescribing information provided by the manufacturer of Paxil brand of paroxetine GlaxoSmithKline and approved by the FDA,[6] the effectiveness of paroxetine in major depressive disorder has been proven by six placebo-controlled clinical trials. For panic disorder, three 10-12-week studies indicated paroxetine superiority to placebo.[6] Similarly, three 12-week trials for adult outpatients with social anxiety disorder demonstrated better response to paroxetine than to placebo.[6]

Unapproved/off-label/investigational

Moreover, studies have suggested that paroxetine can in fact be used in the treatment of premature ejaculation. In particular, intravaginal ejaculation latency time (IELT) found to increase with a 6-13-fold, which was somewhat longer than those of a predessor.. the delay achieved by the treatment with other SSRIs (fluvoxamine, fluoxetine, sertraline and citalopram).[7][8][9] 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 four-fold delay.[9]

There is also evidence that paroxetine may be effective in the treatment of compulsive gambling[10] and hot flashes.[11]

In two double-blind studies of bipolar disorder patients, addition of paroxetine to a mood stabilizer had no advantages over addition of placebo.[12][13] Benefits of paroxetine prescription for diabetic neuropathy[14] or chronic tension headache.[15] are uncertain.

Pharmacology

Paroxetine is the most potent and one of the most specific selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRI).[16] This activity of the drug on brain neurons is thought to be responsible for its antidepressant effects.

Paroxetine is a phenylpiperidine derivative which is chemically unrelated to the tricyclic or tetracyclic antidepressants. In receptor binding studies, paroxetine did not exhibit significant affinity for the adrenergic (α1, α2, β), dopaminergic, serotonergic (5HT1, 5HT2), or histamine receptors of rat brain membrane. A weak affinity for the muscarinic acetylcholine and noradrenaline receptors was evident. The predominant metabolites of paroxetine are essentially inactive as 5-HT reuptake inhibitors.

Chemistry

Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of 120° to 138°C and a solubility of 5.4 mg/mL in water.

Formulations

Paroxetine CR (controlled release) was shown to be associated with a lower rate of nausea during the first week of treatment than paroxetine immediate release. However, the rate of treatment discontinuation due to nausea was not significantly different.[17]. Since both Paxil and Paxil CR are generally dosed once daily, the benefit of Paxil CR has been debated, especially given the significant cost difference between (generic) Paxil and (brand-only) Paxil CR..

Side effects

General side effects are mostly present during the first 1–4 weeks while the body acquires a tolerance to the drug, although once this happens, withdrawal can cause symptoms to re-emerge for very long periods of time. Almost all SSRIs are known to cause either one or more of these symptoms. A person receiving paroxetine treatment may experience a few, all, or none of the following side-effects, and most side-effects will disappear or lessen with continued treatment, though some may last throughout the duration. Side effects are also often dose-dependent, with fewer and/or less severe symptoms being reported at lower dosages, and/or more severe symptoms being reported at higher dosages. Increases or changes in dosage may also cause symptoms to reappear or worsen.[6]

9 December 2004 European Medicines Agency (EMEA), i.e. the Committee for Medicinal Products for Human Use (CHMP), informed patients, prescribers and parents that paroxetine should not be prescribed to children. CHMP gave a warning to prescribers recommending close monitoring of adult patients at high risk of suicidal behaviour and/or suicidal thoughts. In other words, CHMP does not prohibit use of paroxetine with adults but stresses extreme caution in actual usage. Also withdrawal reactions upon stopping treatment is mentioned and therefore it is recommended to gradually reduce the dose over several weeks or months if decision of withdrawal is made.[18]

Most common

Less common

Check with your doctor if these continue or are bothersome.

Other

Paroxetine and other SSRIs have been shown to cause sexual side effects in most patients, both males and females.[21]

Schmitt et al. (2001) suggested that paroxetine negatively affects cognition (i.e., IQ). In their study, healthy participants given paroxetine for 14 days (20mg for days 1–7 and 40mg days 8–14) showed poorer recall of words on day 14 compared to those receiving a placebo. Schmitt and co-workers, however, did not account for significant differences in verbal recall at baseline between those receiving paroxetine and those receiving a placebo, differences which produced the significant finding. Furthermore, participants receiving paroxetine recalled as many words at baseline as they recalled on day 14. Accordingly, the conclusion that paroxetine affects verbal recall was unwarranted.

Withdrawal syndrome

Main article: SSRI discontinuation syndrome

Many psychoactive medications can cause withdrawal symptoms upon discontinuation from administration. Evidence has shown that paroxetine has among the highest incidence rates and severity of SSRI discontinuation syndrome of any medication of its class.[22][23] Common paroxetine withdrawal symptoms include repeated electrical shock sensations of the brain and body (see "brain zaps"), vertigo and hot flashes.[24] Suicidal ideation is a frequently reported experience in those withdrawing from SSRIs.[25] For those experiencing extreme and unusual difficulty discontinuing paroxetine, it is recommended that an SSRI with a longer half-life, such as fluoxetine, be administered for approximately two weeks, then discontinued, to lessen symptoms.[26][27]

For 10 years, GlaxoSmithKline's marketing of the drug stated falsely that it was "not habit forming".[28][23] In 2002, the U.S. FDA published a new product warning about the drug, and the International Federation of Pharmaceutical Manufacturers Associations (IFPMA) declared GSK guilty of misleading the public about paroxetine on US television.[22] The British Medical Journal quoted Charles Medawar, head of Social Audit: "This drug has been promoted for years as safe and easy to discontinue.... The fact that it can cause intolerable withdrawal symptoms of the kind that could lead to dependence is enormously important to patients, doctors, investors, and the company. GlaxoSmithKline has evaded the issue since it was granted a licence for paroxetine over 10 years ago, and the drug has become a blockbuster for them, generating about a tenth of their entire revenue. The company has been promoting paroxetine directly to consumers as 'non-habit forming' for far too long."[22] As of 2008, GlaxoSmithKline's prescribing information acknowledges the symptoms but eschews the term "withdrawal" in favor of the phrases "serious discontinuation symptoms" and "discontinuation syndrome."[29]

Patients considering paroxetine should be warned in advance of these risks, and withdrawal from any SSRI should be closely medically supervised by the prescribing provider.

Warning for pregnant women

Pregnant women and those who might become pregnant should avoid taking the antidepressant Paxil because of a high risk of birth defects, according to a committee of obstetricians who published their opinion in the December 2006 issue of the journal Obstetrics & Gynecology.[30]

The obstetric practice committee of the American College of Obstetricians and Gynecologists said pregnant women should not take Paxil because two previous studies found that the drug posed up to double the risk of heart defects in fetuses.

Nearly a year ago, the U.S. Food and Drug Administration (FDA) and GlaxoSmithKline—which makes Paxil—changed the warnings on the drug to include the results of the studies. The FDA then advised pregnant women to merely switch from Paxil to another SSRI drug, such as Prozac or Zoloft.

The FDA's enhanced warning on Paxil followed the results of a review of Sweden's birth registry that found pregnant women who took Paxil were 1.5 to 2 times more likely to give birth to a baby with heart defects than women who took other SSRIs or who did not take antidepressants at all.

Neonatal withdrawal symptoms from Paxil have also been documented from mothers taking Paxil during pregnancy.[31]

Controversy

In May 2007 a US court approved a settlement in a class action lawsuit brought on behalf of everyone in the United States who purchased Paxil or Paxil CR prescribed for a minor. The lawsuit alleged that GlaxoSmithKline promoted Paxil or Paxil CR for prescription to children and adolescents while withholding and concealing material information about the medication's safety and effectiveness for minors. GSK denied all claims. The settlement terms entitled everyone, who previously purchased Paxil or Paxil CR for their child or ward, to recover up to 100% of the documented out-of-pocket expenses or $100, if documentation was not available.[32] [33]

In the UK since 2001 lawsuits have been filed representing people who have been prescribed Seroxat. They allege that the drug has serious side effects, which GlaxoSmithKline downplayed in patient information.[34][35]

In March 2004 the FDA ordered a black box warning placed on SSRI and other antidepressants, warning of the risk for potential suicidal thinking in children and adolescents.[36][37] ABC News reported that the prescribing of these medications to children subsequently dropped by 20 percent. [38] According to the Center for Disease Control and Prevention's Annual Summary of Vital Statistics, the suicide rate rose more than 18 percent in those 1 to 19 years old, from 2.2 per 100,000 in 2003 to 2.6 per 100,000 in 2004. In those 15 to 19 years old, the figures reflected a more than 12 percent rise in suicide, from 7.3 per 100,000 in 2003 to 8.2 per 100,000 in 2004.[38] This led many experts to conclude that the warning, and subsequent reduction in the use of antidepressants, led to an increased suicide rate in this age group.[39] The finding is consistent with an earlier finding, reported to the 2003 FDA Advisory Committee by Dr David Shaffer, that suicide rates in the United States fell during the 1990s, in line with the introduction of SSRIs.[40]

Since the FDA approved paroxetine in 1992, approximately 5,000 U.S. citizens have sued GSK. Most of these people feel they were not sufficiently warned in advance of the drug's side effects—particularly the withdrawal syndrome discussed above, after GSK had specifically advertised the drug as "not habit forming."[28]

On January 29 2007, the BBC broadcast a fourth documentary in its Panorama series about the drug Seroxat.[41] This programme, entitled Secrets of the Drug Trials, focused on three GSK paediatric clinical trials on depressed children and adolescents. Data from the trials show that Seroxat could not be proven to work for teenagers. Also, one clinical trial indicated that adolescents were six times more likely to become suicidal after taking it.

In 2008, it was also suggested that Paroxetine could affect fertility in male patients.[42]

Footnotes

  1. ↑ 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.". Drug Topics, Mar 5, 2007. Retrieved on 2007-04-08.
  2. ↑ Baldwin DS, Anderson IM, Nutt DJ, Bandelow B, Bond A, Davidson JR, den Boer JA, Fineberg NA, Knapp M, Scott J, Wittchen HU (2005). "Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology". Journal of Psychopharmacology 19 (6): 567–596. doi:10.1177/0269881105059253. PMID 16272179. 
  3. ↑ D Baldwin, J Bobes, DJ Stein, I Scharwachter and M Faure (1999). "Paroxetine in social phobia/social anxiety disorder. Randomised, double-blind, placebo-controlled study. Paroxetine Study Group". The British Journal of Psychiatry 175: 120–126. PMID 10627793. 
  4. ↑ Yonkers KA, Gullion C, Williams A, Novak K, Rush AJ. (1996). "Paroxetine as a treatment for premenstrual dysphoric disorder". Journal of Clinical Psychopharmacology. 16 (1): 3–8. doi:10.1097/00004714-199602000-00002. PMID 8834412. 
  5. ↑ Turner, Francis Joseph (2005). Social Work Diagnosis in Contemporary Practice. Oxford University Press US. ISBN 019516878X. 
  6. ↑ 6.0 6.1 6.2 6.3 "PAXIL (paroxetine hydrochloride) Tablets and Oral Suspension: PRESCRIBING INFORMATION" (PDF). Research Triangle Park, NC: GlaxoSmithKline (August 2007). Retrieved on 2007-08-14.
  7. ↑ Waldinger MD, Hengeveld MW, Zwinderman AH, Olivier B (1998). "Effect of SSRI antidepressants on ejaculation: a double-blind, randomized, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine, and sertraline". Journal of clinical psychopharmacology 18 (4): 274–81. doi:10.1097/00004714-199808000-00004. PMID 9690692. 
  8. ↑ Waldinger MD, Zwinderman AH, Olivier B (2001). "SSRIs and ejaculation: a double-blind, randomized, fixed-dose study with paroxetine and citalopram". Journal of clinical psychopharmacology 21 (6): 556–60. PMID 11763001. 
  9. ↑ 9.0 9.1 Waldinger MD, Zwinderman AH, Olivier B (2004). "On-demand treatment of premature ejaculation with clomipramine and paroxetine: a randomized, double-blind fixed-dose study with stopwatch assessment". Eur. Urol. 46 (4): 510–5; discussion 516. doi:10.1016/j.eururo.2004.05.005. PMID 15363569. 
  10. ↑ Kim SW, Grant JE, Adson DE, Shin YC, Zaninelli R (2002). "A double-blind placebo-controlled study of the efficacy and safety of paroxetine in the treatment of pathological gambling". Journal of Clinical Psychiatry 63 (6): 501–507. PMID 12088161. 
  11. ↑ Weitzner MA, Moncello J, Jacobsen PB, Minton S. (2002). "A pilot trial of paroxetine for the treatment of hot flashes and associated symptoms in women with breast cancer". Journal of Pain and Symptom Management 23 (4): 337–345. doi:10.1016/S0885-3924(02)00379-2. PMID 11997203. 
  12. ↑ Nemeroff CB, Evans DL, Gyulai L, Sachs GS, Bowden CL, Gergel IP, Oakes R, Pitts CD (2001). "Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression". The American journal of psychiatry 158 (6): 906–12. PMID 11384898. 
  13. ↑ Sachs GS, Nierenberg AA, Calabrese JR, Marangell LB, Wisniewski SR, Gyulai L, Friedman ES, Bowden CL, Fossey MD, Ostacher MJ, Ketter TA, Patel J, Hauser P, Rapport D, Martinez JM, Allen MH, Miklowitz DJ, Otto MW, Dennehy EB, Thase ME (2007). "Effectiveness of adjunctive antidepressant treatment for bipolar depression". N. Engl. J. Med. 356 (17): 1711–22. doi:10.1056/NEJMoa064135. PMID 17392295. 
  14. ↑ Vieta E, Martinez-Aran A, Goikolea JM, Torrent C, Colom F, Benabarre A, Reinares M (1999). "The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms". Pain 42 (2): 135–144. doi:10.1016/0304-3959(90)91157-E. PMID 2147235. 
  15. ↑ Langemark M, Olesen J (1994). "Sulpiride and paroxetine in the treatment of chronic tension-type headache. An explanatory double-blind trial". Headache 34 (1): 20–4. doi:10.1111/j.1526-4610.1994.hed3401020.x. PMID 8132436. 
  16. ↑ Mellerup, Erling T.; Plenge, Per (July 1986). "High affinity binding of3H-paroxetine and3H-imipramine to rat neuronal membranes". Psychopharmacology (Springer Berlin / Heidelberg) 89 (4): 436–439. doi:10.1007/BF02412117. http://www.springerlink.com/content/5888x32v705t336r/. 
  17. ↑ Golden RN, Nemeroff CB, McSorley P, Pitts CD, Dube EM. (2002). "Efficacy and tolerability of controlled-release and immediate-release paroxetine in the treatment of depression". Journal of Clinical Psychiatry 63 (7): 577–584. PMID 12143913. 
  18. ↑ "Press release, CHMP meeting on Paroxetine and other SSRIs". European Medicines Agency (2004-12-09). Retrieved on 2007-08-24.
  19. ↑ "Important Safety Information about Paxil CR" (HTML). GlaxoSmithKline.
  20. ↑ "Paroxetine hydrochloride (marketed as Paxil) Information: Persistent Pulmonary Hypertension". Food and Drug Administration (July 2006).
  21. ↑ Clayton, A; Keller A, McGarvey EL. (2006). "Burden of phase-specific sexual dysfunction with SSRIs". Journal of Affective Disorders 91: 27–32. doi:10.1016/j.jad.2005.12.007. PMID 16430968. 
  22. ↑ 22.0 22.1 22.2 Withdrawal from paroxetine can be severe, warns FDA - Tonks 324 (7332): 260 - BMJ
  23. ↑ 23.0 23.1 BBC NEWS | Health | Anti-depressant addiction warning
  24. ↑ Skaehill, Penny A.; Welch, E.B. (October 1997). "Clinical Reviews: SSRI Withdrawal Syndrome". American Society of Consultant Pharmacists. Retrieved on 2007-08-15.
  25. ↑ Yerevanian B, Koek R, Feusner J, Hwang S, Mintz J (2004). "Antidepressants and suicidal behaviour in unipolar depression". Acta Psychiatrica Scandinavica 110 (6): 452–8. doi:10.1111/j.1600-0447.2004.00437.x. PMID 15521830. 
  26. ↑ Haddad P (2001). "Antidepressant discontinuation syndromes". Drug Saf 24 (3): 183–97. doi:10.2165/00002018-200124030-00003. PMID 11347722. 
  27. ↑ "Quitpaxil.info". Frank W. Streicher. Retrieved on 2007-08-15.
  28. ↑ 28.0 28.1 USATODAY.com - Judge: Paxil ads can't say it isn't habit-forming
  29. ↑ Paxil (paroxetine hydrochloride) prescribing information
  30. ↑ ACOG Committee Opinion No. 354: Treatment with selective serotonin reuptake inhibitors during pregnancy. The American College of Obstetricians and Gynecologists. PMID 17138801. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17138801&query_hl=2&itool=pubmed_docsum. 
  31. ↑ Haddad, PM; Pal BR, Clarke P, Wieck A, Sridhiran S.. Neonatal symptoms following maternal paroxetine treatment: serotonin toxicity or paroxetine discontinuation syndrome?. PMID 16166193. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16166193&query_hl=6&itool=pubmed_docsum. 
  32. ↑ "Hoorman, et al. v. SmithKline Beecham Corp.: Paxil Pediatric Settlement". Retrieved on 2007-08-15.
  33. ↑ "The Litigation Group: Paxil Pediatric Settlement". Public Citizen. Retrieved on 2007-08-15.
  34. ↑ "The Chemistry of Happiness". The Guardian. Retrieved on 2007-09-09.
  35. ↑ Stayton, Jonathan (2008-01-22). "Punk rocker sues over anti-depressant", The Argus. Retrieved on 2008-01-23. 
  36. ↑ FDA Orders Strict Antidepressant Warnings
  37. ↑ NIMH · Antidepressant Medications for Children and Adolescents: Information for Parents and Caregivers
  38. ↑ 38.0 38.1 6abc.com: Child Suicide Rate Spikes Nearly 20 Percent 2/06/07
  39. ↑ Topic Galleries - chicagotribune.com
  40. ↑ Child And Adolescent Bipolar Disorder: Measurement
  41. ↑ "Secrets of the drug trials". BBC (2007-01-29). Retrieved on 2007-08-15.
  42. ↑ "Antidepressants may harm sperm". BBC (2008-09-24). Retrieved on 2008-09-25.

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