Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline. Generic formulations have been available since 2003 when the patent expired. In both adults and children the efficacy of paroxetine for depression is comparable to that of placebo. Differences with newer antidepressants are subtler and mostly confined to side effects. It shares the common side effects and contraindications of other SSRIs, with high rates of nausea, somnolence, and sexual side effects. Paroxetine is associated with clinically significant weight gain. Discontinuing paroxetine is associated with a high risk of withdrawal syndrome. Because of the increased risk of birth defects, pregnant women or women planning to become pregnant are recommended to stop the medication if possible.
Paroxetine was the first antidepressant formally approved in the United States for the treatment of panic attacks.
When both published and unpublished trials are looked at, paroxetine does not appear to be any better than placebo in adults with moderate or severe depression. Overall the available evidence does not support the efficacy of paroxetine in children, although one positive randomised double-blind placebo-controlled clinical trial in children does exist. In 1999 paroxetine was the second SSRI (after fluvoxamine) to be approved in Japan. The efficacy of paroxetine is significantly inferior to sertraline, escitalopram, mirtazapine and venlafaxine.
Menopausal hot flashes
On June 28, 2013 U.S. FDA approved low dose paroxetine mesylate – for the treatment of moderate-to-severe vasomotor symptoms (e.g. hot flashes and night sweats) associated with menopause. Paroxetine became the first and only non-hormonal prescription therapy for menopausal hot flashes approved by FDA.
The American College of Obstetricians and Gynecologists recommends that for pregnant women and women planning to become pregnant, "treatment with all SSRIs or selective norepinephrine reuptake inhibitors or both during pregnancy be individualized and paroxetine use among pregnant women or women planning to become pregnant be avoided, if possible." According to the prescribing information "epidemiological studies have shown that infants born to women who had first trimester paroxetine exposure had an increased risk of cardiovascular malformations, primarily ventricular and atrial septal defects (VSDs and ASDs). In general, septal defects range from those that are symptomatic and may require surgery to those that are asymptomatic and may resolve spontaneously. If a patient becomes pregnant while taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant. For women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after consideration of the other available treatment options." These conclusions are supported by multiple systematic reviews and meta-analyses that found that, on average, the use of paroxetine during pregnancy is associated with about 1.5–1.7-fold increase in congenital birth defects, in particular, heart defects. A recent non-systematic review, reporting to have received support from GSK, came to a different conclusion: "the teratogenic potential of paroxetine that has been reported in some studies remains unproven". Other reviews vary on whether the teratogenic risks outweigh the risk of disease relapse if the drug is discontinued: some advocate discontinuation, while others suggest caution; even where the overview of antidepressants generally is favorable, paroxetine is singled out for specific risks. Paroxetine use during pregnancy increases the risk of spontaneous abortion.
A large 2010 study — using the Swedish Medical Birth Register (MBR) from 1 July 1995 up to 2007 identified women who reported the use of antidepressants in early pregnancy or were prescribed antidepressants during pregnancy by antenatal care — found a specific association between Paxil use and infant cardiovascular defects. A strong association between Paxil and hypospadias was also concluded in this study, though the researchers concluded that it is not clear if these effects were due to drug use or underlying pathology.
Abrupt discontinuation of psychotropic drugs during pregnancy can also lead to serious adverse effects.
Paroxetine shares many of the common adverse effects of SSRIs, including: nausea (15–24%), diarrhoea (10–15%), constipation (10–15%), dry mouth (15–20%), somnolence (20–25%), insomnia (11–24%), headache (17%), hypomania (a dangerously elated/irritable mood; 0.3–2.2%), blurred vision (5–10%), loss of appetite (5–10%), nervousness (2–5%), paraesthesia (2–5%), dizziness (10–15%), asthenia (weakness; 10–15% incidence), tremor (10–15%), anxiety (5–10%), sweating (10–15%) and sexual dysfunction (≥10% incidence). Most of these adverse effects are transient and go away with continued treatment. Excess 5-HT2 receptor stimulation in the brain results in the increased anxiety, insomnia, reduced libido and irritability. Excess 5-HT2receptor stimulation in the spinal cord results in the physical (as opposed to psychological, namely reductions in libido) aspects of sexual dysfunction such as erectile dysfunction, ejaculatory delay and anorgasmia (trouble achieving orgasm). Central and peripheral 5-HT3 receptor stimulation is believed to result in the gastrointestinal effects observed with SSRI treatment. Compared to other SSRIs it has a lower incidence of diarrhoea, a higher incidence of anticholinergic effects (e.g. dry mouth, constipation, blurred vision, etc.), sedation/somnolence/drowsiness, sexual side effects and weight gain.
Sexual side effects often include difficulty becoming aroused, lack of interest in sex, and anorgasmia. Genital anaesthesia, loss of or decreased response to sexual stimuli, and ejaculatory anhedonia are also possible. Although usually reversible, these sexual side effects can last for months or years after the drug has been completely withdrawn. This is known as post SSRI sexual dysfunction.
On 9 December 2004, the European Medicines Agency's (EMEA) Committee for Medicinal Products for Human Use (CHMP) informed patients, prescribers, and parents that paroxetine should not be prescribed to children. CHMP also gave a warning to prescribers recommending close monitoring of adult patients at high risk of suicidal behaviour and/or suicidal thoughts. CHMP does not prohibit use of paroxetine with high risk adults but urges extreme caution. Due to reports of adverse withdrawal reactions upon terminating treatment, CHMP recommends to reduce gradually over several weeks or months if the decision to withdraw is made. See also Discontinuation syndrome (withdrawal).
Schmitt et al. (2001) suggested that paroxetine negatively affects long-term memory, but not short-term, although the result has not been independently verified. In their study, healthy participants given paroxetine for 14 days (20 mg for days 1–7 and 40 mg days 8–14) showed poorer recall of words on day 14 compared to those receiving a placebo. Serotonin reuptake inhibitors, like paroxetine, may also impair vigilance, perhaps by interacting with the 5-HT2C receptors which regulate the release of dopamine in the prefrontal cortex.
Paroxetine may increase the risk of suicidal ideation and suicidal behaviour in children and adolescents. Because suicide is rare, it is difficult to test its relationship with the use of paroxetine. Some studies instead analyze suicidality, which generally refers to suicidal ideation and suicidal behaviour. The FDA conducted a statistical analysis of paroxetine clinical trials in children and adolescents in 2004, finding an increase in "suicidality" and ideation as compared to placebo; the trend for increased "suicidality" was observed in both trials for depression and for anxiety disorders. A University of North Carolina review of SSRIs found the average risk of suicide among adolescents was 4%, versus 2% on placebo, and among all patients "the greatest risk of self-harm was among paroxetine users."
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 withdrawal syndrome of any medication of its class. 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 crying 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.
In addition, The Lancet published an analysis of World Health Organization data showing SSRIs taken during pregnancy may cause withdrawal symptoms, including convulsions, in newborn children: among "93 suspected cases of SSRI-induced neonatal withdrawal syndrome...64 were associated with paroxetine, 14 with fluoxetine, nine with sertraline, and seven with citalopram."
The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including treatment with PAXIL, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs that impair metabolism of serotonin (including MAOIs), or with 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.
CYP2D6 for which it is both a substrate and a potent inhibitor. Its interaction with theCYP2D6 substrate (which is activated by CYP2D6 into its pharmacologically active form) and breast cancer medication,tamoxifen, is so great that the risk of mortality from breast cancer is increased by 24–91% (depending on the time and extent of coexposure) in patients coadministered paroxetine during tamoxifen treatment.
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 200–2000 μg/L in poisoned patients. Postmortem blood levels have ranged from 1–4 mg/L in acute lethal overdose situations. It is usually considered, along with the other SSRIs, sertraline and fluoxetine to be a low-risk drug in cases of overdose.
Paroxetine is the most potent and one of the most specific selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRI). It also binds to the allosteric site of the serotonin transporter, similarly, but less potently than escitalopram. This activity of the drug on brain neurons is thought to be responsible for its antidepressant effects. Paroxetine inhibits the reuptake of norepinephrine more than the other SSRIs, just as sertraline inhibits the reuptake of dopamine more than the other SSRIs.
Paroxetine has been shown to have antimicrobial activity against several groups of microorganisms, mainly Gram positive microorganisms. It also shows synergistic activity when combined with some antibiotics against several bacteria. Additionally, paroxetine has demonstrated antifungal activity, being most potent against the hypersusceptible Candida albicans strain DSY1204.
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.
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 license 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." Paroxetine prescribing information posted at GlaxoSmithKline now acknowledges the occurrence of a discontinuation syndrome, including serious discontinuation symptoms.
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, after GSK had specifically advertised the drug as non-habit forming.
In February 1998, 60-year-old Donald Schell was diagnosed with an anxiety state and placed on Paxil. Within forty-eight hours of being put on Paxil Schell killed his wife, daughter, infant granddaughter, and himself. Tim Tobin, Schell’s son-in-law, took legal action against SmithKline Beecham. Psychiatrist David Healy was retained as an expert witness in the case. The Tobin case was heard in Cheyenne, Wyoming from May 21 to June 6, 2001. On the stand SmithKline Beecham representative Ian Hudson indicated that no matter how many physicians or clinicians reported to the company that they thought suicide was related to the Paxil, SmithKline Beecham would deny causation. The jury returned a guilty verdict against SmithKline Beecham and awarded Tobin $6.4 million. This was the first verdict returned guilty against a pharmaceutical company regarding adverse behavioral effects of a psychotropic drug".
In 2001, GSK increased its American TV advertising of Paxil after the September 11 attacks; in October 2001, GSK spent nearly twice as much as in October 2000. The difficulty of withdrawal from paroxetine, and GSK's concealment of it, was later reported on ABC.
Since 2001 in the UK, 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.
In early 2004, GSK agreed to settle charges of consumer fraud for $2.5 million (a tiny fraction of the over $2.7 billion in yearly Paxil sales at that time). The legal discovery process also uncovered evidence of deliberate, systematic suppression of unfavorable Paxil research results. One of GSK's internal documents had said, "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".
In June 2004, FDA published a violation letter to GSK in response to a "false or misleading" TV ad for Paxil CR; FDA stated, "This ad is concerning from a public health perspective because it broadens the use of Paxil CR [beyond the conditions it was approved for] while also minimizing the serious risks associated with the drug." GSK claimed the ad had been previously reviewed by FDA, but said the ad would not run again.
On January 29, 2007, the BBC broadcast a fourth documentary in its Panorama series about the drug Seroxat. 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. Results from Study 329, one of the trials, were reported in a way that misled readers about paroxetine's safety and efficacy, and contributed to repeated distortions in the assessment of the drug's value in paediatric depression in the scientific literature.[unreliable source?]
The court documents released as a result of one of the lawsuits in October 2008 indicated that GSK "and/or researchers may have suppressed or obscured suicide risk data during clinical trials" of paroxetine. One of the investigators, "Charles Nemeroff, former chairman of the Department of Psychiatry at Emory University, was the first big name 'outed' ...In early October 2008, Nemeroff stepped down as department chair amid revelations that he had received over $960,000 from GSK in 2006, yet reported less than $35,000 to the school. Subsequent investigations revealed payments totaling more than $2.5 million from drug companies between 2000 and 2006, yet only a fraction was disclosed."
In 2012 the U.S. Justice Department announced that GSK had agreed to plead guilty and pay a $3 billion fine, in part for promoting the use of Paxil for children.
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 United States retail market, with more than 19.7 million prescriptions. In 2007, sales had dropped slightly to 18.1 million but paroxetine remained the fifth-most prescribed antidepressant in the U.S.
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 6–13-fold, which was somewhat longer than the delay achieved by the treatment with other SSRIs (fluvoxamine, fluoxetine, sertraline, and citalopram). 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. The reason it causes a delay in ejaculation is because it greatly reduces sex drive, in some cases, causing an inability to gain an erection or ejaculate. SSRIs are also effective in the treatment of severe premenstrual syndrome; however, paroxetine is contraindicated in women who may become pregnant due to its teratogenicity and its high risk of withdrawal syndrome in both adults and neonates. See Paroxetine and pregnancy.
^ abBarbui, C; Furukawa, TA; Cipriani, A (2008 Jan 29). "Effectiveness of paroxetine in the treatment of acute major depression in adults: a systematic re-examination of published and unpublished data from randomized trials". CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne178 (3): 296–305. doi:10.1503/cmaj.070693. PMC2211353. PMID18227449.Check date values in: |date= (help)
^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 Psychopharmacology19 (6): 567–596. doi:10.1177/0269881105059253. PMID16272179.
^Turner, Francis Joseph (2005). Social Work Diagnosis in Contemporary Practice. Oxford University Press US. ISBN0-19-516878-X.
^Moreno, C; Roche, AM; Greenhill, LL (October 2006). "Pharmacotherapy of Child and Adolescent Depression". Child and Adolescent Psychiatric Clinics of North America15 (4): 977–998. doi:10.1016/j.chc.2006.05.006. PMID16952771.
^Higuchi, T; Briley, M (February 2007). "Japanese experience with milnacipran, the first serotonin and norepinephrine reuptake inhibitor in Japan". Neuropsychiatric Disease and Treatment3 (1): 41–58. doi:10.2147/NDT.S. PMC2654524. PMID19300537.
^ abBellantuono C, Migliarese G, Gentile S (2007). "Serotonin reuptake inhibitors in pregnancy and the risk of major malformations: a systematic review". Hum Psychopharmacol22 (3): 121–8. doi:10.1002/hup.836. PMID17397101.
^Bar-Oz B, Einarson T, Einarson A, et al (May 2007). "Paroxetine and congenital malformations: meta-Analysis and consideration of potential confounding factors". Clin Ther29 (5): 918–26. doi:10.1016/j.clinthera.2007.05.003. PMID17697910.
^Gentile S, Bellantuono C (March 2009). "Selective serotonin reuptake inhibitor exposure during early pregnancy and the risk of fetal major malformations: focus on paroxetine". J Clin Psychiatry70 (3): 414–22. doi:10.4088/JCP.08r04468. PMID19254517.
^ abReis M, Kallen B (2010). "Delivery outcome after maternal use of antidepressant drugs in pregnancy: an update using Swedish data". Psychological Medicine40 (10): 1723–33. doi:10.1017/S0033291709992194. PMID20047705.
^Ramasubbu R (2004). "Antidepressant treatment-associated behavioural expression of hypomania: a case series". Prog. Neuropsychopharmacol. Biol. Psychiatry28 (7): 1201–7. doi:10.1016/j.pnpbp.2004.06.015. PMID15610935.
^Nishida T, Wada M, Wada M, Ito H, Narabayashi M, Onishi H (2008). "Activation syndrome caused by paroxetine in a cancer patient". Palliat Support Care6 (2): 183–5. doi:10.1017/S1478951508000278. PMID18501054.
^Ochiai Y, Katsu H, Okino S, Wakutsu N, Nakayama K (2003). "[Case of prolonged recovery from serotonin syndrome caused by paroxetine]". Seishin Shinkeigaku Zasshi (in Japanese) 105 (12): 1532–8. PMID15027311.
^Terao T, Hikichi T (2007). "Serotonin syndrome in a case of depression with various somatic symptoms: the difficulty in differential diagnosis". Prog. Neuropsychopharmacol. Biol. Psychiatry31 (1): 295–6. doi:10.1016/j.pnpbp.2006.07.007. PMID16916568.
^Kelly CM, Juurlink DN, Gomes T,et al. (2010). "Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study". BMJ340: c693. doi:10.1136/bmj.c693. PMC2817754. PMID20142325.
^Goeringer KE, Raymon L, Christian GD, Logan BK (May 2000). "Postmortem forensic toxicology of selective serotonin reuptake inhibitors: a review of pharmacology and report of 168 cases". J. Forensic Sci.45 (3): 633–48. PMID10855970.
^R. Baselt,Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1190–1193.
^Mansari, ME; Wiborg, O; Mnie-Filali, O; Benturquia, N; Sánchez, C; Haddjeri, N (February 2007). "Allosteric modulation of the effect of escitalopram, paroxetine and fluoxetine: in-vitro and in-vivo studies". The International Journal of Neuropsychopharmacology10 (1): 31–40. doi:10.1017/S1461145705006462. PMID16448580.
^Roth, BL; Driscol, J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 22 November 2013.
^Munoz-Bellido JL, Munoz-Criado S, Garcìa-Rodrìguez JA (2000). "Antimicrobial activity of psychotropic drugs: selective serotonin reuptake inhibitors". Int. J. Antimicrob. Agents14 (3): 177–80. doi:10.1016/S0924-8579(99)00154-5. PMID10773485.
^Young TJ, Oliver GP, Pryde D, Perros M, Parkinson T (2003). "Antifungal activity of selective serotonin reuptake inhibitors attributed to non-specific cytotoxicity". J. Antimicrob. Chemother.51 (4): 1045–7. doi:10.1093/jac/dkg184. PMID12654745.
^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 Psychiatry63 (7): 577–584. doi:10.4088/JCP.v63n0707. PMID12143913.
^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". Drug Topics. February 18, 2008. Retrieved 2008-10-23.
^Waldinger MD, Hengeveld MW, Zwinderman AH, Olivier B (August 1998). "Effect of SSRI antidepressants on ejaculation: a double-blind, randomized, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine, and sertraline". Journal of Clinical Psychopharmacology18 (4): 274–81. doi:10.1097/00004714-199808000-00004. PMID9690692.
^Waldinger MD, Zwinderman AH, Olivier B (2001). "SSRIs and ejaculation: a double-blind, randomized, fixed-dose study with paroxetine and citalopram". Journal of Clinical Psychopharmacology21 (6): 556–60. doi:10.1097/00004714-200112000-00003. PMID11763001.
^ abWaldinger 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. PMID15363569.
^Brown J, O' Brien PM, Marjoribanks J, Wyatt K (2009). "Selective serotonin reuptake inhibitors for premenstrual syndrome". In Brown, Julie. Cochrane Database Syst Rev (2): CD001396. doi:10.1002/14651858.CD001396.pub2. PMID19370564.
^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 Psychiatry63 (6): 501–7. doi:10.4088/JCP.v63n0606. PMID12088161.
^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 Management23 (4): 337–345. doi:10.1016/S0885-3924(02)00379-2. PMID11997203.
^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". Pain42 (2): 135–144. doi:10.1016/0304-3959(90)91157-E. PMID2147235.
^Gartlehner G, Gaynes BN, Hansen RA, et al. (November 2008). "Comparative benefits and harms of second-generation antidepressants: background paper for the American College of Physicians". Ann. Intern. Med.149 (10): 734–50. doi:10.7326/0003-4819-149-10-200811180-00008. PMID19017592.
Wikimedia Commons has media related to Paroxetine.