Paroxetine

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Paroxetine
Paroxetine-2D-skeletal.svg
Paroxetine-3D-balls.png
Systematic (IUPAC) name
(3S,4R)-3-[(2H-1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine
Clinical data
Trade names Paxil, Pexeva, Seroxat, Brisdelle, Rexetin
AHFS/Drugs.com monograph
MedlinePlus a698032
Licence data US FDA:link
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: ℞-only
  • ℞ (Prescription only)
Routes of
administration		 Oral
Pharmacokinetic data
Bioavailability Extensively absorbed from the GI tract, but extensive first-pass metabolism in the liver[1][2][3][4]
Protein binding 93–95%[1][2][3]
Metabolism Extensive, hepatic (mostly CYP2D6-mediated)[1][2][3]
Biological half-life 21 hours[1][2][3]
Excretion Renal (64%; 2% unchanged and 62% as metabolites), Faecal (36%; <1% unchanged)[1][2][3]
Identifiers
CAS Number 61869-08-7 YesY
ATC code N06AB05
PubChem CID: 43815
IUPHAR/BPS 4790
DrugBank DB00715 YesY
ChemSpider 39888 YesY
UNII 41VRH5220H YesY
KEGG D02362 YesY
ChEBI CHEBI:7936 N
ChEMBL CHEMBL490 YesY
Chemical data
Formula C19H20FNO3
Molecular mass 329.3 g/mol
 N (what is this?)  (verify)

Paroxetine (also known by the trade names Paxil and Seroxat, among others) is an antidepressant drug of the selective serotonin reuptake inhibitor (SSRI) type. Paroxetine is used to treat major depression, obsessive-compulsive disorder, panic disorder, social anxiety, posttraumatic stress disorder, generalized anxiety disorder and vasomotor symptoms (e.g. hot flashes and night sweats) associated with menopause[5][6] in adult outpatients.

Differences between newer antidepressants are usually fairly subtle and mostly confined to side effects. Paroxetine shares the common side effects and contraindications of other SSRIs.[7] Discontinuing paroxetine is associated with a high (7%) risk of withdrawal syndrome.[8][9] It may be associated with a slightly increased risk of birth defects.[10][11][12] Several studies have associated paroxetine with suicidal thinking and behavior in teenagers.[13]

Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, known since 2000 as GlaxoSmithKline. Generic formulations have been available since 2003 when the patent expired.[14] The United States Department of Justice fined GlaxoSmithKline $3 billion in 2012, including a sum for withholding data on paroxetine, unlawfully promoting it for the under-18s, and preparing an article, following one of its clinical trials, study 329, that misleadingly reported the drug was effective in treating adolescent depression.[n 1]

Medical uses[edit]

Paroxetine is primarily used to treat major depression, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), panic disorder, generalized anxiety disorder (GAD),[18] social phobia/social anxiety disorder,[19] premenstrual dysphoric disorder (PMDD)[20] and menopausal hot flashes.

Paroxetine was the first antidepressant formally approved in the United States for the treatment of panic attacks.[21]

Depression[edit]

A variety of meta analyses have been conducted to evaluate the efficacy of paroxetine in depression. They have variously concluded that paroxetine is superior[22][23][24] or equivalent[25] to placebo and that it is equivalent[26][27] or inferior[28] to other antidepressants.

Menopausal hot flashes[edit]

On June 28, 2013 U.S. FDA approved low dose paroxetine for the treatment of moderate-to-severe vasomotor symptoms (e.g. hot flashes and night sweats) associated with menopause.[29] Randomized controlled trials have shown modest relief in such cases. At the low dose used for menopausal hot flashes side effects are similar to placebo and dose tapering is not required for discontinuation.[30]

Adverse effects[edit]

See also: List of adverse effects of paroxetine

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%) and sexual dysfunction (≥10% incidence).[4] 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.[31] 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.[32]

Due to reports of adverse withdrawal reactions upon terminating treatment, the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency recommends to reduce gradually over several weeks or months if the decision to withdraw is made.[33] 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.[34] This side effect can occur in individuals with no history of mania but it may be more likely to occur in those with bipolar or with a family history of mania.[35]

Suicide[edit]

Like other antidepressants, paroxetine may increase the risk of suicidal thinking and behaviour in children and adolescents.[36][37] 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.[38] In 2015 a paper published in the BMJ that reanalysed the original case notes, argued that in Study 329,[39] assessing paroxetine and imipramine against placebo in adolescents with depression, the incidence of suicidal behavior had been under-reported and efficacy exaggerated for paroxetine.[40]

Pregnancy[edit]

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."[10] According to the prescribing information[41] "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." 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.[42][43][44][45][46]

Discontinuation syndrome[edit]

See also: 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 withdrawal syndrome of any medication of its class.[47][medical citation needed] 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.[medical citation needed] 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.[8][48][49]

Overdose[edit]

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.[50][51] It is usually considered, along with the other SSRIs, sertraline and fluoxetine to be a low-risk drug in cases of overdose.[52]

Interactions[edit]

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.[41]

Paroxetine interacts with the following cytochrome P450 enzymes:[32]

Pharmacology[edit]

Paroxetine is the most potent and one of the most specific selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs).[53] It also binds to the allosteric site of the serotonin transporter, similarly, but less potently than escitalopram.[54] 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.[32]

Its affinities are as follows:[55][31]

Society and culture[edit]

GlaxoSmithKline has paid substantial fines, paid settlements in class action lawsuits, and become the subject of several highly critical books in relation to 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][17]

Withdrawal symptoms[edit]

In 2002 the U.S. FDA published a warning regarding "severe" discontinuation symptoms among those terminating paroxetine treatment, including paraesthesia, bad dreams, 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.[9]

Paroxetine prescribing information posted at GlaxoSmithKline now acknowledges the occurrence of a discontinuation syndrome, including serious discontinuation symptoms.[41]

Off-label marketing for children[edit]

See also: Study 329

In early 2004, GSK agreed to settle charges of consumer fraud for $2.5 million.[56] 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".[57]

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.[58]

Sales[edit]

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.[59] In 2007, sales had dropped slightly to 18.1 million but paroxetine remained the fifth-most prescribed antidepressant in the U.S.[60][61]

Trade names[edit]

Aropax, Brisdelle, Deroxat, Paxil,[62] Pexeva, Paxtine, Paxetin, Paroxat, Paraxyl,[63] Sereupin and Seroxat.

Research[edit]

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).[64][65][66] 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.[66]

There is also evidence that paroxetine may be effective in the treatment of compulsive gambling[67] and hot flashes.[68]

Benefits of paroxetine prescription for diabetic neuropathy[69] or chronic tension headache[70] 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.[71]

Notes[edit]

  1. ^ United States Department of Justice, July 2012: "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."[15][16][17]

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