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.[26][27][28] 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.[29]
Anxiety disorders
Paroxetine was the first antidepressant approved in the United States for the treatment of panic disorder.[30][page needed] Several studies have concluded that paroxetine is superior to placebo in the treatment of panic disorder.[28][31]
Paroxetine has demonstrated efficacy for the treatment of social anxiety disorder in adults and children.[32][33] It is also beneficial for people with co-occurring social anxiety disorder and
alcohol use disorder.[34] It appears to be similar to a number of other SSRIs.[35]
Paroxetine is used in the treatment of obsessive-compulsive disorder.[36] Comparative efficacy of paroxetine is equivalent to that of
clomipramine and
venlafaxine.[37][38] Paroxetine is also effective for children with obsessive-compulsive disorder.[39]
Paroxetine is approved for treatment of PTSD in the United States, Japan, and Europe.[40][41][42] In the United States, it is approved for short-term use.[41]
Paroxetine is also FDA-approved for generalized anxiety disorder.[43]
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.[8] At the low dose used for menopausal hot flashes, side effects are similar to placebo and dose tapering is not required for discontinuation.[44]
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.[45][46]
Common side effects include drowsiness, dry mouth, loss of appetite, sweating, insomnia, and
sexual dysfunction.[7] Serious side effects may include suicide in those under the age of 25, serotonin syndrome, and
mania.[7] While the rate of side effects appears similar compared to other SSRIs and SNRIs, antidepressant discontinuation syndromes may occur more often.[9][10] Use in pregnancy is not recommended, while use during
breastfeeding is relatively safe.[11]
Paroxetine shares many of the common adverse effects of SSRIs, including (with the corresponding rates seen in people treated with placebo in parentheses):
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.[47] 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.[48]
Mania or
hypomania may occur in 1% of patients with depression and up to 12% of patients with
bipolar disorder.[50] 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.[51]
Suicide
Like other antidepressants, paroxetine may increase the risk of suicidal thinking and behaviour in people under the age of 25.[52][53] 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.[54] In 2015 a paper published in The BMJ that reanalysed the original case notes argued that in
Study 329,[55] 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.[56][57][58][59][60]
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%.[61] Symptoms of sexual dysfunction have been reported to persist after discontinuing SSRIs, although this is thought to be occasional.[62][63][64]
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).[65][66] 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.[67][68]
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.[69] 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.[70][71][72][73][74]
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.[75] 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.[76][77][78]
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.[79]
Paroxetine prescribing information posted at GlaxoSmithKline has been updated related to the occurrence of a discontinuation syndrome, including serious discontinuation symptoms.[69]
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.[80][81] Along with the other SSRIs,
sertraline and
fluoxetine, paroxetine is considered a low-risk drug in cases of overdose.[82]
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.[69]
Paroxetine is the most potent and one of the most specific selective
serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs).[87] It also binds to the
allosteric site of the serotonin transporter, similarly to
escitalopram, though less potently so.[88] Paroxetine also inhibits the reuptake of
norepinephrine to a lesser extent (<50 nmol/L).[89] 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.[83]
Paroxetine is well-absorbed following oral administration.[83] It has an absolute
bioavailability of about 50%, with evidence of a saturable
first pass effect.[93] When taken orally, it achieves maximum concentration in about 6–10 hours[83] and reaches steady-state in 7–14 days.[93] Paroxetine exhibits significant interindividual variations in volume of distribution and clearance.[93] Less than 2% of an oral dose is excreted in urine unchanged.[93]
Paroxetine is a mechanism-based inhibitor of
CYP2D6.[86][94]
Society and culture
Paroxetine was approved for medical use in the United States in 1992 and initially sold by
GlaxoSmithKline.[7][95] It is available as a
generic medication.[14] In 2021, it was the 95th most commonly prescribed medication in the United States, with more than 7million prescriptions.[15][16]
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.[18][19]
In early 2004, GSK agreed to settle charges of consumer fraud for $2.5 million.[96] 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".[97]
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.[18][19][20]
In 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.[98] On 18 April 2016, appeals were lodged with the
Competition Appeal Tribunal by the companies which were fined.[99][100][101][102][103]
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.[104]
Economics
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.[105] In 2007, sales had dropped slightly to 18.1 million but paroxetine remained the fifth-most prescribed antidepressant in the U.S.[106][107]
Brand names
Brand names include Aropax, Paretin, Brisdelle, Deroxat, Paxil,[108][109] Pexeva, Paxtine, Paxetin, Paroxat, Paraxyl,[110] 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).[111][112][113] 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.[113]
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.[118]
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.[84][85][119]
Paroxetine is a common finding in waste water.[121] It is highly toxic to the alga Pseudokirchneriella subcapitata (syn. Raphidocelis subcapitata).[121]
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