A variety of meta-analyses have been conducted to evaluate the efficacy of paroxetine in depression. They have variously concluded that paroxetine is superior to placebo and that it is equivalent to other antidepressants.[22][23][24] 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.[25]
Paroxetine was the first antidepressant approved in the United States for the treatment of panic disorder.[26][page needed] Several studies have concluded that paroxetine is superior to placebo in the treatment of panic disorder.[24][27]
Paroxetine has demonstrated efficacy for the treatment of social anxiety disorder in adults and children.[28][29] It is also beneficial for people with co-occurring social anxiety disorder andalcohol use disorder.[30] It appears to be similar to a number of other SSRIs.[31]
Paroxetine is used in the treatment of obsessive-compulsive disorder.[32] Comparative efficacy of paroxetine is equivalent to that ofclomipramine andvenlafaxine.[33][34] Paroxetine is also effective for children with obsessive-compulsive disorder.[35]
Paroxetine is approved for the treatment of PTSD in the United States, Japan, and Europe.[36][37][38] In the United States, it is approved for short-term use.[37]
Paroxetine is also FDA-approved for generalized anxiety disorder.[39]
In 2013, low-dose paroxetine was approved in the US for the treatment of moderate-to-severevasomotor symptoms such as hot flashes andnight sweats associated with menopause.[7] At the low dose used for menopausal hot flashes, side effects are similar to placebo and dose tapering is not required for discontinuation.[40]
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.[41][42]
Common side effects include drowsiness, dry mouth, loss of appetite, sweating, insomnia, andsexual dysfunction.[6] Serious side effects may include suicide in those under the age of 25,serotonin syndrome, andmania.[6] While the rate of side effects appears similar compared to other SSRIs and SNRIs, antidepressant discontinuation syndromes may occur more often.[8][9] Use in pregnancy is not recommended, while use duringbreastfeeding is relatively safe.[10]
The Federal Aviation Administration (FAA), the U.S. agency responsible for regulating civil aviation, considers paroxetine to be an antidepressant medication that is ineligible for an FAA Authorization of Special Issuance (SI) or Special Consideration (SC) of amedical certificate.[43]
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 peripheral5-HT3 receptor stimulation is believed to result in the gastrointestinal effects observed with SSRI treatment.[44] 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.[45]
Mania orhypomania may occur in 1% of patients with depression and up to 12% of patients withbipolar disorder.[47] 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.[48]
Paroxetine is described as a 'hepatoxic agent'[49] and has been associated with hepatoxicity and jaundice.[50]
Like other antidepressants, paroxetine may increase the risk of suicidal thinking and behaviour in people under the age of 25.[51][52] TheFDA 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.[53] In 2015, a paper published inThe BMJ that reanalysed the original case notes argued that inStudy 329,[54] assessing paroxetine andimipramine against placebo in adolescents with depression, the incidence of suicidal behavior had been under-reported and the efficacy exaggerated for paroxetine.[55][56][57][58][59]
Sexual dysfunction, including loss oflibido,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%.[60] Symptoms of sexual dysfunction have been reported to persist after discontinuing SSRIs, although this is thought to be occasional.[61][62][63]
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 lowerApgar scores (by <0.4 points).[64][65] TheAmerican 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 ofbirth defects.[66][67]
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.[68] 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.[69][70][71][72][73]
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.[74] Common withdrawal symptoms for paroxetine include nausea, dizziness, lightheadedness and vertigo; insomnia, nightmares, and vivid dreams; feelings of electricity in the body, as well asrebound depression and anxiety. A 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 tofluoxetine, which has a longerhalf-life and thus decreases the severity of discontinuation syndrome.[75][76][77]
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", theInternational Federation of Pharmaceutical Manufacturers Associations said GSK had breached two of the federation's codes of practice.[78]
Paroxetine prescribing information posted at GlaxoSmithKline has been updated related to the occurrence of a discontinuation syndrome, including serious discontinuation symptoms.[68]
Acute overdosage is often manifested byvomiting,lethargy,ataxia,tachycardia, andseizures. 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.[79][80] Along with the other SSRIs,sertraline andfluoxetine, paroxetine is considered a low-risk drug in cases of overdose.[81]
Interactions with other drugs acting on the serotonin system or impairing the metabolism of serotonin may increase the risk ofserotonin syndrome orneuroleptic malignant syndrome (NMS)-like reaction. Such reactions have been observed with SNRIs and SSRIs alone, but particularly with concurrent use oftriptans,MAO inhibitors, antipsychotics, or other dopamine antagonists.
The prescribing information states that paroxetine should "not be used in combination with anMAOI (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 withpimozide,thioridazine,tryptophan, orwarfarin.[68]
Paroxetine is the most potent and one of the most specific selectiveserotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs).[86] It also binds to theallosteric site of the serotonin transporter, similarly toescitalopram, though less potently so.[87] Paroxetine also inhibits the reuptake ofnorepinephrine to a lesser extent (<50 nmol/L).[88] 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 theprefrontal cortex.[82] Paroxetine is a phenylpiperidine and might have some affinity for opioid receptors.[89][90]
Paroxetine is well-absorbed following oral administration.[82] It has an absolutebioavailability of about 50%, with evidence of a saturablefirst pass effect.[93] When taken orally, it achieves maximum concentration in about 6–10 hours[82] 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 ofCYP2D6.[85][94]
GlaxoSmithKline has paid substantial fines, paid settlements inclass-action lawsuits, and become the subject of several highly critical books about its marketing of paroxetine, in particular, theoff-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 the use of the drug.[97][98]
In 2004, GSK agreed to settle charges of consumer fraud for $2.5 million.[99] Thelegal 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".[100]
In 2012, theUnited States Department of Justice finedGlaxoSmithKline $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 trialstudy 329.[97][98][101]
In February 2016, the UKCompetition and Markets Authority imposed record fines of £45 million on companies that were found to have infringedEuropean Union and UK Competition law by entering into agreements to delay the market entry ofgeneric versions of the drug in the UK.GlaxoSmithKline received the bulk of the fines, being fined £37,600,757. Other companies that 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 generic manufacturers who incurred losses as a result of the anticompetitive conduct.[102] In April 2016, appeals were lodged with theCompetition Appeal Tribunal by the companies which were fined.[103][104][105][106][107]
GSK marketed paroxetine through television advertisements in the 1990s and 2000s. Commercials also aired for the CR version of the drug beginning in 2003.[108]
In 2007, paroxetine was ranked 94th on thelist 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.[109] In 2007, sales had dropped slightly to 18.1 million but paroxetine remained the fifth-most prescribed antidepressant in the U.S.[110][111]
Several studies have suggested that paroxetine can be used in the treatment ofpremature ejaculation. In particular, intravaginal ejaculation latency time (IELT) was found to increase 6- to 13-fold, which was somewhat longer than the delay achieved by the treatment with other SSRIs (fluvoxamine, fluoxetine, sertraline, and citalopram).[115][116][117] 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 toclomipramine, which induced a fourfold delay.[117]
Although the evidence is conflicting, paroxetine may be effective for the treatment ofdysthymia, a chronic disorder involving depressive symptoms for most days of the year.[122]
There is evidence to support that paroxetine selectively binds to and inhibitsG protein-coupled receptor kinase 2 (GRK2) in mice with heart failure. Since GRK2 regulates the activity of the betaadrenergic receptor, which becomes desensitized in cases ofheart failure, paroxetine (or a paroxetine derivative) could be used as a heart failure treatment in the future.[83][84][123]
Paroxetine may be useful in the treatment of canine or feline behavioral diagnoses and is effective in the treatment of social anxiety, depression, and agitation associated with depression.[125]
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