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Paroxetine

An Update of Its Use in Psychiatric Disorders in Adults

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Summary

Abstract

Paroxetine is a selective serotonin reuptake inhibitor (SSRI), with antidepressant and anxiolytic activity.

In 6- to 24-week well designed trials, oral paroxetine 10 to 50 mg/day was significantly more effective than placebo, at least as effective as tricyclic antidepressants (TCAs) and as effective as other SSRIs and other antidepressants in the treatment of major depressive disorder. Relapse or recurrence over 1 year after the initial response was significantly lower with paroxetine 10 to 50 mg/day than with placebo and similar to that with imipramine 50 to 275 mg/day.

The efficacy of paroxetine 10 to 40 mg/day was similar to that of TCAs and fluoxetine 20 to 60 mg/day in 6- to 12-week trials in patients aged ≥60 years with major depression. Paroxetine 10 to 40 mg/day improved depressive symptoms to an extent similar to that of TCAs in patients with comorbid illness, and was more effective than placebo in the treatment of dysthymia and minor depression.

Paroxetine 20 to 60 mg/day was more effective than placebo after 8 to 12 weeks’ treatment of obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder (social phobia), generalised anxiety disorder (GAD) and post-traumatic stress disorder (PTSD). Improvement was maintained or relapse was prevented for 24 weeks to 1 year in patients with OCD, panic disorder, social anxiety disorder or GAD. The efficacy of paroxetine was similar to that of other SSRIs in patients with OCD and panic disorder and similar to that of imipramine but greater than that of 2′chlordesmethyldiazepam in patients with GAD.

Paroxetine is generally well tolerated in adults, elderly individuals and patients with comorbid illness, with a tolerability profile similar to that of other SSRIs. The most common adverse events with paroxetine were nausea, sexual dysfunction, somnolence, asthenia, headache, constipation, dizziness, sweating, tremor and decreased appetite.

In conclusion, paroxetine, in common with other SSRIs, is generally better tolerated than TCAs and is a first-line treatment option for major depressive disorder, dysthymia or minor depression. Like other SSRIs, paroxetine is also an appropriate first-line therapy for OCD, panic disorder, social anxiety disorder, GAD and PTSD. Notably, paroxetine is the only SSRI currently approved for the treatment of social anxiety disorder and GAD, which makes it the only drug of its class indicated for all five anxiety disorders in addition to major depressive disorder. Thus, given the high degree of psychiatric comorbidity of depression and anxiety, paroxetine is an important first-line option for the treatment of major depressive disorder, OCD, panic disorder, social anxiety disorder, GAD and PTSD.

Pharmacodynamic Properties

Paroxetine is a potent and selective inhibitor of presynaptic serotonin reuptake and enhances serotonergic neurotransmission by prolonging serotonin activity at its postsynaptic receptors. Paroxetine is a moderate inhibitor of noradrenaline (norepinephrine) and a weak inhibitor of dopamine transporters in human brain tissue in vitro.

In healthy volunteers, paroxetine 30 mg/day has a suppressant effect on rapid eye movement (REM) sleep; it reduces the number of REM phases and prolongs REM latency. However, available data on sleep efficiency are equivocal. Although there were no significant changes associated with sleep efficiency in one study, it was significantly lowered compared with baseline values in another study.

Paroxetine 20 mg/day had little appreciable effect on psychomotor activity in healthy volunteers, and paroxetine 30 mg/day did not potentiate alcohol-induced psychomotor impairment. Paroxetine 40 mg/day was associated with minimal psychomotor impairment and less impairment than that seen with amitriptyline, amylobarbitone (amylobarbital), doxepin, haloperidol, lorazepam, oxazepam or trazodone.

Paroxetine 30 mg/day was not associated with any clinically significant haemodynamic or electrophysiological effects in healthy volunteers. At a dosage of 20 mg/day it reduced platelet activation in patients with depression and ischaemic heart disease and normalised platelet activation in patients with major depression.

Pharmacokinetic Properties

The pharmacokinetic parameters of paroxetine show wide interindividual variability. Paroxetine is well absorbed after oral administration, and absorption is not affected by the presence of food or antacids. Steady state was reached after 7 to 14 days in healthy volunteers administered paroxetine 30 mg/day. A maximum plasma concentration (Cmax) of 62 μg/L was reached after 5 to 6 hours. Paroxetine has a large volume of distribution (3 to 12 L/kg) after an intravenous bolus of 5 to 10mg; only about 1% of the administered dose remains free in the plasma. Paroxetine has been found in human breast milk after oral administration.

Paroxetine is extensively metabolised in the liver to inactive glucuronide and sulphate metabolites. It is primarily metabolised by the cytochrome P450 (CYP) 2D6 isoenzyme in extensive metabolisers; saturation of this enzyme results in accumulation of the drug after repeated administration or high dosages. The elimination half-life of paroxetine is approximately 21 hours. 62% of the administered dose is excreted in the urine and 36% in the faeces; <2% of the drug is excreted unchanged.

In elderly individuals the plasma concentration of the drug at steady state was increased and the elimination half-life was prolonged in comparison with younger individuals. In individuals with renal impairment [creatinine clearance <1.8 L/h (<30 ml/min)], mean Cmax was 4-fold that of healthy volunteers. In patients with hepatic impairment and in individuals with creatinine clearance 1.8 to 3.6 L/h (30 to 60 ml/min), Cmax and area under the plasma concentration-time curve were increased 2-fold.

Paroxetine, like fluoxetine and sertraline, is highly plasma protein bound and has the potential for drug-drug interactions with other highly protein-bound drugs. All selective serotonin reuptake inhibitors (SSRIs) inhibit CYP enzymes, which potentially results in drug interactions with agents metabolised by these enzymes; paroxetine, like fluoxetine, is a potent inhibitor of CYP2D6 and thus has the potential for interactions with other SSRIs, certain tricyclic antidepressants (TCAs), antipsychotics and antiarrhythmics.

Therapeutic Use in Adult Patients with Psychiatric Disorders

Major Depressive Disorder:Paroxetine 10 to 50 mg/day, in short- to medium- term (6- to 24-week) well designed trials, has shown significantly superior effi-cacy to that of placebo, and similar efficacy to TCAs (amitriptyline 50 to 250 mg/day, imipramine 50 to 275 mg/day, lofepramine 140 to 210 mg/day), all other investigated SSRIs (fluoxetine 20 to 80 mg/day, sertraline 50 to 200 mg/day, fluvoxamine 50 to 200 mg/day), and all other antidepressant comparators (maprotiline 50 to 100 mg/day, mianserin 60 mg/day, mirtazapine 30 to 45 mg/day, nefazodone 200 to 600 mg/day, tianeptine 37.5 mg/day, trazodone 146.1 to 154.3 mg/day and venlafaxine 75 mg/day) in the treatment of adult in- or outpatients with mainly moderate to severe major depressive disorder. Baseline Hamilton Depression Rating Scale (HDRS) or Montgomery and Åsberg Rating Scale (MÅDRS) scores were reduced by 31 to 47% with paroxetine and 11 to 27% with placebo (p ≤ 0.05). The decreases from baseline HDRS or MÅDRS scores were similar with paroxetine to those with the TCAs amitriptyline (39 to 68 vs 44 to 71%), imipramine (31 to 63% vs 25 to 59%) and lofepramine (57 vs 54%), and the SSRIs fluoxetine (48 to 67% vs 45 to 68%), sertraline (64 and 66% vs 68 and 73%) and fluvoxamine (50 and 53% vs 47 and 55%). Response rates (defined as 50% reduction in MADRS or HDRS score from baseline) were similar with paroxetine to those with TCAs (60 to 74% with paroxetine vs 65 to 87% with amitriptyline, 63% with paroxetine vs 54% with lofepramine and 71% with paroxetine vs 60% with imipramine) and SSRIs (58 to 77% with paroxetine vs 57 to 78% with fluoxetine, 69 and 77% with paroxetine vs 72 and 86% with sertraline, and 53% with paroxetine vs 50% with fluvoxamine).

The incidence of relapse or recurrence over 1 year of extended treatment after the initial response was significantly lower with paroxetine 10 to 50 mg/day (10 to 17%) than with placebo (49%; p < 0.05) and similar to that with imipramine 50 to 275 mg/day (4 to 14%).

In elderly patients (≥60 years of age) with depression, baseline HDRS scores were reduced to a similar extent with paroxetine 10 to 40 mg/day to those with amitriptyline 50 to 150 mg/day (65 and 61% vs 63 and 55%, respectively), nortriptyline (plasma concentrations 50 to 150 μg/L) [55 vs 60%], doxepin ≤200 mg/day (53 vs 47%) and clomipramine 25 to 75 mg/day (70 vs 70%). Baseline HDRS scores were decreased by 31% with paroxetine 20 to 40 mg/day and 20% with fluoxetine 20 to 60 mg/day. The response rates (percentage of patients with a 50% reduction in HDRS baseline score) were 64 and 76% with paroxetine versus 58 and 86% with amitriptyline, 65% with paroxetine versus 72% with clomipramine and 38% with paroxetine versus 17% with fluoxetine (p < 0.05). Furthermore, 66% of paroxetine and 78% of nortripty line recipients metresponse criteria defined as HDRS score ≤10.

Paroxetine 10 to 40 mg/day prevented the development of depression when administered for 2 weeks prior to and 12 weeks during treatment with high-dose interferon-α in patients with malignant melanoma; the incidence of major depression [Diagnostic and Statistical Manual (DSM)-IV criteria] at the end of treatment was 11% with paroxetine and 45% with placebo (p < 0.05).

The addition of the β-blocker pindolol 7.5 to 15 mg/day for 4 to 6 weeks to treatment with paroxetine 20 mg/day significantly shortened the time to antidepressant response in comparison with the addition of placebo in patients with major depressive disorder. The addition of paroxetine 20 mg/day or amitriptyline 75 mg/day to long-term lithium treatment (serum concentrations 0.5 to 0.8 mmol/L) in patients with breakthrough episodes of major depression resulted in response rates of 79 and 39%, respectively, after 4 weeks (p < 0.05 for paroxetine vs amitriptyline), with no significant differences after 6 weeks, in a well designed trial.

In well designed trials, baseline MÅDRS scores were reduced by 45 and 42%, respectively, in patients with dementia receiving paroxetine 20 to 40 mg/day or imipramine 25 to 100 mg/day, by 44 and 40%, respectively, in patients with cancer receiving paroxetine 20 to 40 mg/day or amitriptyline 75 to 150 mg/day, and by 45% each in paroxetine 20 to 40 mg/day or amitriptyline 75 to 150 mg/day recipients with rheumatoid arthritis. Reductions in HDRS of 50, 81 and 41%, respectively, were observed in patients with HIV infection receiving paroxetine 10 to 40 mg/day, imipramine 50 to 200 mg/day or placebo; 54 and 61 % of paroxetine 10 to 40 mg/day or nortriptyline (plasma concentrations 50 to 150 μg/L) recipients with ischaemic heart disease had a reduction in HDRS scores from baseline.

There were no significant differences in antidepressant efficacy between treatment groups in 6 to 12 week, randomised, double-blind trials involving patients with depression and anxiety; MADRS scores were decreased from baseline by 83% with paroxetine 20 mg/day versus 76% with fluoxetine 20 mg/day, by 58% with paroxetine 20 to 40 mg/day versus 57% with clomipramine 25 to 150 mg/day, and by 58% with paroxetine 20 mg/day versus 57% with tianeptine 37.5 mg/day. Decreases from baseline HARS or Clinical Anxiety Scale scores (measures of anxiolytic activity) were similar for paroxetine and the comparator drugs [85 vs 75% (paroxetine vs fluoxetine); 53 vs 53% (paroxetine vs clomipramine); and 52 vs 52% (paroxetine vs tianeptine)].

Dysthymia and Minor Depression: Paroxetine (up to 40 mg/day) and psychotherapy [problem solving treatment — primary care (PST-PC)] have been compared with placebo for the treatment of dysthymia and minor depression in large randomised trials in adults ≥60 years of age and patients aged 18 to 59 years. Paroxetine was effective in the treatment of both conditions, but was not significantly different from PST-PC. These multicentre trials were of identical design and there was ≈50% division between patients with dysthymia and minor depression. All patients aged 60 years or older showed improvement over 11 weeks: paroxetine was significantly more effective than placebo (p = 0.004) in the intent-to-treat analysis of the change in the 20-item Hopkins Symptom Checklist Depression Scale, and produced a slightly greater rate of symptom resolution compared with placebo from weeks 2 through 11. The effects on depressive symptoms were similar in patients with dysthymia and those with minor depression. In the trial in younger patients, all three groups showed a significant decline in depressive symptoms over 11 weeks and there were no significant differences between interventions or when groups were analysed by diagnosis. Remission rates (HDRS ≤6 or 7) in patients with dysthymia receiving paroxetine or PST-PC were significantly greater than in placebo recipients but did not differ across treatment groups in patients with minor depression.

Anxiety Disorders:

Obsessive-Compulsive Disorder (OCD): Paroxetine 20 to 60 mg/day significantly improved symptoms of Diagnostic and Statistical Manual third edition revised (DSM-III-R) defined OCD compared with placebo in two well controlled 12-week trials. Preliminary data (presented in an abstract) indicate that improvement relative to placebo was observed with the 40 and 60 mg/day dosages but not the 20 mg/day dosage. Fewer paroxetine than placebo recipients relapsed and the mean time to relapse was significantly greater with active treatment than with placebo in a 12-month study.

Paroxetine recipients (evaluable n = 198) experienced a similar reduction in the symptoms of OCD to that observed in clomipramine recipients (evaluable n = 94) in a well controlled, 12-week trial, and the reduction in symptoms was similar with paroxetine to that observed with fluvoxamine and citalopram in a small (n = 30), single-blind trial of 10 weeks’ duration.

Panic Disorder: Compared with placebo, paroxetine 20 to 60 mg/day significantly improved panic disorder (across multiple assessment parameters) in short-term (10- to 12-week) double-blind, randomised trials involving 120 to 278 (ITT) patients, with paroxetine being effective in all five domains (panic attacks, anxiety, phobia, well-being and disability). In the fixed dosage trial, results were significant for the higher dosage of paroxetine (40 mg/day) only. In addition, paroxetine 20 to 60 mg/day relative to placebo reduced the occurrence of panic attacks for up to 36 weeks in a double-blind extension phase in one trial.

The drug at a dosage of 20 to 60 mg/day was at least as effective as clomipramine 50 to 150 mg/day in the treatment of panic disorder in two well controlled 12-week trials and had similar efficacy to clomipramine in a long-term (36-week) extension phase in one trial. In addition, paroxetine (but not clomipramine) was significantly more effective at reducing the occurrence of panic attacks to zero than cognitive-behavioural therapy in one of the short-term trials. Paroxetine (up to 50 mg/day) appeared to reduce the symptoms of DSM-IV diagnosed panic disorder to a similar extent to citalopram (up to 50 mg/day) in a small (evaluable n = 45) trial, although there was a trend towards a higher proportion of paroxetine than citalopram recipients being free of panic attacks at study end (60 days).

Social Anxiety Disorder (Social Phobia): Paroxetine 20 to 50 mg/day significantly improved the severity of anxiety compared with placebo in patients with social anxiety disorder (evaluable n = 92 to 360) in five well controlled, 12-week trials. A greater proportion of those receiving paroxetine (43 to 70.5%) than placebo (8.3 to 47.8%) were much or very much improved on the Clinical Global Impression-Improvement (CGI-I) scale (p < 0.0001 to p < 0.05) and, in most cases, there were significantly greater reductions in Liebowitz Social Anxiety Scale total scores from baseline in paroxetine (27.5 to 47.4%) than placebo (11.0 to 25.1%) recipients (p < 0.0001 to p < 0.05). Abstract reports from an extension study and a long-term relapse prevention trial indicate that the efficacy of paroxetine in the treatment of patients with social anxiety disorder may be sustained for up to 36 weeks.

Generalised Anxiety Disorder (GAD): Paroxetine 20 to 50 mg/day significantly improved symptoms of anxiety (measured using HARS total score) compared with placebo in two 8-week, randomised, double-blind trials involving 324 (ITT) and 426 (evaluable) outpatients. In a third 8 week trial, the reduction in HARS total score from baseline was numerically greater with paroxetine 20 to 50 mg/day than with placebo. The drug at a dosage of 20 mg/day demonstrated similar efficacy to imipramine 50 to 100 mg/day but greater efficacy than 2′chlordesmethyldiazepam 3 to 6 mg/day in the treatment of GAD in a small (evaluable n = 63) randomised trial. In addition, significantly fewer paroxetine (10.9%) than placebo (39.9%) recipients relapsed during a 32 week relapse prevention study.

Post-Traumatic Stress Disorder (PTSD): Paroxetine 20 to 50 mg/day significantly improved symptoms of PTSD from baseline (p < 0.001) as assessed by the Clinician Administered PTSD Scale and increased the proportion of responders (much or very much improved on CGI-I) [both p < 0.001] compared with placebo in two randomised, double-blind trials of 12 weeks’ duration. Significant improvements with paroxetine relative to placebo were observed across all three symptom clusters (re-experiencing, avoidance and hyperarousal) and in both male and female patients. In addition, treatment benefit was observed across all trauma types.

Tolerability

In patients receiving paroxetine for various psychiatric disorders the most common adverse events occurring with an incidence of ≥5% included nausea, sweating, headache, dizziness, somnolence, constipation, asthenia and sexual dysfunction. In general, these adverse events were mild and events such as nausea and dizziness were transient.

Sexual dysfunction is common to all SSRIs. In patients with depression administered paroxetine 20 to 50 mg/day, the incidence of abnormal ejaculation was approximately 13%. In patients with OCD, social anxiety disorder, GAD or panic disorder the incidence ranged from 21 to 28% with paroxetine 10 to 60 mg/day.

A meta-analysis of 39 studies including over 3700 patients confirmed a significantly lower incidence of adverse events and a trend towards a lower withdrawal rate due to adverse events with paroxetine than with TCAs such as amitriptyline, imipramine, maprotiline and clomipramine.

Paroxetine appeared to have similar tolerability to fluoxetine, fluvoxamine and sertraline in randomised, double-blind trials of 6 weeks’ to 6 months’ duration. The overall incidence of adverse events with paroxetine was similar to that with the other SSRIs with which it was compared and there were no consistent statistically significant differences between paroxetine and the various SSRIs with regards to individual adverse events. Large, placebo-controlled, active-comparator trials are required to further clarify the relative tolerability of SSRIs.

Upon discontinuation of treatment with an SSRI, some patients may experience mild to moderate, self-limiting discontinuation symptoms (e.g. dizziness, paraesthesia, headache and vertigo). As with other SSRIs, slow tapering of the paroxetine dosage over several weeks minimises the extent of these symptoms.

Dosage and Administration

The information in this section is based on the US and UK prescribing information. Paroxetine tablets should be administered once daily, preferably in the morning with or without food, and should be swallowed whole rather than chewed. The recommended initial dosage for all indications except panic disorder is 20 mg/day; in the latter condition the initial dosage should be 10 mg/day. If efficacy is not achieved, paroxetine should be increased at weekly intervals in 10mg increments to a maximum dosage of between 50 and 60 mg/day depending on the condition being treated and local recommendations. Reliable studies of long-term (>1 year) maintenance therapy with paroxetine are not available but, as many of the conditions which respond to the drug are chronic, it is reasonable to consider continuing extended treatment of responding patients, with periodic reassessment and possible adjustment of dosage. The UK guidelines and WHO recommendations suggest that patients should receive treatment for at least 4 to 6 months after recovery from depression, and perhaps longer for OCD and panic disorder. As with many psychoactive medications, abrupt discontinuation should be avoided.

In elderly or debilitated patients or those with severe kidney or hepatic impairment, the recommended initial dosage of paroxetine is 10 mg/day. The dosage may be increased if indicated but should not exceed 40 mg/day.

Serotonin syndrome (which includes changes in mental status, agitation, myoclonus, hyperreflexia, diaphoresis, hyperthermia, and incoordination) may occur with the concomitant use of an SSRI and a monoamine oxidase inhibitor (MAOI). Therefore, paroxetine should not be administered in combination with an MAOI or for at least 14 days after discontinuation of treatment with an irreversible MAOI and at least 1 day after discontinuation of treatment with a reversible MAOI. Paroxetine should be discontinued for at least 1 day before the initiation of therapy with a reversible MAOI and for at least 2 weeks before beginning treatment with other MAOIs.

Caution is advised when paroxetine is coadministered with drugs that are metabolised by CYP2D6 [e.g. antidepressants (nortriptyline, amitriptyline, imipramine, desipramine and fluoxetine), phenothiazines, and type C antiarrhythmics (e.g. propafenone, flecainide and encainide)] or that inhibit this enzyme (e.g. quinidine). In particular, the coadministration of paroxetine and thioridazine is contraindicated. In addition, the concomitant use of paroxetine and tryptophan is not recommended and caution is advised when paroxetine is coadministered with warfarin, sumatriptan, lithium or digoxin.

The safety of paroxetine in pregnancy has not been established and the drug should only be used during pregnancy if the benefits to the mother outweigh the possible risk to the foetus. Paroxetine is secreted in breast milk and discontinuation of breast feeding should be considered in this situation. The safety and effectiveness of paroxetine in paediatric populations has not been established.

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Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, New Zealand

    Antona J. Wagstaff, Susan M. Cheer, Anna J. Matheson, Douglas Ormrod & Karen L. Goa

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  1. Antona J. Wagstaff
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  2. Susan M. Cheer
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  3. Anna J. Matheson
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  4. Douglas Ormrod
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  5. Karen L. Goa
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Correspondence to Antona J. Wagstaff.

Additional information

Various sections of the manuscript reviewed by: M. Ansseau, CHU Sart Tilman, Psychiatric Unit, Liege, Belgium; R. Hoehn-Saric, Johns Hopkins Medical Institutions, Department of Psychiatry and Behavioral Sciences, Baltimore, Maryland, USA; S. Kasper, University of Vienna, Department of General Psychiatry, Vienna, Austria; B. Lydiard, Medical University of South Carolina, Department of Psychiatry and Behavioral Sciences, Charleston, South Carolina, USA; R.Zanardi, University of Milan, Department of Neuropsychiatric Sciences, Milan, Italy

Data Selection

Sources: Medical literature published in any language since 1980 on paroxetine, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘paroxetine’ or ‘FG 7051’. EMBASE search terms were ‘paroxetine’ or ‘BRL 29060’ or ‘FG 7051’. AdisBase search terms were ‘paroxetine’. Searches were last updated 21 January 2002.

Selection: Studies in patients with major depressive disorder, dysthymia, obsessive-compulsive disorder, panic disorder, social anxiety disorder, generalised anxiety disorder or post-traumatic stress disorder who received paroxetine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Major depressive disorder, obsessive-compulsive disorder, panic disorder, social anxiety disorder, social phobia, generalised anxiety disorder, post-traumatic stress disorder, paroxetine, pharmacodynamics, pharmacokinetics, therapeutic use.

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Wagstaff, A.J., Cheer, S.M., Matheson, A.J. et al. Paroxetine. Drugs 62, 655–703 (2002). https://doi.org/10.2165/00003495-200262040-00010

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