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Paroxetine is a potent and selective inhibitor of the neuronal reuptake of serotonin (5-hydroxytryptamine; 5-HT), which was previously reviewed as an antidepressant in Drugs in 1991. Since then, more comparative trials with other antidepressants have become available, and its use in the elderly and as long term maintenance therapy has been investigated. Paroxetine has also been studied in several other disorders with a presumed serotonergic component, primarily obsessive compulsive disorder (OCD) and panic disorder.
In short term clinical trials in patients with depression, paroxetine produced clinical improvements that were significantly greater than those with placebo and similar to those achieved with other agents, including tricyclic antidepressants (TCAs), maprotiline, nefazodone and the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, fluvoxamine and sertraline. Long term data suggest that paroxetine is effective in preventing relapse or recurrence of depression in patients treated for up to 1 year. In the elderly, the overall efficacy of paroxetine was at least as good as that of comparator agents.
In short term clinical trials involving patients with OCD or panic disorder, paroxetine was significantly more effective than placebo and of similar efficacy to clomipramine. Limited long term data show that paroxetine is effective in maintaining a therapeutic response over periods of 1 year (OCD) and up to 6 months (panic disorder). Preliminary data suggest that paroxetine has potential in the treatment of social phobia, premenstrual dysphoric disorder and chronic headache.
Like the other SSRIs, paroxetine is better tolerated than the TCAs, causing few anticholinergic adverse effects. The most commonly reported adverse event associated with paroxetine treatment is nausea, although this is generally mild and subsides with continued use. Fewer withdrawals from treatment due to adverse effects occurred with paroxetine treatment than with TCAs. The adverse events profile of paroxetine appears to be broadly similar to that of other SSRIs, although data from comparative trials are limited. Serious adverse effects associated with paroxetine are very rare.
In conclusion, paroxetine is effective and well tolerated, and suitable as first-line therapy for depression. It also appears to be a useful alternative to other available agents for the treatment of patients with OCD or panic disorder.
Paroxetine potentiates serotonergic neurotransmission by the selective and potent inhibition of neuronal reuptake of serotonin. It possesses very weak inhibitory effects on noradrenaline (norepinephrine) and dopamine reuptake, and unlike the tricyclic antidepressants (TCAs), has negligible affinity for various central neurotransmitter receptors except for displaying weak affinity for the muscarinic receptor.
Long term administration of paroxetine has not been associated with down-regulation of central β-adrenoceptors in rats; however, a decrease in the responsiveness of somatodendritic (5-HT1A) and terminal (5-HT1B/1D) serotonin autoreceptors has been observed after 2 to 3 weeks’ paroxetine administration.
Various studies involving healthy volunteers and patients with depression have indicated that paroxetine is associated with a reduction in REM sleep time and prolongation of REM latency. In addition, although paroxetine has an alerting effect on sleep, particularly in terms of the number of awakenings, it improves the subjective quality of sleep in patients with depression.
When administered within the therapeutic range, paroxetine did not significantly impair psychomotor function in studies involving healthy volunteers, patients with depression and the elderly, and neither did it potentiate the CNS-depressant effects of alcohol. Paroxetine does not produce significant haemodynamic or electrophysiological cardiac effects in healthy volunteers or depressed patients with coexisting ischaemic heart disease.
Paroxetine is almost completely absorbed after oral administration. There is considerable interindividual variation in plasma paroxetine concentrations, although no correlation between plasma drug concentration and clinical efficacy or tolerability has been demonstrated. Peak plasma paroxetine concentrations are reached about 5 hours after oral administration and steady-state plasma concentrations are reached after 7 to 14 days’ administration. Plasma protein binding is approximately 95% and volume of distribution ranged from 3.1 to 28.0 L/kg.
Paroxetine is extensively metabolised by the cytochrome P450 (CYP) system in the liver, producing essentially inactive metabolites. Saturation of the CYP2D6 enzyme accounts for the nonlinear kinetics observed during repeated administration or after dosage increases. Paroxetine also inhibits the CYP2D6 enzyme. Only 1 to 2% of a paroxetine dose is excreted unchanged in the urine. The rest is excreted as metabolites in both the urine and the faeces. Paroxetine has an elimination half-life of approximately 21 hours.
In elderly individuals, plasma concentration, elimination half-life and the area under the plasma concentration-time curve for paroxetine are increased compared with values obtained in younger subjects. Increased plasma drug concentrations are also observed after single doses of paroxetine in patients with severe renal impairment (creatinine clearance <1.8 L/h) and after repeated administration in patients with hepatic impairment.
In patients with depression, paroxetine produced therapeutic responses that were approximately equivalent to those produced by tricyclic and related antidepressants. The proportion of paroxetine-treated patients who achieved ≥50% reduction from baseline Hamilton Depression Rating Scale (HDRS) scores after 6 to 12 weeks’ treatment ranged from 60 to 74%, compared with 60 to 87% for patients receiving tricyclic and related antidepressants. Response rates according to other scales, such as the Montgomery Åsberg Depression Rating Scale and Clinical Global Impression (CGI) were similar between treatment groups. Paroxetine was also effective in relieving anxiety associated with depression. Similar reductions in Clinical Anxiety Scale were seen with paroxetine and clomipramine in patients with coexisting depression and anxiety. One study provided some evidence to suggest a more rapid effect in improving depression and anxiety symptoms with paroxetine than imipramine.
Paroxetine also showed equivalent efficacy to fluoxetine, fluvoxamine and sertraline. One study suggested paroxetine has an earlier onset of action and may be more effective in relieving associated anxiety than fluoxetine. Paroxetine also had equivalent efficacy to nefazodone.
Paroxetine remains an effective maintenance treatment of depression for up to 1 year. The drug had comparable efficacy to imipramine in maintaining euthymia in patients who had responded to short term therapy.
Paroxetine is effective in the treatment of depression in the elderly. Comparative studies show that there is no difference in efficacy between paroxetine and amitriptyline in this group, although there is some evidence to suggest an earlier onset of action for paroxetine. Therapeutic equivalence with doxepin has also been reported. Paroxetine showed advantages over fluoxetine in 1 study in elderly patients, although response rates to both treatments were low.
Paroxetine has been used successfully in the treatment of patients with obsessive compulsive disorder (OCD). It was significantly more effective than placebo at dosages of 40 and 60 mg/day, but not at 20 mg/day. In a large comparative, placebo-controlled trial, paroxetine demonstrated similar efficacy to clomipramine. About 55% of patients in each active treatment group had a ≥25% reduction from baseline in Yale-Brown Obsessive-Compulsive Scale score at week 12. In a trial evaluating long term treatment of OCD, paroxetine was effective in maintaining a therapeutic response and preventing relapse over a period of 1 year.
Paroxetine 40 mg/day is significantly more effective than placebo in the short term treatment of panic disorder and at least as effective as clomipramine. Some evidence suggests an earlier onset of action for paroxetine than clomipramine. A long term trial found that fewer paroxetine-treated patients relapsed compared with placebo recipients.
Preliminary data have showed that paroxetine was significantly more effective than placebo in the treatment of social phobia. The drug has also been used successfully in the treatment of premenstrual dysphoric disorder and may be effective in treating chronic headache.
In general, paroxetine is well tolerated in the overall patient population and the elderly. Nausea, the most common adverse event during paroxetine treatment, occurs in 22% of patients compared with 14% of those receiving other anti-depressants (mainly TCAs). The next most common adverse events include headache, somnolence, dry mouth, abnormal ejaculation, insomnia, asthenia, sweating, constipation and tremor. The anticholinergic adverse effects of dry mouth and constipation occurred at a much lower incidence with paroxetine (14 and 9%) than with other antidepressants (mainly TCAs) [32 and 13%] according to data from a clinical trial database. Overall, the tolerability profile of paroxetine resembles those of the other selective serotonin reuptake inhibitors, although data from comparative trials are limited.
Adverse events associated with paroxetine treatment tend to be mild and lead to fewer withdrawals from treatment than those associated with the TCAs. Furthermore, the incidence of nausea, the most common adverse event, decreases after a few weeks’ treatment.
There is no evidence to suggest that paroxetine is associated with either physiological or psychological dependence. However, upon discontinuation of paroxetine treatment, some patients may experience mild to moderate, self-limiting discontinuation symptoms such as dizziness, sweating, nausea, diarrhoea, insomnia, fatigue and headache. Slow tapering of the paroxetine dosage over several weeks minimises the extent of these symptoms.
The pharmacoeconomics of paroxetine in depression have been assessed in 4 simulation models. Despite higher acquisition costs for paroxetine, 3 of these models showed that the total direct cost per successfully treated patient was slightly less for paroxetine than for TCAs (amitriptyline and imipramine). This was due to the higher treatment failure rates with TCAs and the consequent costs of additional physician visits, hospitalisation and alternative therapy. The other model found treatment costs for successfully treated patients to be slightly greater for paroxetine than those for imipramine or amitriptyline.
A retrospective cost analysis of prescription data suggests that the cost of paroxetine treatment may be less than that of fluoxetine or sertraline. Cost differences were attributed to fewer dosage adjustments required with paroxetine, and hence a reduction in associated physician and pharmacist labour costs. However, another retrospective cost analysis of data from patients in a health maintenance organisation found an increase in the direct healthcare costs of treatment with paroxetine compared with fluoxetine.
Paroxetine is both a substrate and an inhibitor of the hepatic enzyme CYP2D6. Consequently, it has the potential to interact with other drugs that either inhibit or are metabolised by CYP2D6.
Elevated plasma concentrations of desipramine and imipramine have been noted during the coadministration of paroxetine. Plasma concentrations of the anticonvulsant agents carbamazepine, phenytoin or valproic acid were not significantly affected by the coadministration of paroxetine to 20 patients with epilepsy. The bioavailability of paroxetine may be increased by cimetidine and decreased by phenytoin.
Although no significant pharmacokinetic interaction between paroxetine and warfarin has been demonstrated, 1 study found clinically significant bleeding occurred in 5 out of 27 individuals who received both drugs. Consequently, caution is required when these drugs are coadministered.
Development of the potentially fatal serotonin syndrome has been reported during concomitant use of paroxetine and other drugs including trazodone and nefazodone. Adverse effects indicative of potentiated serotonergic activity were also observed in a study involving the coadministration of paroxetine and moclobemide.
Dosage and Administration
The recommended starting dosage of paroxetine for the treatment of patients with depression is 20 mg/day taken orally as a single dose. This may also be the optimal dose for most patients. However, in those who do not show an adequate therapeutic response after 2 to 3 weeks, dosage increases of 10 mg/day at a minimum of weekly intervals to a maximum of 50 mg/day may be made.
The recommended starting dose for the treatment of patients with OCD is 20 mg/day, and the optimum target daily dose is 40 mg/day. For the treatment of patients with panic disorder, starting and target daily dosages are 10 and 40 mg/day, respectively. For both indications dosage increases are implemented in the same manner as for depressive illness to a maximum not exceeding 60 mg/day.
The dosage of paroxetine should not exceed 40 mg/day in elderly or debilitated patients or those with severe renal or hepatic impairment, and should be initiated at 10 mg/day.
Concomitant use of monoamine oxidase inhibitors (MAOIs) and paroxetine is contraindicated, and a 2-week washout period is required before switching treatment between these agents.
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