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Paroxetine

A Review of its Pharmacology, Therapeutic Use in Depression and Therapeutic Potential in Diabetic Neuropathy

  • Drug Evaluation
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Summary

Synopsis

Paroxetine is a selective serotonin reuptake inhibitor effective in a once-daily administration regimen in the treatment of depression. In elderly patients (aged ⩾ 60 years) with major depression, short term (6 weeks) treatment with paroxetine produces clinical improvements significantly superior to those seen with placebo and similar to those with tricyclic antidepressant agents, mianserin and fluoxetine. There is evidence that paroxetine has positive effects on co-existing anxiety and does not precipitate agitation. Paroxetine has also shown potential in the symptomatic treatment of diabetic neuropathy; however, further clinical experience is needed to confirm this preliminary result.

Short term paroxetine therapy is associated with fewer anticholinergic and CNS adverse effects, but generally more gastrointestinal disturbances, than tricyclic antidepressants and mianserin. Unlike the tricyclic agents, paroxetine does not significantly affect cardiovascular function or impair psychomotor performance. This tolerability profile should be particularly beneficial in elderly patients, who are generally more susceptible than younger patients to the anticholinergic and CNS adverse events associated with tricyclic antidepressant drugs, and in whom there is a higher prevalence of pre-existing cardiovascular disease. It also suggests an important potential advantage over tricyclic antidepressants in the setting of overdosage.

Thus, primarily because of its better tolerability profile and potentially lower toxicity in overdosage and in patients with cardiovascular disease, paroxetine appears to be a more attractive option than tricyclic antidepressants for the treatment of depression in late life. Future research should attempt to define more fully the efficacy of paroxetine as long term prophylactic therapy for recurrent depression and to assess how its overall therapeutic profile compares with other selective serotonin reuptake inhibitors in the elderly.

Pharmacological Properties

Paroxetine selectively blocks presynaptic reuptake of serotonin by interacting with the active transport mechanism for the neurotransmitter. The resulting increase in the synaptic concentration of serotonin appears to induce secondary neuronal adaptive changes which facilitate serotonergic neurotransmission.

In vitro studies have shown that paroxetine has virtually no inhibitory effect on the reuptake of noradrenaline (norepinephrine) and other neurotransmitter amines. In radioligand binding studies the affinity of paroxetine for central neurotransmitter receptor sites was substantially less than that of tricyclic antidepressants. Additional receptor binding studies provide preliminary evidence for a serotonergic deficit in patients with neurodegenerative diseases which may be an interesting area for further research with paroxetine and similarly acting drugs.

Electroencephalographical recordings in healthy volunteers and adult patients with depression indicate that paroxetine does not cause sedation or epileptiform activity. In healthy elderly volunteers, no significant differences between paroxetine and placebo in subjective measures of sedation were noted. Electrophysiological studies in animals and humans have shown, that paroxetine causes alterations in normal sleep patterns. However, subjective assessments have indicated that paroxetine does not significantly affect quality of sleep in healthy elderly volunteers and may produce improvements in sleep quality in depressed elderly patients.

In contrast to amitriptyline, single or multiple dose administration of paroxetine 30mg does not significantly affect psychomotor function including that related to motor vehicle driving ability in healthy adult volunteers nor does it potentiate the CNS-depressant effects of haloperidol 3mg, amobarbital (amylobarbitone) 100mg, oxazepam 30mg or ethanol 50g or 0.6 g/kg. In healthy elderly volunteers, paroxetine 20mg did not significantly affect psychomotor performance compared with placebo.

Preliminary data in healthy volunteers and patients with depression indicate that paroxetine 30 to 40 mg/day has no clinically significant effect on cardiovascular function. Data from patients with pre-existing cardiac disease are not available. Wide interindividual variability in the pharmacokinetics of paroxetine exists and there are preliminary data suggesting that plasma paroxetine concentrations and the clinical effects of the drug are not directly correlated. Paroxetine is extensively absorbed from the gastrointestinal tract but substantial first-pass metabolism limits bioavailability of the drug to about 50%. Peak plasma concentrations are attained within 0.5 to 11 (mean 5) hours of administration of single doses of paroxetine 20 to 50mg in healthy volunteers while steady-state plasma paroxetine concentrations are reached after 7 to 14 days. Advanced age does not appear to affect the rate of absorption of paroxetine.

Metabolism of paroxetine is almost complete with less than 2% of an oral dose excreted unchanged in the urine. Paroxetine metabolites have negligible pharmacological activity. The elimination half-life of paroxetine in healthy adult volunteers is approximately 20 hours, although there is wide intersubject variation. Elderly healthy volunteers generally showed prolonged elimination half-lives and higher plasma concentrations compared with nonelderly adult volunteers. However, because there was considerable overlap in individual values between the 2 age groups, the clinical significance of these observations is unclear. There is also evidence of reduced clearance in patients with hepatic disease or severe renal impairment.

Therapeutic Efficacy

The efficacy of paroxetine 10 to 40 mg/day administered for up to 6 weeks has been assessed in clinical trials involving a total of 633 elderly patients (aged ⩾ 60 years) with major depressive disorders. In 3 noncomparative studies paroxetine 20 to 40 mg/day produced modest reductions in Hamilton Depression Rating Scale (HAMD) scores with 67% of patients in one study achieving a complete or partial clinical response. Initial comparative studies have shown that the efficacy of paroxetine 10 to 40 mg/day is superior to placebo and equivalent to the tricyclic antidepressants, amitriptyline, clomipramine and doxepin; the tetracyclic agent, mianserin; and the serotonin reuptake inhibitor, fluoxetine, when administered at standard dosages to elderly patients with major depression.

Limited clinical data indicate that paroxetine has beneficial effects on sleep quality in elderly depressed patients. Paroxetine may be effective in the prophylactic treatment of recurrent depression, although data are restricted to a single study in nonelderly adult patients. There is also evidence that paroxetine reduces symptoms of coexisting anxiety and does not precipitate agitation in depressed elderly patients.

Paroxetine, administered at a dosage of 40 mg/day, has also been reported to reduce pain scores to a significantly greater extent than placebo in 2 preliminary studies in adult patients with diabetic neuropathy.

Tolerability

The tolerability profile of short term (6 weeks) treatment with paroxetine in elderly patients is similar to that seen in the general adult population. The incidence of anticholinergic and CNS adverse events in comparative trials was consistently lower with paroxetine than with tricyclic agents or mianserin. While paroxetine was associated with more gastrointestinal adverse events, these were generally mild and resolved with ongoing treatment. Paroxetine does not significantly affect cardiovascular function or psychomotor performance. Falls due to dizziness or postural hypotension during paroxetine therapy have not been reported to date. The tolerability of longer term paroxetine therapy in elderly patients has not been assessed.

Paroxetine has not been associated with an increased risk of suicidal tendency and clinical case reports suggest that the toxicity of paroxetine in overdosage is low.

Preliminary data indicate that plasma tricyclic antidepressant concentrations may increase during the concomitant administration of these drugs with paroxetine. This interaction may be of clinical importance in elderly patients who are particularly susceptible to the adverse effects of tricyclic antidepressant drugs.

Dosage and Administration

The recommended starting dosage of paroxetine for the treatment of depressed elderly patients is 20 mg/day in the UK and 10 mg/day in the US, administered once daily in the morning with food. This may be increased to a maximum of 40 mg/day depending on the patient’s clinical response. The dosage should be restricted to the lower end of the therapeutic range in patients with hepatic or renal impairment. Concomitant use of paroxetine and monamine oxidase inhibitors is contraindicated. Coprescribing paroxetine with tryptophan is not recommended and caution is advised when using paroxetine concurrently with warfarin or tricyclic antidepressants.

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  1. Adis International Limited, Private Bag 65901, 41 Centorian Drive, Mairangi Bay, Auckland 10, New Zealand

    Stephen M. Holliday & Greg L. Plosker

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  1. Stephen M. Holliday
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Various sections of the manuscript reviewed by: I.M. Anderson, School of Psychiatry and Behavioural Sciences, Manchester Royal Infirmary, Manchester, England; D.G. Blazer, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina, USA; P. Blier, Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada; D.L. Dunner, University of Washington Outpatient Psychiatry, Seattle, Washington, USA; K. Ghose, Medicines Adverse Reactions Monitoring Centre, National Toxicology Group, Otago University Medical School, Dunedin, New Zealand;I. Hindmarch, Robens Institute of Health and Safety, University of Surrey, Milford Hospital, Godalming, Surrey, England; P.P. Lamy, Center for the Study of Pharmacy and Therapeutics for the Elderly, University of Maryland at Baltimore, School of Pharmacy, Baltimore, Maryland, USA; J. Lundmark, Department of Psychiatry, Faculty of Health Sciences, University Hospital, Linkoping, Sweden; Y. Nakane, Department of Neuropsychiatry, WHO Collaborating Center for Research and Training in Mental Health, Nagasaki University School of Medicine, Nagasaki, Japan; B.G. Pollock, Psychiatry and Pharmacology, University of Pittsburgh, Geriatric Health Services, School of Medicine, Pittsburgh, Pennsylvania, USA; R.E. Vestal, Clinical Pharmacology and Gerontology Research Unit, Veterans Administration Medical Center, Boise, Idaho, USA; S.J. Warrington, Charterhouse Clinical Research Unit Limited, London, England.

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Holliday, S.M., Plosker, G.L. Paroxetine. Drugs & Aging 3, 278–299 (1993). https://doi.org/10.2165/00002512-199303030-00008

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