Summary
Synopsis
Paroxetine is a potent and selective inhibitor of the neuronal reuptake of serotonin, thereby facilitating serotoninergic transmission; this action appears to account for the antidepressant activity observed with this drug. A mean terminal elimination half-life of approximately 24 hours permits once daily administration.
Results of short term clinical trials have shown paroxetine to be significantly superior to placebo, and comparable to amitriptyline, clomipramine, imipramine, dothiepin and mianserin in relieving symptoms associated with major depressive disorders. Paroxetine has shown some preliminary promise in the treatment of depressive illness resistant to tricyclic antidepressant therapy but further studies are required before any conclusions can be drawn.
Paroxetine in therapeutic doses has been very well tolerated, and the favourable tolerability profile of this agent appears to be its primary advantage over traditional antidepressant agents. Paroxetine causes minimal anticholinergic-type adverse effects, and unlike tricyclic antidepressants, it does not precipitate cardiovascular effects or provoke cardiac conduction disturbances. Nausea has been the most frequently reported adverse event during short term use of paroxetine, but it is generally mild and transient and subsides with continued use. With longer term use headache, sweating and constipation were the most frequently reported side effects but the incidence rate was not significantly different from that noted for comparator antidepressants. Furthermore, the frequency of withdrawal due to adverse effects is less with paroxetine than with tricyclic antidepressant agents.
Overall, available data appear to indicate that while the efficacy of paroxetine is similar to that of traditional antidepressant drugs, the newer agent possesses much improved tolerability. In addition, the wide therapeutic index of paroxetine may be beneficial when treating patients with an increased risk of suicide. Thus, paroxetine clearly looks to become a valuable addition to the range of drugs currently available to treat depressive illness. Future research may help to further define the relative place of this newer agent in antidepressant therapy and determine how its overall therapeutic efficacy compares with that of other related antidepressant agents such as fluoxetine.
Pharmacodynamic Properties
Paroxetine potently and selectively inhibits synaptosomal reuptake of serotonin by interacting competitively with the active transport mechanism for the neurotransmitter in the neuronal membrane. This inhibition should result in accumulation of serotonin at the synaptic cleft and hence facilitation of serotoninergic transmission. Comparison of in vitro uptake of various neurotransmitters into rat brain hypothalamus synaptosomes has demonstrated that the concentration constant of paroxetine for inhibition of noradrenaline (norepinephrine) uptake was 320-fold greater than that for inhibition of serotonin reuptake. Paroxetine also possesses negligible affinity for the reuptake of dopamine and other neurotransmitter amines. Receptor binding studies have revealed that paroxetine does not interact directly with any of the central neurotransmitter receptor sites, including those for serotonin, except for displaying a very weak affinity for the muscarinic receptor.
Paroxetine causes depletion of serotonin from blood platelets by interacting with the active uptake transporter mechanism for serotonin at the platelet membrane.
While paroxetine has no effect on the number or sensitivity of β-adrenoceptors in central neuronal membranes, a decrease in responsiveness of terminal serotonin autoreceptors has been observed during long term administration. Although not yet clearly established, this decrease in sensitivity of serotonin receptors may be intrinsically involved in the mechanism of action of paroxetine and many other antidepressant drugs.
Electroencephalogram recordings in animal species and healthy volunteers have shown that paroxetine does not appear to possess sedative properties. Nevertheless, somnolence was reported in association with paroxetine therapy in clinical trials although the incidence was less than that observed with other active antidepressant agents (mainly tricyclics).
Electrophysiological measures in animals and humans have demonstrated that paroxetine increases vigilance and produces alterations in normal sleep patterns. In a study in 12 volunteers who were ‘poor sleepers’, paroxetine 30mg administered in the morning produced more pronounced effects on sleep than the same dose given at night time. However, in 98 patients with depression, significant improvements in 8 of 10 parameters relating to sleep occurred from weeks 1 to 6 with morning but not evening doses of paroxetine 30mg.
Paroxetine in single-or multiple-dose regimens of 30 mg/day did not affect objective measures of psychomotor performance in humans and did not potentiate the effects of single doses of haloperidol 3mg, amobarbital (amylobarbitone) 100mg, oxazepam 30mg or alcohol 50g. Unlike amitriptyline 50mg, repeated doses of paroxetine 30mg did not cause impairment of psychomotor performance in healthy volunteers and did not potentiate the effects of alcohol (in an acute dose of 0.6g/kg).
Paroxetine 40mg produced less impairment of psychomotor performance related to motor function than amitriptyline 75mg, and did not affect driving performance in healthy volunteers on either day 1 or 8 of administration.
Paroxetine did not significantly affect indices of cardiac conduction in dogs, and doses approximately 2 to 4 times higher than those of amitriptyline were required to produce significant changes in blood pressure, heart rate and electrocardiographic parameters in other animal species. In volunteers and patients with major depressive illnesses, paroxetine 30 to 40mg did not significantly affect heart rate, blood pressure or cardiac conduction.
Pharmacokinetic Properties
Paroxetine reached peak plasma concentrations in approximately 5 hours following oral administration of single 30mg doses to healthy volunteers. During multiple-dose administration, plasma concentrations increased in approximate proportion to the daily dose except in those subjects with initial low plasma paroxetine levels. Steady-state plasma concentrations were attained after 7 to 14 days. A wide range of intersubject variability was noted, however, in the pharmacokinetic parameters of paroxetine.
Paroxetine undergoes extensive first-pass metabolism — which is estimated at about 50% — and is partially saturable. Only 1 to 2% of a dose appears in the urine unchanged, and the metabolites are inactive. The mean terminal elimination half-life of paroxetine is approximately 24 hours in adult patients, although considerable individual variation exists in this parameter. Longer elimination half-lives and higher plasma concentrations are generally observed in the elderly but overlap the range seen in adults.
There was a tendency for maximum plasma concentrations and values for the area under the plasma concentration-time curve to increase with deteriorating renal function in renally impaired patients administered single oral doses of paroxetine 20mg. However, elimination half-life was significantly prolonged only in those patients with severe renal impairment. In patients with hepatic disease, pharmacokinetic values following a single dose of paroxetine 20mg were unaltered compared with values from healthy subjects although with continued administration there is some evidence for reduced clearance. Thus, in this type of patient it is advisable to commence paroxetine treatment at the lower end of the recommended therapeutic range.
Therapeutic Potential
Paroxetine in doses of 20 to 50 mg/day is an effective antidepressant agent in the treatment of major depressive illness. Similar to that observed with tricyclic antidepressant agents, significant improvements in symptoms of depression are generally not apparent until approximately 2 weeks after starting paroxetine therapy.
In noncomparative studies, 50 to 70% of patients achieved ‘marked’ or ‘moderate’ clinical improvement with paroxetine therapy, while in the majority of controlled short term trials, paroxetine displayed superior efficacy to placebo and comparable efficacy to imipramine, clomipramine, amitriptyline, dothiepin and mianserin. Results from 2 comparative studies suggested that paroxetine may not be as effective as imipramine, and clomipramine in the treatment of depression, but the majority of trials indicate therapeutic equivalence. Importantly, comparative trials consistently showed paroxetine to have a significant advantage over other active antidepressant drugs in terms of its tolerability profile.
In a number of clinical trials involving elderly patients (> 60 years) paroxetine was titrated up to a dosage of 30mg daily and compared with standard antidepressant regimens. Paroxetine was shown to be as effective as clomipramine 75mg daily and amitriptyline 100mg daily, and to be more effective than mianserin 60mg daily. Furthermore, in these studies paroxetine was better tolerated compared with clomipramine, and produced more significant improvements in sleep quality than mianserin.
Although data are very limited, paroxetine has shown some preliminary promise in the treatment of patients with depression resistant to tricyclic agents. In a noncomparative trial in 26 patients with depression primarily resistant to amitriptyline, 70% of 26 évaluable patients showed good response to 6 weeks’ therapy with paroxetine 30 me/day.
Tolerability
Paroxetine has been very well tolerated by patients in clinical trials. The adverse events reported most often during short term therapy (< 6 weeks) have been nausea (with an incidence of 12% over that seen with placebo), somnolence (11%), sweating (9%) and tremor (8%), followed by asthenia (7%), dry mouth (7%) and insomnia (6%). Importantly, paroxetine caused significantly fewer anticholinergic-type side effects (e.g. dry mouth, constipation) and cardiovascular symptoms (e.g. postural hypotension, tachycardia) than tricyclic antidepressant agents. However, paroxetine therapy was associated with an increased incidence of ejaculation difficulties.
The incidence of adverse effects decreased with time and during longer term therapy reports of nausea were virtually absent, and the percentages of patients experiencing somnolence, tremor and dry mouth were greatly reduced. In long term clinical trials headache, sweating and constipation were the most frequently observed side effects with paroxetine but the rate of occurrence was no greater than that noted for comparator antidepressants. Furthermore, adverse effects associated with paroxetine therapy led to fewer patient withdrawals than those of the tricyclic antidepressant agents.
Dosage and Administration
The recommended dose of paroxetine is 20 mg/day in adult patients. This may be adjusted as required, depending on patient response and tolerability, within the therapeutic range of 20 to 50 mg/day. Paroxetine should be administered once daily, in the morning, with food. The maximum recommended daily dose in elderly patients is 40 mg/day. Patients with renal or hepatic impairment should have dosages restricted to the lower end of the therapeutic range.
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Various sections of the manuscript reviewed by: A.J. Bayer, University Department of Geriatric Medicine, Cardiff Royal Infirmary, Cardiff, Wales; JM. Davis, Illinois State Psychiatric Institute, Chicago, Illinois, USA; M.J. Eadie Department of Medicine, Royal Brisbane Hospital, Brisbane, Queensland, Australia; J.Guy Edwards, Department of Psychiatry, Royal Southhants Hospital, Southampton, England; J.P. Feighner, Feighner Research Institute Poway California, USA; I. Hindmarch, Robens Institute of Health and Safety, University of Surrey, Guildford’ England; Y.Nakane, Department of Neuropsychiatry, Nagasaki University School of Medicine, Nagasaki Japan; K.Rickels, Department of psychiatry, University of Pennsylvania, University Hospital, Philadelphia, Pennsylvania, USA; S.J. Warrngton, Charterhouse Clinical Research Unit Limited, Boundary House London England.
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Dechant, K.L., Clissold, S.P. Paroxetine. Drugs 41, 225–253 (1991). https://doi.org/10.2165/00003495-199141020-00007
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DOI: https://doi.org/10.2165/00003495-199141020-00007