Paroxetine: A Review

Abstract

Paroxetine is a potent and selective serotonin reuptake inhibitor (SSRI) with currently approved indications for the treatment of depression, obsessive-compulsive disorder, panic disorder and social phobia. It is also used in the treatment of generalized anxiety disorder, post traumatic stress disorder, premenstrual dysphoric disorder and chronic headache.Paroxetine, a phenylpiperidine derivative, is the most potent inhibitor of the reuptake of serotonin (5-hydroxytryptamine, 5-HT) of all the currently available antidepressants including the class of SSRIs. It is a very weak inhibitor of norepinephrine (NE) uptake but it is still more potent at this site than the other SSRIs. The selectivity of paroxetine, i.e., the ratio of inhibition of uptake of norepinephrine to serotonin (NE/5-HT) is amongst the highest of the SSRIs. Paroxetine has little affinity for catecholaminergic, dopaminergic or histaminergic systems and by comparison with tricyclic antidepressants (TCAs) has, therefore, has a reduced propensity to cause central and autonomic side effects. Paroxetine exhibits some affinity for the muscarinic cholinergic receptor but much less than the TCAs. In addition, the adaptive changes of somatodendritic (5-HT 1A ) and terminal (5-HT 1B/1D ) autoreceptors observed with paroxetine are different to those observed with TCAs; it also inhibits nitric oxide synthase. It is both a substrate and an inhibitor of cytochrome isoenzyme P450 2D6. Paroxetine is well absorbed orally and undergoes extensive first pass metabolism that is partially saturable. Its metabolites are pharmacologically inactive in vivo. Steady state levels are achieved after 4-14 days and an elimination half-life of 21 h is consistent with once-daily dosing. There is wide inter-individual variation in the pharmacokinetics of paroxetine in adults as well as in the young and the elderly with higher plasma concentrations and slower elimination noted in the latter. Elimi- 25

Polymorphisms in the 5-Hydroxytryptamine 2A Receptor and CytochromeP4502D6 Genes Synergistically Predict Fluvoxamine-Induced Side Effects in Japanese Depressed Patients

“…Since elderly patients are thought to have pharmacodynamic and pharmacokinetic profiles different from those of younger patients, the difference in age may explain the discrepancy between the two studies. In addition, the difference in medication, paroxetine vs fluvoxamine, may cause disagreement of the results, since the two SSRIs have been reported to have different pharmacodynamic and pharmacokinetic profiles (Bourin et al, 2001). On the contrary, Yoshida et al (2003) reported that the A-1438G polymorphism of the 5-HT2A gene had no significant effect on the incidence of nausea.…”

Contribution of the dopaminergic system to the effect of chronic fluoxetine in the rat forced swim test.

“…The physiopathology of depression has been traditionally associated to dysfunction in noradrenergic and dopaminergic systems (Porsolt, Le Pichon, & Jalfre, 1977;Andrews, Ninan, & Nemeroff, 1996;Anttila & Leinonen, 2002;Bourin, Chue, & Guillon, 2001;Chalon et al, 2003;Delgado & Moreno, 2000;Gupta, Nihalani, & Masand, 2007;O'Leary et al, 2007). There is growing evidence that dopaminergic systems play an important role in both depression physiopathology and therapeutic mechanisms of some antidepressants (Ainsworth, Smith, & Sharp, 1998;Benloucif & Galloway, 1991;Willner, 1983;Willner, 1997;D'Aquila, Collu, Gessa, & Serra, 2000;D'Aquila, Monleon, Borsini, Brain, & Willner, 1997;D'Aquila et al, 2003;D'Aquila et al, 2000).…”

Therapeutic monitoring of psychoactive drugs - antidepressants: A review

“…Elderly subjects taking paroxetine have higher plasma concentrations and slower elimination than younger subjects 22 . Elimination is also reduced in severe renal and hepatic impairment 23 . Paroxetine is characterized by large interindividual pharmacokinetic variability and heterogeneous response patterns 24 .…”