RESEARCH MONOGRAPH · KDC-MN-203
Paroxetine
Paroxetine (Paxil) is an SSRI with the strongest grip on the serotonin pump in its entire class, but it also blocks acetylcholine receptors strongly enough to produce dry mouth, constipation, and the cognitive fog usually associated with older tricyclic antidepressants. GSK launched it in 1992. It has a notoriously rough discontinuation profile because its short half-life means the drug clears before the brain has time to adjust, producing the so-called brain zaps and flu-like symptoms patients describe when stopping abruptly. It is also a potent blocker of the CYP2D6 liver enzyme, which creates real interaction problems for people taking other medications. Approved for depression, panic, OCD, social anxiety, PTSD, and generalized anxiety. Not stocked by Kodiac. This monograph is provided for research and educational reference.
Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.
Selective serotonin reuptake inhibitor
A piperidine SSRI with the highest SERT affinity in the class and clinically significant muscarinic antagonism.
Abstract
Paroxetine ((3S,4R)-3-[(2H-1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine; CAS 61869-08-7; molecular formula C19H20FNO3; molecular weight 329.36) is a phenylpiperidine SSRI developed at Ferrosan and licensed to SmithKline Beecham (now GSK), approved by the FDA in 1992 under the trade name Paxil. SERT affinity is the highest of any SSRI (Ki approximately 0.13 nM); off-target activity at muscarinic acetylcholine receptors (Ki approximately 100 nM) produces sedation and dry mouth at clinical doses, and weak NET inhibition contributes to noradrenergic effects at higher doses. Plasma half-life is approximately 21 hours with significant interpatient variability driven by CYP2D6 polymorphism (paroxetine is both a substrate and a potent inhibitor of CYP2D6, producing nonlinear pharmacokinetics at high doses). The compound exhibits the most pronounced discontinuation syndrome of the SSRI class, attributed to the relatively short half-life and muscarinic rebound on cessation. Used as a high-affinity SERT reference compound in receptor binding assays and as a comparator in OCD and anxiety disorder research.
Mechanism of action
Highest-affinity SERT inhibition in the SSRI class; muscarinic M1-M3 antagonism contributes to anticholinergic profile. Potent CYP2D6 inhibitor with nonlinear PK at high doses.
Reported research dose ranges
Reported research dose ranges in the literature.
References
- Bourin M, et al. Paroxetine: a review. CNS Drug Rev 2001.
- Kaye CM, et al. A review of the metabolism and pharmacokinetics of paroxetine in man. Acta Psychiatr Scand Suppl 1989.
- Tatsumi M, et al. Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol 1997.
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The full reference document is provided strictly for research use only. It reports research dose ranges from the published literature, not instructions for use in humans or animals.
FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.