Paroxetine: SSRI with Potent Anticholinergic and CYP2D6-Inhibiting Properties
Paroxetine (Paxil, Seroxat) is a selective serotonin reuptake inhibitor (SSRI) with additional significant muscarinic (anticholinergic), noradrenergic, and sigma-1 receptor activity. It is the most anticholinergic of the SSRIs and the most potent CYP2D6 inhibitor.
Approved for MDD, panic disorder, GAD, social anxiety disorder, PTSD, and OCD. Widely used but notable for high discontinuation syndrome risk and sexual dysfunction.
Mechanism of Action
Potently inhibits the serotonin transporter (SERT), raising synaptic 5-HT levels. Additional anticholinergic and noradrenergic properties account for some side effects (dry mouth, constipation, weight gain) and may contribute to anxiolytic efficacy.
Indications & Use
MDD, panic disorder, social anxiety disorder (SAD), generalised anxiety disorder (GAD), PTSD, OCD, premenstrual dysphoric disorder (PMDD). Among the most approved indications of any SSRI.
Dosage
MDD/anxiety: start 20 mg/day, target 20–40 mg/day (max 60 mg). PMDD: 20 mg/day continuously or only during luteal phase. Controlled-release (CR) formulation available. Reduce dose in elderly, renal and hepatic impairment.
Side Effects
Common: sexual dysfunction (highest among SSRIs), weight gain, dry mouth, constipation, sedation. Important: severe discontinuation syndrome if stopped abruptly (dizziness, 'brain zaps', irritability). Not recommended in pregnancy (cardiac malformations, neonatal withdrawal).
Drug Interactions
Potent CYP2D6 inhibitor: dramatically increases levels of codeine, tamoxifen (reduces efficacy), TCAs, risperidone, metoprolol. MAOIs: contraindicated. Tamoxifen: paroxetine converts tamoxifen to active endoxifen — paroxetine abolishes this — avoid in breast cancer.
Contraindications
Concurrent MAOIs, concurrent thioridazine/pimozide (risk of fatal arrhythmia via CYP2D6), pregnancy (particularly 1st and 3rd trimester). Not recommended in children/adolescents.
Frequently Asked Questions
Why is paroxetine difficult to stop?
Paroxetine has a short half-life (~21 hours) and no active metabolites, causing a rapid drop in serotonin levels on cessation. This produces a severe discontinuation syndrome — 'brain zaps', dizziness, flu-like symptoms. Always taper slowly (weeks to months).
Can paroxetine be taken during pregnancy?
It is generally avoided — associated with cardiac septal defects (first trimester) and neonatal adaptation syndrome (third trimester). If used in pregnancy, switch before delivery if possible. Discuss risks/benefits with the prescriber.
Why does paroxetine interact with tamoxifen?
Paroxetine is a potent CYP2D6 inhibitor. Tamoxifen is converted by CYP2D6 to its active metabolite endoxifen, which provides most of the anti-cancer benefit. Paroxetine blocks this conversion, reducing tamoxifen efficacy — avoid this combination in breast cancer patients.
References
- NICE NG222 Depression 2022
- EMA Seroxat/Paxil SPC 2023
- Jordan S et al. BMJ 2019 (SSRI discontinuation)
Medical Disclaimer: This information is for educational purposes only and does not replace professional medical advice.