Paroxetine

Indications

• FDA-approved in adults for major depressive disorder at 20-50 mg/day of the immediate-release tablet, dosed once daily in the morning.
• FDA-approved for obsessive-compulsive disorder and panic disorder, both of which are usually titrated toward the 60 mg/day ceiling.
• FDA-approved for social anxiety disorder, generalized anxiety disorder, and post-traumatic stress disorder, making its anxiety labeling the broadest.
• Paroxetine CR is approved for major depressive disorder, panic disorder, social anxiety disorder, and premenstrual dysphoric disorder.
• Brisdelle, a 7.5 mg paroxetine mesylate capsule, is approved for moderate to severe vasomotor symptoms of menopause, not for depression.
• Off-label for premature ejaculation and for hot flashes in breast cancer survivors, though tamoxifen users should receive a different agent.

Mechanism of action

• The most potent serotonin transporter inhibitor of the marketed SSRIs, producing near-complete transporter occupancy at standard clinical doses.
• Weak norepinephrine transporter inhibition emerges at higher doses and may add antidepressant effect while worsening sweating and insomnia.
• Meaningful muscarinic antagonism gives it the anticholinergic profile of dry mouth, constipation, blurred vision, and cognitive dulling in elders.
• Nitric oxide synthase inhibition contributes to sexual dysfunction rates that are the highest reported among the SSRI class.
• Potent mechanism-based CYP2D6 inhibition is essentially irreversible, so its interaction effect persists for days after the drug is stopped.

Pharmacokinetics

• Completely absorbed with extensive first-pass metabolism; food has no clinically meaningful effect on the extent of absorption.
• Half-life is about 21 hours with no active metabolites, which is why missed doses so reliably produce discontinuation symptoms.
• Metabolized almost entirely by CYP2D6, an enzyme it saturates and inactivates, producing markedly nonlinear dose-concentration relationships.
• Because of that autoinhibition, raising the dose from 20 to 40 mg/day can more than double plasma concentrations rather than simply doubling them.
• Poor CYP2D6 metabolizers and patients on fluoxetine or bupropion reach substantially higher exposures at any given prescribed dose.

Dosing

• Start 20 mg PO daily in the morning for depression, social anxiety, generalized anxiety, or PTSD; use 10 mg/day to start in panic disorder.
• Titrate by 10 mg no more often than weekly; maximum is 50 mg/day for depression, generalized anxiety, and PTSD, and 60 mg/day for OCD and panic.
• Controlled-release starts at 25 mg/day for depression with a 62.5 mg/day maximum, and at 12.5 mg/day for panic with a 75 mg/day maximum.
• In severe renal or hepatic impairment and in older adults, start at 10 mg/day and do not exceed 40 mg/day of the immediate-release form.
• Formulations include 10, 20, 30, and 40 mg tablets, 10 mg/5 mL suspension, 12.5, 25, and 37.5 mg CR tablets, and 7.5 mg mesylate capsules.
• Taper very slowly, often by 10 mg monthly with a liquid formulation at the end, because withdrawal is the most severe in the SSRI class.

Adverse effects

• Somnolence, fatigue, dry mouth, and constipation are more common than with other SSRIs and reflect its antimuscarinic and antihistaminic load.
• Weight gain averages 2 to 4 kg over a year, the highest among SSRIs, and is a frequent reason patients ask to switch agents.
• Sexual dysfunction occurs in 60-70 percent of treated patients, with delayed or absent orgasm the most commonly reported complaint.
• Discontinuation syndrome with dizziness, electric-shock sensations, irritability, and vivid dreams begins within one to two days of a missed dose.
• Hyponatremia, increased bleeding with NSAIDs or anticoagulants, serotonin syndrome, and treatment-emergent mania are the serious concerns.
• First-trimester exposure has been linked to a small excess of cardiac septal defects, which changes prescribing in women of childbearing potential.

Monitoring

• Monitor suicidality, activation, and agitation weekly for the first four weeks and after each dose change, most closely in patients under 25.
• Confirm contraception plans or pregnancy status before starting in reproductive-age patients given the fetal cardiac signal.
• Check sodium at baseline and within two to four weeks in older adults and diuretic users, and whenever confusion or falls emerge.
• Track weight and waist circumference at baseline and every three months, since weight gain accumulates gradually and drives discontinuation.
• Review the full medication list for CYP2D6 substrates at every visit rather than only at initiation, since inhibition is durable.

Interactions

• Contraindicated with MAOIs, linezolid, methylene blue, pimozide, and thioridazine, the latter two because of QT prolongation risk.
• Potent CYP2D6 inhibition roughly halves tamoxifen conversion to endoxifen, so avoid it entirely in patients taking tamoxifen for breast cancer.
• Raises levels of tricyclics, metoprolol, atomoxetine, risperidone, and aripiprazole, and blocks the analgesic activation of codeine and tramadol.
• Additive serotonergic risk with triptans, tramadol, fentanyl, and St. John's wort; additive anticholinergic burden with antihistamines and oxybutynin.
• Increases bleeding risk with aspirin, NSAIDs, and warfarin, and its own levels fall substantially with phenytoin, carbamazepine, or rifampin.

Special populations

• Generally avoided in pregnancy, especially the first trimester, because of the association with cardiac septal defects reported in several cohorts.
• Compatible with breastfeeding at low relative infant doses, but sertraline remains the usual first choice when starting during lactation.
• Not approved in pediatric patients, and pediatric trials showed both poor efficacy in depression and elevated suicidality signals.
• In older adults limit to 40 mg/day and expect anticholinergic cognitive effects, falls, and hyponatremia at a higher rate than with sertraline.
• Start at 10 mg/day with a 40 mg/day ceiling in severe renal impairment with creatinine clearance under 30 mL/min or in severe hepatic impairment.

Clinical pearls

• Worst discontinuation syndrome of any SSRI: never stop abruptly, and taper with liquid at the end.
• Never combine with tamoxifen; 2D6 inhibition blocks conversion to active endoxifen.
• Most sedating, most weight gain, most anticholinergic, and most sexual dysfunction of the SSRIs.