Paroxetine

Paroxetine is an SSRI used for depression, obsessive-compulsive disorder, panic disorder, social anxiety disorder, generalised anxiety disorder and post-traumatic stress disorder. It is the most anticholinergic and most sedating SSRI, has the highest rate of discontinuation symptoms, and is a strong CYP2D6 inhibitor.

Classification. SSRI, phenylpiperidine structure.

Mechanism. The most potent serotonin transporter inhibition among SSRIs, with weak muscarinic receptor antagonism and weak noradrenaline reuptake inhibition. Response builds over 2 to 4 weeks.

Pharmacokinetics. Well absorbed and unaffected by food. Extensive CYP2D6 metabolism to inactive metabolites. Metabolism saturates and inhibits CYP2D6, so levels rise more than proportionally with dose. Half-life about 21 hours, with no active metabolite.

All regimens are oral with no loading dose.

Major depression, adults.

• Start 20 mg once daily in the morning with food.
• Titration: increase in steps of 10 mg at intervals of at least 1 week.
• Maintenance 20 to 40 mg daily. Maximum 50 mg daily.
• Duration: at least 6 months after remission; 2 years or more for recurrent illness.

Obsessive-compulsive disorder. Start 20 mg daily, increase by 10 mg weekly to a usual 40 mg daily. Maximum 60 mg daily.

Panic disorder. Start 10 mg daily, increase by 10 mg weekly to a usual 40 mg daily. Maximum 60 mg daily.

Social anxiety disorder, generalised anxiety disorder, post-traumatic stress disorder. Start 20 mg daily; increase by 10 mg weekly if needed. Maximum 50 mg daily.

Dose limits. Adults over 65 years: maximum 40 mg daily. Severe kidney impairment (creatinine clearance under 30 mL/min) or severe liver impairment: start 10 mg, maximum 40 mg daily.

Contraindications. MAOI use now or within 14 days of stopping it, pimozide, thioridazine, linezolid, intravenous methylene blue, hypersensitivity.

Serious adverse effects. Boxed-warning-level risk of suicidal thinking and behaviour in under 25 years. Serotonin syndrome, hyponatraemia, bleeding, mania, seizures, angle-closure glaucoma, severe discontinuation syndrome. Anticholinergic effects can cause urinary retention and confusion in older adults.

Common adverse effects. Nausea, sedation, dry mouth, constipation, sweating, weight gain, sexual dysfunction, tremor.

Interactions. Strong CYP2D6 inhibition raises tricyclic antidepressants, metoprolol, flecainide, propafenone, atomoxetine and risperidone. It reduces the activation of codeine and tramadol and the formation of endoxifen from tamoxifen, so tamoxifen is avoided. Bleeding risk rises with NSAIDs and anticoagulants. Serotonin syndrome risk rises with tramadol, triptans and linezolid.

Common prescribing errors. Prescribing during pregnancy or when planning pregnancy when alternatives exist; stopping abruptly; combining with tamoxifen; using in older adults with dementia or retention.

Special groups.

• Pregnancy: avoid when possible because of an increased risk of cardiac malformation with first-trimester exposure; if already taking it, weigh the risks of stopping against continuing.
• Breastfeeding: low infant levels; acceptable.
• Children: not advised in under 18 years.
• Older adults: maximum 40 mg daily; anticholinergic burden, falls and hyponatraemia.
• Kidney impairment: levels rise when creatinine clearance is under 30 mL/min; start 10 mg and cap at 40 mg daily.
• Liver impairment: in severe impairment start 10 mg and cap at 40 mg daily.

Formulations. Tablets 10 mg, 20 mg and 30 mg; oral suspension 10 mg/5 mL in some regions; controlled-release tablets exist with different dosing. Give once daily in the morning with food.

Baseline. Mood history including past mania, suicide risk, pregnancy status and contraception, sodium in older adults, bleeding risk, medicines list, prostate or bladder outlet symptoms.

Monitoring. Review within 1 to 2 weeks and after each dose change for suicidality and activation. Check sodium 2 to 4 weeks after starting in high-risk patients; review the need for the drug if sodium falls under 130 mmol/L and stop it if under 125 mmol/L or if symptomatic. Weigh at each review.

Stopping. Taper slowly over 4 weeks or longer, in steps of 10 mg every 1 to 2 weeks, and more slowly at the lowest doses. Dizziness, paraesthesia, irritability and flu-like symptoms are typical if stopped abruptly.

Referral and escalation. Refer to psychiatry for suicidal intent, psychosis, mania, or failure of two adequate courses. Suspected serotonin syndrome needs emergency care.