Venlafaxine

Venlafaxine is a serotonin and noradrenaline reuptake inhibitor (SNRI) used for depression, generalised anxiety disorder, social anxiety disorder and panic disorder. It is serotonergic at low doses and adds noradrenergic effects from about 150 mg daily, with dose-related hypertension, marked discontinuation symptoms and greater toxicity in overdose than SSRIs.

Classification. SNRI, phenylethylamine structure.

Mechanism. Inhibits serotonin reuptake at all doses and noradrenaline reuptake at higher doses, with weak dopamine reuptake inhibition at the highest doses.

Pharmacokinetics. Well absorbed; food slows but does not reduce absorption of the extended-release form. Converted by CYP2D6 to O-desmethylvenlafaxine (desvenlafaxine), which is active. Half-life about 5 hours for venlafaxine and 11 hours for the metabolite. Renal excretion of drug and metabolites.

All regimens are oral with no loading dose.

Major depression, adults.

• Extended-release: start 75 mg once daily with food (37.5 mg for 4 to 7 days if tolerance is a concern).
• Immediate-release: start 37.5 mg twice daily, or 75 mg daily in 2 to 3 divided doses.
• Titration: increase by up to 75 mg at intervals of at least 4 days (2 weeks or more is usual).
• Maintenance 75 to 225 mg daily. Maximum 225 mg daily as an outpatient; immediate-release up to 375 mg daily in severely ill hospital patients.
• Duration: at least 6 months after remission; 2 years or more for recurrent illness.

Generalised anxiety disorder and social anxiety disorder. Extended-release 75 mg once daily; maximum 225 mg daily.

Panic disorder. Extended-release 37.5 mg daily for 7 days, then 75 mg daily; maximum 225 mg daily.

Dose limits. Creatinine clearance 30 to 89 mL/min: reduce the daily dose by 25%. Under 30 mL/min or haemodialysis: reduce by 50% and give after dialysis. Mild to moderate liver impairment: reduce by 50%; severe liver impairment: reduce by more than 50% under specialist advice.

Contraindications. MAOI use now or within 14 days of stopping it, linezolid, intravenous methylene blue, uncontrolled hypertension, hypersensitivity. Avoid in patients at high risk of serious ventricular arrhythmia.

Serious adverse effects. Boxed-warning-level risk of suicidal thinking and behaviour in under 25 years. Dose-related hypertension and tachycardia, serotonin syndrome, hyponatraemia, bleeding, mania, seizures, angle-closure glaucoma, QT prolongation, severe discontinuation syndrome. In overdose: seizures, tachycardia, QRS widening and cardiac arrest.

Common adverse effects. Nausea, headache, sweating, dry mouth, dizziness, insomnia, constipation, sexual dysfunction, raised blood pressure.

Interactions. Serotonin syndrome risk rises with tramadol, triptans, linezolid and lithium. Bleeding risk rises with NSAIDs and anticoagulants. CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion) raise venlafaxine levels. Khat and other sympathomimetics add to blood pressure and heart rate effects.

Common prescribing errors. Starting extended-release at too high a dose; not checking blood pressure; stopping abruptly; supplying large quantities to patients at risk of self-harm.

Special groups.

• Pregnancy: use only if benefit outweighs risk; may increase maternal blood pressure, neonatal adaptation symptoms with late exposure and a small risk of postpartum haemorrhage.
• Breastfeeding: moderate transfer; monitor the infant for sedation and poor feeding.
• Children: not advised in under 18 years.
• Older adults: raised risk of hyponatraemia and falls; titrate slowly.
• Kidney impairment: reduce the daily dose by 25% when creatinine clearance is 30 to 89 mL/min and by 50% when under 30 mL/min or on haemodialysis.
• Liver impairment: reduce the daily dose by 50% in mild to moderate impairment.
• Regional: CYP2D6 ultrarapid phenotypes are reported at higher frequency in some East African populations and may lower exposure; genotyping is rarely available, so titrate to clinical response. Ask about khat use.

Formulations. Immediate-release tablets 37.5 mg, 75 mg; extended-release capsules 37.5 mg, 75 mg, 150 mg. Swallow extended-release capsules whole with food at the same time each day.

Baseline. Blood pressure (control hypertension first), pulse, mood history including past mania, suicide risk, sodium in older adults, ECG if cardiac disease, bleeding risk.

Monitoring. Blood pressure and pulse at baseline, after each dose increase and regularly while on doses over 150 mg daily; reduce the dose or switch if sustained hypertension develops. Review within 1 to 2 weeks and after each dose change for suicidality. 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. Check lipids and lipid-related risk periodically at higher doses.

Stopping. Taper over at least 4 weeks and longer if symptoms occur, as dizziness, paraesthesia, nausea and irritability are common.

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