Desvenlafaxine

Desvenlafaxine is the active metabolite of venlafaxine, formulated as an extended-release salt, and is used for major depression. It has a fixed-dose profile with limited added benefit over 50 mg daily, little CYP metabolism and dose-related blood pressure effects. Availability varies widely by region.

Classification. SNRI.

Mechanism. Inhibits serotonin and noradrenaline reuptake, with a higher noradrenaline-to-serotonin balance than many SSRIs at usual doses.

Pharmacokinetics. Bioavailability about 80%, unaffected by food. Metabolised mainly by glucuronidation, with minor CYP3A4 oxidation; about 45% is excreted unchanged in urine. Half-life about 11 hours. Few CYP-mediated interactions.

Oral extended-release; no loading dose.

Major depression, adults.

• Start and usual dose 50 mg once daily.
• Titration: higher doses add adverse effects without clear added benefit, so a dose increase is rarely used; where it is used, increase to 100 mg daily, the highest dose in routine use (labels in some regions permit more).
• Maintenance 50 mg daily.
• Duration: at least 6 months after remission; 2 years or more for recurrent illness.

Dose limits. Creatinine clearance 30 to 50 mL/min: maximum 50 mg daily. Under 30 mL/min or end-stage kidney disease: 25 mg daily or 50 mg on alternate days; no supplement after dialysis. Moderate to severe liver impairment: maximum 100 mg daily.

Contraindications. MAOI use now or within 14 days of stopping it, linezolid, intravenous methylene blue, hypersensitivity to desvenlafaxine or venlafaxine.

Serious adverse effects. Boxed-warning-level risk of suicidal thinking and behaviour in under 25 years. Hypertension, serotonin syndrome, hyponatraemia, bleeding, mania, seizures, angle-closure glaucoma, raised cholesterol and triglycerides, severe discontinuation syndrome.

Common adverse effects. Nausea, dizziness, dry mouth, sweating, 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. Strong CYP3A4 inhibitors (ketoconazole) raise levels modestly. Taking it with venlafaxine duplicates therapy.

Common prescribing errors. Prescribing 100 mg or more routinely; not reducing the dose in kidney impairment; crushing or splitting the tablet; stopping abruptly.

Special groups.

• Pregnancy: use only if benefit outweighs risk; late exposure can cause neonatal adaptation symptoms.
• Breastfeeding: transfers into milk; monitor the infant for sedation and poor feeding.
• Children: not advised in under 18 years.
• Older adults: raised risk of hyponatraemia and falls; kidney function often limits the dose.
• Kidney impairment: maximum 50 mg daily when creatinine clearance is 30 to 50 mL/min; 25 mg daily or 50 mg on alternate days when under 30 mL/min.
• Liver impairment: maximum 100 mg daily in moderate to severe impairment.

Formulations. Extended-release tablets 25 mg, 50 mg and 100 mg. Swallow whole at the same time daily, with or without food. Do not crush, chew or split.

Baseline. Blood pressure (control hypertension first), mood history including past mania, suicide risk, sodium in older adults, creatinine clearance, lipids.

Monitoring. Blood pressure at baseline and at each review; reduce the dose or switch if hypertension is sustained. 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 periodically.

Stopping. Taper over at least 4 weeks, for example 25 mg daily or 25 mg on alternate days before stopping.

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