Vortioxetine

Vortioxetine is a multimodal antidepressant used for major depression. It combines serotonin transporter inhibition with direct effects at several serotonin receptors. It has a low rate of sexual dysfunction and weight gain compared with SSRIs, nausea is its leading adverse effect, and its half-life is long.

Classification. Multimodal antidepressant, bis-aryl-sulphanyl amine.

Mechanism. Inhibits the serotonin transporter, agonises 5-HT1A, partially agonises 5-HT1B, and antagonises 5-HT3, 5-HT1D and 5-HT7 receptors. The clinical importance of these receptor effects is still debated.

Pharmacokinetics. Bioavailability about 75%, unaffected by food. Metabolised mainly by CYP2D6 with minor CYP3A4, CYP2C9, CYP2C19 and CYP2A6 contributions to an inactive carboxylic acid. Half-life about 66 hours. Steady state takes about 2 weeks.

Oral; no loading dose.

Major depression, adults.

• Start 10 mg once daily.
• Titration: increase to 20 mg daily after at least 1 week if tolerated and response is inadequate; reduce to 5 mg if tolerance is poor.
• Maintenance 10 to 20 mg daily. Maximum 20 mg daily.
• Duration: at least 6 months after remission.

Dose limits. Adults over 65 years: start 5 mg. CYP2D6 poor metabolisers, or use with strong CYP2D6 inhibitors (bupropion, fluoxetine, paroxetine, quinidine): maximum 10 mg daily. Use with strong CYP inducers (rifampicin, carbamazepine, phenytoin): consider increasing the dose, to no more than three times the original dose, and reduce when the inducer stops.

Contraindications. MAOI use now or within 14 days of stopping it, 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 or hypomania, seizures, angle-closure glaucoma.

Common adverse effects. Nausea (the most frequent, usually settling in 1 to 2 weeks), diarrhoea, constipation, vomiting, dizziness, pruritus, abnormal dreams.

Interactions. Strong CYP2D6 inhibitors double exposure. Rifampicin, carbamazepine and phenytoin lower levels. Bleeding risk rises with NSAIDs, aspirin and anticoagulants. Serotonin syndrome risk rises with tramadol, triptans, lithium and linezolid.

Common prescribing errors. Prescribing 20 mg with a CYP2D6 inhibitor; not reducing the dose in poor metabolisers; stopping abruptly; assuming it is free of sexual dysfunction.

Special groups.

• Pregnancy: limited data; use only if benefit outweighs risk.
• Breastfeeding: limited data; avoid unless benefit is clear.
• Children: not advised in under 18 years.
• Older adults: start 5 mg; check sodium.
• Kidney impairment: no adjustment for mild to moderate; caution in severe impairment.
• Liver impairment: no adjustment for mild to moderate; not studied in severe impairment.

Formulations. Tablets 5 mg, 10 mg, 15 mg and 20 mg; oral drops in some regions. Give once daily with or without food. Availability is limited in many regions.

Baseline. Mood history including past mania, suicide risk, sodium in older adults, bleeding risk, medicines list for CYP2D6 inhibitors and inducers.

Monitoring. Review within 1 to 2 weeks and after each dose change for suicidality and tolerability. 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. If there is no improvement after 4 to 6 weeks at an adequate dose, increase the dose or switch.

Stopping. From 15 mg or 20 mg daily, reduce to 10 mg daily for 1 week before stopping; from 10 mg, taper over 1 to 2 weeks or longer if symptoms occur.

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