Mirtazapine × Venlafaxine

Both drugs enhance serotonergic transmission. Venlafaxine inhibits serotonin and noradrenaline reuptake; mirtazapine blocks presynaptic α2 receptors and increases noradrenergic and serotonergic transmission. Together they raise the risk of serotonin syndrome (both SmPCs). Post-marketing reports of QT prolongation and torsades de pointes exist for both drugs, mostly in overdose or with other risk factors. In a dedicated QT study, mirtazapine 45 and 75 mg prolonged QT by an amount not considered clinically meaningful (FDA mirtazapine label).

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, fever. Signs of arrhythmia: palpitations, skipped beats, fainting.

Mirtazapine is added to venlafaxine on purpose when depression has not responded, or has responded only partly, to an antidepressant. NICE allows such a combination of drugs from different classes, but advises warning the patient about a possible higher side-effect burden and considering a specialist consultation. Observe the patient closely at the start of co-treatment and after each dose increase (both SmPCs). If signs of serotonin syndrome appear, stop both drugs at once and start symptomatic treatment (FDA labels of both drugs). Before starting venlafaxine, measure blood pressure and bring existing hypertension under control; then check blood pressure regularly and after each dose increase (venlafaxine labels). In patients at high risk of serious arrhythmia or QT prolongation, weigh benefit and risk before prescribing venlafaxine (venlafaxine SmPC). In known cardiovascular disease or a family history of QT prolongation, prescribe mirtazapine with caution (mirtazapine labels).