Major
Amitriptyline × Sertraline
Tricyclic antidepressants (TCA)×Selective serotonin reuptake inhibitors (SSRIs)
Mechanism
Dual risk. Sertraline blocks CYP2D6 – the amitriptyline metabolic route – and amitriptyline plasma levels rise 2- to 4-fold. Both drugs are also serotonergic.
Symptoms
Serotonin syndrome (agitation, tremor, tachycardia). Amitriptyline anticholinergic effects (dry mouth, constipation, confusion in older patients). QT prolongation.
Management
If combined for augmentation, halve amitriptyline and check ECG at 2 weeks. Alternative: mirtazapine or agomelatine (no CYP2D6 dependence).