Major
Amitriptyline × Fluoxetine
Tricyclic antidepressants (TCA)×Selective serotonin reuptake inhibitors
Mechanism
Dual mechanism. Fluoxetine raises synaptic serotonin and strongly blocks CYP2D6 – the amitriptyline metabolic route. Amitriptyline plasma levels rise 2- to 4-fold while serotonergic activity adds up.
Symptoms
Serotonin syndrome (agitation, tremor, tachycardia, hyperthermia). Amitriptyline anticholinergic effects intensify (dry mouth, constipation, urinary retention, confusion in older patients). QT prolongation.
Management
Avoid the combination. If combined for augmentation, halve amitriptyline and check ECG at 2 weeks. Alternative antidepressant: mirtazapine or agomelatine (no CYP2D6 dependence).