Major
Amitriptyline × duloxetine
Tricyclic antidepressants (TCA)×SNRI
Mechanism
Duloxetine moderately blocks CYP2D6 (an amitriptyline metabolic route); amitriptyline plasma levels rise. Both drugs are also serotonergic and noradrenergic – serotonin syndrome and cardiotoxicity risk.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.
Management
Avoid the combination. For neuropathic pain, choose one: duloxetine (better profile in diabetic neuropathy) or gabapentin/pregabalin. Alternative for anxious depression: mirtazapine.
Check the full regimen, not just this pair
Opens the checker with these two drugs prefilled. Add the rest of the regimen and recompute additive risks.