Major
Amitriptyline × fluvoxamine
Tricyclic antidepressants (TCA)×SSRI
Mechanism
Fluvoxamine blocks CYP1A2 and CYP2C19 – the main amitriptyline demethylation routes. TCA plasma levels rise 2- to 4-fold. Plus serotonin syndrome 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. Alternative antidepressants if fluvoxamine fails: sertraline or escitalopram (no CYP1A2 effect). For neuropathic pain, replace amitriptyline with gabapentin or pregabalin.