A 61-year-old woman, a nonsmoker, was admitted to the hospital because of endogenous depression. No concomitant disease, especially kidney or liver dysfunction, was diagnosed. After 9 days of treatment with 125 mg of amitriptyline (AMI) daily, she developed signs of a severe anticholinergic syndrome. Plasma concentrations of AMI (510 ng/ml) and nortriptyline (NOR; 320 ng/ml) were very high and the half-life of AMI was about 120 h. The debrisoquine metabolic ratio was 0.55 and 0.79 on two occasions, which shows that she had no deficiency of cytochrome P450IID6. This result was confirmed with a dextromethorphan test, analysis of restriction fragment length polymorphisms (29/29-kb fragments), and genotyping with allele-specific polymerase chain reaction (homozygous 29 kb wild-type alleles). Patients with high plasma levels of tricyclic antidepressants are usually poor metabolizers of debrisoquine. Before the administration of AMI, our patient was pretreated with fluoxetine. A slowly reversible interaction with fluoxetine or an extremely long-lasting metabolite may be responsible for the long plasma half-life of AMI.