Background: Recently, new polymorphisms were described in connection with intermediate and ultrarapid CYP2D6 metabolism. These may allow a much desired prediction of metabolic activity within the extensive metabolizer group. The functional consequences are still being discussed with few data available for clinical patients. Methods: We conducted a prospective, blinded twocenter study seeking correlations between CYP2C19 (*2,*3, and *4; conventional PCR) and CYP2D6 genotypes (*1 to *10, *35, and *41; real-time and multiplex PCR) and drug concentrations (Emit ® and HPLC) in 50 Caucasians receiving amitriptyline (AT; 75 mg twice a day). Results: Eighteen CYP2C19 heterozygotes (*1/*2) had higher AT (P ‫؍‬ 0.033) and lower nortriptyline (NT; P ‫؍‬ 0.059) concentrations than 30 homozygotes (*1/*1). For CYP2D6, we calculated two new indices, i.e., the allelespecific change of concentration on identical background (ASCOC) and a quantitative functional gene

Background: Amitriptyline has been replaced in many countries by alternative and more expensive drugs based on claims of improved tolerability and toxicity and despite slightly reduced efficacy. Preliminary studies indicate that adverse effects could be linked to polymorphisms of drug-metabolizing enzymes, but information on their clinical impact remains scanty and includes mainly case reports. We conducted a prospective blinded two-center study seeking correlations between CYP2C19 and CYP2D6 genotypes, drug concentrations, adverse events, and therapy response. Methods: Fifty Caucasian inpatients with at least medium-grade depressive disorder received amitriptyline at a fixed dose of 75 mg twice a day. Blood samples for concentration monitoring of amitriptyline and nortriptyline were taken weekly until discharge along with evaluations of depression (Hamilton Depression Scale and Clinical Global Impression Scale) and side effect (Dosage Record and Treatment Emergent Symptoms Scale; DOTES) scores. Results: In a ROC analysis, nortriptyline but not amitriptyline concentrations correlated with side effects (DOTES sum score >5; area under the curve, 0.733; P ‫؍‬ 0.008). Carriers of two functional CYP2D6 alleles had a