This study was performed in elderly patients (1) to assess in vivo the degree to which CYP2D6- mediated metabolism of debrisoquine at baseline determines plasma concentration to dose quoti- ents for nortriptyline or paroxetine after 4 weeks of treatment, and (2) to compare the effects of nortriptyline and paroxetine on debrisoquine me- tabolism after 6 weeks of treatment. CYP2D6 activity was estimated in 66 subjects (71.4  7.2 years) before initiating treatment and again after 6 weeks of treatment with either nor- triptyline or paroxetine under randomized, double- blind conditions according to a standard protocol. CYP2D6 activity was estimated by the debrisoquine recovery ratio in a 6- to 8-hour urine sample col- lected after oral administration of 10 mg debriso- quine sulfate. Nortriptyline and paroxetine plasma concentrations were obtained weekly. Baseline debrisoquine recovery ratio values were significantly correlated with the plasma concentra- tion to dose quotient at 4 weeks for both nor- triptyline (r 0.75, p  0.0001, N  29) and paroxetine (r 0.50, p  0.003, N  33). Treat- ment with either nortriptyline or paroxetine was associated with a significant decrease in the me- dian debrisoquine recovery ratio, reflecting inhibi- tion of CYP2D6 metabolism. The percent decrease associated with nortriptyline was significantly smaller than that with paroxetine ( p < 0.0001). None of the patients treated with nortriptyline but 19 of the 32 extensive metabolizers treated with paroxetine were converted to phenotypic poor metabolic status. Our observations of CYP2D6 inhibition are con- sistent with in vitro data and results obtained in younger healthy volunteers. The significant corre- lations between baseline debrisoquine recovery ra- tio and the plasma concentrations to dose quotients at 4 weeks for both nortriptyline and paroxetine are consistent with CYP2D6 playing a major role in the metabolism of both drugs. CYP2D6 inhibition by pa- roxetine, which effectively converted 59% of pa- tients to phenotypic PMs, may be especially rele- vant for elderly patients given their generally higher concentration of paroxetine. (J Clin Psychopharm- acol 2002;22:481–486) C YP2D6 (debrisoquine hydroxylase) is involved in the oxidative metabolism of many psychotropics. This enzyme shows genetic polymorphism leading to si- multaneous occurrence of variant forms of the gene product. 1,2 It is clinically difficult to predict who lacks this enzyme, which may lead to excessive substrate con- centrations, or who may have a duplicate allele, which may lead to therapeutic failures at typical drug doses as a result of enhanced metabolism. There has been dra- matic progress in the molecular techniques for deter- mining an individual’s CYP2D6 genotype. 3 However, CYP2D6 genotype reveals a patient’s inherent capacity to metabolize CYP2D6 substrates but provides no infor- mation on the enzyme activity, which varies markedly due to modulation by a host of environmental factors, including concomitant drugs. 4 This problem is particu- larly pertinent for geriatric patients on multiple med- ications. 5 Thus, the more relevant information is the es- timated enzyme activity or phenotype, which can be assessed by using a probe drug. Currently, debrisoquine sulfate, dextromethorphan hydrobromide, and sparteine are standard probes used for the assessment of CYP2D6 phenotype. Debrisoquine (DBQ) and sparteine (both unavailable in the United States) are highly selective probes for CYP2D6, while dextromethorphan is partially metabolized by CYP3A4 481 DOI: 10.1097/01.jcp.0000033398.43191.6a 0271-0749/02/2205-0481/0 Journal of Clinical Psychopharmacology Vol. 22, No. 5 Copyright © 2002 by Lippincott Williams & Wilkins, Inc. Printed in U.S.A. Effect of Nortriptyline and Paroxetine on CYP2D6 Activity in Depressed Elderly Patients LALITHKUMAR K. SOLAI, MD*, BRUCE G. POLLOCK, MD, PHD*, BENOIT H. MULSANT, MD*†, REGINALD F. FRYE, PHARMD, PHD‡, MARK D. MILLER, MD*, ROBERT A. SWEET, MD*, MAGGIE KIRSHNER, BA*, DENISE SORISIO, BS*, AMY BEGLEY, MA*, AND CHARLES F. REYNOLDS, III, MD* *Mental Health Intervention Research Center for the Study of Late-Life Mood Disorders and Department of Psychiatry, University of Pittsburgh School of Medicine; †Geriatric Research, Education, and Clinical Center, VA Pittsburgh Health Care System; and ‡University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania Received October 20, 2000; accepted after revision January 8, 2002. Address requests for reprints to: LalithKumar K. Solai, MD, West- ern Psychiatric Institute and Clinic, Beaver Valley Mental Health Ser- vices, 176 Virginia Avenue, Rochester, PA 15074. Address e-mail to: solail@msx.upmc.edu