human psychopharmacology Hum Psychopharmacol Clin Exp 2004; 19: 293–298. Published online 27 May 2004 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hup.598 Clomipramine, fluoxetine and CYP2D6 metabolic capacity in depressed patients P. Vandel 1 *, E. Haffen 1 , S. Nezelof 1 , F. Broly 2 , J. P. Kantelip 3 and D. Sechter 1 1 Fe ´de ´ration de Psychiatrie et Psychologie Me ´dicale, Centre Hospitalo-Universitaire, 25030 Besanc ¸on, France 2 De ´partement de Biochimie, Ho ˆpital Calmette, 59000 Lille, France 3 Laboratoire de Pharmacologie, Centre Hospitalo-Universitaire, 25030 Besanc ¸on, France Cytochrome P450-2D6 may be involved in the metabolism of many drugs such as psychotropic drugs and its genetic poly- morphism is responsible for inter-individual differences in the therapeutic effect and toxicity of these drugs. Moreover with the same genetic basis, CYP2D6 metabolic capacity variations are observed. Different factors of variation may be involved, among them the prescribed drugs. The aim of this study was to compare the influence of two types of antidepressants, tricyclic (clomipramine) and sero- tonergic specific recapture inhibitor (SSRI) (fluoxetine), on the CYP2D6 metabolic capacity of depressed inpatients. The CYP2D6 phenotype (dextromethorphan test) was determined in 56 genotyped (PCR-SSCP) depressed caucasian inpatients with a heterozygous genotype. Forty-five subjects were treated with clomipramine and eleven received fluoxetine. The dex- tromethorphan metabolic ratio (MR) median was significantly higher in the fluoxetine group (0.255) than in the clomipra- mine group (0.083, p < 0.014). In this study, fluoxetine involved a greater decrease of CYP2D6 metabolic capacity than clomipramine. Clinical implications and the possible connection between a decreased CYP2D6 activity and adverse drug effects were discussed. Caution should be taken when drugs with a low therapeutic index must be coprescribed in such patients. Copyright # 2004 John Wiley & Sons, Ltd. key words — CYP2D6; phenotype; clomipramine; fluoxetine INTRODUCTION Cytochrome P450-2D6 (CYP2D6) is involved in the metabolism of many psychotropic drugs, among them specific serotonin reuptake inhibitors (SSRIs) and tri- cyclic antidepressants (TCAs) that are widely pre- scribed (Baumann, 1986; Bertilsson and Dahl, 1996; Brosen and Gram, 1989; Cholerton et al., 1992; Eichelbaum and Gross, 1990; Tanaka, 1998). Its genetic polymorphism is responsible for inter-indivi- dual differences in the therapeutic effect and toxicity of many drugs (Brosen and Gram, 1989; Chen et al., 1996; Spina et al., 1992; Spina et al., 1994; Vandel et al., 1999). Moreover with the same genetic basis, intra-individual CYP2D6 metabolic capacity varia- tions are observed in patients, with possible clinical implications. Different factors of variation may be involved, drug treatment being an important one. Patients receiving CYP2D6 substrate medications are likely to experience a temporary decrease of their CYP2D6 metabolic capacity. The CYP2D6 affinity varies among psychotropic drugs. Fluoxetine, a SSRI antidepressant, is characterized in vitro by a CYP2D6 affinity higher than clomipramine, a tricyclic antide- pressant, for example (Crewe et al., 1992; Nielsen et al., 1996; Ball et al., 1997). Fluoxetine and its active metabolite norfluoxetine are considered as strong inhibitors of CYP2D6 metabolic capacity (Brosen and Skjelbo, 1991; Crewe et al., 1992). Among the tricyclic antidepressants, clomipramine may also diminish the CYP2D6 activity to a lesser extent (Crewe et al., 1992). The consequence of these affinities for the CYP2D6 isoenzyme is that coprescription of these drugs may Received 22 December 2003 Copyright # 2004 John Wiley & Sons, Ltd. Accepted 31 March 2004 *Correspondence to: Dr P. Vandel, Fe ´de ´ration de Psychiatrie et Psychologie Me ´dicale, Centre Hospitalo-Universitaire 25030 Besanc ¸on Cedex, France. Tel: 03 81 21 81 54. Fax: 03 81 21 88 17. E-mail: pvandel@chu-besancon.fr