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Selection of an antidepressant is influenced by many factors, including the patient's current drug regimen and the drug's potential for drug-drug interactions. Many psychotropic agents are known to be involved in drug-drug interactions because they are metabolized by various cytochrome pigment 450 (CYP) isoenzymes. In vitro testing with human hepatic microsomal preparations and monoclonal antibody techniques has allowed for the identification and investigation of many of these isoenzymes. Also, screening of substrates (both drug and probe) at the level of the various enzymes expressed in the human liver has allowed for the development of models that predict the risk for drug-drug interactions in vivo. Antidepressants are metabolized by and are competitive inhibitors of several isoenzymes: CYP1A2, CYP2D6, CYP3A3/4, CYP2C8/9, CYP2C19, and others. Of these, CYP2D6 has been the most thoroughly investigated and is the most extensively characterized, whereas CYP3A3/4 are more abundant and play a major role in the metabolism of many commonly used drugs. CYP2D6, but not CYP3A3/4, is subject to genetic polymorphism, which has been identified through the administration of a probe drug (sparteine, debrisoquin, or dextromethorphan). This analysis allows for the determination of an individual's "metabolizer status." This article discusses the CYP isoenzyme system in general terms and presents selected in vitro information that has been used to determine the likelihood of in vivo drug-drug interactions with various antidepressants. Of the marketed antidepressants, venlafaxine seems to have one of the most favorable drug-interaction profiles, and data specific to it are highlighted. In vitro and in vivo data indicate that venlafaxine either does not significantly inhibit or weakly inhibits the activity of isoenzymes CYP2C9, CYP2D6, CYP1A2, or CYP3A3/4.