3 The overall aim of pharmacogenetics is to contribute to drug choice and dosage according to the individual genetic makeup, thus leading to a personalized, more efficacious, and less harmful therapy. This review will give a brief summary of the progress in the field and assess the prospects for

future success in this area. Polymorphic drug-metabolizing enzymes All ADs are highly lipophilic compounds and, as such, subject to extensive metabolism by a number of enzymes, including Inhibitors,research,lifescience,medical those of the cytochrome P-450 (CYP) family. The CYPs were recognized quite as major source of pharmacokinetic variability, as they typically show large interlude vidual and sometimes intraindividual differences in activities due to genetic variants. More than 50 CYP genes have been described in the human genome to date, but less than 10 of them are of major significance in psychiatry Among those are Inhibitors,research,lifescience,medical CYP 3 A, which metabolizes about 50% of all psychotropic drugs, followed by CYP 2D6, CYP 2C19, CYP 1A2, and CYP 2C9.4 CYPs show distinct but overlapping substrate specificities; their activities may be induced or inhibited by certain drugs or foodstuffs, such as grapefruit juice (an overview of the major CYPs, their AD substrates, inhibitors, and inducers is given in Table I).5 Thus, swallowing the drugs with juice or combining

them with other drugs (which is rather common in Inhibitors,research,lifescience,medical clinical psychiatry) might have uncontrollable, interactive effects on their bioavailability6 Table I. Major cytochrome P450 isoenyzmes (CYP), their antidpressant (AD) substrates, enzyme inhibitors, and inducers.5 TCA, tricyclic AD; SSRI, selective serotonin reuptake inhibitor. The presence of allelic variants in CYP enzymes with varying degrees of functional Inhibitors,research,lifescience,medical significance may result in three

Inhibitors,research,lifescience,medical main phenotypes, poor see more metabolizers (PMs), normal metabolizers (NMs), and extensive metabolizers (EMs). The PMs lack an active form of the expressed enzyme due to an inactivating allelic variant; NMs have at least one copy of an active gene; and EMs contain duplicated or amplified gene copies, thus leading to either increased (maybe toxic) or decreased (maybe ineffective) concentrations of for the drug.7 CYP 2D6 is the most extensively studied P-450 isoenzyme in psychiatry. More than 70 allelic variants have been identified so far, but only a few are clinically relevant, eg, CYP 2D6*3A, CYP 2D6*4B, and CYP 2D6*5, which all lead to the PM phenotype. Moreover, there are considerable ethnic variations in the frequencies of CYP 2D6 mutations, which are more common in Caucasians (7%) anci Africans (7% to 8%) than in the Asian population (1%).8 In contrast, the incidence of PMs of CYP 2C19 substrates is much higher in Asians (15% to 30%) than in Caucasians.5 Several studies have shown a significant contribution of the CYP 2D6 genotype on plasma concentrations of different ADs, and PMs had a higher incidence of side effects.