Pharmacogenetics and psychopharmacotherapy

Response to drugs can vary between individuals and between different ethnic populations. The biological (age, gender, disease and genetics), cultural and environmental factors which contribute to these variations are consider ed in this review. The most important aspect is the genetic variability bet ween individuals in their ability to metabolize drugs due to expression of 'polymorphic' enzymes. Polymorphism enables division of individuals within a given population into at least two groups, poor metabolisers (PMs) and ex tensive metabolisers (EMs) of certain drugs. The two most extensively studied genetic polymorphisms are those involving cytochrome P450 2D6 (CYP2D6) and CYP2C19. CYP2D6 metabolizes a number of an tidepressants, antipsychotics, beta-adrenoceptor blockers, and antiarrhythm ic drugs. About 7% of Caucasians and 1% of Asians are PMs of CYP2D6 substra tes. CYP2C19 enzyme participates in the metabolism of omeprazole, propranol ol and psychotropic drugs such as hexobarbital, diazepam, citalopram, imipr amine, clomipramine and amitriptyline. The incidence of PMs of CYP2C19 subs trates is much higher in Asians (15-30%) than in Caucasians (3-6%). Variati ons in metabolism of psychotropic drugs result in variations in their pharm acokinetic parameters. This may lead to clinically significant intra- and i nter-ethnic differences in pharmacological responses. Such variations are d iscussed in this review. Differential receptor-mediated response may play a role in ethnic differenc es in responses to antipsychotics and tricyclic antidepressants, but such p harmacodynamic factors remain to be systematically investigated. The result s of studies of ethnic differences in response to psychopharmacotherapy app ear to be discrepant, most probably due to limitations of study design, sma ll sample size, inadequately defined study sample, and lack of control of c onfounding factors. The clinical value of understanding pharmacogenetics is in its use to optim ize therapeutic efficacy, to prevent toxicity of those drugs whose metaboli sm is catalysed by polymorphic isoenzymes, and to contribute to the rationa l design of new drugs. Finally, applications and impact of pharmacogenetics in the field of psychopharmacotherapy are discussed.