Objective:~The preliminary results indicate that pharmacological factors (AP, dose and drug availability depending on cytochrome activity) are risk factors for AP-induced EPS.~In this clinical trial, the investigators will study, in healthy volunteers, the effects on pharmacokinetics, occupancy of striatal dopaminergic receptors and the appearance of EPS according to genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3). The investigators will compare a typical AP (Haloperidol) with an atypical AP (Risperidone), both of which are metabolized by CYP2D6 and CYP3A5.~Specific objectives:~Study the relationship between genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3) and plasmatic levels of Haloperidol and Risperidone.~Study the relationship between genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3) and the grade of occupancy of striatal dopaminergic receptors with Haloperidol and Risperidone.~Study the relationship between plasmatic levels of Haloperidol and Risperidone and the grade of occupancy of striatal dopaminergic receptors with these two drugs.~Study the relationship between genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3), plasmatic levels of Haloperidol and Risperidone, and the grade of occupancy of striatal dopaminergic receptors with these two drugs, with the appearance of AP-induced EPS.~Methodology:~From a cohort of 200 healthy volunteers (males and females with ages between 18-30 years), previously genotyped for CYP2D6 and CYP3A5 genes (from January to June 2010), the investigators have selected subjects depending on their metabolizer phenotype (poor metabolizers, intermediate metabolizers, extensive metabolizers and ultrarapid metabolizers) by DNA extraction from whole blood samples and SNP detection approaches.~Finally, the investigators will include the following four phenotypical groups with 6-8 subjects in each of the groups (a total of N=32 subjects, approximately):~poor metabolizers (PM) CYP2D6*~poor metabolizers (PM) CYP3A5**~extensive metabolizers (EM) CYP2D6/CYP3A~ultrarapid metabolizers (UM) CYP2D6*~The design corresponds to a three ways cross-over randomized and double-blind trial, with a wash-out period of one week among each treatment.~Measurements of occupancy of striatal dopaminergic receptors will be done by single photon emission computed tomography -SPECT- and SEP will be measured based on the Simpson-Angus scale and actimetry.~General protocol:~One week before their participation in the trial, volunteers will undergo clinical and physical explorations (blood test, electrocardiography, urine drug screening...) and will be trained in the different tests of the study (to minimize differences regarding to experience).~During the study, participants will be treated with a single dose of an AP drug (5mg Haloperidol or 2.5mg Risperidone) or a single dose of placebo (2.5mL physiological serum).~Plasma levels will be measured at +0.5h, +1h, +2h, +4h, +6h, +8h and +12h of drug/placebo administration.~The tracer [123I]IBZM will be administered at +3h of drug/placebo administration and SPECT will be performed at +5h.~Status of EPS, as well as positive and negative AP-derived symptoms, will be measured at -1h and at different time frames post-drug/placebo administration, beginning at +3h and until +24h (depending on each Scale used).~Participants will be hospitalized for three complete days (separated between them by one wash-out week after each treatment) from 8.00h to 8.00h of the following day at Phase I Unit of Hospital de Sant Pau i de la Santa Creu, in Barcelona, in order to monitor the results obtained after each treatment. During their hospitalization, participants will be given food and drink every two hours.~This clinical trial will start in February 2011 and finish in November 2011.
The purpose of this study is to determine in healthy volunteers treated with typical or atypical antipsychotics -AP-, the relationship between genetic polymorphisms in cytochrome genes CYP2D6 (*3, *4, *5, *6 and Nxn) and CYP3A5 (*3) with antipsychotic pharmacokinetics, occupancy of striatal dopaminergic receptors and the appearance of extrapyramidal symptomatology -EPS-.