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Typical Versus Atypical Antipsychotics; Occupation of Striatal Receptors and the Appearance of Extrapyramidal Symptomatology, in Healthy Volunteers

Information source: Hospital Clinic of Barcelona
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Pharmacogenetics; Healthy

Intervention: Risperidone (Drug); Placebo (Drug); Haloperidol (Drug)

Phase: Phase 1

Status: Enrolling by invitation

Sponsored by: Hospital Clinic of Barcelona

Official(s) and/or principal investigator(s):
Miquel Bernardo Arroyo, Head of Psychiatry, Principal Investigator, Affiliation: Hospital Clinic of Barcelona
Amalia Lafuente Flo, Pharmacology professor, Study Director, Affiliation: Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of Barcelona
Sergi Mas Herrero, Pos-doc assistant professor, Study Chair, Affiliation: Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of Barcelona
Patricia Gassó Astorga, Pos-doc associated professor, Study Chair, Affiliation: Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of Barcelona
Gemma Trias Lafuente, Psychologist, Study Chair, Affiliation: Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of Barcelona
Eva Ferrando Martorell, Pre-doc, Study Chair, Affiliation: Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of Barcelona
Rosa M Antonijoan, Clinical Pharmacologist, Study Chair, Affiliation: Clinical Pharmacology Service, Hospital de la Santa Creu i Sant Pau
Analía Azaro, Clinical Pharmacologist, Study Chair, Affiliation: Clinical Pharmacology Service, Hospital de la Santa Creu i Sant Pau
Ignasi Carrió Gasset, Head of Nuclear Med Service, Study Chair, Affiliation: Nuclear Medicine Service, Hospital de la Santa Creu i Sant Pau
Manuel Barbanoj J Rodríguez, Head of Clinical Pharmacology, Head of Clinical Pharmacology, Study Chair, Affiliation: Clinical Pharmacology service, Hospital de la Santa Creu i Sant Pau

Summary

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-.

Clinical Details

Official title: Phase I Clinical Trial. Study of the Impact of Pharmacogenetic Markers in Predicting the Appearance of Extrapyramidal Symptomatology After the Treatment With Typical vs. Atypical Antipsychotics, in Healthy Volunteers

Study design: Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator)

Primary outcome:

Changes among genotypes in 24 h monitored Haloperidol and Risperidone pharmacokinetics

Changes from placebo in occupancy of striatal dopaminergic receptors by Haloperidol and Risperidone at 5h

Changes from baseline in Extrapyramidal Symptomatology (EPS) at 3h, measured by Simpson-Angus Rating Scale (SARS)and Barnes Akathisia Rating Scale (BARS), and during 24 h, measured by actimetry

Secondary outcome:

Changes from baseline in Positive and Negative Symptomatology at 3h, measured by Brief Psychiatric Rating Scale (BPRS) and Scale for the Assessment of Negative Symptoms (SANS), and at 24h, measured by Subjective Deficit Syndrome Scale (SDSS)

Changes from baseline in 24h prolactin kinetics

Changes from baseline in anticholinergic activity through Whole Saliva Test (WST) during 8h

Changes from baseline in cardiovascular effects through Orthostatism measurement during 8h

Changes from baseline in sedative effects during 8h

Detailed description: 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.

Eligibility

Minimum age: 18 Years. Maximum age: 30 Years. Gender(s): Both.

Criteria:

Inclusion Criteria that chosen participants must fulfill: 1. Subjects of both genders with ages between 18-30 years. 2. Subjects with normal values of clinical history and physical exploration. 3. Subjects without evidence of significant disease, organic or psychiatric, according to anamnesis (medical history), physical exploration and complementary tests. 4. Subjects with normal values of laboratory tests (hemogram and biochemical tests). 5. Subjects with normal values of vital signs (Blood pressure, Heart rate, Temperature) and Electrocardiography. 6. Female subjects must be using safe contraceptive methods, different from oral contraceptives. 7. Subjects could not have taken part in other clinical trials during the three previous months before to the beginning of this study. 8. Subjects could not have given blood during four weeks before the beginning of this study. 9. Subjects must accept freely their participation, with written informed consent. 10. After previous genotyping for CYP2D6 and CYP3A4/A5 genes, chosen participants must have one of the following genotypes of interest for this study:

- poor metabolizers (PM) CYP2D6*

- poor metabolizers (PM) CYP3A5**

- extensive metabolizers (EM) CYP2D6/CYP3A

- ultrarapid metabolizers (UM) CYP2D6*

11. Subjects must accept to undergo neuroimaging (SPECT). Exclusion Criteria to reject potential participants: 1. Subjects with previous medical history of alcoholism or drug dependency. 2. Subjects with clinical history of allergy, idiosyncrasy or hypersensitivity to drugs. 3. Subjects with clinical history or current treatment with drugs whose metabolism could interfere in the action of CYP2D6 and CYP3A5 cytochromes, particularly if they are not able to give up the treatment for a period of 3-4 weeks before the beginning of the study and during its execution. 4. Subjects with clinical history or current consumption of drugs that could interfere in the action of CYP2D6 and CYP3A5 cytochromes (St John's wort, cruciferae, grapefruit ...), particularly if they are not able to give up their consumption for a period of 3-4 weeks before the beginning of the study and during its execution. 5. Subjects with contraindications for antipsychotic treatments due to: familiar/clinical history of hypersensitivity to antipsychotic drugs, deep depression of central nervous system, coma, Parkinson's disease. 6. Pregnant women, women in breastfeeding period or women that do not use safe contraceptive methods, different from oral contraception. 7. Subjects with positive serology for hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV). 8. Subjets with positive test in urine for ethanol, cannabis, cocaine, amphetamines, benzodiazepines and/or opiates.

Locations and Contacts

Hospital Clinic of Barcelona, Barcelona 08036, Spain

Hospital de la Santa Creu i Sant Pau, Barcelona 08025, Spain

Additional Information

Related publications:

Lafuente A, Bernardo M, Mas S, Crescenti A, Aparici M, Gassó P, Catalan R, Mateos JJ, Lomeña F, Parellada E. Dopamine transporter (DAT) genotype (VNTR) and phenotype in extrapyramidal symptoms induced by antipsychotics. Schizophr Res. 2007 Feb;90(1-3):115-22. Epub 2006 Dec 5.

Lafuente A, Bernardo M, Mas S, Crescenti A, Aparici M, Gasso P, Deulofeu R, Mane A, Catalan R, Carne X. Polymorphism of dopamine D2 receptor (TaqIA, TaqIB, and-141C Ins/Del) and dopamine degradation enzyme (COMT G158A, A-278G) genes and extrapyramidal symptoms in patients with schizophrenia and bipolar disorders. Psychiatry Res. 2008 Nov 30;161(2):131-41. doi: 10.1016/j.psychres.2007.08.002. Epub 2008 Oct 15.

Crescenti A, Mas S, Gassó P, Parellada E, Bernardo M, Lafuente A. Cyp2d6*3, *4, *5 and *6 polymorphisms and antipsychotic-induced extrapyramidal side-effects in patients receiving antipsychotic therapy. Clin Exp Pharmacol Physiol. 2008 Jul;35(7):807-11. doi: 10.1111/j.1440-1681.2008.04918.x. Epub 2008 Mar 12.

Gassó P, Mas S, Bernardo M, Alvarez S, Parellada E, Lafuente A. A common variant in DRD3 gene is associated with risperidone-induced extrapyramidal symptoms. Pharmacogenomics J. 2009 Dec;9(6):404-10. doi: 10.1038/tpj.2009.26. Epub 2009 Jun 9.

Gassó P, Mas S, Crescenti A, Alvarez S, Parramon G, Garcia-Rizo C, Parellada E, Bernardo M, Lafuente A. Lack of association between antipsychotic-induced extrapyramidal symptoms and polymorphisms in dopamine metabolism and transport genes. Psychiatry Res. 2010 Jan 30;175(1-2):173-5. doi: 10.1016/j.psychres.2009.07.006. Epub 2009 Nov 5.

Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther. 2007 Dec;116(3):496-526. Epub 2007 Oct 9. Review.

Mauri MC, Volonteri LS, Colasanti A, Fiorentini A, De Gaspari IF, Bareggi SR. Clinical pharmacokinetics of atypical antipsychotics: a critical review of the relationship between plasma concentrations and clinical response. Clin Pharmacokinet. 2007;46(5):359-88. Review.

Zanger UM, Turpeinen M, Klein K, Schwab M. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem. 2008 Nov;392(6):1093-108. doi: 10.1007/s00216-008-2291-6. Epub 2008 Aug 10. Review.

Catafau AM, Penengo MM, Nucci G, Bullich S, Corripio I, Parellada E, García-Ribera C, Gomeni R, Merlo-Pich E; Barcelona Clinical Imaging in Psychiatry Group. Pharmacokinetics and time-course of D(2) receptor occupancy induced by atypical antipsychotics in stabilized schizophrenic patients. J Psychopharmacol. 2008 Nov;22(8):882-94. doi: 10.1177/0269881107083810. Epub 2008 Feb 28.

Starting date: February 2011
Last updated: April 15, 2011

Page last updated: August 23, 2015

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