Clinical trial NCT01259973: Typical Versus Atypical Antipsychotics; Occupation of Striatal Receptors and the Appearance of Extrapyramidal Symptomatology, in Healthy Volunteers
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 type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Pharmacogenetics
Healthy
Keywords: Pharmacogenetics
Antipsychotics
Extrapyramidal Symptoms
Lead sponsor: Hospital Clinic of Barcelona
Sponsor class: OTHER
Collaborators: name: Fundacion Clinic per a la Recerca Biomédica
name: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
name: University of Barcelona
First posted: 2010-12-15
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 30
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER

Brief 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-.

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 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.

Primary outcomes:
measure: Changes among genotypes in 24 h monitored Haloperidol and Risperidone pharmacokinetics
timeFrame: + 0.5h, +1h, +2h, +4h, +6h, +8h, +12h and +24h post-treatment
measure: Changes from placebo in occupancy of striatal dopaminergic receptors by Haloperidol and Risperidone at 5h
timeFrame: +3h post-treatment: tracer injection. +5h post-treatment: image acquisition
measure: 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
timeFrame: Heteroadministered scales will be measured at -1h pre-treatment (basal level) and at +3h. Actimetry will be measured continuosly since -1h pre-treatment until +24h
Secondary outcomes:
measure: 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)
timeFrame: BPRS and SANS scales will be measured at -1h pre-treatment (basal level) and at +3h. SDSS scale will be measured at -1h pre-treatment (basal level) and at +24h
measure: Changes from baseline in 24h prolactin kinetics
timeFrame: At -1h pre-treatment (basal level) and at +0.5h, +1h, +2h, +4h, +6h, +8h, +12h and +24h post-treatment
measure: Changes from baseline in anticholinergic activity through Whole Saliva Test (WST) during 8h
timeFrame: At -1h pre-treatment (basal level) and at +1h, +2h, +4h, +6h and +8h post-treatment
measure: Changes from baseline in cardiovascular effects through Orthostatism measurement during 8h
timeFrame: At -1h pre-treatment (basal level) and at +1h, +2h, +4h, +6h and +8h post-treatment
measure: Changes from baseline in sedative effects during 8h
timeFrame: At -1h pre-treatment (basal level) and at +1h, +2h, +4h, +6h and +8h post-treatment
Other outcomes:
Locations:
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Clinic of Barcelona
Study officials:
affiliation: Hospital Clinic of Barcelona
name: Miquel Bernardo Arroyo, Head of Psychiatry
role: PRINCIPAL_INVESTIGATOR
affiliation: Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of Barcelona
name: Amalia Lafuente Flo, Pharmacology professor
role: STUDY_DIRECTOR
affiliation: Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of Barcelona
name: Sergi Mas Herrero, Pos-doc assistant professor
role: STUDY_CHAIR
affiliation: Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of Barcelona
name: Patricia Gassó Astorga, Pos-doc associated professor
role: STUDY_CHAIR
affiliation: Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of Barcelona
name: Gemma Trias Lafuente, Psychologist
role: STUDY_CHAIR
affiliation: Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of Barcelona
name: Eva Ferrando Martorell, Pre-doc
role: STUDY_CHAIR
affiliation: Clinical Pharmacology Service, Hospital de la Santa Creu i Sant Pau
name: Rosa M Antonijoan, Clinical Pharmacologist
role: STUDY_CHAIR
affiliation: Clinical Pharmacology Service, Hospital de la Santa Creu i Sant Pau
name: Analía Azaro, Clinical Pharmacologist
role: STUDY_CHAIR
affiliation: Nuclear Medicine Service, Hospital de la Santa Creu i Sant Pau
name: Ignasi Carrió Gasset, Head of Nuclear Med Service
role: STUDY_CHAIR
affiliation: Clinical Pharmacology service, Hospital de la Santa Creu i Sant Pau
name: Manuel Barbanoj J Rodríguez, Head of Clinical Pharmacology, Head of Clinical Pharmacology
role: STUDY_CHAIR
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