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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Pharmacogenetics, Healthy

Intervention / Treatment
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* Drug: Risperidone
* Drug: Placebo
* Drug: Haloperidol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria that chosen participants must fulfill: Subjects of both genders with ages between 18-30 years. Subjects with normal values of clinical history and physical exploration. Subjects without evidence of significant disease, organic or psychiatric, according to anamnesis (medical history), physical exploration and complementary tests. Subjects with normal values of laboratory tests (hemogram and biochemical tests). Subjects with normal values of vital signs (Blood pressure, Heart rate, Temperature) and Electrocardiography. Female subjects must be using safe contraceptive methods, different from oral contraceptives. Subjects could not have taken part in other clinical trials during the three previous months before to the beginning of this study. Subjects could not have given blood during four weeks before the beginning of this study. Subjects must accept freely their participation, with written informed consent. 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* Subjects must accept to undergo neuroimaging (SPECT). Exclusion Criteria to reject potential participants: Subjects with previous medical history of alcoholism or drug dependency. Subjects with clinical history of allergy, idiosyncrasy or hypersensitivity to drugs. 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. 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. 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. Pregnant women, women in breastfeeding period or women that do not use safe contraceptive methods, different from oral contraception. Subjects with positive serology for hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency virus (HIV). Subjets with positive test in urine for ethanol, cannabis, cocaine, amphetamines, benzodiazepines and/or opiates.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Risperidone<br> | Drug: Risperidone<br>* 1 single dose of 2.5mg masked in 250 mL of peach juice, for 1 day. Oral administration.<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* 1 single dose of 2.5mL physiological serum masked in 250 mL of peach juice, for 1 day. Oral administration.<br>|
| Experimental: Haloperidol<br> | Drug: Haloperidol<br>* 1 single dose of 5mg masked in 250 mL of peach juice, for 1 day. Oral administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes among genotypes in 24 h monitored Haloperidol and Risperidone pharmacokinetics | Through a catheter, blood samples will be obtained at different time frames. Samples will be kept with anticoagulants and centrifuged immediately to separate the plasmatic fraction, which will be kept at -70ºC. In order to determine the concentration of Haloperidol (and reduced Haloperidol) and Risperidone (and 9-OH Risperidone), high performance liquid chromatography -HPLC- will be achieved. A poblation-pharmacokinetic model of the two AP drugs will be designed, and drug vs. placebo treatment results will be compared. Parameters determined: AUC, Cmax, Tmax, T(1/2), Vd, CL and MRT. | + 0.5h, +1h, +2h, +4h, +6h, +8h, +12h and +24h post-treatment | 
| Changes from placebo in occupancy of striatal dopaminergic receptors by Haloperidol and Risperidone at 5h | The tracer [123I]IBZM, a dopaminergic antagonist, will be administered by means of intravenous injection (at +3h post-treatment) at the opposite arm from which blood samples will be obtained. Neuroimaging will be done in SPECT gamma chambers and images will be quantified comparing drug vs. placebo treatment results. Parameters determined: Average Count Striatum and Count Occipital Cortex, Specific Uptake Ratio, D2 Occupational Receptor. 100% of volunteers will undergo SPECT after placebo treatment and, among them, 50% after Haloperidol treatment and 50% after Risperidone treatment. | +3h post-treatment: tracer injection. +5h post-treatment: image acquisition | 
| 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 | AP-induced EPS measured by: Heteroadministered scales: Simpson-Angus Rating Scale (SARS). Assesses drug-induced parkinsonism (tremor, hypokinesia, rigidity, and postural instability). Barnes Akathisia Rating Scale (BARS). Assesses drug-induced akathisia (restlessness and inability to sit still). Actimetry: Continuous recording of movement, in terms of count of movements per minute, by using a wrist actimeter (model AW4) fitted to the arm not used for writing. Differences observed by comparing EPS after drug vs. placebo treatment will be considered. | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | AP-induced positive/negative symptoms measured by: Brief Psychiatric Rating Scale (BPRS). Heteroadministered and semi structured interview (20 min) to determine hostility, suspiciousness, hallucination, and grandiosity. Scale for the Assessment of Negative Symptoms (SANS). Heteroadministered interview (20 min) to determine affective blunting, alogia, avolition/apathy, anhedonia/asociality and disturbance of attention. Subjective Deficit Syndrome Scale (SDSS). Autoadministered interview (20 min) to determine emotionless. Drug vs. placebo treatment will be compared. | 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 | 
| Changes from baseline in 24h prolactin kinetics | Blood samples analyzed will be the ones obtained for measuring plasmatic levels of antipsychotic drugs. Plasmatic levels of prolactin will be measured by enzymatic immunoassay approaches. Differences observed after drug vs. placebo treatment will be compared. | At -1h pre-treatment (basal level) and at +0.5h, +1h, +2h, +4h, +6h, +8h, +12h and +24h post-treatment | 
| Changes from baseline in anticholinergic activity through Whole Saliva Test (WST) during 8h | Salivette Containers (from Sarstedt) will be used to determine the saliva flow accumulated during 2 min. Differences observed after drug vs. placebo treatment will be compared. | At -1h pre-treatment (basal level) and at +1h, +2h, +4h, +6h and +8h post-treatment | 
| Changes from baseline in cardiovascular effects through Orthostatism measurement during 8h | In order to determine orthostatic hypotension, Systolic Arterial Pressure (SAP), Diastolic Arterial Pressure (DAP) and Cardiac frequency (CF) will be measured both after 3 min in supine position and after 3 min in erect position. Differences observed after drug vs. placebo treatment will be compared. | At -1h pre-treatment (basal level) and at +1h, +2h, +4h, +6h and +8h post-treatment | 
| Changes from baseline in sedative effects during 8h | AP-induced sedative effects measured by: Psychomotricity Flicker-Fusion Critical Frequency (FFCF). Detection of a flickering/stable red light. Simple Reaction Time (SRT). Detection of a simple red light switched on/off. Digit Symbol Substitution Test (DSST). Measures the amount of digits substituted correctly by its corresponding symbol. Tapping Test (TT). Average of tappings per second. Pupilometry. Detect pupil's response in basal conditions. Visual Analog Scales (VAS). Detect agreement to a statement by indicating a position within two end-points. | At -1h pre-treatment (basal level) and at +1h, +2h, +4h, +6h and +8h post-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacogenetics, Antipsychotics, Extrapyramidal Symptoms