Typical Versus Atypical Antipsychotics; Occupation of Striatal Receptors and the Appearance of Extrapyramidal Symptomatology, in Healthy Volunteers (APSEP)
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Purpose
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-.
| Condition | Intervention | Phase |
|---|---|---|
|
Pharmacogenetics Healthy |
Drug: Risperidone Drug: Placebo Drug: Haloperidol |
Phase 1 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Investigator) |
| 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 |
- Changes among genotypes in 24 h monitored Haloperidol and Risperidone pharmacokinetics [ Time Frame: + 0.5h, +1h, +2h, +4h, +6h, +8h, +12h and +24h post-treatment ] [ Designated as safety issue: Yes ]
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.
- Changes from placebo in occupancy of striatal dopaminergic receptors by Haloperidol and Risperidone at 5h [ Time Frame: +3h post-treatment: tracer injection. +5h post-treatment: image acquisition ] [ Designated as safety issue: Yes ]
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.
- 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 [ Time Frame: 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 ] [ Designated as safety issue: Yes ]
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.
- 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) [ Time Frame: 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 ] [ Designated as safety issue: Yes ]
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.
- Changes from baseline in 24h prolactin kinetics [ Time Frame: At -1h pre-treatment (basal level) and at +0.5h, +1h, +2h, +4h, +6h, +8h, +12h and +24h post-treatment ] [ Designated as safety issue: Yes ]
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.
- Changes from baseline in anticholinergic activity through Whole Saliva Test (WST) during 8h [ Time Frame: At -1h pre-treatment (basal level) and at +1h, +2h, +4h, +6h and +8h post-treatment ] [ Designated as safety issue: Yes ]
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.
- Changes from baseline in cardiovascular effects through Orthostatism measurement during 8h [ Time Frame: At -1h pre-treatment (basal level) and at +1h, +2h, +4h, +6h and +8h post-treatment ] [ Designated as safety issue: Yes ]
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.
- Changes from baseline in sedative effects during 8h [ Time Frame: At -1h pre-treatment (basal level) and at +1h, +2h, +4h, +6h and +8h post-treatment ] [ Designated as safety issue: Yes ]
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.
| Estimated Enrollment: | 24 |
| Study Start Date: | February 2011 |
| Estimated Study Completion Date: | December 2011 |
| Estimated Primary Completion Date: | November 2011 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
| Experimental: Risperidone |
Drug: Risperidone
1 single dose of 2.5mg masked in 250 mL of peach juice, for 1 day. Oral administration.
|
| Placebo Comparator: Placebo |
Drug: Placebo
1 single dose of 2.5mL physiological serum masked in 250 mL of peach juice, for 1 day. Oral administration.
|
| Experimental: Haloperidol |
Drug: Haloperidol
1 single dose of 5mg masked in 250 mL of peach juice, for 1 day. Oral administration.
|
Show Detailed Description Eligibility| Ages Eligible for Study: | 18 Years to 30 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | Yes |
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.
Contacts and Locations| Spain | |
| Hospital Clinic of Barcelona | |
| Barcelona, Spain, 08036 | |
| Hospital de la Santa Creu i Sant Pau | |
| Barcelona, Spain, 08025 | |
| Principal Investigator: | Miquel Bernardo Arroyo, Head of Psychiatry | Hospital Clinic of Barcelona |
| Study Director: | Amalia Lafuente Flo, Pharmacology professor | Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of Barcelona |
| Study Chair: | Sergi Mas Herrero, Pos-doc assistant professor | Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of Barcelona |
| Study Chair: | Patricia Gassó Astorga, Pos-doc associated professor | Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of Barcelona |
| Study Chair: | Gemma Trias Lafuente, Psychologist | Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of Barcelona |
| Study Chair: | Eva Ferrando Martorell, Pre-doc | Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of Barcelona |
| Study Chair: | Rosa M Antonijoan, Clinical Pharmacologist | Clinical Pharmacology Service, Hospital de la Santa Creu i Sant Pau |
| Study Chair: | Analía Azaro, Clinical Pharmacologist | Clinical Pharmacology Service, Hospital de la Santa Creu i Sant Pau |
| Study Chair: | Ignasi Carrió Gasset, Head of Nuclear Med Service | Nuclear Medicine Service, Hospital de la Santa Creu i Sant Pau |
| Study Chair: | Manuel Barbanoj J Rodríguez, Head of Clinical Pharmacology, Head of Clinical Pharmacology | Clinical Pharmacology service, Hospital de la Santa Creu i Sant Pau |
More Information
Publications:
| Responsible Party: | Miquel Bernardo Arroyo (Principal Investigator and Leader of Hospital Clinic psychiatric department), Hospital Clinic of Barcelona |
| ClinicalTrials.gov Identifier: | NCT01259973 History of Changes |
| Other Study ID Numbers: | TRA-065, 2009-016519-40, TRA-065 |
| Study First Received: | December 13, 2010 |
| Last Updated: | April 15, 2011 |
| Health Authority: | Spain: Agencia Española de Medicamentos y Productos Sanitarios Spain: Ministry of Health |
Keywords provided by Hospital Clinic of Barcelona:
|
Pharmacogenetics Antipsychotics Extrapyramidal Symptoms |
Additional relevant MeSH terms:
|
Haloperidol Haloperidol decanoate Antipsychotic Agents Risperidone Antiemetics Autonomic Agents Peripheral Nervous System Agents Physiological Effects of Drugs Pharmacologic Actions Central Nervous System Agents Therapeutic Uses |
Gastrointestinal Agents Tranquilizing Agents Central Nervous System Depressants Psychotropic Drugs Dopamine Antagonists Dopamine Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action Anti-Dyskinesia Agents Serotonin Antagonists Serotonin Agents |
ClinicalTrials.gov processed this record on May 22, 2013