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

This study is enrolling participants by invitation only.
Sponsor:
Collaborators:
Fundacion Clinic per a la Recerca Biomédica
Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
University of Barcelona
Information provided by:
Hospital Clinic of Barcelona
ClinicalTrials.gov Identifier:
NCT01259973
First received: December 13, 2010
Last updated: April 15, 2011
Last verified: January 2011
  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

Resource links provided by NLM:


Further study details as provided by Hospital Clinic of Barcelona:

Primary Outcome Measures:
  • 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.



Secondary Outcome Measures:
  • 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
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01259973

Locations
Spain
Hospital Clinic of Barcelona
Barcelona, Spain, 08036
Hospital de la Santa Creu i Sant Pau
Barcelona, Spain, 08025
Sponsors and Collaborators
Hospital Clinic of Barcelona
Fundacion Clinic per a la Recerca Biomédica
Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
University of Barcelona
Investigators
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:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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
Risperidone
Antipsychotic Agents
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 October 19, 2014