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

NCT01259973 | Unknown Phase 1

• 2 other identifiers: TRA-0652009-016519-40
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 2

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-.

Conditions

Pharmacogenetics; Healthy

Keywords

Pharmacogenetics; Antipsychotics; Extrapyramidal Symptoms

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (5)

• 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)

  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

  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

  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

  At -1h pre-treatment (basal level) and at +1h, +2h, +4h, +6h and +8h post-treatment

• Changes from baseline in sedative effects during 8h

  At -1h pre-treatment (basal level) and at +1h, +2h, +4h, +6h and +8h post-treatment

Study Arms (3)

Risperidone

EXPERIMENTAL

Drug: Risperidone

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Haloperidol

EXPERIMENTAL

Drug: Haloperidol

Interventions

Risperidone DRUG

1 single dose of 2.5mg masked in 250 mL of peach juice, for 1 day. Oral administration.

Risperidone

Placebo DRUG

1 single dose of 2.5mL physiological serum masked in 250 mL of peach juice, for 1 day. Oral administration.

Placebo

Haloperidol DRUG

1 single dose of 5mg masked in 250 mL of peach juice, for 1 day. Oral administration.

Haloperidol

Eligibility Criteria

• Age: 18 Years - 30 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Hospital Clinic of Barcelona: lead
• Fundacion Clinic per a la Recerca Biomédica: collaborator
• Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau: collaborator
• University of Barcelona: collaborator

Study Sites (2)

Hospital de la Santa Creu i Sant Pau

Barcelona, Barcelona, 08025, Spain

Location

Hospital Clinic of Barcelona

Barcelona, Barcelona, 08036, Spain

Location

Related Publications (10)

• Lafuente A, Bernardo M, Mas S, Crescenti A, Aparici M, Gasso P, Catalan R, Mateos JJ, Lomena 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. doi: 10.1016/j.schres.2006.09.031. Epub 2006 Dec 5.

  PMID: 17150335 BACKGROUND

• 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.

  PMID: 18922583 BACKGROUND

• Crescenti A, Mas S, Gasso 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.

  PMID: 18346175 BACKGROUND

• Gasso 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.

  PMID: 19506579 BACKGROUND

• Gasso 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.

  PMID: 19892410 BACKGROUND

• 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. doi: 10.1016/j.pharmthera.2007.09.004. Epub 2007 Oct 9.

  PMID: 18001838 BACKGROUND

• 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. doi: 10.2165/00003088-200746050-00001.

  PMID: 17465637 BACKGROUND

• 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.

  PMID: 18695978 BACKGROUND

• Catafau AM, Penengo MM, Nucci G, Bullich S, Corripio I, Parellada E, Garcia-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.

  PMID: 18308793 BACKGROUND

• Mas S, Gasso P, Fernandez de Bobadilla R, Arnaiz JA, Bernardo M, Lafuente A. Secondary nonmotor negative symptoms in healthy volunteers after single doses of haloperidol and risperidone: a double-blind, crossover, placebo-controlled trial. Hum Psychopharmacol. 2013 Nov;28(6):586-93. doi: 10.1002/hup.2350. Epub 2013 Oct 7.

  PMID: 24519692 DERIVED

MeSH Terms

Interventions

Risperidone; Haloperidol

Intervention Hierarchy (Ancestors)

Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Butyrophenones; Ketones; Organic Chemicals

Study Officials

• Miquel Bernardo Arroyo, Head of Psychiatry

  Hospital Clinic of Barcelona

  PRINCIPAL INVESTIGATOR

• Amalia Lafuente Flo, Pharmacology professor

  Dept. Pathologic Anatomy, Pharmacology and Microbiology, Medical Service, UB University of Barcelona

  STUDY DIRECTOR

• 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

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: December 13, 2010
• First Posted: December 15, 2010
• Study Start: February 1, 2011
• Primary Completion: November 1, 2011
• Study Completion: December 1, 2011
• Last Updated: April 18, 2011

Record last verified: 2011-01

Locations

ES (2)