Prospective Cytochrome P450 Genotyping and Clinical Outcomes in Patients With Psychosis

This study is currently recruiting participants.
Verified January 2014 by North Shore Long Island Jewish Health System
Sponsor:
Information provided by (Responsible Party):
Jianping Zhang, North Shore Long Island Jewish Health System
ClinicalTrials.gov Identifier:
NCT01878513
First received: June 3, 2013
Last updated: January 28, 2014
Last verified: January 2014
  Purpose

The aim of the study is to examine whether determining treatment strategies based upon Cytochrome P450 2D6 (CYP2D6) genotype will improve drug response rates and clinical outcome in patients with psychosis.

The investigators predict that prospectively testing CYP2D6 genotype and using this information to treat psychotic patients with risperidone will improve clinical outcomes. Specifically, CYP2D6 poor metabolizers who are treated with low dose and slow titration of risperidone will do better than those who are treated with usual dose and titration approach in terms of rates of side effects and clinical improvement.


Condition Intervention
Schizophrenia
Schizoaffective Disorder
Psychotic Disorder NOS
Severe Bipolar Disorder With Psychotic Features
Drug: risperidone

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Prospective Cytochrome P450 Genotyping and Clinical Outcomes in Patients With Psychosis

Resource links provided by NLM:


Further study details as provided by North Shore Long Island Jewish Health System:

Primary Outcome Measures:
  • Efficacy [ Time Frame: 6 weeks or discharge up to 6 weeks ] [ Designated as safety issue: No ]

    Scores on:

    1. Schedule for Assessment of Negative Symptoms (SANS)
    2. Brief Psychiatric Rating Scale (BPRS)
    3. Global Impression - Improvement scale (CGI-I)


Secondary Outcome Measures:
  • Adverse Drug Effects [ Time Frame: 6 weeks, discharge or discontinuation up to 6 weeks ] [ Designated as safety issue: Yes ]

    As measured by:

    1. Hillside Hospital Adverse Events Rating Scale
    2. Abnormal Involuntary Movement Scale (AIMS)
    3. Barnes Rating Scale for Drug-Induced Akathisia
    4. Simpson-Angus Rating Scale for Extrapyramidal symptoms


Other Outcome Measures:
  • Number of days before discontinuation [ Time Frame: 6 weeks, discontinuation or discharge up to 6 weeks ] [ Designated as safety issue: No ]
  • Days of Inpatient Stay [ Time Frame: 6 weeks, discontinuation or discharge up to 6 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 264
Study Start Date: September 2009
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Low-dose-titration condition
Poor and intermediate CYP2D6 metabolizers will be randomized to either low-dose-titration condition or treatment-as-usual condition. In the low-dose-titration condition, patients will be treated with risperidone 0.5mg bid for 5 days, then 1mg bid for 5 days, which may be increased to 1.5mg bid for another 5 days.
Drug: risperidone
3 levels of dosing dependent on which condition a patient is assigned to.
Other Name: Risperdal
Experimental: Treatment-as-usual condition
Poor and intermediate CYP2D6 metabolizers will be randomized to either low-dose-titration condition or treatment-as-usual condition. In the treatment-as-usual condition, patients will be treated with risperidone 1mg bid for 5 days, then 2mg bid for 5 days, which may be increased to 3mg bid for another 5 days.
Drug: risperidone
3 levels of dosing dependent on which condition a patient is assigned to.
Other Name: Risperdal
Experimental: Open-label treatment-as-usual condition
Extensive and ultrarapid CYP2D6 metabolizers will be treated open-label in the treatment-as-usual condition. Patients will be treated with risperidone 1mg bid for 5 days, then 2mg bid for 5 days, which may be increased to 3mg bid for another 5 days.
Drug: risperidone
3 levels of dosing dependent on which condition a patient is assigned to.
Other Name: Risperdal

Detailed Description:

Recent large scale clinical trials have demonstrated that a substantial proportion of patients with psychotic disorders, such as schizophrenia and bipolar disorder, discontinue their antipsychotic medications due to either lack of efficacy or intolerable side effects, especially extrapyramidal symptoms (EPS). In clinical practice, it is essentially a trial and error process in deciding the best antipsychotic drug to start or switch to after a failed trial as there is little empirical data available to guide clinicians in drug selection. One promising tool, which can potentially provide valuable information to help guide medication management, is pharmacogenetic analysis of cytochrome P450 enzymes that metabolize most antipsychotics. CYP450 is a family of liver enzymes responsible for metabolizing many drugs and toxins. Genes coding for some of these enzymes have many polymorphisms, some of which produce essentially non-functional enzymes that result in poor metabolism of drugs. For example, CYP2D6 has more than 70 known mutations. Poor metabolizers may have a higher plasma concentration of a particular drug at usual dosages, which may lead to more severe side effects and potential drug discontinuation. On the other hand, rapid metabolizers tend to have a lower drug concentration in the body and may require a higher-than-usual dose to achieve clinical efficacy.

Until recently, genotyping CYP450 polymorphisms has been expensive and time-consuming, therefore clinically unfeasible. However, the recent FDA approval of a commercially available genotyping product (Roche Diagnostics, AmpliChip) as well as the greater availability of other CYP450 genotyping platforms makes it possible to quickly obtain CYP450 genotypes for clinical applications. The AmpliChip tests polymorphisms of CYP450 2D6 and 2C19, and stratifies genotype into poor metabolizer, extensive/intermediate metabolizer, and ultra-rapid metabolize groups.

Of particular importance in the treatment of psychotic disorders, such as schizophrenia and bipolar disorder with psychotic features, CYP2D6 is critical in the metabolism of risperidone, one of the most widely used atypical antipsychotic agents. Several studies have assessed CYP450 genotype in patients who were able to tolerate risperidone versus patients who were not able to. The CYP2D6 poor metabolizer phenotype was shown to be associated with risperidone side effects and discontinuation of the drug. Recent evidence suggest that intermediate metabolizers also tend to have higher rates of side effects when taking regular doses of risperidone.

A major limitation of the previous studies is their case-control and retrospective design. To date, no study has prospectively examined the clinical utility of CYP450 polymorphism genotyping in psychosis. Therefore, we will conduct a prospective study in which patients with psychosis undergo CYP450 genotyping at study entry, and antipsychotic drug dosage is determined by CYP2D6 genotype.

In this study, we are conducting a randomized double blind trial of risperidone treatment for psychotic patients who are admitted to inpatient units due to acute relapse. We anticipate to recruit 264 subjects and test their CYP2D6 polymorphism genotypes, based on which they will be randomly assigned to either a low dose slow titration group or a treatment as usual group. They will be assessed every five days for 15 days, and then at follow-ups at 4-weeks and 6-weeks from study entry.

It is hoped that this study will provide prospective data on whether pharmacogenetic information such as CYP450 2D6 polymorphism genotypes can have a significant clinical impact on patients with psychotic disorders.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 18-60;
  2. DSM-IV(Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, or psychotic disorder NOS (Not otherwise specified), bipolar disorder with psychotic features
  3. Having moderate to severe psychotic symptoms resulting in inpatient admission
  4. Able to provide informed consent

Exclusion Criteria:

  1. Evidence of serious medical conditions,
  2. Evidence of liver disease, as shown in elevated liver function test
  3. Female patients who are pregnant or breast feeding;
  4. History of allergic reactions to risperidone or Invega;
  5. History of risperidone or Invega treatment failure.
  6. History of receiving any long-acting injectable form of antipsychotic medications such as haloperidol decanoate, fluphenazine decanoate, Risperdal Consta, Invega Sustenna, and Zyprexa IntraMuscular in the past two months.
  7. History of treatment with clozapine.
  8. Medications that potentially interfere with the CYP450 2D9 enzyme family, including bupropion, fluoxetine, paroxetine, duloxetine, sertraline, cinacalcet, quinidine, terbinafine, amiodarone, and cimetidine, and as per clinical review by study physicians.
  9. Patients who are not able to provide informed consent due to impairment in decision-making capacity.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01878513

Contacts
Contact: Jianping Zhang, MD, PhD 718-470-8471 jzhang1@nshs.edu
Contact: Yaniv Shaya, MA 718-470-8588 yshaya@nshs.edu

Locations
United States, New York
Zucker Hillside Hospital Recruiting
Glen Oaks, New York, United States, 11004
Contact: Jianping Zhang, MD, PhD    718-470-8471    jzhang1@nshs.edu   
Contact: Yaniv Shaya, MA    718-470-8588    yshaya@nshs.edu   
Principal Investigator: Jianping Zhang, MD/PhD         
Sponsors and Collaborators
North Shore Long Island Jewish Health System
Investigators
Principal Investigator: Jianping Zhang, MD, PhD Zucker Hillside Hospital, Division of Psychiatry Research
  More Information

No publications provided

Responsible Party: Jianping Zhang, Psychiatrist, North Shore Long Island Jewish Health System
ClinicalTrials.gov Identifier: NCT01878513     History of Changes
Other Study ID Numbers: 08-252B
Study First Received: June 3, 2013
Last Updated: January 28, 2014
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Psychotic Disorders
Mental Disorders
Affective Disorders, Psychotic
Schizophrenia and Disorders with Psychotic Features
Bipolar Disorder
Schizophrenia
Mood Disorders
Risperidone
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Central Nervous System Agents
Therapeutic Uses
Psychotropic Drugs
Dopamine Antagonists
Dopamine Agents

ClinicalTrials.gov processed this record on April 15, 2014