Prospective Cytochrome P450 Genotyping and Clinical Outcomes in Patients With Psychosis
Condition: Schizophrenia; Schizoaffective Disorder; Psychotic Disorder Not Otherwise Specified; Severe Bipolar Disorder With Psychotic Features
MeSH terms: Schizophrenia; Bipolar Disorder; Psychotic Disorders; Mental Disorders
Study type: Interventional

Summary: 
      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.
    

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.
    

Intervention name(s): risperidone
Intervention type(s): Drug
Intervention description(s): 3 levels of dosing dependent on which condition a patient is assigned to.
Other intervention name(s): Risperdal
Intervention MeSH terms: Risperidone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment