Clozapine Plasma Levels and the Relationship to the Genetic Polymorphism in Shizophrenic Patients

Summary

Approximately 30-60% of all schizophrenia patients who fail to respond to typical antipsychotics may respond to Clozapine. Clozapine has long been considered the "gold standard" within the atypical neuroleptic spectrum, backed by years of clinical experience and research, but uncertainties remain in some aspects of this drug. One such question is the link between dose, blood levels and patient clinical response. The Clozapine therapeutic plasma levels range between 250 - 450 ng/mL creating difficulties in using these results in routine clinical practice. Approximately 30% - 51% of "treatment-resistant schizophrenia" patients do not fully respond to Clozapine, a poorly understood phenomenon. Factors relevant to Clozapine-resistance include co-morbidity, drug misuse, poor adherence, inadequate duration of treatment and inadequate dose/plasma-levels. Pharmacogenetic factors such as different polymorphisms in involved genes may play a role. Pharmacodynamic and genetic data appear important in determining the clinical response to Clozapine. Clozapine-treated patients possessing different 3A4 polymorphisms, may respond differently as compared to other patients having normal 3A4 alleles. Recently, the CYP2D6 has also been involved in this drug metabolic pathway. Population pharmacokinetics of clozapine evaluated with the nonparametric maximum likelihood method. This pharmacogenetic explanation/hypothesis may explain Clozapine- resistance in schizophrenics.

The high variability in plasma levels requires a large study in order to be able to determine correlation between clinical efficacy and plasma levels and genotyping. A preliminary study will enable power analysis and adequate determination of sample size.

Conditions

• Schizophrenia

Interventions

DRUG

Clozapine

A fixed dose of Clozapine 300 mg/day (150 mg x 2)for 3 month

Sponsors & Collaborators

• Technion, Israel Institute of Technology

  collaborator OTHER

• Ben-Gurion University of the Negev

  collaborator OTHER

• Beersheva Mental Health Center

  collaborator OTHER_GOV

• Sha'ar Menashe Mental Health Center

  collaborator OTHER

• HaEmek Medical Center, Israel

  collaborator OTHER

• The Nazareth Hospital, Israel

  collaborator OTHER

• Tirat Carmel Mental Health Center

  lead OTHER_GOV

Principal Investigators

• Anatoly Kreinin, MD, Phd · Tirat Carmel Mental Health Center

• Yedidia Bentur, MD · Rambam Health Care Campus, Haifa

• Norberto Krivoy, MD · Rambam Health Care Campus, Haifa

• David Rabinowitz, MD · Rambam Health Care Campus, Haifa

• Kamal Farhat, MD · The Nazareth Hospital-EMM

• Vladimir Lerner, MD, Phd · Beersheva Mental Health Center

• Boaz Bloch, MD · Haemek Hospital, Afula

• Alexander Grinshpoon, MD, MHA, PhD · Shaar Menashe MHC

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Max Age

65 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2012-10-31

Primary Completion

2016-11-30

Completion

2016-12-31

Countries

• Israel

Study Locations