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

Clozapine Fixed Dose Steady State Plasma Levels and the Relationship to the Polymorphism of CYP1A2, CYP3A4, CYP3A5 and CYP2D6 in Clinically Stable Schizophrenic Adult Patients

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.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Clozapine

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 4

Contacts and Locations

Study Locations

• Israel
  • Tirat Carmel, Israel, 30200
    • Tirat Carmel Mental Health Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• DSM-IV criteria for schizophrenia (American Psychiatric Association 2000)
• All clozapine mono-therapy patients (only 300 mg/day) who respond to treatment and achieved symptomatic remission (45, 46) and were stable for at least 3 month will be included
• No change in benzodiazepine medications for the trial period.
• Legal ability and willingness to sign an informed consent form for participation in the study.

Exclusion Criteria:

• Evidence of serious neurologic or endocrine disorder, for example severe head trauma, seizure disorder, dementia, Cushing's disease, thyroid disorder, mental retardation, alcohol or drug abuse, substance dependence (other than nicotine dependence), or presenting symptoms likely substance- induced, as judged by a study physician.
• Unstable medical illness or neurologic illness (seizures, CVA); breast, uterine, or ovarian cancer.
• Pregnant women, use of oral contraceptives or other hormonal supplementation such as estrogen. [Female patients will also have a pregnancy test.].

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Clozapine; Clozapine tablet 150 mg at the day and 150 mg in the evening by mouth per day for 3 month	Drug: Clozapine; A fixed dose of Clozapine 300 mg/day (150 mg x 2)for 3 month; Other Names: Leponex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Clozapine steady state plasma level	3 month

Secondary Outcome Measures

Outcome Measure	Time Frame
Polymorphism of CYP1A2, CYP3A4, CYP3A5 and CYP2D6 in clinically stable schizophrenic adult patients	Once

Collaborators and Investigators

• Sponsor: Tirat Carmel Mental Health Center
• Collaborators: Technion, Israel Institute of Technology; HaEmek Medical Center, Israel; Beersheva Mental Health Center; Ben-Gurion University of the Negev; The Nazareth Hospital, Israel; Sha'ar Menashe Mental Health Center
• Investigators: Study Director: Anatoly Kreinin, MD, Phd, Tirat Carmel Mental Health Center; Principal Investigator: Yedidia Bentur, MD, Rambam Health Care Campus, Haifa; Principal Investigator: Norberto Krivoy, MD, Rambam Health Care Campus, Haifa; Principal Investigator: David Rabinowitz, MD, Rambam Health Care Campus, Haifa; Principal Investigator: Kamal Farhat, MD, The Nazareth Hospital-EMM; Principal Investigator: Vladimir Lerner, MD, Phd, Beersheva Mental Health Center; Principal Investigator: Boaz Bloch, MD, Haemek Hospital, Afula; Principal Investigator: Alexander Grinshpoon, MD, MHA, PhD, Shaar Menashe MHC

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): November 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: July 25, 2012
• First Submitted That Met QC Criteria: August 8, 2012
• First Posted (Estimate): August 13, 2012

Study Record Updates

• Last Update Posted (Actual): October 12, 2017
• Last Update Submitted That Met QC Criteria: October 11, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Schizophrenia; Clozapine; polymorphism; Remissia
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Serotonin Antagonists; GABA Agents; GABA Antagonists; Clozapine
• Other Study ID Numbers: KBK2012; 03/11 (Other Identifier: Tirat Carmel Mental Health Center Review Board)