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

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ClinicalTrials.gov Identifier: NCT01663077
Recruitment Status : Completed
First Posted : August 13, 2012
Last Update Posted : October 12, 2017
Information provided by (Responsible Party):

Study Description
Brief 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.

Condition or disease Intervention/treatment Phase
Schizophrenia Drug: Clozapine Phase 4

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : October 2012
Primary Completion Date : November 2016
Study Completion Date : December 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia
Drug Information available for: Clozapine
U.S. FDA Resources

Arms and Interventions

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 Name: Leponex

Outcome Measures

Primary Outcome Measures :
  1. Clozapine steady state plasma level [ Time Frame: 3 month ]

Secondary Outcome Measures :
  1. Polymorphism of CYP1A2, CYP3A4, CYP3A5 and CYP2D6 in clinically stable schizophrenic adult patients [ Time Frame: Once ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.].
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01663077

Tirat Carmel Mental Health Center
Tirat Carmel, Israel, 30200
Sponsors and Collaborators
Tirat Carmel Mental Health Center
Technion, Israel Institute of Technology
Ben-Gurion University of the Negev
Beersheva Mental Health Center
Sha’ar Menashe Mental Health Center
HaEmek Medical Center, Israel
The Nazareth Hospital, Israel
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
More Information

Responsible Party: Anatoly Kreinin, MD, PHD, Director of Psychiatric Department, Tirat Carmel Mental Health Center
ClinicalTrials.gov Identifier: NCT01663077     History of Changes
Other Study ID Numbers: KBK2012
03/11 ( Other Identifier: Tirat Carmel Mental Health Center Review Board )
First Posted: August 13, 2012    Key Record Dates
Last Update Posted: October 12, 2017
Last Verified: October 2017

Keywords provided by Anatoly Kreinin, MD, PHD, Tirat Carmel Mental Health Center:

Additional relevant MeSH terms:
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
GABA Antagonists
GABA Agents