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

Schizophrenia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01663077
• Other study ID #: KBK2012
• Secondary ID: 03/11
• Status: Completed
• Phase: Phase 4
• First received: July 25, 2012
• Last updated: October 11, 2017
• Start date: October 2012
• Est. completion date: December 2016

Study information

• Verified date: October 2017
• Source: Tirat Carmel Mental Health Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: December 2016
• Est. primary completion date: November 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.].

Related Conditions & MeSH terms

• Schizophrenia

Intervention

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

Locations

Country	Name	City	State
Israel	Tirat Carmel Mental Health Center	Tirat Carmel

Sponsors (7)

Lead Sponsor	Collaborator
Tirat Carmel Mental Health Center	Beersheva Mental Health Center, Ben-Gurion University of the Negev, HaEmek Medical Center, Israel, Sha’ar Menashe Mental Health Center, Technion, Israel Institute of Technology, The Nazareth Hospital, Israel

Country where clinical trial is conducted

Israel, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clozapine steady state plasma level		3 month
Secondary	Polymorphism of CYP1A2, CYP3A4, CYP3A5 and CYP2D6 in clinically stable schizophrenic adult patients		Once