Clinical trial NCT01663077: Clozapine Plasma Levels and the Relationship to the Genetic Polymorphism in Shizophrenic Patients
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Schizophrenia
Keywords: Clozapine
Schizophrenia
Remissia
polymorphism
Lead sponsor: Tirat Carmel Mental Health Center
Sponsor class: OTHER_GOV
Collaborators: name: Technion, Israel Institute of Technology
name: Ben-Gurion University of the Negev
name: Beersheva Mental Health Center
name: Sha'ar Menashe Mental Health Center
name: HaEmek Medical Center, Israel
name: The Nazareth Hospital, Israel
First posted: 2012-08-13
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: 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. \[Female patients will also have a pregnancy test.\].

Primary outcomes:
measure: Clozapine steady state plasma level
timeFrame: 3 month
Secondary outcomes:
measure: Polymorphism of CYP1A2, CYP3A4, CYP3A5 and CYP2D6 in clinically stable schizophrenic adult patients
timeFrame: Once
Other outcomes:
Locations:
city: Tirat Carmel
country: Israel
facility: Tirat Carmel Mental Health Center
Study officials:
affiliation: Tirat Carmel Mental Health Center
name: Anatoly Kreinin, MD, Phd
role: STUDY_DIRECTOR
affiliation: Rambam Health Care Campus, Haifa
name: Yedidia Bentur, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rambam Health Care Campus, Haifa
name: Norberto Krivoy, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rambam Health Care Campus, Haifa
name: David Rabinowitz, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Nazareth Hospital-EMM
name: Kamal Farhat, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Beersheva Mental Health Center
name: Vladimir Lerner, MD, Phd
role: PRINCIPAL_INVESTIGATOR
affiliation: Haemek Hospital, Afula
name: Boaz Bloch, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Shaar Menashe MHC
name: Alexander Grinshpoon, MD, MHA, PhD
role: PRINCIPAL_INVESTIGATOR
References: