Clozapine Plasma Levels and the Relationship to the Genetic Polymorphism in Shizophrenic Patients
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Purpose
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 | Intervention | Phase |
|---|---|---|
|
Schizophrenia |
Drug: Clozapine |
Phase 4 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Pharmacokinetics/Dynamics Study Intervention Model: Single Group Assignment Masking: 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 |
- Clozapine steady state plasma level [ Time Frame: 3 month ] [ Designated as safety issue: Yes ]
- Polymorphism of CYP1A2, CYP3A4, CYP3A5 and CYP2D6 in clinically stable schizophrenic adult patients [ Time Frame: Once ] [ Designated as safety issue: Yes ]
| Estimated Enrollment: | 20 |
| Study Start Date: | October 2012 |
| Estimated Study Completion Date: | October 2013 |
| Estimated Primary Completion Date: | May 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
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
|
Eligibility| Ages Eligible for Study: | 18 Years to 65 Years |
| Genders Eligible for Study: | Both |
| 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| Contact: Anatoly Kreinin, MD, PhD | +97248559325 | ANATOLY.KREININ@PSTIRA.HEALTH.GOV.IL |
| Israel | |
| Tirat Carmel Mental Health Center | Not yet recruiting |
| Tirat Carmel, Israel, 30200 | |
| Contact: Anatoly Kreinin, MD, PhD | |
| Principal Investigator: Anatoly Kreinin, MD, PhD | |
| 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
No publications provided
| Responsible Party: | Anatoly Dr. Kreinin, Director of Psychiatric Department, Tirat Carmel Mental Health Center |
| ClinicalTrials.gov Identifier: | NCT01663077 History of Changes |
| Other Study ID Numbers: | KBK2012, 03/11 |
| Study First Received: | July 25, 2012 |
| Last Updated: | August 8, 2012 |
| Health Authority: | Israel: Ministry of Health |
Keywords provided by Tirat Carmel Mental Health Center:
|
Clozapine Schizophrenia Remissia polymorphism |
Additional relevant MeSH terms:
|
Schizophrenia Schizophrenia and Disorders with Psychotic Features Mental Disorders Clozapine Serotonin Antagonists Serotonin Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action Pharmacologic Actions |
Physiological Effects of Drugs Antipsychotic Agents Tranquilizing Agents Central Nervous System Depressants Central Nervous System Agents Therapeutic Uses Psychotropic Drugs GABA Antagonists GABA Agents |
ClinicalTrials.gov processed this record on May 23, 2013