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Response to Clozapine in Treatment Resistant Schizophrenia: A Longitudinal Magnetic Resonance Spectroscopy Study

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ClinicalTrials.gov Identifier: NCT02714894
Recruitment Status : Recruiting
First Posted : March 22, 2016
Last Update Posted : February 7, 2020
Sponsor:
Collaborator:
Canadian Institutes of Health Research (CIHR)
Information provided by (Responsible Party):
Ariel Graff, Centre for Addiction and Mental Health

Brief Summary:
The purpose of this study is to investigate the relationship between glutamate and related brain chemicals and treatment response to clozapine in patients with treatment-resistant schizophrenia.

Condition or disease Intervention/treatment
Schizophrenia Drug: Clozapine

Detailed Description:
This study will be a prospective proton spectroscopy (1H-MRS) study designed to compare the levels of glutamate, glutamine, glx, and glutathione in age- and gender- matched patients with poor response to clozapine (URS), patients with good response to clozapine (non-URS), and healthy controls. Participants with schizophrenia who fail to respond to optimal treatment with at least two different non-clozapine antipsychotics (i.e. treatment-resistant schizophrenia [TRS]) and who are starting clozapine as part of their clinical care will be recruited. A sample of healthy controls will also be recruited. Participants with TRS will have two 1H-MRS scans. The 1H-MRS scan will be performed within 1 week and 12 weeks after clozapine initiation. Clinical assessments will be performed within 1 week of each 1H-MRS scan and after 6 weeks of clozapine treatment. Cognitive assessments will also be performed within 1 week of 1H-MRS scans. Healthy controls will also undergo two 1H-MRS scans with a 12-week interval. Cognitive assessments will also be performed within 1 week of 1H-MRS scans.

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Study Type : Observational
Estimated Enrollment : 108 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Glutamatergic System and Response to Clozapine in Patients With Treatment-Resistant Schizophrenia: a Prospective Proton Magnetic Resonance Spectroscopy Study
Study Start Date : April 2016
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : March 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia
Drug Information available for: Clozapine

Group/Cohort Intervention/treatment
Clozapine Responders (Non-URS)

Definition of non-URS

(1) ≥30% decrease in the PANSS positive subscale score, CGI-severity ≤3 and CGI-Improvement ≤2 after 12 weeks of treatment.

Drug: Clozapine
Patient participants will be starting clozapine as part of their clinical care.
Other Name: Clozaril

Clozapine Non-Responders (URS)

Definition of URS

  1. Taking clozapine for ≥ 12 weeks, attaining a plasma clozapine level ≥350 ng/ml.
  2. CGI-Severity score of ≥4 and score of ≥4 on 2 PANSS positivesymptom items.
Drug: Clozapine
Patient participants will be starting clozapine as part of their clinical care.
Other Name: Clozaril

Healthy Controls
Healthy controls will be matched as closely as possible on age and gender with participants in the patient groups.



Primary Outcome Measures :
  1. Change in 1H-MRS glutamatergic metabolites before and after clozapine. [ Time Frame: Change from baseline (pre-clozapine) of 1H-MRS glutamatergic metabolites at 12 weeks ]
    1H-MRS will be employed to quantify glutamatergic metabolites, specifically glutamate, glutamine, glx and glutathione.


Biospecimen Retention:   Samples With DNA
Blood sample


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Participants with schizophrenia who fail to respond to optimal treatment with at least two different non-clozapine antipsychotics (i.e. treatment-resistant schizophrenia [TRS]) and are starting clozapine will be recruited. A sample of healthy controls will also be recruited.
Criteria

Inclusion Criteria for Participants with TRS:

  • DSM-IV/SCID diagnosis of schizophrenia, schizoaffective disorder, delusional disorder, or psychotic disorder NOS.
  • Age 18 years or older at time of scanning
  • History of failure to respond to at least two previous sequential antipsychotic treatments different to clozapine, each attaining a chlorpromazine daily dose of≥ 400 mg for a duration ≥ 6 consecutive weeks.Long-acting antipsychotic treatment will not be allowed during the last trial prior to clozapine in order to avoid residual concentrations or effects.Failure of treatment will be defined by a Clinical Global Impression Severity (CGI-Severity) score of ≥4 and score of ≥4 on 2 Positive and Negative Syndrome Scale (PANSS) positive symptom items. The CGI-Severity or Global Assessment of Functioning (GAF) will be completed retrospectively based on information provided by the participant, participant's psychiatrist, medical chart, or other sources of available collateral information.

Exclusion Criteria for Participants with TRS:

  • Incapacity to provide consent to participate in the research study.
  • Substance abuse or dependence (within past six months), excluding nicotine and caffeine.
  • Positive urine drug screen for drugs of abuse.
  • Metal implants or a pace-maker that would preclude the MRI scan.
  • History of head trauma resulting in loss of consciousness > 30 minutes that required medical attention.
  • Unstable physical illness or significant neurological disorder including a seizure disorder.
  • Size of head, neck, and body being unable to fit MRI scanners.
  • Refusal to provide consent to investigator to communicate with physician of record to obtain collateral information.
  • Psychiatric concerns raised by the physician of record regarding participation in the study.
  • Currently taking medications that may directly impact the glutamatergic system (i.e. lamotrigine, topiramate, memantine or N-acetylcysteine)
  • ECT, MST or TMS in the past 6 months

Inclusion criteria for Healthy Controls:

  • Age of 18 and older at time of scanning
  • Being capable to consent to study procedures
  • Absence of history of psychiatric illness using the Mini-International Neuropsychiatric Interview (MINI)

Exclusion criteria for Healthy Controls:

  • First degree family member with primary psychotic disorder
  • Substance abuse or dependence (within past six months), excluding nicotine and caffeine.
  • Positive urine drug screen for drugs of abuse
  • Pacemakers, metallic cardiac valves, magnetic material such as surgical clips, implanted electronic infusion pumps or any other conditions that would preclude the MRI scan
  • Clinically significant claustrophobia
  • History of head trauma resulting in loss of consciousness > 30 minutes that required medical attention
  • Size of head, neck, and body being unable to fit MRI scanners
  • Unstable physical illness or significant neurological disorder including a seizure disorder

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): NCT02714894


Contacts
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Contact: Ariel Graff, MD, PhD 416-535-8501 ext 34834 ariel.graff@camh.ca

Locations
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Canada, Ontario
Centre for Addiction and Mental Health Recruiting
Toronto, Ontario, Canada, M5T 1R8
Sponsors and Collaborators
Centre for Addiction and Mental Health
Canadian Institutes of Health Research (CIHR)
Investigators
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Principal Investigator: Ariel Graff, MD, PhD Centre for Addiction and Mental Health
Additional Information:
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Responsible Party: Ariel Graff, Ariel Graff MD, PhD, Centre for Addiction and Mental Health
ClinicalTrials.gov Identifier: NCT02714894    
Other Study ID Numbers: 122-2015
First Posted: March 22, 2016    Key Record Dates
Last Update Posted: February 7, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Ariel Graff, Centre for Addiction and Mental Health:
magnetic resonance imaging
magnetic resonance spectroscopy
Additional relevant MeSH terms:
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Schizophrenia
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Clozapine
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