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

June 2, 2022 updated by: Ariel Graff, Centre for Addiction and Mental Health

Glutamatergic System and Response to Clozapine in Patients With Treatment-Resistant Schizophrenia: a Prospective Proton Magnetic Resonance Spectroscopy Study

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Active, not recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
108

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5T 1R8
        • Centre for Addiction and Mental Health

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

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.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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 Names:
  • 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 Names:
  • Clozaril
Healthy Controls
Healthy controls will be matched as closely as possible on age and gender with participants in the patient groups.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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.
Change from baseline (pre-clozapine) of 1H-MRS glutamatergic metabolites at 12 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Centre for Addiction and Mental Health

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Canadian Institutes of Health Research (CIHR)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Ariel Graff, MD, PhD, Centre for Addiction and Mental Health

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 1, 2016

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
July 30, 2022

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
July 30, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
March 14, 2016

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 16, 2016

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 22, 2016

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 3, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 2, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
June 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 122-2015

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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