The Role of Glutamatergic Function in the Pathophysiology of Treatment-resistant Schizophrenia (RESTORE)

March 4, 2024 updated by: King's College London

The goal of this basic science study is to to explore the responsivity of glutamate in the brain of treatment-resistant schizophrenia patients to the drug riluzole. The main aims of the study are:

To assess the role of glutamate in treatment-resistant schizophrenia using magnetic resonance spectroscopy.

To assess the relationship between glutamate levels and brain structural and functional measures (using: structural MRI; functional MRI (fMRI) and arterial spin labelling (ASL)) at baseline.

To assess the relationship between longitudinal change in glutamate levels and brain structural and functional measures.

To assess the relationship between longitudinal change in glutamate levels and changes in psychopathology.

The researchers will compare the changes with healthy controls and those without treatment-resistant schizophrenia.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

288

Phase

  • Early Phase 1

Contacts and Locations

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

Study Contact

Study Contact Backup

Study Locations

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

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion criteria for treatment-resistant schizophrenia patients:

  1. Aged 18 years old or older;
  2. Diagnosis of schizophrenia or other psychotic disorder (Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5);
  3. Treatment resistance according to the Treatment Response and Resistance in Psychosis (TRRIP) Working Group consensus criteria. This requires a PANSS score of more than 70 and the presence of at least one positive and one negative symptom rated as ≥ 4 on the Positive and Negative Syndrome Scale (PANSS) and at least moderate functional impairment on the Social and Occupational Function Assessment Scale (SOFAS) despite at least 2 adequate trials of different antipsychotics;
  4. On a stable dose of antipsychotic (no dose changes in the past 1 month);
  5. Able to give fully informed written consent and likely to comply with the requirements of the study, after reading the information and consent form, and after having the opportunity to discuss the study with the investigator or his delegate;
  6. Capacity to provide informed consent, as judged by an investigator and as assessed by the McArthur scale;
  7. Ability to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of the entire study.

Exclusion criteria for treatment-resistant schizophrenia patients:

  1. History of significant co-morbid central nervous system (CNS) disorder (including significant head trauma or significant loss of consciousness, Parkinson's Disease, Epilepsy, Alzheimer's Dementia, Huntington's Disease);
  2. Current use of medication with recognized effect on glutamatergic signaling (e.g. lamotrigine, lithium, carbamazepine, opiates, and psychostimulants) OR medication that is known to interact with riluzole (eg: ciprofloxacin, combined hormonal contraceptives, enoxacin, fluvoxamine, charcoal boiled (grilled) foods, methoxasalen, rucaparib, osilodrostat, mexiletine, nicergoline, pipemidic acid, rifampicin, tiabendazole, vemurafenib);
  3. Any absolute contra-indication to riluzole according to the British National Formulary (such as interstitial lung disease, current pregnancy or lactation, severe hepatic impairment liver function tests more than 3x Upper limit of normal, acute porphyria, pancreatitis);
  4. Pregnancy and/or breast-feeding;
  5. Substance dependence/abuse other than to cigarettes;
  6. Current high suicide risk or other significant safety risk as judged by the patient's psychiatrist or study physician;
  7. Current homicidal ideation or intent;
  8. Participation in a clinical study of unlicensed medicines within the previous 30 days;
  9. Clinically relevant abnormal findings at the screening assessment as judged significant by the principal investigator (e.g.: history of liver disease or transaminases more than 2 times the upper limit of normal);
  10. Presence of other acute or chronic illness or history of chronic illness sufficient to invalidate the volunteer's participation in the study or raise safety concerns;
  11. Any risk factors for liver damage (eg. alcohol dependence or history of liver disease) or patients who are receiving potentially hepatotoxic medications;
  12. Likelihood that the subject will not comply with study requirements or other reason the investigator judges the subject is not suitable;
  13. Objection by subject's physician;
  14. Any contraindication to MRI scanning (e.g. metallic implants);
  15. Any comorbidity that could compromise scanning safety (e.g. severe asthma).

Inclusion criteria for treatment-responsive schizophrenia patients:

  1. Aged 18 years old or older;
  2. Diagnosis of schizophrenia or other psychotic disorder (Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5);
  3. On a stable dose of antipsychotic (no dose changes in the past 1 month);
  4. Able to give fully informed written consent and likely to comply with the requirements of the study, after reading the information and consent form, and after having the opportunity to discuss the study with the investigator or his delegate;
  5. Capacity to provide informed consent, as judged by an investigator and as assessed by the McArthur scale;
  6. Ability to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of the entire study.

Exclusion criteria for treatment-responsive schizophrenia patients:

  1. Treatment resistance according to the Treatment Response and Resistance in Psychosis (TRRIP) Working Group consensus criteria;
  2. History of significant co-morbid CNS disorder (including significant head trauma or significant loss of consciousness, Parkinson's Disease, Epilepsy, Alzheimer's Dementia, Huntington's Disease);
  3. Substance dependence/abuse other than to cigarettes;
  4. Current high suicide risk or other significant safety risk as judged by the patient's psychiatrist or study physician;
  5. Current homicidal ideation or intent;
  6. Participation in a clinical study of unlicensed medicines within the previous 30 days;
  7. Likelihood that the subject will not comply with study requirements or other reason the investigator judges the subject is not suitable;
  8. Objection by subject's physician;
  9. Any contraindication to MRI scanning (e.g. metallic implants);
  10. Any comorbidity that could compromise scanning safety (e.g. severe asthma);

Inclusion criteria for healthy controls:

  1. Aged 18 years old or older;
  2. No diagnosis of schizophrenia, schizophreniform or any psychotic disorder;
  3. Sufficient understanding of the nature of the study and any hazards of participating in it;
  4. Ability to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of the entire study;
  5. Willingness to give written consent to participate after reading the information and consent form, and after having the opportunity to discuss the study with the investigator or his delegate;
  6. Capacity to provide informed consent, as judged by an investigator.

Exclusion criteria for healthy controls

  1. Co-morbid psychiatric or other CNS disorder;
  2. Family history of Schizophrenia or Psychotic disorders;
  3. History of head trauma or loss of consciousness;
  4. Substance dependence/abuse other than to cigarettes;
  5. Presence of acute or chronic illness or history of chronic illness sufficient to invalidate the volunteer's participation in the study or make it unnecessarily hazardous and judge significant by the principal investigator;
  6. Likelihood that the volunteer will not comply with the requirements of the study or other reason the investigator judges the subject is not suitable;
  7. Objection by a General Practitioner (GP), or another doctor responsible for their treatment, to the healthy control entering study.

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

  • Primary Purpose: Basic Science
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: Healthy controls
Experimental: Treatment-resistant schizophrenia patients receiving riluzole
Drug: Riluzole
50mg twice daily (100mg total daily) for 56 days.
No Intervention: Treatment-responsive schizophrenia patients

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in glutamate levels (using magnetic resonance spectroscopy) pre- and post-riluzole administration
Time Frame: Brain measurements will be conducted at baseline (day -7 to day -1 before riluzole administration), day 7 and day 56 (+- 14 days)
Change in glutamate levels will be assessed (using magnetic resonance spectroscopy) in treatment-resistant schizophrenia patients compared with controls and patients without treatment-resistant schizophrenia
Brain measurements will be conducted at baseline (day -7 to day -1 before riluzole administration), day 7 and day 56 (+- 14 days)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Correlation of glutamate (using magnetic resonance spectroscopy) with brain functional measures at baseline (using functional magnetic resonance imaging)
Time Frame: Brain measurements will be conducted at baseline (day -7 to day -1 before riluzole administration), day 7 and day 56 (+- 14 days)
Brain measurements will be conducted at baseline (day -7 to day -1 before riluzole administration), day 7 and day 56 (+- 14 days)
Longitudinal change in glutamate levels (using magnetic resonance spectroscopy) correlated with longitudinal change in brain functional measures (using functional magnetic resonance imaging)
Time Frame: Brain measurements will be conducted at baseline (day -7 to day -1 before riluzole administration), day 7 and day 56 (+- 14 days)
Brain measurements will be conducted at baseline (day -7 to day -1 before riluzole administration), day 7 and day 56 (+- 14 days)
Longitudinal change in glutamate levels (using magnetic resonance spectroscopy) correlated with changes in psychopathology
Time Frame: Brain measurements will be conducted at baseline (day -7 to day -1 before riluzole administration), day 7 and day 56 (+- 14 days)
Changes in psychopathology assessed using rating scales Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression scale (CGI), Calgary Depression Scale for Schizophrenia (CDSS), Montgomery and Asberg Depression Rating Scale (MADRS), Hopkins Verbal Learning Test (HVLT) and a computerised cognitive task
Brain measurements will be conducted at baseline (day -7 to day -1 before riluzole administration), day 7 and day 56 (+- 14 days)

Collaborators and Investigators

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

Sponsor

King's College London

Collaborators

South London and Maudsley NHS Foundation Trust

Investigators

  • Principal Investigator: Oliver D Howes, King's College London

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)

November 14, 2022

Primary Completion (Estimated)

December 31, 2024

Study Completion (Estimated)

December 31, 2024

Study Registration Dates

First Submitted

January 29, 2024

First Submitted That Met QC Criteria

February 13, 2024

First Posted (Actual)

February 21, 2024

Study Record Updates

Last Update Posted (Estimated)

March 5, 2024

Last Update Submitted That Met QC Criteria

March 4, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 22/SS/0040
  • 299382 (Other Identifier: Integrated Research Application System)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

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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