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

NCT06270108 | Recruiting Early Phase 1 DMC

• 2 other identifiers: 22/SS/0040299382
• Study Type: interventional
• Target: 288
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Treatment-resistant Schizophrenia; Treatment-responsive Schizophrenia; Healthy Controls

Keywords

schizophrenia; treatment-resistant schizophrenia; glutamate; riluzole

Outcome Measures

Primary Outcomes (1)

• Change in glutamate levels (using magnetic resonance spectroscopy) pre- and post-riluzole administration

  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 Outcomes (3)

• Correlation of glutamate (using magnetic resonance spectroscopy) with brain functional measures at baseline (using functional magnetic resonance imaging)

  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)

  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

  Brain measurements will be conducted at baseline (day -7 to day -1 before riluzole administration), day 7 and day 56 (+- 14 days)

Study Arms (3)

Treatment-resistant schizophrenia patients receiving riluzole

EXPERIMENTAL

Drug: Riluzole

Treatment-responsive schizophrenia patients

NO INTERVENTION

Healthy controls

NO INTERVENTION

Interventions

Riluzole DRUG

50mg twice daily (100mg total daily) for 56 days.

Treatment-resistant schizophrenia patients receiving riluzole

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Aged 18 years old or older;
• Diagnosis of schizophrenia or other psychotic disorder (Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5);
• 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;
• On a stable dose of antipsychotic (no dose changes in the past 1 month);
• 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;
• Capacity to provide informed consent, as judged by an investigator and as assessed by the McArthur scale;
• Ability to communicate satisfactorily with the investigator and to participate in, and comply with the requirements of the entire study.

You may not qualify if:

• 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);
• 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);
• 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);
• Pregnancy and/or breast-feeding;
• Substance dependence/abuse other than to cigarettes;
• Current high suicide risk or other significant safety risk as judged by the patient's psychiatrist or study physician;
• Current homicidal ideation or intent;
• Participation in a clinical study of unlicensed medicines within the previous 30 days;
• 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);
• 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;
• Any risk factors for liver damage (eg. alcohol dependence or history of liver disease) or patients who are receiving potentially hepatotoxic medications;
• Likelihood that the subject will not comply with study requirements or other reason the investigator judges the subject is not suitable;
• Objection by subject's physician;
• Any contraindication to MRI scanning (e.g. metallic implants);
• Any comorbidity that could compromise scanning safety (e.g. severe asthma).

Sponsors & Collaborators

• King's College London: lead
• South London and Maudsley NHS Foundation Trust: collaborator

Study Sites (1)

Institute of Psychiatry, Psychology and Neuroscience

London, SE5 8AB, United Kingdom

RECRUITING

MeSH Terms

Conditions

Schizophrenia, Treatment-Resistant; Schizophrenia

Interventions

Riluzole

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Benzothiazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Oliver D Howes

  King's College London

  PRINCIPAL INVESTIGATOR

Central Study Contacts

James Scott

CONTACT

+44 207 848 0002; james.1.scott@kcl.ac.uk

Guy Gitlin-Leigh

CONTACT

guy.1.gitlin-leigh@kcl.ac.uk

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a basic science study the purpose of which is to to explore the responsivity of glutamate in treatment-resistant schizophrenia to a given challenge (riluzole).

Study Record Dates

• First Submitted: January 29, 2024
• First Posted: February 21, 2024
• Study Start: November 14, 2022
• Primary Completion: December 31, 2024
• Study Completion: December 31, 2024
• Last Updated: March 5, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)