Exploring glutamate's role in treatment-resistant schizophrenia

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

This study is testing if the drug riluzole can help people with treatment-resistant schizophrenia by looking at how it affects glutamate levels in the brain and comparing those levels to healthy individuals and those who respond to other treatments.

Quick facts

• Phase: Early Phase 1
• Study type: Interventional
• Enrollment: 288 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: King's College London (Academic / other)
• Locations: 1 site (London)
• Trial ID: NCT06270108 on ClinicalTrials.gov

What this trial studies

This study investigates how glutamatergic function affects patients with treatment-resistant schizophrenia by administering the drug riluzole. Researchers will use magnetic resonance spectroscopy to measure glutamate levels in the brain and assess their relationship with brain structure and function through various imaging techniques, including structural MRI and functional MRI. The study aims to compare these findings with healthy controls and individuals with responsive schizophrenia to better understand the underlying mechanisms of treatment resistance. Longitudinal changes in glutamate levels will also be correlated with changes in psychopathology.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older diagnosed with treatment-resistant schizophrenia who meet specific criteria for symptom severity and functional impairment.

Not a fit: Patients who do not have treatment-resistant schizophrenia or those who are not stable on their antipsychotic medication may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could lead to improved treatment strategies for patients with treatment-resistant schizophrenia.

How similar studies have performed: While studies exploring glutamatergic function in schizophrenia exist, this specific approach using riluzole in treatment-resistant cases is relatively novel.

Eligibility criteria

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.

Where this trial is running

London

• Institute of Psychiatry, Psychology and Neuroscience — London, United Kingdom (Recruiting)

Study contacts

• Principal investigator: Oliver D Howes — King's College London
• Study coordinator: James Scott

Conditions Treatment-resistant Schizophrenia; Treatment-responsive Schizophrenia; Healthy Controls; schizophrenia; treatment-resistant schizophrenia; glutamate; riluzole