Characterizing Response to Antipsychotics in Schizophrenia

Study Overview
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Brief Summary
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The goal of this research project is to develop MRI-based biomarkers to identify patients with schizophrenia who are most likely to benefit from first-line antipsychotic or clozapine treatment. The MRI sequences (NM-MRI, MRS and rsfMRI) will be created by translating the best scientific evidence into a potential clinical product that has the highest chance of being clinically relevant predictor of treatment response. This study has the potential to significantly improve patient outcomes and reduce unnecessary interventions and costs at the Royal's Integrated Schizophrenia Recovery Program.

Detailed Description
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Currently, we cannot predict who will get better on first-line antipsychotic versus clozapine treatment. Although much evidence shows that dopamine and glutamate function are related to treatment response in schizophrenia, the utility of neuromelanin sensitive MRI (NM-MRI) as a measure of dopamine and magnetic resonance spectroscopy (MRS) as a measure of glutamate & glycine (a co-agonist of glutamate receptors) in predicting response to treatment have never been measured in the same sample. The evidence suggests that the function of these two neurotransmitter systems partially determines the response to antipsychotic medications. Additionally, an emerging type of resting-state functional MRI (rsfMRI), naturalistic movie-watching, has been shown to outperform traditional rsfMRI for functional connectivity-based prediction of behaviour and will be explored in the current study. Given the background information, our hypotheses are: 1.1) First-line antipsychotic users will have higher dopamine turnover resulting in a higher NM-MRI signal in the substantia nigra relative to clozapine users. 1.2) First-line antipsychotic users will have lower glutamate and/or glycine concentration as indicated by the MRS signal in the dorsal anterior cingulate relative to clozapine users.

Official Title
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A Study Investigating the Relationship Between the Antipsychotic Response and Non-invasive Proxies of Neurochemistry in Schizophrenia

Conditions
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Schizophrenia, Schizoaffective Disorder

Intervention / Treatment
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* Drug: Olanzapine
* Drug: Clozapine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are voluntary and competent to consent to the study Are between the ages of 18-55 Are English literate Have a diagnosis of schizophrenia or schizoaffective disorder Are currently taking primarily olanzapine or clozapine Exclusion Criteria: Medication for the treatment of schizophrenia or schizoaffective disorder has changed in the past month Have a significant neurologic, neurodevelopmental, cardiovascular, renal, hepatic, hematological, gastrointestinal, pulmonary, or metabolic-endocrine disorder Are pregnant or breastfeeding Acquire positive urine test result for all drugs of abuse including cannabis Have met DSM-5 criteria for substance use disorder other than tobacco in the last 6 months Have a history of significant head trauma with loss of consciousness for more than 5 minutes Have any contraindication to MRI Have any other condition that in the opinion of the investigator(s) could create a hazard to the subject's safety, endanger the study procedures, or interfere with the interpretation of study results

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| First-line treatment group<br>This group will consist of 20 patients with schizophrenia or schizoaffective disorder who are primarily prescribed olanzapine. Treatment will be carried out by the physicians within their circle of care, however, we will record their symptoms as they continue treatment. | Drug: Olanzapine<br>* Antipsychotic medication<br>* Other names: Zyprexa;|
| Treatment-resistant group<br>This group will consist of 20 patients with schizophrenia or schizoaffective disorder who are primarily prescribed clozapine due to poor treatment response to first-line antipsychotic agents. Treatment will be carried out by the physicians within their circle of care, however, we will record their symptoms as they continue treatment. | Drug: Clozapine<br>* Antipsychotic medication<br>* Other names: Clozaril;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neuromelanin-sensitive magnetic resonance imaging (MRI) contrast-to-noise ratio (CNR) | Indexes dopamine function | Will be examined cross-sectionally on an as-recruited basis. | 
| Glutamate/glycine magnetic resonance sptrectroscopy (MRS) | Indexes glutamate & glycine concentration | Will be examined cross-sectionally on an as-recruited basis. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antipsychotic treatment response