Characterizing Response to Antipsychotics in Schizophrenia

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

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.

Study Overview

• Status: Recruiting
• Conditions: Schizophrenia; Schizoaffective Disorder
• Intervention / Treatment: Drug: Olanzapine; Drug: Clozapine

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 40

Contacts and Locations

• Study Contact: Name: Lauri Tuominen, MD, PhD; Phone Number: 6337 (613) 722-6521; Email: Lauri.Tuominen@theroyal.ca
• Study Contact Backup: Name: Coleka Masama, BSc; Phone Number: 6337 (613) 722-6521; Email: coleka.masama@theroyal.ca

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1Z 7K4
      • Recruiting
      • The Royal's Institute of Mental Health Research
      • Contact: Alexis Dorland; Phone Number: 6952 613-722-6521; Email: Alexis.Dorland@theroyal.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Individuals with a diagnosis of schizophrenia or schizoaffective disorder

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
First-line treatment group; 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; Antipsychotic medication; Other Names: Zyprexa
Treatment-resistant group; 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; Antipsychotic medication; Other Names: Clozaril

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: The Royal Ottawa Mental Health Centre
• Collaborators: The Royal's Institute of Mental Health Research
• Investigators: Principal Investigator: Lauri Tuominen, MD, PhD, The Royal's Institute of Mental Health Research; Principal Investigator: Clifford Cassidy, PhD, The Royal's Institute of Mental Health Research

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2023
• Primary Completion (Estimated): January 30, 2024
• Study Completion (Estimated): January 30, 2024

Study Registration Dates

• First Submitted: April 10, 2022
• First Submitted That Met QC Criteria: November 28, 2023
• First Posted (Estimated): December 6, 2023

Study Record Updates

• Last Update Posted (Estimated): December 6, 2023
• Last Update Submitted That Met QC Criteria: November 28, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Antipsychotic treatment response
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Psychotic Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Serotonin Antagonists; GABA Agents; GABA Antagonists; Selective Serotonin Reuptake Inhibitors; Olanzapine; Clozapine
• Other Study ID Numbers: 2021033

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD will not be shared.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No