The purpose of this study is to investigate the relationship between glutamate and related brain chemicals and treatment response to clozapine in patients with treatment-resistant schizophrenia.

This study will be a prospective proton spectroscopy (1H-MRS) study designed to compare the levels of glutamate, glutamine, glx, and glutathione in age- and gender- matched patients with poor response to clozapine (URS), patients with good response to clozapine (non-URS), and healthy controls. Participants with schizophrenia who fail to respond to optimal treatment with at least two different non-clozapine antipsychotics (i.e. treatment-resistant schizophrenia [TRS]) and who are starting clozapine as part of their clinical care will be recruited. A sample of healthy controls will also be recruited. Participants with TRS will have two 1H-MRS scans. The 1H-MRS scan will be performed within 1 week and 12 weeks after clozapine initiation. Clinical assessments will be performed within 1 week of each 1H-MRS scan and after 6 weeks of clozapine treatment. Cognitive assessments will also be performed within 1 week of 1H-MRS scans. Healthy controls will also undergo two 1H-MRS scans with a 12-week interval. Cognitive assessments will also be performed within 1 week of 1H-MRS scans.

Inclusion Criteria for Participants with TRS:

• DSM-IV/SCID diagnosis of schizophrenia, schizoaffective disorder, delusional disorder, or psychotic disorder NOS.
• Age 18 years or older at time of scanning
• History of failure to respond to at least two previous sequential antipsychotic treatments different to clozapine, each attaining a chlorpromazine daily dose of≥ 400 mg for a duration ≥ 6 consecutive weeks.Long-acting antipsychotic treatment will not be allowed during the last trial prior to clozapine in order to avoid residual concentrations or effects.Failure of treatment will be defined by a Clinical Global Impression Severity (CGI-Severity) score of ≥4 and score of ≥4 on 2 Positive and Negative Syndrome Scale (PANSS) positive symptom items. The CGI-Severity or Global Assessment of Functioning (GAF) will be completed retrospectively based on information provided by the participant, participant's psychiatrist, medical chart, or other sources of available collateral information.

Exclusion Criteria for Participants with TRS:

• Incapacity to provide consent to participate in the research study.
• Substance abuse or dependence (within past six months), excluding nicotine and caffeine.
• Positive urine drug screen for drugs of abuse.
• Metal implants or a pace-maker that would preclude the MRI scan.
• History of head trauma resulting in loss of consciousness > 30 minutes that required medical attention.
• Unstable physical illness or significant neurological disorder including a seizure disorder.
• Size of head, neck, and body being unable to fit MRI scanners.
• Refusal to provide consent to investigator to communicate with physician of record to obtain collateral information.
• Psychiatric concerns raised by the physician of record regarding participation in the study.
• Currently taking medications that may directly impact the glutamatergic system (i.e. lamotrigine, topiramate, memantine or N-acetylcysteine)
• ECT, MST or TMS in the past 6 months

Inclusion criteria for Healthy Controls:

• Age of 18 and older at time of scanning
• Being capable to consent to study procedures
• Absence of history of psychiatric illness using the Mini-International Neuropsychiatric Interview (MINI)

Exclusion criteria for Healthy Controls:

• First degree family member with primary psychotic disorder
• Substance abuse or dependence (within past six months), excluding nicotine and caffeine.
• Positive urine drug screen for drugs of abuse
• Pacemakers, metallic cardiac valves, magnetic material such as surgical clips, implanted electronic infusion pumps or any other conditions that would preclude the MRI scan
• Clinically significant claustrophobia
• History of head trauma resulting in loss of consciousness > 30 minutes that required medical attention
• Size of head, neck, and body being unable to fit MRI scanners
• Unstable physical illness or significant neurological disorder including a seizure disorder

Participants with schizophrenia who fail to respond to optimal treatment with at least two different non-clozapine antipsychotics (i.e. treatment-resistant schizophrenia [TRS]) and are starting clozapine will be recruited. A sample of healthy controls will also be recruited.