Glutamate, Brain Connectivity and Duration of Untreated Psychosis

Study Overview
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Brief Summary
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The early stages of schizophrenia are associated with significant decreases in social and intellectual abilities, with more declines in chronic disease. Studies have identified relationships between duration of untreated psychosis (the duration between the onset of positive symptoms and treatment) and worse long term outcomes. However, the neurobiology of this phenomenon and its implications for response to antipsychotic medications remain poorly understood. Glutamatergic excess altering brain connectivity might provide an explanation for why those with longer duration of untreated psychosis have worse clinical outcomes. The investigators propose to use neuroimaging to study 67 first episode psychosis subjects before and after sixteen weeks of treatment with risperidone, a common antipsychotic. We will measure (1) glutamate and (2) structural and functional brain connectivity and test the hypotheses that glutamatergic abnormalities are present in first episode patients and that longer duration of untreated psychosis is associated with greater connectivity abnormalities that set the stage for poor response to treatment. 67 demographic-matched controls will also be recruited as a comparison group - healthy controls will not receive antipsychotic medication. The investigator's previous studies have made progress in the understanding of abnormalities in the glutamate system and brain connectivity in unmedicated patients with schizophrenia and modulation of these by antipsychotic medication. Two indices of glutamatergic dysfunction have been identified. While antipsychotic medications appear to modulate glutamate, the disturbance in the relationship between metabolites is not restored with treatment. In addition, the investigators found that both structural and functional connectivity abnormalities in unmedicated patients with schizophrenia predict patients' response to treatment. To the investigator's knowledge, no other group has performed a study that uses a combination of complementary neuroimaging techniques that will allow generating a broad characterization of glutamatergic function and brain connectivity in first episode psychosis and change with treatment. The results of the proposed studies could suggest a mechanism by which the duration of untreated psychosis is associated with poor treatment response which might lead to new interventions to target the illness.

Official Title
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Glutamate, Brain Connectivity and Duration of Untreated Psychosis

Conditions
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Schizophrenia, Psychosis, Schizoaffective Disorder

Intervention / Treatment
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* Drug: Risperidone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Persons with first episode psychosis Healthy controls will be matched to first episode psychosis participants on a one to one basis Exclusion Criteria: inability to understand and sign informed consent assessed by the Evaluation to sign Consent form diagnosable central nervous system illnesses poorly controlled acute or chronic medical conditions aside from psychosis history of head trauma with loss of consciousness for > 2 minutes active substance abuse or dependence (exclusive of nicotine dependence) suspected substance induced psychotic symptoms clinically significant symptoms of depression, hypomania, or mania patients concomitantly treated with drugs known to affect glutamate, such as: valproate, topiramate, gabapentin, levetiracetam, lamotrigine, lithium, and acamprosate

Ages Eligible for Study
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Minimum Age: 17 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| first episode psychosis<br>Unmedicated first episode psychosis patients that wish to enroll in a 16 week treatment regimen with the drug Risperidone. | Drug: Risperidone<br>* Patients with psychosis will be provided a 16 week regimen of the antipsychotic drug Risperidone in accordance with standard care.<br>* Other names: Risperdal;|
| healthy demographic-matched controls<br>healthy controls will be matched to patients one to one based on: age, smoking status, parental socio-economic status, and gender. Healthy controls must be free from current or past Axis I mental disorders, 1st degree relative current or past Axis I mental disorders, and any other neurological conditions. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of indices of glutamate as measured by 1H-MRS in unmedicated first episode psychosis patients before and after antipsychotic treatment and with healthy controls. |  | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of structural and functional brain connectivity in first episode psychosis patients before and after antipsychotic treatment and healthy controls | Structural brain connectivity (using diffusion tensor imaging) and functional brain connectivity (using resting state connectivity) will be compared between healthy controls and first episode psychosis patients. Additionally within first episode psychosis patients duration of untreated psychosis (DUP) will be correlated with both structural and functional brain connectivity to determine the impact of DUP on both metrics of brain connectivity. | Up to 5 years | 
| Evaluation of the contribution of structural and functional connectivity to eventual antipsychotic treatment response in first episode psychosis patients. | The investigators will evaluate the relationship between both structural brain connectivity (using diffusion tensor imaging) and functional brain connectivity (using resting state connectivity) before treatment and treatment response after 16 weeks of risperidone therapy in first episode psychosis patients. | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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duration of untreated psychosis, glutamate, functional connectivity, structural connectivity, schizophrenia, psychosis