Trajectories of Treatment Response as Window Into the Heterogeneity of Psychosis: a Longitudinal Multimodal Imaging Study

Study Overview
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Brief Summary
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Psychosis is a heterogeneous disorder and present treatment only works for a limited number of patients. In order to identify new therapeutic targets, this study will longitudinally characterize the underlying pathologies in those with poor treatment response using complimentary brain imaging modalities.

Detailed Description
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Schizophrenia is a heterogeneous disorder that likely involves multiple underlying pathological mechanisms, which has plagued attempts to identify rational therapeutic targets. All available antipsychotic drugs (APD) are dopamine receptor antagonists, but clinical response is variable, with a third of patients being partial responders, and a third non-responders. Arguably, those who respond well to APD have primarily dopaminergic abnormalities but it is imperative to also characterize the specific underlying pathologies in those with poor response in order to unravel the heterogeneity of psychosis and effectively develop new treatments. The investigators propose to longitudinally follow treatment response to APD for eight months in medication-naïve first episode psychosis (FEP) subjects using complementary brain imaging techniques. The investigators have already identified provisional markers for several different pathophysiological mechanisms underlying psychosis, including abnormalities in glutamate, brain connectivity, and neurodevelopment that they can track with brain imaging. In addition, the investigators propose to study the changes that occur in the brain in early compared to delayed treatment responders and changes that occur over time in response to treatment. By characterizing treatment trajectories and their relationship to baseline pathophysiologic alterations, the investigators will further complement their mechanistic understanding of the heterogeneity of psychosis. The investigators propose to study 117 well-characterized FEP subjects who are medication naïve and treat them with the most frequently used APD for 32 weeks. The investigators will follow a rigorous longitudinal design to capture treatment response whereby those without an adequate response after 16 weeks of treatment will be switched to another APD for 16 weeks. All patients will be scanned four times: at baseline and after 6, 16, and 32 weeks of treatment. The investigators will use (1) proton MR Spectroscopy (MRS), (2) task and resting state functional MRI and (3) MRI and diffusion weighted imaging (DWI) to measure brain biochemistry, function and structure. Using several imaging modalities has the potential to interrogate different neurobiological aspects of treatment response and will offer greater opportunities for clustering the patterns and combinations of the underlying pathologies in those with poor response. Deconstructing the heterogeneity of psychosis has broad implications for the identification of specific targets for drug development, and to lay the groundwork needed to conduct therapeutic trials on patients characterized by their specific underlying psychopathology.

Official Title
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Trajectories of Treatment Response as Window Into the Heterogeneity of Psychosis: a Longitudinal Multimodal Imaging Study in Medication-naïve First Episode Psychosis Patients

Conditions
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Psychosis

Intervention / Treatment
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* Drug: Patients with psychosis will be treated with known antipsychotic medication


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A diagnosis of first episode psychosis Never been treated with an antipsychotic medication Between the age of 17 and 35 Exclusion Criteria: Inability to sign informed consent assessed by the Evaluation to sign - - Consent form Poorly controlled acute or chronic medical and neurological conditions History of head trauma with loss of consciousness for >2 minutes Clinically significant depression, hypomania, or mania Active substance abuse or dependence (except for nicotine) Suspected substance-induced psychosis Treatment with drugs known to affect brain glutamate levels Pregnant females

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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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Treatment group<br>These participants are newly diagnosed with psychosis. | Drug: Patients with psychosis will be treated with known antipsychotic medication<br>* Subjects with first episode psychosis will be treated with risperidone, the most frequently used antipsychotic drug (APD) for 32 weeks. The study will follow a rigorous longitudinal design to capture treatment response whereby those without an adequate response after 16 weeks of treatment will be switched to aripiprazole, another APD for 16 weeks. All patients will be scanned four times: at baseline and after 6, 16, and 32 weeks of treatment.<br>* Other names: Brain imaging scans will be obtained 4 times during the study;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measures of brain structure | Measures of brain structure, as measured with diffusion tensor imaging (DTI) that are associated at baseline (when patients are unmedicated) with subsequent treatment response to antipsychotic medication. | 32 weeks | 
| Measures of brain function | Measures of brain function, as measured with functional MRI (fMRI) that are associated at baseline (when patients are unmedicated) with subsequent treatment response to antipsychotic medication. | 32 weeks | 
| Measures of brain biochemistry | Measures of brain biochemistry, as measured with MR Spectroscopy, that are associated at baseline (when patients are unmedicated) with subsequent treatment response to antipsychotic medication. | 32 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in measures of brain structure | Changes in measures of brain structure over time that are associated with treatment response to antipsychotic medication. | 32 weeks | 
| Changes in measures of brain function | Changes in measures of brain function over time that are associated with treatment response to antipsychotic medication. | 32 weeks | 
| Changes in measures of brain biochemistry | Changes in measures of brain biochemistry over time that are associated with treatment response to antipsychotic medication. | 32 weeks |