Striatal Connectivity and Clinical Outcome in Psychosis

In this proposed study, the study will examine treatment-related effects on functional brain
circuitry in first episode schizophrenia. Converging lines of evidence suggest a key role for
striatal disconnectivity in the pathophysiology of psychosis. The proposed study will utilize
resting state functional magnetic resonance imaging (rs-fMRI), as well as fMRI tasks derived
from the Research Domain Criteria (RDoC) framework, to: 1) develop and validate a prognostic
biomarker to predict antipsychotic treatment response; and 2) to model the underlying neural
circuitry changes associated with state changes in psychotic symptomatology. As a prognostic
biomarker, a neuroimaging assay of striatal connectivity can potentially provide a clinically
useful tool to advance the goal of precision medicine. As a longitudinal index of symptom
change, our model can serve as an objective index against which to measure potential efficacy
of newly developed antipsychotic treatments.

A large, well-characterized cohort of patients presenting with a first episode active
psychosis (regardless of DSM diagnosis) will be recruited, along with matched controls. The
study will utilize two well-validated fMRI tasks capturing two portions of the positive
valence system: probabilistic category learning and reward responsiveness; these tasks are
designed to interrogate dorsal and ventral corticostriatal circuits, respectively. The design
will be longitudinal, with two scanning sessions performed for each patient: at baseline, and
after 12 weeks of treatment. Treatment will be standardized across all patients to reduce
potential confounds, and healthy controls will also be scanned at baseline and 12 weeks in
order to control for effects of time and practice. Level of psychotic symptomatology
(hallucinations, delusions, and thought disorder) will be measured at regular intervals using
a comprehensive battery of rating scales. As secondary measures, electroencephalography (EEG)
will be performed coinciding with neuroimaging on a subset of patients who provide consent.
We will utilize Kaplan-Meier estimators and hierarchical linear modeling to examine the
association of baseline striatal connectivity, and changes in connectivity over time, with
clinical response of psychotic symptoms to antipsychotic treatment. Deliverables will include
both baseline and longitudinal biomarkers that can subsequently be tested in broader, more
heterogeneous populations of patients with psychosis.

Patients

Inclusion Criteria:

1. current DSM-IV-defined diagnosis of schizophrenia, schizophreniform, schizoaffective
disorder, brief psychotic disorder, psychotic disorder NOS, bipolar I with psychotic
features (acute manic or mixed episode), major depressive disorder with psychotic
features as assessed using the Structured Clinical Interview for Axis I DSM-IV
Disorders (SCID-I/P) (First et al, 1994);

2. does not meet DSM-IV criteria for a current substance-induced psychotic disorder, a
psychotic disorder due to a general medical condition, delusional disorder, shared
psychotic disorder, or a mood disorder with psychotic features;

3. current positive symptoms rated ≥4 (moderate) on one or more of these BPRS (Woerner et
al., 1988) items: conceptual disorganization, grandiosity, hallucinatory behavior,
unusual thought content;

4. is in a early phase of illness as defined by having taken antipsychotic medications
for a cumulative lifetime period of 4 weeks or less,

5. age 15 to 40;

6. competent and willing to sign informed consent; and

7. for women, negative pregnancy test and agreement to use a medically accepted birth
control method.

Exclusion Criteria:

1. serious neurological or endocrine disorder or any medical condition or treatment known
to affect the brain

2. any medical condition which requires treatment with a medication with psychotropic
effects

3. significant risk of suicidal or homicidal behavior

4. cognitive or language limitations, or any other factor that would preclude subjects
providing informed consent

5. medical contraindications to treatment with risperidone monotherapy (e.g. neuroleptic
malignant syndrome with prior risperidone exposure)

6. lack of response to a prior adequate trial of risperidone

7. requires treatment with an antidepressant or mood stabilizing medication

Healthy Volunteers

Inclusion

1. age 15 to 40

2. competent to sign informed consent

Exclusion

1. lifetime history of any mood disorder or any psychotic disorder as determined by
clinical interview using the SCID-NP

2. MR imaging contraindications

3. neurologic conditions

4. any serious non-psychiatric disorder that could affect brain functioning

5. mental retardation