Glutamate, Brain Connectivity and Duration of Untreated Psychosis

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.