Duration of Untreated Psychosis, Treatment Response, and Resting State Functional Connectivity in Antipsychotic-Naïve First-Episode Psychosis Patients.

Background: Meta-analyses consistently link longer duration of untreated psychosis (DUP) to worse clinical outcomes, but the underlying neurobiological mechanisms remain unclear. This study examined whether DUP influences resting-state functional connectivity (FC) and if FC mediates the relationship between DUP and treatment response following antipsychotic drug (APD) treatment. Hypotheses: We hypothesized that longer DUP would be associated with both reduced FC and worse treatment response, and that FC would mediate the relationship between DUP and response to antipsychotic treatment. Study Design: One hundred antipsychotic-naïve first- episode psychosis patients underwent resting state fMRI. We extracted signal from regions within the default mode (posterior cingulate), salience (anterior cingulate), and central executive (right posterior parietal cortex) networks, correlating them with whole-brain activity. Associations between DUP and FC were examined while controlling for age, sex, and framewise displacement. Mediation analyses tested whether FC of these networks mediated the relationship between DUP and treatment response. Study Results: Findings indicated that longer DUP was associated with reduced functional connectivity in all networks of interest. Further, we found that functional connectivity of the central executive and salience networks mediated the relationship between DUP and treatment response. Conclusions: These results suggest that there are pathophysiological processes inherent in the DUP. These results are also consistent with the possibility that brain network connectivity is a neurological link between longer DUP and poor treatment response. Our data emphasize the importance of early intervention targeting DUP's adverse effects on the brain.