Urban built density and brain connectivity predict antipsychotic response in a sex-specific manner in Schizophrenia

Urbanicity is a well-established environmental risk factor for schizophrenia, particularly in males, yet it is also associated with better antipsychotic treatment response. We aimed to identify resting-state functional connectivity (rsFC) correlates of neighborhood geospatial features in a hypothesis-free, whole-brain analysis of individuals with first-episode schizophrenia (FES). We further examined whether these geospatial variables and their rsFC correlates interact with sex to predict response to oral risperidone over six weeks.

We studied 48 antipsychotic-naïve individuals with FES residing in or around Bangalore, India. Whole-brain within-network connectivity analyses were conducted to identify rsFC correlates of neighborhood built-density and green space. We tested whether sex moderated the relationship between geospatial variables (or their rsFC correlates) and treatment response using a moderation analysis framework implemented through structural equation modelling.

Higher built density was associated with increased connectivity in the superior occipital and default mode networks, and decreased connectivity in the basal ganglia-thalamic network. While built density and rsFC measures were not significantly associated with treatment response in the overall sample, sex-specific disordinal interactions were observed: in males, higher built density and associated rsFC predicted greater symptom improvement; in females, the same features predicted poorer treatment response.

In FES, built density and its rsFC correlates are associated with treatment response in opposite directions, depending on sex - beneficial in males and detrimental in females - supporting a differential susceptibility model. These findings highlight the importance of incorporating neurourbanism and sex-specific approaches into personalized psychiatric care.