Cortical brain changes from early to mid-adolescence in offspring at familial high risk for schizophrenia or bipolar disorder

Objective: Schizophrenia (SZ) and bipolar disorder (BP) emerge in late adolescence or adulthood. Offspring at familial high risk for SZ (FHR-SZ) or BP (FHR-BP) are more likely to develop psychiatric disorders. Prior work from the Danish High Risk and Resilience (VIA) Study found sex-specific volumetric brain differences in offspring at FHR-SZ and FHR-BP aged 11-12 years. This study builds upon these findings by testing whether they reflect group differences in rate of change or stable group differences from early to mid-adolescence. Methods: This study investigated MRI data from offspring at FHR-SZ, FHR-BP, and population- based controls (PBC) at baseline (11-12 years; n=288) and follow-up (15-16 years; n=249). FreeSurfer longitudinal processing derived total brain volume, cortical measures, and intracranial volume (ICV). Linear mixed-effects models tested group-by-age interactions and sex-specific group effects, as well as associations with psychotic experiences (PE) and lifetime Axis-I mental disorders. Results: The analysis did not detect group-by-age interactions, indicating similar developmental slopes across groups. However, at both time points, males at FHR-SZ demonstrated reduced brain and cortical volumes compared to PBC and FHR-BP males. These effects were attenuated after adjusting for ICV, which was reduced in males at FHR-SZ. The analysis additionally detected volumetric reductions in males with PE, after controlling for risk status. Conclusions: These results extend the previous findings to ages 15-16 years, indicating group differences are stable and persist into mid-adolescence. Associations with ICV suggest early neurodevelopmental effects, and volumetric reductions in males with PE suggest convergent effects with FHR-SZ.