Hippocampal Shape and Volume Changes with Antipsychotics in Early Stage Psychotic Illness

Progression of hippocampal shape and volume abnormalities has been described in psychotic disorders such as schizophrenia. However it is unclear how specific antipsychotic medications influence the development of hippocampal structure. We conducted a longitudinal, randomized, controlled, multisite, double-blind study involving 14 academic medical centers (United States 11, Canada 1, Netherlands 1, and England 1). One hundred thirty-four first-episode psychosis patients (receiving either haloperidol [HAL] or olanzapine [OLZ]) and 51 healthy controls were followed for up to 104 weeks using magnetic resonance imaging and large-deformation high-dimensional brain mapping of the hippocampus. Changes in hippocampal volume and shape metrics (i.e., percentage of negative surface vertex slopes, and surface deformation) were evaluated. Mixed-models analysis did not show a significant group-by-time interaction for hippocampal volume. However, the cumulative distribution function of hippocampal surface vertex slopes showed a notable left shift with HAL treatment compared to OLZ treatment and to controls. OLZ treatment was associated with a significantly lower percentage of “large magnitude” negative surface vertex slopes compared to HAL treatment (p = 0.004). Surface deformation maps however did not localize any hippocampal regions that differentially contracted over time with OLZ treatment, after FDR correction. These results indicate that surface analysis provides supplementary information to volumetry in detecting differential treatment effects of the hippocampus. Our results suggest that OLZ is associated with less longitudinal hippocampal surface deformation than HAL, however the hippocampal regions affected appear to be variable across patients.