Comparing brain structural effects of dopaminergic antagonism and partial agonism in antipsychotic-naïve patients with first-episode psychosis using normative modeling

AimSchizophrenia is associated with subtle brain structural alterations but separating disease from medication effects is challenging. Antipsychotic dopamine D2 receptor (D2R) antagonism has been associated with striatal volume increases, but effects of partial D2R agonism by newer antipsychotics are largely unexplored. This study aimed to compare short-term brain changes associated with either D2R antagonism or partial D2R agonism using normative modeling. Secondarily, the study aimed to explore long-term effects following naturalistic treatment. MethodsPatients received 6 weeks of monotherapy with either amisulpride (D2R antagonist) (N=41) or aripiprazole (partial D2R agonist) (N=45). All patients underwent structural magnetic resonance imaging before and after 6 weeks of treatment. A subset was re-scanned at 6 months, 1 year, and 2 years of naturalistic treatment. A pre-trained normative model was applied to 186 subcortical and cortical regions. We used Wilcoxon signed-rank tests to identify longitudinal structural deviations. ResultsAmisulpride and aripiprazole were associated with striatal volume increases after six weeks. No cortical effects were observed with amisulpride. Thinning of the temporal lobe was observed with aripiprazole. After 6 months, and 1 and 2 years, the striatal changes abated but cortical thinning in the frontal lobes emerged. ConclusionsBoth partial D2R agonism and D2R antagonism appear linked to striatal volume increases, however changes appear transient. Conversely, frontal thinning occurs over time and appears less closely linked to antipsychotic treatment. Interpretating structural brain changes in patients with psychosis require consideration of short-term pharmacological effects as well as factors related to illness progression.