Exploring brain structural effects of dopaminergic antagonism and partial agonism in antipsychotic‐naïve patients with first‐episode psychosis using normative modeling
Year: 2026
Type: article
Abstract: AIM: Schizophrenia 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. METHODS: Antipsychotic-naïve patients with first-episode psychosis 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 pretrained normative model was applied to 186 subcortical and cortical regions. We used Wilcoxon signed-rank tests to identify longitudinal structural deviations. RESULTS: Amisulpride and aripiprazole were associated with striatal volume increases after 6 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. CONCLUSIONS: Both 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. Interpreting structural brain changes in patients with psychosis require consideration of short-term pharmacological effects as well as factors related to illness progression.
DOI: 10.1111/pcn.70017
Institutions: Mental Health Services, Glostrup Hospital, Copenhagen University Hospital, Tbilisi State Medical University, Rigshospitalet, University of Copenhagen, Radboud University Nijmegen, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, The University of Melbourne
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: BRAINCHART: Normative brain charting for predicting and stratifying psychosis, BRAINCHART: Normative brain charting for predicting and stratifying psychosis, G1784641593, PRECOGNITION: Learning latent cognitive profiles to predict psychosis, G4545711105, G4929831872, Integrating biology and behaviour for precision stratification of mental disorders, PRECOGNITION: Learning latent cognitive profiles to predict psychosis, G839280970, G907259581
OpenAlex ID: W7118573228