The etiology of psychotic disorders is multifactorial and developmental, influenced significantly by genetic factors and various environmental factors, such as childhood adversity. Psychotic disorders, such as schizophrenia, are associated with structural and functional changes in the brain circuits, especially in the frontal and temporal areas. We examined the amygdala subnuclei and hippocampus subfield structures in patients with early psychosis and control subjects. We tested whether the morphology of these structures is linked to psychiatric symptomatology, environmental factors, and metabolic parameters (I, II). Finally, we examined whether antipsychotic drugs affect cortical morphology with respect to different aspects of functional and structural cortical organization (III).

We found that the volume of the lateral nucleus of the amygdala was smaller both in clinical high-risk patients (CHR) and in first episode of psychosis patients (FEP), with the basal nucleus only smaller in FEP. Adverse childhood experiences were associated with the smaller lateral nucleus in FEP (I). Hippocampal subfield volumes were consistently lower in FEP, especially in non-affective psychoses, with less marked changes in CHR. These morphological changes remained stable during the one-year follow-up. Higher fasting plasma insulin and insulin resistance were associated with smaller hippocampal tail volumes in non-diabetic FEP. The glucometabolic deterioration during the follow-up period, independent of antipsychotic drugs, was associated with clinical outcomes such as the transition to psychosis and poor functioning in CHR (II). Study III suggests multiple neurobiological mechanisms, potentially contributing to antipsychotic-associated cortical thinning.

Specific morphological changes in the amygdala and hippocampus are observed in the early psychosis. Some of these changes likely reflect early neurodevelopmental vulnerabilities, while others may emerge at the onset of the first psychotic episode. These features could serve as biomarkers for identifying individuals at high risk of psychosis. The worsening of glucose metabolism parameters, linked to functional impairment in CHR, suggests that careful management of metabolic health should be included in early intervention programs. Finally, our findings on brain features associating with antipsychotic-related cortical thickness could provide further leads in the understanding of antipsychotic drug action.