Age of onset: static and dynamic brain regional activity in first-episode drug-naïve schizophrenia

The age at which schizophrenia manifests is a critical factor influencing long-term outcomes. It is essential to distinguish the effects of the illness phase from those of the age of onset. We assessed static/dynamic brain regional activity from 428 participants, split into four groups based on onset-age (early-onset schizophrenia [EOS] and adult-onset schizophrenia [AOS]) and treatment status: (1) drug-naïve first-episode patients (48 EOS and 62 AOS); (2) patients treated for ≤ 12 months (60 EOS and 53 AOS); (3) patients treated for > 12 months (56 EOS and 56 AOS); and (4) 93 healthy controls (32 age-matched with EOS, 61 age-matched with AOS). We conducted a principal component analysis and subsequent 2 × 2 factorial analysis on the extracted first component representing static/dynamic regional activity, followed by an out-of-sample imaging transcriptomics analysis. The stability of results from the drug-naïve groups were tested on the treated groups to account for antipsychotic effects. Onset-age had a notable interaction with diagnosis on the static activity of the thalamus, mid-cingulate cortex (MCC), cerebellum posterior lobe (CPL), precuneus, and putamen, and on the dynamic stability of the CPL, thalamus, and superior parietal lobule (SPL). Phase of illness and medication exposure did not affect the onset-age effect seen at the MCC, thalamus, and SPL. Transcriptomics analysis pointed to the possibility of a shared disruption in neuronal differentiation across the MCC, thalamus and SPL. Onset-age affects thalamo-fronto-parietal regional hemodynamic activity, possibly through disrupted neuronal differentiation, in schizophrenia. Exposure to antipsychotics do not reverse this functional imprint of the earlier illness onset, raising the question of alternate therapeutic approaches to close the observed "neurophysiological gap".