Stress and synaptic density in psychosis and clinical high risk: evidence from [18F]SynVesT-1 PET

Synaptic dysfunction is implicated in the pathophysiology of schizophrenia, and positron emission tomography (PET) studies demonstrate in vivo reductions in synaptic density across illness stages. Stress is a key modifiable risk factor, and while animal studies show it disrupts synaptic function, its effects on humans remain unclear. We examined the relationship between stress and synaptic density in individuals with first-episode psychosis (FEP) and those at clinical high risk (CHR). Seventy-eight participants, including 25 FEP, 32 CHR, and 21 healthy controls (HC), underwent 90-min [18F]SynVesT-1 PET scans to quantify synaptic density measured as SV2A binding across prioritized brain regions. Stress-related measures included the Hassles and Uplifts Scale and the Trier Inventory for Chronic Stress (TICS). Depressive symptoms were evaluated using the Hamilton Depression Rating Scale (HDRS). Across all participants, greater acute stress was associated with lower [18F]SynVesT-1 binding (F1449 = 12.0, p < 0.001), with no significant group interaction (F2449 = 2.44, p = 0.09). Group differences emerged for chronic stress and depressive symptoms (TICS × Group: F2431 = 3.87, p = 0.02; sqHDRS × Group: F2443 = 4.47, p = 0.01). Post hoc analyses revealed that higher chronic stress was associated with lower synaptic density in HC (F1119 = 7.07, p = 0.009) but not in clinical groups. Lower mood symptoms were associated with lower synaptic density in FEP (F(1141) = 5.19, p = 0.02) only. These findings indicate that the relationship between stress and synaptic density differs between clinical and healthy groups. The changes in the relationship between stress and synaptic density in FEP may reflect impaired adaptive neuroplasticity, providing a potential mechanism by which stress contributes to psychosis vulnerability.