SAN 2026

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Disorders of the Nervous System

Synaptic density in early stages of psychosis and clinical high risk: An association with negative symptoms

M. Belen Blasco1, 2.
Kankana Nisha-Aji2.
Christian Ramos-Jiménez1, 2.
Ilana Ruth Leppert4.
Christine Lucas Tardif4, 5.
Johan Cohen3.
Pablo M. Rusjan1, 3.
Romina Mizrahi1, 2, 3.
  • 1. Department of Psychiatry, McGill University, Montreal, Quebec, Canada
  • 2. Douglas Research Centre, Clinical and Translational Sciences Lab, Montreal, Quebec, Canada
  • 3. Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada
  • 4. McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
  • 5. Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada

Presenting Author:

Maira Belén

Blasco

maira.blasco@mail.mcgill.ca

Importance: Synaptic dysfunction has been implicated in schizophrenia. However, whether synaptic density is reduced during the earliest stages of psychosis, including clinical high-risk (CHR) states and first-episode psychosis (FEP) was unclear.

Objective: To investigate synaptic density in FEP and CHR, examine the impact of cannabis use, and assess associations with negative symptoms and gray matter microstructure.

Methods: In this cross-sectional study, antipsychotic-free or minimally exposed FEP participants, CHR individuals, and healthy controls underwent 90-minute [18F]SynVesT-1 PET imaging to quantify synaptic vesicle glycoprotein 2A (SV2A) binding. Gray matter microstructure was assessed using diffusion MRI, and cannabis use was confirmed by urine drug screening.

Results: Forty-nine participants were included (16 FEP, 17 CHR, 16 controls). Synaptic density differed significantly across groups, with lower SV2A binding in FEP and CHR than in controls. Cannabis users also showed lower synaptic density. Across groups, reduced SV2A binding was associated with greater negative symptom severity and lower neurite density.

Conclusions: Lower synaptic density is detectable during early stages of psychosis, including CHR, and are associated with negative symptoms and altered gray matter microstructure. These findings support synaptic dysfunction as an early feature of psychosis and highlight the need for longitudinal studies investigating the effects of cannabis.