Early Psychosis and Synaptic Density Reductions Linked, Particularly With Cannabis Use
A recent study found synaptic density reductions in the early stages of psychosis and its risk states, particularly in individuals who use cannabis, according to recent results published in JAMA Psychiatry.
“Current medications largely target hallucinations, but they don't address symptoms that make it difficult to manage social relationships, work, or school," noted lead author Belen Blasco, MD, Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada, and co-authors. "By focusing on synaptic density, we may eventually develop therapies that enhance social function and quality of life for those affected."
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The cross-sectional study aimed to assess whether synaptic density, measured by synaptic vesicle glycoprotein 2A (SV2A) binding potential, is reduced in first-episode psychosis (FEP) and clinical high-risk (CHR) states. Conducted at a tertiary psychiatric hospital from July 2021 to October 2023, the study included patients with minimal antipsychotic exposure and healthy controls. Synaptic density was quantified using 90-minute [18F]SynVesT-1 PET scans, and gray matter microstructure was evaluated with diffusion-weighted MRI. Researchers also investigated the effects of cannabis use on synaptic density and its relationship with psychotic symptoms and gray matter changes.
The study included 49 participants: 16 with FEP, 17 at CHR, and 16 healthy controls. Synaptic density was significantly reduced in FEP and CHR groups compared to controls, with notable group and region-of-interest interactions (F2,273 = 4.02, P = .02, Cohen F = 0.17; ROI: F5,273 = 360.18, P < .01, Cohen F = 2.55). Cannabis users had lower synaptic density (F1,272 = 5.31, P = .02, Cohen F = 0.14), and reductions in synaptic density were associated with more severe negative symptoms (Positive and Negative Syndrome Scale negative scores: F1,81 = 4.31, P = .04, Cohen F = 0.23; Scale of Psychosis-Risk Symptoms negative scores: F1,90 = 4.12, P = .04, Cohen F = 0.21). Additionally, SV2A binding potential was significantly correlated with neurite density index (F1,138 = 6.76, P = .01, Cohen F = 0.22), linking synaptic changes to gray matter microstructure.
Study authors called attention to several limitations that should inform interpretation of its findings. The clinical heterogeneity of early psychosis stages and limited diagnostic stability may affect generalizability. While SV2A is a validated synaptic density marker due to its correlation with synaptophysin, reductions in SV2A may also reflect alternative mechanisms, such as changes in synaptic vesicle production or SV2A protein concentration. The use of the simplified reference tissue model (SRTM) for binding potential estimates may lead to group-dependent variability, particularly in white matter reference regions. Additionally, the small sample size, inherent to PET studies, and limitations in using neurite density index (NDI) to represent gray matter neurite density should be considered.
“Future studies should investigate the impact of cannabis use on synaptic density in CHR longitudinally,” authors concluded.
