Synaptic Dysfunction in Psychosis Explored at ACNP Meeting

During the 63rd Annual Meeting of the American College of Neuropsychopharmacology (ACNP), Romina Mizrahi, MD, PhD, and M. Belen Blasco, MD, presented their findings on synaptic density reductions in the early stages of psychosis and their connection to clinical high-risk (CHR) states. They also explored the effects of cannabis use on synaptic density, psychotic symptoms, and grey matter microstructures.¹

The study included 49 participants: 16 antipsychotic-free or minimally exposed patients with FEP, 12 individuals who were CHR, and 16 healthy controls. Using [18F]SynVesT-1 PET scans and diffusion-weighted MRI, the study revealed that “synaptic density was lower in cannabis users” and that reductions in synaptic density were linked to more severe negative symptoms, as measured by PANSS and SOPS scores. Mizrahi and Blasco noted they also found significant associations between synaptic density and neurite density index (NDI), suggesting potential microstructural abnormalities in grey matter​​.

In an exclusive video interview with Psychiatric Times, Mizrahi and Blasco emphasized the clinical relevance of these findings. “In these clinical groups, compared to healthy volunteers, there was a reduction in synaptic density levels,” Blasco said. They explained that the study provided critical evidence that negative symptoms in psychosis—such as reduced motivation and interest in social engagement—are tied to disruptions in brain connectivity. “This ability that we have to connect with others and to be engaged in society really seems to be related to how our brain connects within itself,” Mizrahi said.

Mizrahi also highlighted the impact of cannabis on synaptic density and the importance of further longitudinal studies to explore this relationship. The findings underscore the need for continued investigation into synaptic dysfunction as a key mechanism in psychosis and CHR states, with implications for targeted interventions.

Mizrahi added that these results contribute to a growing understanding of how early synaptic changes influence psychosis onset and progression, paving the way for more precise diagnostics and treatment strategies.

Beyond their findings, Mizrahi and Blasco praised the ACNP conference for its forward-thinking focus and commitment to translational research. For instance, Mizrahi was intrigued by discussions on the role of glia in schizophrenia, "instead of just looking at the standard mechanism of action for antipsychotics... the next frontier is to actually start to understand the brain and see whether we can actually prevent disease.”

Blasco was also impressed with the networking opportunities. “This is the first time that I’m coming as a PhD student,” she said. “It’s a great opportunity to share and network... and also to learn from the best scientists on how to develop a career in science.”

Reference
1. Blasco M Belen. Synaptic Density in Early Stages of Psychosis and Clinical High Risk: A Link with Negative Symptoms. Presented at: The 63rd Annual Meeting of the American College of Neuropsychopharmacology. Phoenix, Arizona; December 8 - 12, 2024.