Toward new treatments for psychotic disorders: identifying key mechanisms behind synaptic loss in early disease stages in order to improve early diagnosis and prediction of disease progression

Psychotic disorders such as schizophrenia typically affects young individuals, and cause suffering and devastating loss of function that often persist throughout life, despite treatment. Pharmacological approaches have remained the same for decades, and work primarily by dampening positive symptoms.

The overall goal of this proposal is to enable new treatments that change the disease course, by targeting causal mechanisms.

The project is based on the emerging hypothesis that excessive synaptic elimination is a key disease mechanism for the development of psychosis, and that immune factors may be underlying this process.

We will utilize a novel positron emission tomography (PET) method to measure synaptic density in a large cohort of patients with recent onset of psychosis, as well as individuals with clinical high risk for psychosis, i.e. before manifest disease. Results will be compared to healthy controls.

Using a combination of cross-sectional and longitudinal analyses we will attempt to capture the critical period for synaptic loss during the developent of psychosis.

PET data will be integrated with functional magnetic resonance imaging and neurophysiology methods to validate the causal role of synaptic loss for the emergence of symptoms.

Cerebrospinal fluid will be analyzed to identify candidate markers that can predict synaptic loss and disease progression, thus paving the way for patient stratification in future clinical trials of novel, disease-modifying drugs.