Unveil Psychosis Heterogeneity: Stratification via Circuit-Based Biomarkers

Abstract: Professor Kim Q. Do's presentation will discuss a translational program aimed at early detection and intervention in schizophrenia. It requires mechanism-based biomarkers that capture neural circuitry dysfunction, enabling better patient stratification, personalized treatments and disease progression monitoring.

She will illustrate how the interplay between genetic and environmental risk factors during neurodevelopment converges upon a central hub characterized by neuroinflammation, NMDA receptor hypofunction, mitochondrial dysfunction, dopamine dysregulation, and disrupted redox balance. These factors give rise to oxidative stress, reinforcing one another in a detrimental feedforward mechanism. This cascade affects parvalbumin interneurons (PVI), including their associated gamma synchronization, and impacts myelination. Consequently, structural and functional alterations emerge within local microcircuits and long-range connections, both of which are pivotal for cognitive, affective, and social functioning.

Professor Do will review the challenges and prospects encountered when translating preclinical models into clinical trials, particularly those involving the supplementation of antioxidants in individuals at the early stages of psychosis. Furthermore, she will delve into a newly discovered molecular mechanism linking mitochondrial bioenergetics and oxidative stress, which leads to impairments in PVI microcircuits. These resultant biomarkers exhibit remarkable accuracy in patient selection for treatments targeting brain mitochondria dysregulation, and they also serve as a means to validate the clinical and functional efficacy of forthcoming clinical trials.

 

Biography: Kim Q. Do is Professor of Translational Psychiatry at Lausanne University, Switzerland, and Visiting Professor at the Swiss Federal Institute of Technology Lausanne (EPFL), Harvard Medical School in Boston, USA, and the Institute of Psychiatry, Psychology & Neuroscience at King’s College London, UK. Until 2019, she was Director of the Center for Psychiatric Neuroscience (Department of Psychiatry, Lausanne University Hospital).

Her unique research bridges basic neurobiology and clinical investigation, with a focus on understanding the causes and mechanisms of psychosis. Her aim is to develop early diagnostic markers, identify new drug targets, and advance preventive and therapeutic approaches.

Dr Do's studies are centered on oxidative stress/redox dysregulation, which interacts with NMDAR hypofunction, neuroinflammation, and dopamine imbalance. They have revealed circuit-based mechanisms underlying impairments of neural connectivity and synchronization, and leading to cognitive deficits as observed in patients. Her pioneering work has resulted in proof-of-concept clinical trials with the antioxidant N-acetylcysteine.

Recently, she and her team identified blood exosomal markers that detect mitochondria-induced oxidative stress in the microcircuits of parvalbumin interneurons. These biomarkers are instrumental in selecting patients for treatments targeting brain mitochondria dysregulation, and validating the effectiveness of future clinical trials.

Dr Do’s translational research paves the way for promising biomarker guided treatment of individuals in the early stages of psychosis.

She has authored over 350 peer-reviewed papers, serves on the editorial boards of prominent biological psychiatry journals, and participates in advisory/evaluation committees for institutions such as the Swiss National Science Foundation (CH), Fondation pour la Recherche Médicale (F), The Wellcome Trust (UK), Medical Research Council (UK), National Institute of Health (USA), and National Science Foundation (USA). She has earned numerous national and international awards, including the 2010 NARSAD Distinguished Investigator Award, the 2018 Outstanding Basic Science Award from the Schizophrenia International Research Society (SIRS), and the 2018 Elsevier Senior Schizophrenia Research Award.