Cerebrospinal fluid studies of major psychiatric disorders

Abstract

Bipolar disorder and schizophrenia are clinically related, severe psychiatric disorders affecting 2–3% of the global population. With early onset, a life-long course, and limited treatment options, they cause major burden. Both disorders have a strong genetic basis thought to influence neuronal development and connectivity, but the mechanism linking inherited risk to disease biology remains unknown. Cerebrospinal fluid is uniquely placed to address this gap, providing minimally invasive access to the molecular composition of the living human brain, enabling the discovery of clinically relevant biomarkers. This thesis presents five papers, each aimed at profiling molecular alterations in cerebrospinal fluid from individuals living with bipolar disorder or schizophrenia compared with non-affected individuals. Using proteomic techniques, we characterized proteins expressed by neurons, glia, and other cell types. Papers 1–3 focused on bipolar disorder, representing among the first large-scale efforts to map the cerebrospinal fluid proteome in any psychiatric disorder. Papers 4–5 broadened the scope to include both bipolar disorder and schizophrenia, focusing on synapse–immune interactions. Together, the findings point to impaired synaptic connectivity—but with a notable absence of overall neurodegeneration—as shared molecular signatures of bipolar disorder and schizophrenia. The findings advance our understanding of the molecular basis of these disorders and provide a foundation for future development of fluid biomarkers to improve clinical care for those affected.