New molecular understanding of mental disorders through deep cerebrospinal fluid phenotyping

Introduction

Psychiatry is lacking truly objective markers, and the limited molecular understanding of disease mechanisms underlying mental disorders inhibits us from designing new therapies. The identification of novel treatment targets is urgently needed. No study has yet conducted deep phenotyping of the cerebrospinal fluid (CSF), which is the biological material closest to the brain that is assessable for direct investigations in vivo. Additionally, no large longitudinal CSF studies on mental disorders currently exist.

Project Aim

I aim at a paradigm change by advancing the current state-of-the-art through novel deep CSF phenotyping on unique CSF samples from individuals with:

1. First episode psychotic disorders
2. Depression
3. Healthy controls

This will be followed up longitudinally, both clinically and in nationwide registers.

Methodology

Pushing the frontiers of knowledge within psychiatry, I will use novel technologies and, for the first time for these disorders, employ cutting-edge single-cell sequencing of cell compartments in the CSF potentially involved in or affected by disease, with a particular focus on T cell alterations.

For the first time, longitudinal omics analyses will be conducted with:

• Targeted metabolomics
• Untargeted metabolomics
• Proteomics

These analyses aim to identify disease-relevant metabolites and proteins in the CSF, thereby increasing the understanding of molecular mechanisms of psychiatric symptoms and diagnosis.

Analytical Approaches

Systems biology and deep learning approaches will provide crucial insights into biological pathways and the interplay between brain pathophysiological mechanisms in a cross-diagnostic manner. This may potentially identify biologically distinct clusters and disentangle the involved molecular mechanisms.

Significance

This approach is unprecedented. The identification of novel therapeutic targets, increasing the understanding of mental disorders, and insights into molecular mechanisms through deep CSF phenotyping has groundbreaking potential for psychiatry and neuroscience, paving the way for more effective and mechanism-based treatment.