Cerebrospinal fluid biomarkers reveal transdiagnostic synaptic dysfunction across major psychiatric disorders
- Andreas Göteson
- Johanna Nilsson
- Elena Camporesi
- Anna Luisa Klahn
- Elin Hörbeck
- Robert Sigström
- Lina Jonsson
- Timea Sparding
- Erik Pålsson
- Aurimantas Pelanis
- Anneli Goulding
- Anniella Isgren
- Sophie Erhardt
- Simon Cervenka
- Cynthia M. Bulik
- Henrik Zetterberg
- Kaj Blennow
- Carl M. Sellgren
- Ann Brinkmalm
- Mikael Landén
2026-07-30
Synaptic dysfunction is increasingly recognized as a core feature of psychiatric disorders, yet fluid biomarkers that reflect such changes in vivo are lacking. Here, we applied targeted mass spectrometry to quantify low-abundant synaptic proteins in cerebrospinal fluid from 672 individuals with anorexia nervosa, attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), schizophrenia spectrum disorders (SCZ + ), and healthy controls. Synaptic protein levels were markedly reduced in SCZ + , with intermediate reductions in BD and ADHD. Using a data-driven approach to model transdiagnostic contrasts—psychotic experience, cognitive and functional impairment—a shared two-biomarker signature emerged: elevated LAMP1, a phagolysosomal marker, and reduced NPTX2, a synaptic activity marker which inhibits complement-dependent synapse elimination. Combining this ratio with polygenic scores improved diagnostic classification. Key findings were extended to an independent cohort at first-episode psychosis. These results support synaptic pathology as a measurable and transdiagnostic feature across several psychiatric disorders and highlight the potential of integrating fluid and genetic biomarkers.