Immune dysregulation in mania: A proof‐of‐concept platelet proteomics study

Aims Bipolar disorder (BD) is a major psychiatric condition with a multifaceted and largely unknown pathophysiology. Mania, the defining feature of BD, remains underinvestigated. Proteomics offers a powerful, data‐driven, unbiased approach to uncover biological alterations. Blood platelets provide a stable and comprehensive reflection of the body's internal milieu. This proof‐of‐concept study explores platelet proteomic alterations in mania. Methods High‐resolution proteomic profiling was performed on platelet samples from hospitalized patients with severe mania ( n = 11) and 1:1 age‐ and sex‐matched healthy controls ( n = 11) using liquid chromatography–tandem mass spectrometry. Platelet proteins were quantified, differentially expressed proteins identified, and functional enrichment analyses conducted to characterize associated biological pathways. Key proteomic predictions were validated by enzyme‐linked immunosorbent assay (ELISA) in platelet and plasma samples. Results Proteomic analysis revealed that mania is associated with proteins primarily enriched in immune activation while lacking those enriched in cell homeostasis. Among shared proteins, mania exhibited a prominent cluster of downregulated proteins, primarily converging on immune‐related pathways. The most robust alteration involved deficits in MHC Class I‐mediated antigen processing. Key immune regulatory hubs – transforming growth factor (TGF)‐β and interleukin‐4 (IL‐4) – were identified, with the association of increased TGF‐β levels with mania validated by ELISA. Conclusions This study highlights platelet proteomics as a valuable tool for investigating biological alterations in psychiatric disorders. Our findings indicate deficits in MHC Class I‐related pathways and immune alterations consistent with chronic low‐grade inflammation, suggesting potential roles for latent viral and autoimmune‐related mechanisms in BD. These results support and refine the concept of immune dysregulation in mania and BD.