Immunoinflammatory and Synaptic Biomarkers in Bipolar Disorder: A Case-Control Study of OLFM4 and LRFN5

Bipolar disorder (BD) is a chronic psychiatric disorder characterized by recurrent episodes of mania, hypomania, and depression, interspersed with periods of euthymia. Increasing evidence suggests that BD is associated with both synaptic dysregulation and immunoinflammatory abnormalities. Alterations in synaptic plasticity, dendritic architecture, and glutamatergic signaling have been implicated in mood instability. In parallel, immune activation, altered cytokine profiles, and elevated peripheral inflammatory markers have been reported in individuals with BD. These findings support the hypothesis that synaptic and immune-inflammatory mechanisms may interact in the pathophysiology of BD.

Leucine-rich repeat and fibronectin type III domain-containing protein 5 (LRFN5), also known as synaptic adhesion-like molecule 5 (SALM5), is a synaptic adhesion molecule primarily expressed in the central nervous system. It is enriched at the postsynaptic density of excitatory synapses and contributes to synapse formation, maintenance, and glutamatergic organization. Olfactomedin-4 (OLFM4) is a secreted extracellular glycoprotein involved in innate immune regulation, apoptosis modulation, and inflammatory signaling pathways. OLFM4 is expressed in hematopoietic tissues and immune cells, particularly neutrophils, and participates in immune homeostasis and stress-response mechanisms.

Despite their biological relevance, circulating levels of LRFN5 and OLFM4 have not previously been systematically investigated in individuals with BD. In addition, the Aggregate Index of Systemic Inflammation (AISI), calculated as (neutrophils × monocytes × platelets) / lymphocytes, represents a composite marker reflecting systemic inflammatory burden. AISI integrates components of innate and adaptive immunity and may provide a practical peripheral indicator of inflammatory activation.

The present study was designed as a cross-sectional observational case-control investigation conducted at Elazığ Mental Health and Diseases Hospital between July 7, 2025, and January 2, 2026. The study enrolled 72 participants, including 37 inpatients diagnosed with BD during acute manic episodes and 35 healthy control (HC) subjects.

Diagnosis of BD was established according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR), through structured clinical interviews conducted by an experienced psychiatrist. All BD participants were hospitalized during an acute manic episode and were medication-free for at least one month prior to admission. Healthy controls were evaluated by the hospital medical board and had no psychiatric or systemic medical disorders. None of the participants had hypertension, diabetes mellitus, chronic kidney disease, autoimmune disease, severe neurological disorder, or other systemic inflammatory conditions.