This cross-sectional observational study evaluated serum levels of Leucine-rich repeat and fibronectin type III domain-containing protein 5 (LRFN5) and Olfactomedin-4 (OLFM4) in patients with schizophrenia during acute exacerbation and in healthy controls. The study also assessed associations between these biomarkers and clinical symptom severity, global functioning, and systemic inflammation measured by the Aggregate Index of Systemic Inflammation (AISI). The study aimed to investigate convergent synaptic and immunoinflammatory dysregulation in schizophrenia.

Schizophrenia is increasingly conceptualized as a disorder characterized by synaptic dysfunction and immune-inflammatory dysregulation. Leucine-rich repeat and fibronectin type III domain-containing protein 5 (LRFN5), also known as synaptic adhesion-like molecule 5 (SALM5), is a postsynaptic adhesion molecule involved in synapse formation, maturation, and stabilization, particularly within glutamatergic pathways. Olfactomedin-4 (OLFM4) is a secreted glycoprotein expressed in neutrophils and other immune cells and is involved in apoptotic regulation and inflammatory processes. Although both molecules have biological relevance to neurodevelopmental and immune mechanisms, their circulating levels in schizophrenia have not been well characterized.

This cross-sectional observational study aimed to compare serum LRFN5 and OLFM4 levels between subjects with schizophrenia during acute exacerbation and healthy control (HC) subjects, and to examine their associations with clinical symptom severity, global functioning, and systemic inflammation.

The study included 60 adult participants aged 18-65 years. The schizophrenia group consisted of consecutive inpatients diagnosed with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR). All patients were hospitalized during an acute exacerbation and had not received psychotropic medication for at least one month prior to admission. The HC group consisted of individuals without current or past psychiatric disorders and without significant medical illnesses. None of the participants had chronic inflammatory, autoimmune, neurological, or systemic diseases.

Venous blood samples were collected at hospital admission prior to initiation of pharmacological treatment in the schizophrenia group. Serum was separated and stored at -80°C until analysis. Serum LRFN5 and OLFM4 levels were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits in accordance with the manufacturer's instructions. Routine complete blood count parameters were obtained, and the Aggregate Index of Systemic Inflammation (AISI) was calculated as: (neutrophils × monocytes × platelets) / lymphocytes.

Clinical assessments in the schizophrenia group included the Positive and Negative Syndrome Scale (PANSS) for symptom severity and the Global Assessment Scale (GAS) for overall functioning. Sociodemographic and clinical data were recorded for all participants.

The primary objective was to compare circulating LRFN5 and OLFM4 levels between schizophrenia and healthy control groups. Secondary objectives included evaluating associations between these biomarkers and symptom severity, global functioning, and systemic inflammation indices, as well as assessing their potential diagnostic performance using logistic regression and receiver operating characteristic (ROC) analyses.

The study was approved by the Fırat University Non-invasive Research Ethics Committee (Approval Number: 2025/07-25) and was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent prior to participation.

For Schizophrenia Group:

*Inclusion Criteria:

• Diagnosis of schizophrenia according to DSM-5-TR
• Acute exacerbation requiring hospitalization
• Medication-free for at least one month prior to admission
• Age ≥ 18 years and <65 years
• Provided informed consent

For Schizophrenia Group:

*Exclusion Criteria:

• Hypertension
• Diabetes mellitus
• Chronic kidney disease
• Rheumatoid arthritis
• Systemic lupus erythematosus
• Cardiac illness
• Severe neurological disorders
• Immunological or systemic illness
• Primary psychiatric disorders other than schizophrenia
• Alcohol/drug/substance use

For Healthy Control Group:

*Inclusion Criteria:

• No psychiatric diagnosis
• No systemic or immunological illness
• Medication-free for at least one month
• Age ≥ 18 years and < 65 years
• Provided informed consent

For Healthy Control Group:

*Exclusion Criteria:

• Hypertension
• Diabetes mellitus
• Chronic kidney disease
• Rheumatoid arthritis
• Systemic lupus erythematosus
• Cardiac illness
• Severe neurological disorders
• Immunological or systemic illness
• Primary psychiatric disorders other than schizophrenia
• Alcohol/drug/substance use

The study population consisted of adult participants aged 18-65 years. The Schizophrenia group included consecutive patients diagnosed with schizophrenia according to DSM-5-TR criteria who were admitted to the psychiatry clinic of Elazığ Mental Health and Diseases Hospital (Turkey). The healthy control (HC) group consisted of individuals from the general population who applied to the hospital medical board and had no current or past psychiatric or significant medical disorders. All participants provided informed consent prior to enrollment.

Deidentified individual participant data (IPD) underlying the results reported in this study (including demographic variables, serum leucine-rich repeat and fibronectin type III domain-containing protein 5 (LRFN5) and Olfactomedin-4 (OLFM4) levels, complete blood count parameters, and Positive and Negative Syndrome Scale (PANSS) for symptom severity and the Global Assessment Scale (GAS) for overall functioning) will be made available to qualified researchers upon reasonable request for academic purposes.

Data will be shared after removal of all direct identifiers and in accordance with applicable ethical approvals and data protection regulations. Access to the data will require a methodologically sound research proposal and a data use agreement. Requests should be directed to the corresponding author.

Data will be available beginning 6 months after publication and will remain available for 5 years.

Access will be granted to researchers who provide a methodologically sound proposal. Requests must be approved by the principal investigator and may require a data use agreement in accordance with institutional and ethical regulations.