LRFN5 and OLFM4 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