Schizoaffective disorder (SAD) is a chronic psychiatric condition characterized by psychotic and mood symptoms. Emerging evidence suggests that Leucine-Rich Repeat and Fibronectin Type-III Domain-Containing Protein 5 (LRFN5) and olfactomedin-4 (OLFM4) may play roles in synaptic organization, neurodevelopment, and neuroinflammation. However, no prior study has investigated these biomarkers in SAD. This cross-sectional case-control study aims to compare peripheral serum levels of LRFN5 and OLFM4 in subjects diagnosed with SAD in remission and healthy control subjects. 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 SAD.

Schizoaffective disorder (SAD) is a chronic psychiatric condition characterized by psychotic and mood symptoms. 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 SAD have not been well characterized. This cross-sectional case-control study aims to compare peripheral serum levels of LRFN5 and OLFM4 in subjects diagnosed with SAD in remission and healthy control subjects. 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). A total of 60 subjects with SAD (30 females, 30 males) and 60 (30 females, 30 males) age- and gender-matched healthy controls will be recruited. Blood samples will be collected after 12-hour fasting and serum levels of LRFN5 and OLFM4 will be measured using ELISA kits. The diagnosis of SAD will be made according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR). All subjects diagnosed with SAD will be included in the study during the acute manic episode phase (immediately before hospitalization).The healthy control group will consist of individuals without current or past psychiatric disorders and without significant medical illnesses. None of the participants will have chronic inflammatory, autoimmune, neurological, or systemic diseases. Venous blood samples will be collected at hospital admission prior to initiation of pharmacological treatment in the SAD group. Serum will be separated and stored at -80°C until analysis. Serum LRFN5 and OLFM4 levels will be measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits in accordance with the manufacturer's instructions. Routine complete blood count parameters will be obtained, and the Aggregate Index of Systemic Inflammation (AISI) will be calculated as: (neutrophils × monocytes × platelets) / lymphocytes. Clinical assessments in the SAD group will be include the Positive and Negative Syndrome Scale (PANSS) for psychotic symptom severity, Young Mania Rating Scale (YMRS) for manic symptom severity, and Beck Depression Inventory (BDI) for depressive symptom severity. Sociodemographic and clinical data will be recorded for all participants. The primary objective was to compare circulating LRFN5 and OLFM4 levels between SAD and healthy control groups. Secondary objectives included evaluating associations between these biomarkers and symptom severity 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: 2025/09-09) and was conducted in accordance with the Declaration of Helsinki. All participants will provide written informed consent prior to participation.

1. For Schizoaffective Disorder (SAD) Group:

   *Inclusion Criteria:

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

   For Schizoaffective Disorder (SAD) 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 SAD

   • Alcohol/drug/substance use

2. 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
• Having psychiatric disorders
• Alcohol/drug/substance use

The study population will consist of adult participants aged 18-65 years. The schizoaffective disorder (SAD) group will include consecutive subjects diagnosed with SAD according to DSM-5-TR criteria who will be admitted to the psychiatry clinic of Elazığ Mental Health and Diseases Hospital (Turkey). The healthy control (HC) group will consist of individuals from the general population who will apply to the hospital medical board and will have no current or past psychiatric or significant medical disorders. All participants will provide 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, Positive and Negative Syndrome Scale (PANSS) for psychotic symptom severity, Young Mania Rating Scale (YMRS) for manic symptom severity, and the Beck Depression Inventory (BDI) for depressive symptoms] 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.