Schizoaffective disorder (SAD) is a severe psychiatric condition characterized by the coexistence of psychotic symptoms and mood episodes. Growing evidence suggests that immune dysregulation and inflammatory processes contribute to the pathophysiology of schizophrenia-spectrum disorders, including SAD. α-N-acetylgalactosaminidase is a lysosomal enzyme involved in glycoprotein metabolism and immune regulation through its effects on Gc protein-derived macrophage activating factor. Previous studies have reported altered α-N-acetylgalactosaminidase levels in schizophrenia and bipolar disorder; however, its role in SAD has not been investigated. The aim of this cross-sectional study is to compare serum α-N-acetylgalactosaminidase levels among patients with SAD during acute exacerbation and remission phases and healthy controls. The study also examines the relationships between α-N-acetylgalactosaminidase levels, symptom severity, and systemic inflammation. Clinical assessments include the Positive and Negative Syndrome Scale, Young Mania Rating Scale, Beck Depression Inventory, and Global Assessment Scale. Systemic inflammation is evaluated using the Aggregate Index of Systemic Inflammation, derived from routine complete blood count parameters. By investigating the association of α-N-acetylgalactosaminidase with clinical and inflammatory features of SAD, this study seeks to improve understanding of the biological mechanisms underlying the disorder and to explore the potential utility of α-N-acetylgalactosaminidase as a biomarker related to disease state and symptom severity.

Schizoaffective disorder (SAD) is a severe psychiatric disorder characterized by the coexistence of psychotic symptoms and major mood episodes, resulting in substantial functional impairment, recurrent hospitalizations, and increased suicide risk. Although accumulating evidence suggests that immune dysregulation and inflammatory abnormalities contribute to the pathophysiology of schizophrenia-spectrum disorders, the biological mechanisms underlying SAD remain incompletely understood.

α-N-acetylgalactosaminidase is a lysosomal enzyme involved in glycoprotein metabolism and immune regulation. Nagalase catalyzes the removal of N-acetylgalactosamine residues from glycoproteins, thereby inhibiting the formation of Gc protein-derived macrophage activating factor, an important mediator of macrophage activation and immune function. Previous studies have demonstrated altered α-N-acetylgalactosaminidase concentrations in several neuropsychiatric disorders, including schizophrenia and bipolar disorder, suggesting a potential role for this enzyme in severe mental illnesses. However, no previous study has investigated circulating α-N-acetylgalactosaminidase levels in patients with SAD or examined whether these levels differ according to illness phase.

The present cross-sectional case-control study aims to compare serum α-N-acetylgalactosaminidase concentrations among patients with SAD during acute exacerbation (SAD-AE), patients with SAD in remission (SAD-R), and healthy control subjects (HC). The study also aims to evaluate associations between α-N-acetylgalactosaminidase levels, psychotic symptom severity, manic symptom severity, depressive symptom severity, global functioning, and systemic inflammatory burden.

A total of 51 patients diagnosed with SAD and 42 HC subjects were included in the study. SAD diagnoses will be established according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision. Participants with SAD were categorized into two groups based on clinical status. The SAD-AE group consisted of subjects experiencing a current manic episode with psychotic symptoms who have not received psychotropic medication for at least one month and have not used regular psychotropic treatment during the preceding three months. The SAD-R group consisted of clinically stable subjects receiving regular maintenance treatment, defined by sustained remission of psychotic symptoms and absence of active mood episodes. Remission status was determined using established criteria including low Positive and Negative Syndrome Scale (PANSS) symptom ratings and Young Mania Rating Scale (YMRS) scores consistent with clinical stability.

HC subjects were recruited from individuals presenting for routine medical evaluations and had no current or lifetime psychiatric disorder and no significant medical illness. Participants with hypertension, diabetes mellitus, chronic kidney disease, autoimmune disorders, systemic inflammatory diseases, severe neurological disorders, active infections, or other significant systemic diseases were excluded. All HC subjects were free of psychotropic and systemic medications for at least one month before blood sampling.

For participants in the SAD-AE group, all assessments and blood collections were performed immediately following hospital admission and prior to initiation of pharmacological treatment or other therapeutic interventions. Sociodemographic variables including age, sex, educational level, marital status, employment status, residence, smoking status, and history of suicidal behavior were recorded for all participants.

Psychopathology and clinical functioning were assessed using standardized instruments. Psychotic symptoms were evaluated using the PANSS, YMRS, depressive symptoms were evaluated using the Beck Depression Inventory (BDI), and overall psychosocial functioning were assessed using the Global Assessment Scale (GAS).

Venous blood samples were collected at hospital admission or study enrollment. Samples were centrifuged within 30 minutes of collection, and serum aliquots will be stored at -80°C until laboratory analyses are performed. Serum α-N-acetylgalactosaminidase concentrations were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits according to the manufacturer's instructions. Routine complete blood count analyses were also obtained. The Aggregate Index of Systemic Inflammation (AISI) was calculated using the formula: (neutrophils × monocytes × platelets) / lymphocytes.

The primary objective of the study was to compare serum α-N-acetylgalactosaminidase concentrations among SAD-AE, SAD-R, and HC groups. Secondary objectives include evaluating relationships between α-N-acetylgalactosaminidase levels and psychotic symptoms, manic symptoms, depressive symptoms, global functioning, illness duration, and systemic inflammation. Additional objectives include determining whether α-N-acetylgalactosaminidase independently predicts illness phase (acute exacerbation versus remission) using hierarchical logistic regression models and assessing its potential diagnostic utility through receiver operating characteristic curve analyses.

The study hypothesis was that patients with SAD demonstrate lower serum α-N-acetylgalactosaminidase concentrations than HCs, and that α-N-acetylgalactosaminidase levels were relatively elevated during acute exacerbation compared with remission due to increased inflammatory activation. It is further hypothesized that α-N-acetylgalactosaminidase concentrations correlate positively with psychotic symptom severity, manic symptom severity, and systemic inflammatory burden.

The study has been approved by the University of Health Sciences Elazığ Fethi Sekin City Hospital Non-Invasive Research Ethics Committee (Approval Number: 2025/8-15) and was conducted in accordance with the ethical principles of the Declaration of Helsinki. Written informed consent was obtained from all participants prior to enrollment.

1. For Schizoaffective Disorder (SAD) Group:

   *Inclusion Criteria:

   • Diagnosis of SAD according to DSM-5-TR
   • Acute exacerbation episode or remission phase
   • Medication-free for at least one month prior to admission for acute exacerbation episode and regular medication use for remission use
   • 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 α-N-acetylgalactosaminidase levels, complete blood count parameters, and Positive and Negative Syndrome Scale (PANSS)) 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.