LRFN5 and OLFM4 in Methamphetamine-Induced Psychosis

Overview

This cross-sectional observational case-control study aimed to examined serum levels of leucine-rich repeat and fibronectin type III domain-containing protein 5 (LRFN5) and olfactomedin-4 (OLFM4) levels in methamphetamine use disorder (MUD), methamphetamine-induced psychotic disorder (MP), and healthy control (HC) groups. The study also aimed to assessed systemic inflammation using the Aggregate Index of Systemic Inflammation (AISI) and examined associations between biomarkers and clinical symptom severity, including Insight Assessment Scale (IAS) and Positive and Negative Syndrome Scale (PANSS) scores.

Methamphetamine is a potent central nervous system stimulant associated with addiction, neurotoxicity, and increased risk of psychosis. Chronic exposure affects dopaminergic systems in the mesolimbic and striatal pathways, potentially contributing to sensitization and psychotic symptom development. Methamphetamine-induced psychotic disorder (MP) occurs in a substantial proportion of users, yet individual vulnerability varies. Biological markers that may predict psychosis in methamphetamine users remain insufficiently studied. Leucine-rich repeat and fibronectin type III domain-containing protein 5 (LRFN5) is a transmembrane synaptic adhesion molecule involved in synapse development, plasticity, and neuroimmune regulation. It contributes to excitatory and inhibitory synaptic differentiation and may influence neuroinflammatory responses. Olfactomedin-4 (OLFM4) is a neutrophil-specific glycoprotein involved in innate immunity, apoptosis regulation, inflammation, and glutamatergic synaptic modulation. These two markers are located in relatively close chromosomal regions and may demonstrate coordinated biological behavior. To date, LRFN5 and OLFM4 have not been investigated in methamphetamine use disorder (MUD) or MP. This study is designed to compare serum levels of LRFN5 and OLFM4 among subjects with MP, subjects with MUD, and healthy controls (HC) subjects. A secondary objective was to evaluate associations between LRFN5, OLFM4 levels, psychotic symptom severity, and systemic inflammation, and to assess its potential predictive value for MP diagnosis. Participants were planned to be consecutive inpatients diagnosed with MUD or MP according to the American Psychiatric Association's Fifth Edition Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR). Participant recruitment began on September 1, 2025, and is planned to be completed on April 1, 2026. All patients were selected/will be selected from those admitted to Elazığ Mental Health and Diseases Hospital. The HC group consisted of individuals without current or past psychiatric disorders or significant medical illnesses. Adult male participants aged 18-65 were included. Venous blood samples were collected/will be collected at hospital admission prior to initiation of treatment. Samples were/will be centrifuged within 30 minutes and serum was stored at -80°C until analysis. Serum LRFN5 and OLFM4 levels were/will be measured using a commercially available enzyme-linked immunosorbent assay (ELISA) kit according to the manufacturer's instructions. Routine biochemical analyses and urine toxicology screening were/will be also performed. The Aggregate Index of Systemic Inflammation (AISI) was/will be calculated as (neutrophils × monocytes × platelets) / lymphocytes. Psychotic symptom severity in the MP group was/will be assessed using the Positive and Negative Syndrome Scale (PANSS). Insight in the MP group was/will be assessed using the Insight Assessment Scale (IAS). Sociodemographic variables and clinical characteristics, including self-mutilation history, drug use onset age, duration of methamphetamine use, and smoking status were/will be recorded. The study was/will be conducted in accordance with the Declaration of Helsinki and approved by the relevant institutional ethics committee. All participants provided/will provide written informed consent prior to participation.