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ObjectivesThis study aimed to compare serum leucine-rich repeat and fibronectin type III domain-containing protein-5 (LRFN5) and olfactomedin-4 (OLFM4) levels and aggregate index of systemic inflammation (AISI) values between hospitalized subjects with bipolar disorder (BD) experiencing acute manic episodes with psychotic features and healthy controls (HCs), and to examine their associations with clinical features and symptom severity.MethodsIn this cross-sectional study, participant characteristics and clinical features were assessed by structured clinical interviews. LRFN5 and OLFM4 levels were measured in the BD (n = 37) and HC (n = 35) groups using Enzyme-Linked ImmunoSorbent Assay kit.ResultsSerum LRFN5 (adjusted P = 0.0117) and OLFM4 (adjusted P = 0.0117) levels were significantly lower, whereas AISI (adjusted P = 0.0005) levels were significantly higher in the BD group compared with HCs, after adjusting for age, gender, body mass index, and smoking status. Within the BD group, a strong positive correlation was observed between LRFN5 and OLFM4 levels (r = 0.702, adjusted P = 0.006) and AISI showed a significant positive correlation with manic symptom severity score after controlling for age, gender, body mass index, and smoking status (r = 0.472, adjusted P = 0.030). In binary logistic regression analysis adjusted for age, gender, body mass index, and smoking status, lower OLFM4 levels (odds ratio (OR) = 0.970, P = 0.020, adjusted P = 0.003) and higher AISI values (OR = 1.008, P = 0.002, adjusted P = 0.001) were independently associated with BD status, alongside smoking status (OR = 19.213, P = 0.005, adjusted P = 0.001) (apparent area under the curve (AUC) = 0.914, optimism-corrected AUC = 0.884). After repeated stratified holdout validation, the mean and median test AUCs were 0.868 and 0.876, respectively.ConclusionsSubjects with BD experiencing acute manic episodes with psychotic features exhibited decreased circulating LRFN5 and OLFM4 levels alongside an increased systemic inflammatory burden, as reflected by AISI. AISI showed the strongest association with BD status and symptom severity and OLFM4 remained significant in adjusted analyses. Rather than indicating definitive diagnostic utility, the observed alterations may instead reflect underlying biological processes related to BD.