Cognitive Impairments and Plasma Metabolic Characteristics in Deficit Schizophrenia: A Two-Year Follow-Up Longitudinal Study

Background: Deficit schizophrenia (DS) is a clinically distinct subtype of schizophrenia (SZ) characterized by enduring primary negative symptoms. However, its long-term cognitive trajectory and metabolic profile remain poorly understood. This study aimed to examine progressive cognitive impairments in DS over a two-year period and to identify associated plasma metabolites and potential diagnostic biomarkers using untargeted metabolomics. Methods: A total of 126 hospitalized patients (51 DS and 75 non-DS) completed cognitive and symptom assessments using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Positive and Negative Syndrome Scale (PANSS) at baseline and two-year follow-up. Fasting plasma samples collected at baseline were analyzed using untargeted metabolomics. Repeated-measures ANOVA assessed cognitive changes in DS patients. LASSO regression, combined with cross-validation, identified potential diagnostic metabolites and their associations with cognitive impairments. Results: Over two years, patients with DS showed significant declines in cognition, mainly in visuospatial/constructional ability, attention, and delayed memory. Untargeted metabolomics identified 34 differential metabolites, primarily amino acids, fatty acids, and acylcarnitines. Pathway enrichment analysis revealed abnormalities in histidine metabolism, alanine-aspartate-glutamate metabolism, and lysine degradation. Further LASSO regression identified a 20-metabolite panel that accurately distinguished DS from non-DS patients, with an AUC of 0.929 (95% CI: 0.887-0.970). Several metabolites, including aminoadipic acid, succinylcarnitine, and gamma-glutamylthreonine, were significantly associated with cognitive impairments. Conclusions: This study is the first to reveal progressive cognitive impairments and distinct plasma metabolites in DS, identifying potential diagnostic markers and insights into its mechanisms.