Peripheral blood correlates of negative symptom severity in schizophrenia: exploratory findings from an Indian cohort

Background Schizophrenia (SCZ) is characterized by positive and negative symptoms, with the latter often poorly responsive to treatment. Negative symptoms are associated with increased cardiovascular risk and metabolic syndrome. Investigation of the cellular and molecular alterations associated with negative symptom severity may provide insights into disease mechanisms and aid in the identification of novel therapeutic targets. Methodology A multi-center case-control study was conducted using peripheral blood as a surrogate tissue. Peripheral blood mononuclear cells were subjected to RNA sequencing. Cellular compositional changes were estimated by digital deconvolution using CIBERSORTx. Transcriptomic correlates of negative symptom severity were identified using weighted gene co-expression network analysis (WGCNA). Results Digital deconvolution of the peripheral blood mononuclear cell transcriptome of 47 participants (25 SCZ and 22 healthy controls) uncovered a nominal inverse association between activated CD4 + memory T-cell proportions and negative symptom severity (p = 0.016). WGCNA revealed modules showing a trend toward positive correlation with negative symptom severity (r = 0.35) that were enriched for genes involved in cytotoxic immune responses. Hub genes identified from these modules included GZMH , NKG7 , GZMM , TBX21 , CTSW , CST7 , FCRL6 , ADGRG1 , and HOPX . Conclusion The nominal inverse association of activated CD4 + memory T-cells with negative symptom severity, together with the enrichment of cytotoxic immune response genes, is consistent with immune remodeling toward terminally differentiated cytotoxic lymphocyte phenotypes in schizophrenia. These novel findings provide preliminary evidence for cellular and molecular immune correlates associated with negative symptom severity in SCZ but warrant validation in larger cohorts.