Lamotrigine Modulates Peripheral dual positive Th2/Th17 cells in Bipolar Disorder: A Role Beyond the Brain

Bipolar disorder is increasingly recognized as a systemic condition involving immune dysregulation, yet the composition of peripheral CD4-positive T-cell subsets and their relevance to disease severity remain poorly defined. We recently identified a distinct CD4-positive T-cell population co-expressing transcriptional features of T helper 2 and T helper 17 cells in the peripheral blood of patients with bipolar disorder. Here, we investigated the clinical relevance of this population and assessed whether lamotrigine, a commonly used mood stabilizer, modulates its abundance and function. Using single-cell RNA sequencing and flow cytometry, we characterized peripheral CD4-positive T cells from patients receiving lamotrigine-containing regimens, non-lamotrigine treatments, or no medication. The abundance of T helper type 2/17 dual-positive cells was inversely correlated with depressive, anxiety, and manic symptom severity. Lamotrigine treatment was associated with a marked expansion of this subset and with transcriptional reprogramming toward an immunosuppressive phenotype, characterized by activation of glucocorticoid receptor and ATP-binding cassette transporter pathways and downregulation of major histocompatibility complex class II-related genes. These findings identify a peripheral immunoregulatory T-cell population intrinsically linked to bipolar disorder severity and demonstrate that lamotrigine exerts defined immunomodulatory effects beyond the central nervous system, supporting a neuroimmune mechanism underlying its therapeutic actions.