Exploring Differential Baseline Expression of Inflammatory Markers in Patients with Severe Depression and Variable Response to Intermittent Theta Burst Stimulation

Background Major depressive disorder (MDD) is a disabling condition characterized by marked heterogeneity in treatment response. Inflammatory signaling pathways—such as cytokine–cytokine receptor interactions, JAK/STAT, and NF-κB activation—have been implicated in treatment resistance, particularly in severe depression. It remains unclear whether baseline inflammatory profiles can distinguish subgroups with variable outcomes following intermittent theta burst stimulation (iTBS), a non-invasive neuromodulatory treatment. Methods In this exploratory study, we applied k-means clustering to baseline inflammatory protein expression data (Olink® Target 96 Inflammation panel) in patients with severe MDD undergoing iTBS. Clinical and general characteristics were compared across clusters. Differentially expressed proteins were identified using volcano plots with false discovery rate (FDR) correction. Kyoto Encyclopedia of Genes and Genomes and Reactome enrichment analyses identified biological pathways associated with each cluster. Results Four inflammatory subgroups were identified. Cluster 1 had the highest proportion of treatment response; Cluster 4, the lowest. Clusters did not differ significantly by age, sex, medication, randomization, or BMI. Volcano plot analysis revealed 28 differentially expressed proteins (FDR < 0.05), with nine showing robust differences (e.g., IL-8, MCP-4, MMP-1, CXCL11, IL-7; |NPX difference| > 1). Enrichment analyses implicated cytokine-cytokine receptor interaction, chemokine signaling, and interleukin signaling pathways in the non-responders group. Limitations Exploratory design, small sample size, and absence of a treatment control group are the main limitations. Lifestyle factors may have influenced immune markers. Conclusions Baseline inflammatory profiles may differentiate iTBS treatment response in severe MDD, supporting immune-based stratification as a step toward personalized psychiatry.