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

Major depressive disorder (MDD) is a biologically heterogeneous condition, with a subset of patients exhibiting elevated inflammatory markers associated with greater symptom burden and lower responsiveness to antidepressants. Treatment outcomes with repetitive transcranial magnetic stimulation (rTMS) are also highly variable, and inflammation may impair neuroplasticity, thereby modulating treatment efficacy. This exploratory study investigated whether baseline inflammatory protein signatures could influence the response to intermittent theta burst stimulation (iTBS). Using the Olink(R) Target 96 Inflammation panel, baseline inflammatory protein levels were analyzed in 54 patients with moderate-to-severe depression (baseline MADRS [&ge;]20) undergoing iTBS treatment. K-means clustering identified two subgroups: Cluster 1 (n = 28) and Cluster 2 (n = 26). Cluster 2 showed the highest proportion of responders, whereas Cluster 1 showed the lowest. The clusters did not differ significantly in age, sex, medication status, randomization arm, or body mass index. Differential protein expression was assessed using volcano plots with false discovery rate (FDR) correction. Pathway enrichment analyses using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases identified biological processes associated with the clustering solution. Volcano analysis identified 10 differentially expressed proteins between clusters (FDR < 0.05 and |{Delta}NPX| [&ge;] 1). Enrichment analyses implicated cytokine-cytokine receptor interaction, chemokine signaling, and interleukin signaling pathways as characteristic of the lower-response subgroup. These findings indicate that baseline inflammatory signatures may help differentiate responsiveness to iTBS in moderate-to-severe depression, supporting future pathway investigations as a potential strategy for personalized psychiatry.