A proteomic feasibility study connecting metabolic and synaptic pathway alterations in serum and extracellular vesicles to characterize treatment-resistant depression

Treatment-resistant depression (TRD) remains a daunting clinical challenge, with the biological processes differentiating TRD from non-treatment-resistant depression (nTRD) still poorly understood. While serum proteomes, found in the blood, can reflect broad systemic changes linked to depression, extracellular vesicles (EVs) may offer a more targeted view of intercellular signaling relevant to treatment resistance.

This pilot study aimed to determine if parallel proteomic analysis of serum and EVs could differentiate healthy controls (CON), nTRD, and TRD individuals.

The findings revealed that serum proteomes displayed significant global differences between the depression groups and controls, largely stemming from shared systemic biology in nTRD and TRD. However, EV proteomes exhibited limited global separation but unveiled subtype-associated pathway variations. Compared to controls, nTRD EVs showed enrichment in immune and inflammatory pathways.

Conversely, TRD EVs were characterized by enrichment in mitochondrial metabolism, oxidative phosphorylation, translational initiation, and MYC-regulated pathways, alongside a depletion of synaptic signaling, membrane trafficking, and cytoskeletal pathways.

When comparing the pathways significant in both contrasts, it was discovered that these bioenergetic and translational signatures were selectively amplified in TRD relative to nTRD. The study's exploratory analysis suggested that the circulating EV cargo might reflect a treatment-resistant-specific reorganization of biological pathways, which is not evident in bulk serum proteomics.

This research underscores the potential of parallel serum and EV proteomics as a complementary method for molecular stratification in the diagnosis of antidepressant resistance.