Background: Major depressive disorder (MDD) is characterized by persistent feelings of sadness and loss of interest. Ketamine has been widely used to treat MDD owing to its rapid effect in relieving depressive symptoms. Importantly, not all patients respond to ketamine treatment. Identifying sub-populations who will benefit from ketamine, as well as those who may not, prior to treatment initiation, would significantly advance precision medicine in patients with MDD.
Methods: Here, we used mass spectrometry-based plasma proteomics to analyze matched pre- and post-ketamine treatment samples from a cohort of 30 MDD patients whose treatment outcomes and demographic and clinical characteristics were considered.
Results: Ketamine responders and non-responders were identified according to their individual outcomes after two weeks of treatment. We analyzed proteomic alterations in post-treatment samples from responders and non-responders and identified a collection of six proteins pivotal to the antidepressive effect of ketamine. Subsequent co-regulation analysis revealed that pathways related to immune response were involved in ketamine response. By comparing the proteomic profiles of samples from the same individuals at the pre- and post-treatment time points, dynamic proteomic rearrangements induced by ketamine revealed that immune-related processes were activated in association with its antidepressive effect. Furthermore, receiver operating characteristic curve analysis of pre-treatment samples revealed three proteins with strong predictive performance in determining the response of patients to ketamine before receiving treatment.
Conclusions: These findings provide valuable knowledge about ketamine response, which will ultimately lead to more personalized and effective treatments for patients.
Trial registration: The study was registered in the Chinese Clinical Trials Registry (ChiCTR-OOC-17012239) on May 26, 2017.
Keywords: Biomarkers; Immune response; Ketamine; MDD; Plasma Proteomics.
© 2025. The Author(s).