Optimizing Antidepressant Efficacy: Multimodal Neuroimaging Biomarkers for Prediction of Treatment Response

Abstract Major depressive disorder (MDD) is a common and often severe condition that profoundly diminishes quality of life for individuals across ages and demographic groups. Unfortunately, current antidepressant and psychotherapeutic treatments exhibit limited efficacy and unsatisfactory response rates in a substantial number of patients. The development of effective therapies for MDD is hindered by the insufficiently understood heterogeneity within the disorder and its elusive underlying mechanisms. To address these challenges, we present a target-oriented multimodal fusion framework that robustly predicts antidepressant response by integrating structural and functional connectivity data (sertraline: R 2 = 0.31; placebo: R 2 = 0.22). Remarkably, the sertraline response biomarker is further tested on an independent escitalopram-medicated cohort of MDD patients, validating its generalizability (p = 0.01) and suggesting an overlap of psychopharmacological mechanisms across selective serotonin reuptake inhibitors. Through the model, we identify multimodal neuroimaging biomarkers of antidepressant response and observe that sertraline and placebo show distinct predictive patterns. We further decompose the overall predictive patterns into constitutive network constellations with generalizable structural-functional co-variation, which exhibit treatment-specific association with personality traits and behavioral/cognitive task performance. Our innovative and interpretable multimodal framework provides novel and reliable insights into the intricate neuropsychopharmacology of antidepressant treatment, paving the way for advances in precision medicine and development of more targeted antidepressant therapeutics. Trial Registration Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC), NCT#01407094