Electrophysiological biomarkers and age characterize phenotypic heterogeneity among individuals with major depressive...

Introduction: Despite the high need for effective treatments for major depressive disorder (MDD), the development of novel medicines is hampered by clinical, genetic and biological heterogeneity, unclear links between symptoms and neural dysfunction, and tenuous biomarkers for clinical trial contexts of use. Methods: In this study, we examined the International Study to Predict Optimized Treatment in Depression (iSPOT-D) clinical trial database for new relationships between auditory event-related potential (ERP) responses, demographic features, and clinical symptoms and behavior, to inform strategies for biomarker-driven patient stratification that could be used to optimize future clinical trial design and drug development strategy in MDD. Results: We replicate findings from previous analyses of the classic auditory oddball task in the iSPOT-D sample showing smaller than typical N1 and P300 response amplitudes and longer P300 latencies for target and standard stimuli in patients with MDD, suggesting altered bottom-up sensory and top-down attentional processes. We further demonstrate that age is an important contributor to clinical group differences, affecting both topographic distribution of the clinically informative ERP responses and the types of the stimuli sensitive to group differences. In addition, the observed brain-behavior associations indicate that levels of anxiety and stress are major contributing factors to atypical sensory and attentional processing among patients with MDD, particularly in the older subgroups. Discussion: Our novel findings support the possibility of accelerated cognitive aging in patients with MDD and identify the frontal P300 latency as an additional candidate biomarker of MDD. These results from a large, well-phenotyped sample support the view that heterogeneity of the clinical population with MDD can be systematically characterized based on age and neural biomarkers of sensory and attentional processing, informing patient stratification strategies in the design of clinical trials.