The METOD study: exploring metabolism, emotional blunting and treatment outcomes in depression – A naturalistic, two-phase observational protocol

Introduction Major depressive disorder (MDD) constitutes a substantial global health burden, profoundly undermining psychosocial functioning and quality of life, and the persistent limitations of treatment efficacy—despite advances in neurobiology and pharmacotherapy—underscore its considerable clinical complexity. Recent research increasingly delineates the heterogeneity of depressive symptomatology, particularly emotional blunting, and emerging evidence further implicates metabolic and inflammatory pathways processes in shaping treatment response . Insulin resistance (IR), immune dysregulation, individual circadian preference, and trait-level vulnerabilities associated with neurodevelopmental or trauma-related characteristics may contribute to reduced responsiveness to standard therapies and limited adherence to antidepressant treatment. Taken together, these converging findings emphasize the need for individualized interventions rather than continued reliance on broad diagnostic categories. Objectives The study consists of two phases with distinct hypotheses: phase I) evaluating emotional blunting along other clinical/psychopathological variables as potential predictors of treatment non-response to SSRI/SNRI in MDD, and phase II) assessing relationships between IR and treatment non-response to vortioxetine in MDD. Further exploratory objectives encompass assessment of: links between psychopathological and metabolic predictors of health status; longitudinal association between emotional blunting and both sexual and cognitive functioning. Materials and Methods The METOD study is an open, non-randomized two-phase observational study conducted in accordance with clinical standards and with all required ethical approvals. The protocol was prepared in line with STROBE recommendations. In Phase I, MDD patients meeting eligibility criteria and initiating antidepressant treatment with one of the first-line SSRIs or SNRIs are observed, whereas in Phase II, individuals showing an inadequate response are switched to vortioxetine as a second-line option. Validated clinical assessment tools are administered alongside anthropometric and laboratory evaluations. Expected Implications/Significance By examining these interrelations within a naturalistic cohort treated in accordance with current clinical standards, this innovative study—with its strong emphasis on patient-reported outcomes—may increase insight into the lived experience of depression, enhance understanding of the pathophysiological mechanisms shaping its diverse symptomatology, and provide a foundation for more precisely targeted therapeutic approaches.