Esketamine-based treatment, depression-specific metacognitive training, and their combination in treatment-resistant depression: 6-month trajectories of depressive symptoms and rumination in a multicenter observational study.

Treatment-resistant depression (TRD) remains a highly burdensome clinical condition, and improvement in depressive severity does not necessarily imply parallel modification of maladaptive cognitive-affective processes such as rumination. We compared 6-month trajectories of depressive symptoms and depressive rumination across three active treatment conditions in routine clinical care: intranasal esketamine-based treatment without depression-specific metacognitive training (ESK), depression-specific metacognitive training without esketamine exposure (D-MCT), and combined esketamine plus D-MCT (D-MCT + ESK). Of 65 screened patients, 12 were excluded because of at least one absolute contraindication and 53 were enrolled (ESK n = 15, D-MCT n = 12, D-MCT + ESK n = 26). Seven participants did not complete the 6-month endpoint assessment (six in ESK and one in D-MCT + ESK), yielding a complete-case analysis set of 46 patients (ESK n = 9, D-MCT n = 12, D-MCT + ESK n = 25). Generalized estimating equations showed significant time effects and time-by-group interactions for both MADRS and RRS total scores. Endpoint ANCOVA models adjusting for baseline outcome value showed significant group effects at 6 months for MADRS (F(2,42) = 24.97, p<.001) and RRS (F(2,42) = 5.59, p=.007). Six-month MADRS response among completers was 3/9 (33.3%) in ESK, 4/12 (33.3%) in D-MCT, and 23/25 (92.0%) in D-MCT + ESK; corresponding intention-to-treat estimates using non-responder imputation were 3/15 (20.0%), 4/12 (33.3%), and 23/26 (88.5%). Concomitant treatment profiles showed marked imbalance in previous non-pharmacological treatment exposure, representing an important potential confounder. Findings support a cautious, hypothesis-generating interpretation because allocation was nonrandomized, assessment was open-label, the sample was modest, and baseline rumination was higher in the combined group.