Dimensional effect profiles in treatment-resistant depression: A naturalistic, prospective head-to-head comparison of arTMS, esketamine nasal spray, and oral brexpiprazole

Introduction Treatment-resistant depression (TRD) is a heterogeneous condition in which symptoms such as anhedonia, rumination, and anxiety contribute to persistent disability. Esketamine nasal spray (ESK-NS), accelerated repetitive transcranial magnetic stimulation (arTMS), and adjunctive brexpiprazole represent novel therapeutic options with distinct mechanisms, though their domain-specific effects in real-world settings remain unclear. Objectives To compare short-term changes in depressive severity across ESK-NS, arTMS, and brexpiprazole, and to explore treatment-related effects on anhedonia, rumination, anxiety, and item-level depressive symptoms. Materials and methods One hundred and one individuals with TRD were enrolled in a prospective, naturalistic, three-arm study and treated with ESK-NS, arTMS (accelerated left DLPFC protocol), or brexpiprazole augmentation (1–2 mg/day). Assessments were conducted at baseline and after one month. Results All treatments produced significant reductions in overall depressive severity and anhedonia. Rumination showed a significant time-by-treatment interaction, with greater improvement under brexpiprazole. Item-level analyses suggested partially distinct profiles, with brexpiprazole preferentially improving pessimistic and ruminative symptoms, ESK-NS enhancing affective responsiveness and cognitive symptoms, and both ESK-NS and arTMS contributing to anxiolysis. Conclusions In routine clinical practice, ESK-NS, arTMS, and brexpiprazole were associated with short-term improvement in TRD, with exploratory signals of partially distinct symptom-domain profiles. These findings support the value of dimensional assessment in TRD and warrant confirmation in randomized studies with longer follow-up.