Trajectories of Irritability Improvement in Depressed Adolescents Treated With 1 Hz and 10 Hz Transcranial Magnetic Stimulation

Objective: Irritability is a debilitating, transdiagnostic symptom in adolescents spanning internalizing and externalizing disorders, and early reduction in irritability with antidepressant treatments has been seen as a positive prognostic sign in depression recovery. There are substantial knowledge gaps regarding how transcranial magnetic stimulation (TMS) treatments impact irritability. Methods: This exploratory study sought to investigate the relationship between irritability and depressive symptoms in adolescents with a DSM-5 diagnosis of major depressive disorder (MDD) undergoing treatment with 2 different doses of TMS. Participants aged 12-18 years (N = 41) underwent 6 weeks of treatment (30 sessions) in a double-blind, randomized trial of 1 Hz vs. 10 Hz TMS for the treatment of MDD. The clinical trial was conducted from September 24, 2018, through March 3, 2023. A linear mixed model was used to assess the change in irritability (assessed with item 8 on the Children's Depression Rating Scale Revised) throughout the treatment course, and a logistic regression was implemented to examine the relationship between early (week 4) irritability improvements and a posttreatment Clinical Global Impressions-Improvement (CGI-I) score. Results: Irritability significantly improved during the course of TMS treatments in conjunction with overall depression improvement across the 6 week trial for the 1 Hz TMS group (P = .0120, d =0.381) and for the 10 Hz TMS group (P = .0288, d = 0.331). There was a significant negative (inverse) relationship between the change in irritability symptoms and CGI-I response for the 10 Hz TMS group (δ log odds = -1.5474, SE = 0.7343, P = .0351) and for the 1 Hz TMS group (δ log odds = -1.2852, SE = 0.5656, P = .0231). Conclusion: These results suggest that irritability is an important correlate of disease severity and predictor of treatment response for MDD in adolescents, replicating similar results found in trials using antidepressant medications. Future research should focus on incorporating assessments of irritability into clinical decision-making and intervention discovery for transdiagnostic symptoms of irritability in youth and adolescents. Clinical Trial Registration: Data used in this secondary analysis came from ClinicalTrials.gov identifier: NCT03363919.