Substance Use and Antidepressant Response to Transcranial Magnetic Stimulation in Major Depressive Disorder

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for major depressive disorder (MDD), but clinical response is heterogeneous, highlighting the need to identify factors associated with individual outcomes. Substance use commonly co-occurs with depression and is associated with worse psychiatric outcomes, yet its relationship with antidepressant response to rTMS remains poorly characterized. Using a naturalistic sample of individuals receiving rTMS for MDD at an academic medical center and affiliated outpatient clinics from 2014 to 2025 (n=356), we examined whether baseline alcohol, nicotine, and cannabis use were associated with percent change in Patient Health Questionnaire-9 (PHQ-9) score from baseline to end of treatment. Patients self-reported alcohol use frequency and typical number of alcoholic drinks in the past year, tobacco use frequency, nicotine vaping in the past 30 days, cannabis as the most often used drug in recent months, and cannabis vaping in the past 30 days. Associations were evaluated using multivariable linear regression adjusted for age, sex, and baseline PHQ-9 score. Alcohol use frequency was associated with percent change in PHQ-9 in the primary categorical analysis; however, this finding was not supported by a linear dose-response pattern or consistent stepwise differences among higher-use categories. Other alcohol, nicotine, and cannabis variables were not clearly associated with percent change in PHQ-9. Overall, the mostly low-to-moderate substance use patterns captured in this clinical dataset were not robustly associated with antidepressant response to rTMS. Prospective studies using detailed, temporally precise substance-use assessments are needed to clarify whether specific use patterns influence rTMS outcomes.