Substance Use Not Robustly Linked to rTMS Response in MDD
Key Clinical Summary
- In a naturalistic study of 356 patients with major depressive disorder (MDD), baseline alcohol, nicotine, and cannabis use was generally not robustly associated with antidepressant response to repetitive transcranial magnetic stimulation (rTMS).
- Alcohol use frequency was associated with percent change in Patient Health Questionnaire-9 (PHQ-9) scores in the primary categorical analysis, but the finding lacked a linear dose-response pattern or consistent differences at higher use levels.
- Researchers called for prospective studies with more detailed and temporally precise substance-use assessments to determine whether specific patterns influence rTMS outcomes.
Baseline alcohol, nicotine, and cannabis use was largely not associated with antidepressant response to rTMS among patients with MDD, according to findings published in the Journal of Affective Disorders. The naturalistic analysis included 356 individuals treated at an academic medical center and affiliated outpatient clinics between 2014 and 2025.
Study Findings
Although rTMS is an effective treatment for MDD, clinical response varies among patients. Because substance use commonly co-occurs with depression and is associated with worse psychiatric outcomes, investigators examined whether substance use at baseline was associated with changes in depressive symptoms following rTMS.
The study included 356 patients receiving rTMS for MDD. Antidepressant response was assessed as the percent change in PHQ-9 score from baseline through the end of treatment.
Patients self-reported alcohol use frequency and their typical number of alcoholic drinks during the previous year.
Assessments also captured tobacco use frequency, nicotine vaping during the previous 30 days, cannabis as the most frequently used drug in recent months, and cannabis vaping during the previous 30 days.
Investigators used multivariable linear regression to assess associations between these substance-use measures and percent change in PHQ-9 scores, adjusting analyses for age, sex, and baseline PHQ-9 score.
In the primary categorical analysis, substance use frequency was significantly associated with percent change in PHQ-9 scores (F(4, 347) = 3.84; p = 0.005), though the association was not supported by a linear dose-response relationship or consistent stepwise differences in categories reflecting higher alcohol use.
Other measures of alcohol, nicotine, and cannabis use were not clearly associated with percent change in PHQ-9 scores.
Clinical Implications
The findings indicate that the mostly low-to-moderate patterns of substance use represented in this clinical dataset were not robustly associated with antidepressant response to rTMS in patients with MDD. Substance use commonly occurs alongside depression and is associated with worse psychiatric outcomes, making its potential relationship with rTMS response clinically relevant.
The results also highlight uncertainty surrounding the observed association between alcohol use frequency and PHQ-9 improvement. Although an association emerged in the categorical analysis, the absence of a linear dose-response pattern or consistent differences among higher-use groups limits the consistency of that finding.
Expert Commentary
“Our findings raise the question of whether recreational substance use, when not posing a safety concern with rTMS, should constitute an additional barrier to access on the basis of concerns for treatment efficacy,” wrote Daniel Alejandro Gonzalez, PhD, assistant professor, Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, and study coauthors.
However, the researchers cautioned that the results “should be viewed as preliminary, given the small higher-use subgroups, predominantly low-to-moderate reported substance use, coarse exposure measures, reliance on self-reported depressive symptoms, and potential residual confounding.” They emphasized the need for “prospective studies using detailed, validated, and temporally precise substance use assessments” to clarify whether specific substance use patterns impact rTMS response in MDD.
