Accelerated Intermittent Theta-Burst Stimulation: Future Paradigms in Neuropsychiatric Disorder Treatment

Abstract

Background: Accelerated intermittent theta-burst stimulation (aiTBS) is a novel form of non-invasive repetitive transcranial magnetic stimulation (rTMS), used in treatment resistant depression (TRD). A recent release of open label results from the Stanford Accelerated Intelligent Neuromodulation Treatment (SAINT) aiTBS paradigm have demonstrated initial efficacy in the treatment of TRD among rTMS naïve, rTMS non-responders and ECT non-responders; however, post-treatment antidepressant durability (time to relapse) and associated predictors of durability remain unexplored. Objective: The objective of this study was to investigate antidepressant durability among individuals with TRD who responded (≥50% reduction in depression scores) to a series of SAINT aiTBS. A second objective was to explore factors predicting durability (e.g. prior rTMS non-response, treatment refractoriness using the Maudsley Staging Method, or baseline depression severity). A third objective was to assess durability in the sub-group of individuals who received a second aiTBS treatment series after depressive symptom worsening or relapse occurred during the 6-month post-SAINT follow-up time-period. Methods: A secondary analysis was conducted on existing data that were extracted from an online data storage tool (Research Electronic Data Capture-REDCap). The sample consisted of 33 individuals with unipolar or bipolar TRD who received 10 daily sessions (10 minutes per session with 50-minute intervals between sessions) of outpatient aiTBS over the course of 5 days, for a total of 50 sessions. Included in the durability study were anti-depressant responders (n=32) who either 1) received one series of SAINT and were followed for up to 6 months post aiTBS treatment (n=16), or 2) experienced symptom worsening (n=15) or partial response (n=1) and received a retreatment series and were followed for up to another 6 months. One participant did not respond to treatment and was excluded from the durability analyses. The primary antidepressant durability outcome measure was the Hamilton Depression Rating Scale (HDRS-6), which was administered pre/post treatment and at follow-up weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 22, and 24. The 17-item Hamilton Depression Rating Scale (HDRS-17) and Montgomery-Asberg Depression Scale (MADRS) were used as secondary depression outcome measures and were administered at pre/post treatment, and follow-up weeks 1, 2, 4, 6 and 8. A secondary aim assessed antidepressant durability and relationships between level of treatment refractoriness (Maudsley Staging Method-MSM) and baseline depression severity (MADRS). Kaplan-Meier survival analyses were used to assess durability up to 24-weeks post SAINT acute and retreatment series time-points. Univariate Cox regression analyses were used to assess associations between post-SAINT anti-depressant durability and potential covariate predictors including 1) clinical (e.g. level of treatment refractoriness, baseline depression severity and day of treatment response), and 2) demographic (e.g. age, sex, illness duration) covariates. Results: The average time to relapse across all participants completing an acute series of SAINT was 14.37 weeks (SE=1.84). Prior rTMS non-responders (n=11) showed a significantly shorter time to relapse (mean=8.46 weeks, SE=2.73 p=.006) than rTMS naïve participants (17.76 weeks, SE=2.11). Among all participants completing the acute SAINT series of aiTBS, 94% (29) were responders at 1-month, 58% were responders at 3-months and 13% were responders at 6-months. All re-treated participants (16/16) reached euthymia within the 5-day retreatment period with a mean of 14.59 weeks (SE=2.56) of anti-depressant durability. Greater baseline depression severity (MADRS) score was associated with longer durability, though this was not a significant predictor of antidepressant durability. The MSM was a significant predictor of durability. Conclusion: Participants who responded to the SAINT intervention without re-treatment rTMS tended to relapse after approximately 3 ½ months. Acute series antidepressant response and baseline treatment refractoriness may be predictors of aiTBS antidepressant durability. SAINT may be a less invasive and more cost-effective option for individuals with TRD, compared with standard rTMS and ECT methods. Further research is needed to explore accelerated iTBS paradigms, the use of retreatment vs maintenance rTMS to increase durability and predictors of anti-depressant response and durability.