Introduction: Repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral prefrontal cortex (DLPFC) is an effective treatment for major depressive disorder (MDD) (Mutz et al., 2019). However, there is a considerable degree of heterogeneity in randomized clinical trials, for instance pertaining to patient characteristics such as age and treatment refractoriness. Higher levels of refractoriness have been shown to predict lower antidepressant efficacy of rTMS (e.g. Lisanby et al., 2009).
Objectives: We examined the degree of treatment refractoriness of patients participating in rTMS and theta burst stimulation (TBS) trials. Additionally, we hypothesized that rTMS trials that included patients who had previously failed fewer treatment attempts find stronger treatment effects.
Materials & Methods: We used data from 39 randomized sham-controlled trials included in a recent meta-analysis of the antidepressant efficacy and acceptability of non-invasive brain stimulation in depression (Mutz et al., 2018). We examined each study’s definition o f treatment refractoriness and, if possible, extracted the mean number of failed treatment attempts per trial. The impact of the trials mean treatment refractoriness on the study effect size was further analysed using meta-regression.
Results: 39 trials (N = 1862 patients) reported the level of treatment refractoriness as trial inclusion criterion but only 13 trials (33%) reported the mean number of failed antidepressants in the current episode. Most studies (49 %; n = 719 patients) used ≥2 failed medication trials as criterion and only two trials (n = 41 patients) included only non-treatment refractory patients. Patients had taken on average 4.4 antidepressant medications in the current episode. We did not find evidence that the mean number of antidepressants (p = 0.6) or the inclusion criterion of the studies (p = 0.7) was significantly associated with the log-odds of response in a meta-regression.
Conclusion: We investigated the different criteria used to define treatment refractoriness and its mean in several rTMS trials and whether these are associated with treatment efficacy. We did not find any evidence supporting this hypothesis. However, few studies were conducted in low treatment refractory or medication-naïve patients. In light of the benign tolerability profile of rTMS and evidence for the antidepressant efficacy in high treatment refractory patients, future trials should investigate the efficacy of rTMS in non-treatment refractory depression (Kiebs et al., 2019).
Kiebs M, Hurlemann R & Mutz J (2020) Clinical Neurophysiology. 131(4):e174. DOI: 10.1016/j.clinph.2019.12.391