Left-handed individuals with treatment-resistant depression show similar response to intermittent theta-burst stimulation and 10 Hz repetitive transcranial magnetic stimulation

To the editor, Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment modality for treatment-resistant depression (TRD), with demonstrated efficacy in treating depressive symptoms including suicidality; rTMS is generally targeted to the left dorsolateral prefrontal cortex (DLPFC), but may be targeted to the right or bilateral DLPFC (see e.g. (Brunoni et al. 2017; Serafini et al. 2021)). Thus, we read with great interest the work by Fitzgerald and colleagues (Fitzgerald et al. 2020), exploring whether brain hemisphere dominance is associated with different clinical effects of rTMS for depression. Pooling results from 11 studies, they found that left-handed subjects experienced a larger reduction in symptoms and higher rates of response for high frequency left-sided rTMS (HFL) but not low frequency right-sided rTMS (LFR). Based on these results, we conducted secondary analyses of the THREE-D trial, as there are no available data on the effect of handedness on response to intermittent theta burst stimulation (iTBS). In this trial, treatment resistant depression patients (TRD) (n1⁄4 414) were randomised to either iTBS or HFL, and iTBS was found to be non-inferior to standard HFL (Blumberger et al. 2018). Clinical and demographic data was gathered as described in (Blumberger et al. 2018). In particular, handedness was determined by self-report. Excluding ambidextrous individuals (n1⁄4 4), and those who did not complete 4weeks of treatment (n1⁄4 29), 381 individuals with TRD remained for analysis. Of 41 left-handed individuals, 24 received iTBS, while 17 received HFL rTMS. Clinical response was measured using the Hamilton Rating Scale for Depression (HRSD) (Hamilton 1967). 50% reduction of HRSD was classified as “response”. Baseline clinical and demographic variables (sex, age, employment status, baseline HRSD, ATHF score, and length of current depressive episode) were compared using independent t-tests or Fisher’s exact test. Change in HRSD was compared between leftand right-handed individuals using independent t-tests, for the overall sample, and separately for iTBS and HFL. To test covariate effects, an ANOVA model with change in HRSD as the dependent variable and independent variables of handedness, stimulation type, sex, age, employment status, baseline HRSD, ATHF score, and length of current depressive episode was used. Fisher’s exact test was used to test for effects of handedness on response. Baseline clinical and demographic variables did not significantly differ between leftand right-handed participants (p> 0.05). Change in HRSD did not differ between leftand right-handed individuals (48.6 ± 33.9% versus 42.5þ 32.1%, t1⁄4 1.14, p1⁄4 0.25). Results were similar analysing separately for patients receiving iTBS (49.9 ± 40.0% versus 42.4 ± 32.3%, t1⁄4 1.03, p1⁄4 0.30) and HFL (46.8 ± 30.1% versus 42.5 ± 32.0%, t1⁄4 0.53, p1⁄4 0.60). In a model including covariates as above, the overall model was non-significant (p1⁄4 0.20), as was handedness (p1⁄4 0.35). The proportion of responders did not differ by handedness, neither in the total sample (24/41 (58.5 %) versus 161/340 (47.3%), p1⁄4 0.19), nor in the iTBS (15/24 (62.5%) versus 79/167 (47.3%), p1⁄4 0.19) or HFL (9/17 (52.9%) versus 82/173 (47.3%), p1⁄4 0.80) subgroups. In summary, we found leftand right-handed individuals with TRD had a similar clinical response to both leftsided iTBS and HFL. In contrast with Fitzgerald et al. there was there was no statistically significant difference between leftand right-handed participants. Our results may differ because we analysed data from a single study, as opposed to pooling results from multiple studies which varied in terms of inclusion criteria, treatment protocol, and clinical scales used. In addition, our sample size of left-handed individuals might not be adequately powered to detect a small effect size. Our findings do not support modification of laterality of rTMS based on handedness for either high-frequency or intermittent theta-burst stimulation. However, handedness may be an important factor for future research examining functional targeting of rTMS.