Source: Brain Stimulation. 14(2):335-343, 2021 Mar-Apr.
Authors: Hebel T; Gollnitz A; Schoisswohl S; Weber FC; Abdelnaim M; Wetter TC; Rupprecht R; Langguth B; Schecklmann M
OBJECTIVE: To investigate whether a four-week course of neuronavigated intermittent theta burst stimulation (iTBS) of the left dorsolateral prefrontal cortex is superior to the non-neuronavigated F3-EEG method of positioning.
METHODS: We conducted a single-center, two-arm, randomized and double-blinded study (clinicaltrials.gov NCT03953521). 37 inpatients with an at least moderate depressive episode were randomized to receive either neuronavigated or 10-20-EEG-system based F3 guided iTBS. Both groups received twenty week daily sessions of iTBS while continuing to receive standard-of-care treatment by their ward physicians. For navigated iTBS, we used magnetic resonance imaging to target the border between the anterior and middle third of the middle frontal gyrus considered to represent the left dorsolateral prefrontal cortex (lDLPFC). Differences in the treatment arms were blinded by completely mimicking the procedures of the respective other treatment group. Rating physicians were not involved in the treatment procedure. Primary outcome was defined as the change of the 21-item version of the Hamilton Depression Score (HAMD) from baseline to end of treatment at week 4. Secondary outcomes included HAMD score during the treatment, Patient Health Questionnaire-9, WHO Quality of Life-BREF and Clinical Global Impression. For primary outcome, we used a planned group comparison for the absolute change in the HAMD. For secondary outcome measures we calculated analyses of variance (ANOVAs) with the within-subjects factor time (primary: baseline vs. week 4; secondary: all visits) and the between-subjects factor group (navigated vs. F3 guided group). We also did planned contrasts between both groups for all variables and all treatment and follow-up visits with the aim not to oversee any group differences. For group contrasts we used Student T-tests for metric and chi-square tests for categorial variables. Significance threshold was set to 5% uncorrected for multiple comparisons.
RESULTS: Enrolment of 80 patients with interim analysis was planned. Interim analysis was performed after 37 patients (intention to treat). 6 patients dropped out, leaving 31 for analysis. With respect to primary outcome criteria, absolute change in the HAMD did not differ significantly between groups. In accordance, relative change and number of responders and remitters were not significantly different. Overall number of responders was 53% and of remitters was 60%. On a descriptive level, the results favor the clinical effects of the F3 group for the absolute and relative change in the HAMD and the number of responders. Number of remitters were exactly the same for both groups. Therefore, we decided to stop the trial due to the added burden of magnetic resonance imaging and neuronavigated treatment in relation to the effect. Secondary outcomes did also not differ significantly between groups. Patients did not differ in their baseline characteristics nor with respect to intake of medication during the trial period and all had access to the same therapeutic interventions.
CONCLUSION: We noticed a high antidepressive effect of add-on iTBS treatment to standard inpatient treatment but failed to demonstrate a clinical superiority of neuronavigated localization. The non-navigated, F3 guided iTBS treatment used as a control group may be sophisticated enough to dilute potential added benefits, and the difference between the localization approaches is either negligible or too small to justify the additional efforts of navigation. The effects of concomitant treatment may mask effects, but our patient population reflects clinical reality in an inpatient setting. Further prospective studies are warranted to compare neuronavigated with surface-based approaches.