High-dose spaced Theta-burst TMS as a rapid-acting antidepressant in highly refractory depression

Abstract

Sir, We read with enthusiasm the article by Li et al. (2014) that describes how a course of intermittent theta-burst stimulation (iTBS) over the left dorsolateral prefrontal cortex (L-DLPFC) produced robust antidepressant responses compared to sham stimulation in patients with treatment-refractory depression (Li et al., 2014). TBS, a patterned form of repetitive transcranial magnetic stimulation (rTMS) modelled after endogenous hippocampal discharge patterns (Larson and Lynch, 1986; Huang et al., 2005), has been shown to be more efficient than standard rTMS in modulating cortical excitability (Cárdenas-Morales et al., 2009). Preliminary results indicate non-inferiority of 600 pulses/day of iTBS versus 3000 pulses/day of conventional rTMS in treating depression (Blumberger et al., 2017). Li et al. found that iTBS in highly refractory depression led to a mean 33% reduction in the 17-item Hamilton Depression Rating Scale (HDRS17) (Li et al., 2014), and degree of refractoriness predicted reduced efficacy (Li et al., 2014). Higher refractoriness may require more rTMS pulses to produce an antidepressant response, which in turn would necessitate more rTMS sessions per acute course (Yip et al., 2017). Multiple spaced TBS sessions can be applied over a day with selected time intervals between sessions in an effort to accelerate the onset of effect, thereby also reducing the number of days required to complete an acute course (Cazzoli et al., 2012). To begin testing this hypothesis, we conducted an open-label trial of spaced iTBS for the treatment of depression in six patients with the highest level of treatment-refractoriness. Eligible participants were 21–70 years of age and had major depressive disorder or bipolar II disorder as diagnosed by the Structured Clinical Interview for DSM-5. Participants were required to meet criteria for the highest non-psychotic treatment-refractoriness on the Maudsley Staging Method (MSM, 14/15) (Fekadu et al., 2009) and have a baseline total score of ≥20 on the HDRS17 (Hamilton, 1960) in the current episode. Participants must have received an FDA-approved rTMS treatment course with ≥60 000 pulses of deep rTMS (Levkovitz et al., 2015) or ≥90 000 pulses of conventional rTMS over L-DLPFC and have failed to meet responder criteria (Lisanby et al., 2009). Participants also were required to have failed to respond to an acute course of electroconvulsive therapy and to meet deep brain stimulation inclusion criteria (Filkowski et al., 2016). Participants were excluded if they had a history of a psychotic disorder, substance use disorder, major systemic illness, lesional neurological disorder, or brain implant. We recruited six participants for this trial. Full written informed consent was obtained for all participants. The study was conducted according to the Declaration of Helsinki and approved by the Stanford Institutional Review Board. All participants were profoundly functionally impaired—either unemployed, on disability, or with significantly reduced workloads due to depressive symptoms. Participant demographics, prior treatments, and baseline measures are included in Table 1. Participant demographics, prior treatments, baseline measures, and results BDI-II SR = Beck Depression Inventory Self Report; BPAD = Bipolar Affective Disorder; CGI-S = Clinical Global Impression - Severity Scale; DBS = deep brain stimulation; ECT = electroconvulsive therapy; HDRS-17 = Hamilton Rating Scale for Depression 17 point; MADRS = Montgomery-Asberg Depression Rating Scale; N/A = not applicable; MDD = Major Depressive Disorder; TMS = transcranial magnetic stimulation; VNS = vagus nerve stimulation. aThis subject previously acquired a doctoral degree and was employed as a professional; currently works part time in service industry. bAt time of enrolment, this subject carried a MDD diagnosis, but was subsequently found to have OCD and withdrew from the study. cThis subject withdrew from the study following 40 of 50 stimulation sessions. dThis subject received retreatment prior to this time point. Participant demographics, prior treatments, baseline measures, and results BDI-II SR = Beck Depression Inventory Self Report; BPAD = Bipolar Affective Disorder; CGI-S = Clinical Global Impression - Severity Scale; DBS = deep brain stimulation; ECT = electroconvulsive therapy; HDRS-17 = Hamilton Rating Scale for Depression 17 point; MADRS = Montgomery-Asberg Depression Rating Scale; N/A = not applicable; MDD = Major Depressive Disorder; TMS = transcranial magnetic stimulation; VNS = vagus nerve stimulation. aThis subject previously acquired a doctoral degree and was employed as a professional; currently works part time in service industry. bAt time of enrolment, this subject carried a MDD diagnosis, but was subsequently found to have OCD and withdrew from the study. cThis subject withdrew from the study following 40 of 50 stimulation sessions. dThis subject received retreatment prior to this time point. All participa