Randomised double-blind controlled trial of connectivity guided theta burst transcranial magnetic stimulation versus repetitive transcranial magnetic stimulation for treatment resistant moderate to severe depression: evaluation of efficacy, cost effectiveness and mechanism of action

Background Major Depressive Disorder (MDD) is the 2nd leading cause of years lived lost worldwide (1) & suicide from MDD is the leading cause of mortality in people aged 15-49 years (2). While antidepressants & psychotherapies are effective in treating depression, 33% patients in secondary care fail to respond (3). Such “treatment resistant depression” (TRD) is associated with escalating suicide rates, hospitalisation & costs with ineffective &/or poorly tolerated treatment e.g ECT. Repetitive transcranial magnetic stimulation (rTMS) is a NICE approved non-invasive treatment for depression with short-term benefit (4). Intermittent theta-burst stimulation (iTBS) may induce long-term potentiation (5). Our pilot RCT of connectivity guided TBS (cgiTBS) with TBS stimulus localised to connectivity to the insula by fMRI suggests a longer duration of clinical effect than rTMS over at least 3 months, especially important in TRD, a long-term condition. Abnormal brain GABA & glutamate mediated synaptic inhibitory/excitatory balance is an important pathophysiological process in depression (6). Our pilot shows on neuroimaging cgiTBS reduces depression affecting inhibitory cortical systems through altering GABA and reduced fronto-insular network connectivity, the insula predicting treatment outcome in MDD (7) including after rTMS (8). There are no multicentre efficacy RCTs of cgiTBS versus rTMS. Such an investigation is vital for improving TMS treatment in depression. Aims The primary aim of this study is to examine the efficacy, cost effectiveness outcomes & patient acceptability of connectivity guided iTBS versus rTMS on depression response at 16 weeks 3 months after TBS in patients with moderately severe TRD. A secondary aim is to examine effects of TBS on the function & structure of the fronto-insular network using Granger Causality Analysis in relation to depression response. Prefrontal GABA & Glx (composite of glutamate & glutamine) will be quantified using magnetic resonance spectroscopy (MRS). Qualitative interviews with patients will assess patient acceptability of TBS. Design and method A 4-centre randomised, 2-arm double blind superiority trial of cgiTBS versus rTMS. Participants will undergo structural MRI, resting fMRI & MRS in a 3T scanner. Scan data identifies an individually tailored left DLPFC (dorsolateral prefrontal cortex) target site for cgiTBS or non-anatomically guided rTMS each given 20 times (5 per week for 4 weeks). Patients undergo repeat scanning at 16 weeks;scans will be compared for changes in fronto-insular connectivity & GABA related to depression response. 368 participants with TRD in total will be recruited from primary and secondary care over 2 years to existing NHS TMS/TRD services at Nottingham, Newcastle, Northampton and London, recruiting 40-50 participants per year with 6 month internal pilot. Patients aged 18 years or over with primary predefined TRD of moderate severity will be eligible to participate.The primary clinical outcome is the proportion of patients with 50% improvement in depression symptoms on the 17 item Hamilton Depression Rating Scale (9) between baseline & 16 weeks (response). Secondary outcome measures include the proportion of responders at 8 & 26 weeks, remitters at 8, 16 & 26 weeks, continuous depression, function, quality of life & cognition scores at 8, 16 & 26 weeks, cost effectiveness at 26 weeks plus side-effects & acceptability assessment after each treatment & follow up