Title: 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
Funder: Department of Health and Social Care

Abstract: 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

Lay abstract: Depression is the 2nd leading cause of disability worldwide and suicide from depression is the biggest killer in people aged 15-49 years. Antidepressants and talking therapies help two thirds people with depression, but the remaining third have ‘treatment resistant depression’ (TRD). Until recently, a few patients with TRD were offered ECT but they may not accept this treatment due to its possible side effects. An alternative treatment called transcranial magnetic stimulation (TMS) has recently been used employing magnets and not requiring an anesthetic. In December 2015, NICE reviewed the evidence for TMS and advised that it may be used to treat depression. NICE reports that TMS is safe and effective in reducing symptoms for a short while, but has asked for further research to be carried out. In this trial we compare a novel type of TMS called theta-burst stimulation (TBS) and rTMS, the standard treatment. A pilot study showed that TBS guided by brain scan can maintain the improvement longer than the rTMS treatment but this needs further research before it is used in clinical practice. Patients with depression experience changes in some parts of the brain particularly in the frontal area. If an intervention is delivered precisely to these specific parts of the brain, it may avoid unwanted effects and improve the outcome. Based on a brain scan, for each patient a specific point in the brain is identified to deliver the magnetic pulses. Once an eligible patient with TRD is referred by their GP or psychiatrist, they provide written informed consent and have a comprehensive clinical assessment from a researcher. Some pen and paper tasks are given to rate their symptoms, day to day function and memory. Following the assessment they will have a MRI brain scan which may last 45 minutes. The researchers will analyse the scan to identify the brain regions that could benefit from the treatment and a week later the patient will start the treatment. 368 patients will receive 5 treatments a week for 4 weeks, half receiving TBS and half rTMS depending on randomisation, a process like flipping a coin. After the treatment course is completed, they will be reassessed using information gathered at the first assessment and will have another MRI scan at 16 weeks to observe any changes. Further follow up assessments of symptoms and costs at 8, 16 and 26 weeks will be compared with the first assessment. They will be asked their views about the treatments and side-effects. For our previous TMS study, we formed an advisory group involving patients and carers who assisted in designing the research and drafting the patient information sheet. For this study we will have 4 centres in Nottingham, Northampton, Newcastle and London, each with an advisory group of patients who have had TMS, TBS treatment or depression. The research team will have regular meetings with this PPI group throughout the study. The findings from the study will be presented at scientific meetings and submitted for publication in scientific journals. A summary of the findings will be presented to local clinicians and service users. We will show the progress of the study to NHS Commissioners and funding authorities as required. Anonymity will be maintained when results are published so that results from individuals are not identified. The participants in the study will be informed of the overall study results through the PPI group and offered copies of the publications from the study

Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: MENTAL HEALTH