Connectivity guided intermittent theta burst stimulation versus repetitive transcranial magnetic stimulation in moderately severe treatment resistant depression: the BRIGhTMIND RCT

Abstract

Background Transcranial magnetic stimulation may lead to short-term improvement in depression symptoms. Pilot work suggested that personalised magnetic resonance imaging connectivity-guided intermittent theta burst stimulation might lead to sustained improvement in depression symptoms in treatment-resistant depression. Objectives To determine the efficacy, acceptability, and cost-effectiveness of connectivity-guided intermittent theta burst stimulation over 8, 16 and 26 weeks on depression symptoms (Hamilton Rating Scale for Depression-17) compared with repetitive transcranial magnetic stimulation. To explore the mechanism of action of transcranial magnetic stimulation through effective and functional connectivity, and gamma-aminobutyric acid and glutamate+glutamine in the prefrontal cortex, subgenual anterior cingulate cortex and right anterior insula. Design A multicentre parallel group, double-blind, randomised controlled trial, to test the efficacy of connectivity-guided intermittent theta burst stimulation versus repetitive transcranial magnetic stimulation without connectivity guidance, in patients with moderate to severe treatment-resistant major depressive disorder (treatment-resistant depression). Setting Secondary care mental health services across five study sites. Participants Aged 18 years or over with major depressive disorder, Massachusetts General Hospital Treatment Resistant Depression staging score ≥ 2, and Hamilton Rating Scale for Depression-17 score ≥ 16. Exclusions: bipolar disorder, secondary depression, suicidality, current substance abuse or dependence, neurological conditions, prior brain surgery, major unstable medical illness, standard contraindications to magnetic resonance imaging, change in prescribed medication or benzodiazepines or hypnotics ≥ 5 mgdiazepam equivalents daily in 2 weeks before baseline. Trial interventions In total 3000 pulses were delivered in each 37.5-minute repetitive transcranial magnetic stimulation or connectivity-guided intermittent theta burst stimulation session for 20 sessions over 4–6 weeks. Personalised transcranial magnetic stimulation stimulation targets were identified from magnetic resonance imaging (F3 site for repetitive transcranial magnetic stimulation, maximum effective connectivity from right anterior insula to left dorsolateral prefrontal cortex for connectivity-guided intermittent theta burst stimulation) using neuronavigation to deliver transcranial magnetic stimulation. Main outcome measures The primary outcome measure was mean change in depression symptoms from baseline and at 8, 16 and 26 weeks using the Grid version of the Hamilton Rating Scale for Depression-17. Secondary outcomes were response, remission, sustained response, self-rated depression (Patient Health Questionnaire-9, Beck Depression Inventory-II), generalised anxiety-7, function (Work and Social Adjustment Scale), quality of life (Euroqol five-dimension five line), overall improvement (Euroqol five-dimension five-line scale), acceptability, with cognition (THINC-it battery), resting state functional magnetic resonance imaging and magnetic resonance spectroscopy (baseline and 16 weeks) and costs from health and society perspectives. Results A total of 255 participants were randomised (128 connectivity-guided intermittent theta burst stimulation, 127 repetitive transcranial magnetic stimulation). There were no significant differences between repetitive transcranial magnetic stimulation and connectivity-guided intermittent theta burst stimulation in the Hamilton Rating Scale for Depression-17 score [intention-to-treat adjusted mean −0.31 (95% confidence interval −1.87 to 1.24)] nor on any secondary outcome. Sustained response rates at 26 weeks were 22/127 (17.3%) repetitive transcranial magnetic stimulation, and 29/128 (22.7%) connectivity-guided intermittent theta burst stimulation. Connectivity-guided intermittent theta burst stimulation was dominant over repetitive transcranial magnetic stimulation in cost-effectiveness (0.009 greater quality-adjusted life-year gain and £180 greater cost saving to health services per individual), albeit overlapping 95% confidence interval between treatment groups demonstrates uncertainties. One serious adverse event in each group (mania, psychosis) was attributable to transcranial magnetic stimulation. Both treatments were equally acceptable. Clinical improvement was associated with measures of effective or functional connectivity between left dorsolateral prefrontal cortex and right anterior insula, subgenual anterior cingulate cortex and left dorsomedial prefrontal cortex, and spectroscopy baseline gamma-aminobutyric acid. Limitations Participants may have benefited from > 20 transcranial magnetic stimulation sessions. There was no sham control group. Conclusion Connectivity-guided intermittent TBS was not superior in efficacy to standard repetitive transcranial magnetic stimulation. Magnetic resonance imaging neuronavigation personalised repetitive transcranial magnetic stimulation or intermittent theta burst stimulation are acceptable methods to reduce depression symptoms over 26 weeks in treatment-resistant depression alongside other reasons for improvement. Study registration Current Controlled Trials ISRCTN19674644. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 16/44/22) and is published in full in Efficacy and Mechanism Evaluation; Vol. 12, No. 2. See the NIHR Funding and Awards website for further award information.