The CoMPACT trial is a randomized double-blinded sham-controlled study aimed at testing a novel accelerated and personalized transcranial Magnetic Stimulation (TMS) treatment for patients with Treatment Resistant Depression (TRD).
CoMPACT consists of 25 sessions of intermittent theta-burst transcranial stimulation (iTBS) consisting of high inter-pulse frequency administered five times daily over five consecutive days.
The trial will include 78 patients with TRD who will be randomly assigned to one of three groups:
* Group 1: Real CoMPACT targeting the left dorsolateral prefrontal cortex (DLPFC). * Group 2: Real CoMPACT targeting a novel site, the left inferior parietal lobule (IPL). * Group 3: Sham CoMPACT targeting the left DLPFC (50%, Group 3a) or left IPL (50%, Group 3b).
The hypothesis is that real prefrontal or parietal CoMPACT targeting will significantly alleviate depression symptoms compared to sham targeting, without compromising safety, feasibility, or tolerability.
The trial incorporates a personalized approach, using electrical field (E-field) modeling based on individual structural brain scans to tailor and standardize iTBS, ensuring accurate targeting of cortical volume and consistent induced electrical field strength. To delineate the treatment mechanism of action at the brain network level, multi brain mapping models will be implemented. Electroencephalography (EEG) records of spontaneous and TMS-evoked electrical brain activity will be obtained before, during, and after iTBS sessions to understand how the high frequency burst protocol functionally engages the stimulated cortex. Structural and functional brain MRI before and after the treatment will be used to study changes in depression-related brain networks. This will offer key insights into how CoMPACT affects depression-related brain networks and may identify neuroimaging markers for predicting treatment response, and thus informing future TBS treatments for TRD.
Age range between 18 and 95 years
In- or outpatients with a moderate to severe single episode or periodic MDD according to ICD-10, verified by a M.I.N.I. interview.
Major Depression Inventory (self-rapport) score higher than 25.
Lacking or insufficient effect of at least two drug trials from two distinct classes, e.g., SSRI, SNRI, TCA, or MAO-inhibitors, used in the current episode, with adequate dose and duration as judged by the investigator.
History of neurologic disease affecting the brain, including dementia and epilepsy
Schizophrenia or any other psychotic disorder except for psychotic depression
Head trauma causing more than 5 minutes loss of consciousness
Suicidal or psychotic symptoms making the transport of participants hazardous
Parallel
MagVenture XP Orange Stimulator and active side of MagVenture COOL-B65 coil.
DeviceIntermittent theta burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex (DLPFC) will be administered over five consecutive days. On each intervention day, patients will undergo five high frequency iTBS sessions (each lasting approximately 10 minutes, excluding preparation) with about 50 minutes of rest between sessions. Each iTBS session delivers 1,800 pulses, resulting in a total of 25 sessions and 45,000 pulses over the course of a standard work week.
Device: MagVenture XP Orange Stimulator and active side of MagVenture COOL-B65 coil.
DeviceIntermittent theta burst stimulation (iTBS) targeting the left inferior parietal lobule (IPL) will be administered over five consecutive days using the stimulation pattern described in the active DLPFC arm.
Sham stimulation of the MagVenture MagPro XP Orange Edition Prototype flipping the active side of the MagVenture Cool-B65 coil
DeviceDevice: Sham stimulation of the left DLPFC or IPL will be administered using the same stimulation duration and repetition as the active iTBS. To match the subjective experience of iTBS, the sham CoMPACT uses a dedicated (Active/Placebo) stimulation coil that has both active and sham functions, generating the same sound level regardless of the type of stimulation.
Change in the Hamilton Rating Scale for Depression-6 (HDS-6) Score
The HDS-6 total score reflects the severity of depression, ranging from 0 to 24, with higher scores indicating more severe symptoms. 0-6 = normal, 7-8= mild depression, 9-11 = moderate depression, 12-22 = severe to very severe depression. A 3-point change is considered to be clinically significant, which is a very conservative criterion.
Change in the Hamilton Rating Scale for Depression-17 (HDS-17) Score
The HDS-17 score ranges from 0 to 52, with higher scores reflecting greater depression severity. 0-7: Normal 8-13: Mild depression 14-18: Moderate depression 19-22: Severe depression ≥23: Very severe depression
Change in the WHO-5 Well-being Index (WHO-5) score
The World Health Organization Five Well-being Index (WHO-5) score measures overall well-being on a scale of 0 to 100, with higher scores indicating better well-being. Score Interpretation: 0-28: Poor well-being, possible clinical depression 29-50: Low mood or well-being 51-100: Good well-being
Change Snaith-Hamilton Pleasure Scale (SHAPS) score
SHAPS measure anhedonia. The score ranges from 0 to 14, with higher scores reflecting greater levels of anhedonia
Change in Overall Anxiety Severity and Impairment Scale (OASIS) score
OASIS The score is between 0 and 20. Higher scores indicates greater levels of anxiety and impairment.
Changes in magnetic resonance imaging (MRI) from baseline to postintervention
Structural MRI (sMRI) gives high-resolution images of the brain anatomy and allows for accurate calculation of different volumes of the brain regions. Diffusion MRI (dMRI) measures the regional diffusion properties of water and provides micro-structural information on the direction of fiber tracts and structural connectivity in relation to our stimulation targets. Functional MRI (fMRI) can map the functional connectivity of the brain during resting periods and during performing reward related tasks.
Changes in Resting-State EEG Power Bands
EEG will be used to assess changes in cortical activity power induced by a single iTBS session, as well as the cumulative effects across an intervention day. The analysis will cover the entire frequency spectrum, with a particular focus on the theta and alpha bands. Additionally, alterations in both periodic and aperiodic components of the power spectrum will be studied.
Immediate changes in EEG power spectrum
EEG will be used to assess acute changes in cortical power spectrum between consecutive burst trains with a particular focus on the theta and alpha band. Additionally, alterations in both periodic and aperiodic components of the power spectrum will be studied.
Changes in EEG-based Connectivity
Exploratory analysis of potential alterations in connectivity within the related network during and after a single iTBS session, compared to baseline. In addition to the investigation of a single session, the cumulative effect of multiple sessions will also be explored.
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Danish Research Centre for Magnetic Resonance
Lead sponsor
Glostrup University Hospital, Copenhagen
Collaborator
Mental Health Center North Zealand
Collaborator
