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.

Repetitive TMS (rTMS) of left DLPFC was approved by the US Food and Drug Administration (FDA) in 2008 as a therapy TRD, and this was extended to the equally effective iTBS protocol in 2018.

Dysfunctional connectivity between the left DLPFC and subgenual anterior cingulate cortex (sgACC) has been implicated in the pathogenesis of depression. It has been hypothesized that rTMS-induced neuroplasticity in left DLPFC modifies functional connectivity between left DLPFC and sgACC, normalizing the underlying brain circuit dysfunction.

A recent development has been a move towards "accelerated" rTMS protocols with more than one session per day. Recently, two studies reported promising results for the Stanford Accelerated Intelligent Neuromodulation Treatment (SAINT) protocol for TRD.

The aim of the COMPACT trial is to introduce and test a novel accelerated iTBS therapy for TRD that is designed to significantly expand existing work on accelerated iTBS.

The novel CoMPACT protocol utilizes high frequency bursts to produce a strong "acceleration" effect, securing therapeutic efficacy and clinical feasibility.

The COMPACT protocol consists of five iTBS sessions per day (rather than 10 sessions per day as given in the "SAINT" protocol) over five consecutive days to increase feasibility. In addition to accelerated iTBS of left DLPFC, the invetigators will test clinical efficacy of a novel parietal target, the left IPL. The investigators hypothesize that accelerated iTBS of the area in left IPL that shows a strong negative functional connectivity with the sgACC will be also highly effective in treating TRD compared to the accelerated sham protocol.

Anatomically guided personalized targeting and dosing will be based on E-field modeling informed by the individual cortical anatomy revealed by the patient's structural brain MRI.

Patients with TRD are recruited from psychiatric departments in Copenhagen. Information material with contact details for the project will be available in waiting rooms at the outpatient clinics so that potential participants can contact the project themselves. Furthermore, we will recruit by advertising via Trialtree.dk After inclusion, participants will undergo a baseline assessment (T0) that includes evaluating depression severity and several widely used psychiatric rating scales measuring anhedonia, cognitive deficits, and treatment-related adverse effects. A list of the tests included can be found in the "Outcome" section.

Within two weeks after T0, patients will undergo 5 days of active iTBS targeting either the left DLPFC or the left IPL, or a sham intervention on the left DLPFC or IPL, for a total of 25 sessions. During the first and last day of intervention week, EEG will be used recorded before, during and after first and last iTBS sessions. This helps to investigate acute changes in the cortical activity patterns induced by a single iTBS and the cumulative functional effects on cortical activity caused by the CoMPACT protocol.

Moreover, EEG response to a single and multi TMS pulse, so-called transcranial evoked potentials (TEPs), will be measured before and after iTBS session. This will allow us to explore how high-frequency burst iTBS modulates cortical excitation and inhibition in targeted regions and its potential correlation with clinical response. Online EEG monitoring during iTBS will be performed can also be used to document safety and capture brain activity during the periods separating consecutive iTBS trains.

The antidepressive effects of the intervention (Hamilton Depression Rating Scale as primary outcome) will be assessed, within 3 days after the last session. The rest of the clinical tests will be performed within 5 days after end of treatment (T1). The long-term effect on symptom of depression and other clinical effect will be tested after 4 weeks (T2) and at potential 6 months follow-up.

Assessments at T0 and T1 will also include structural (T1 and T2 weighted sequences), diffusion sensitive MRI, resting-state, and task-based functional MRI (fMRI). Task-related fMRI will reveal how the active CoMPACT intervention modifies brain activity and connectivity within key brain networks compared to sham COMPACT. Cognitive performance will be also probed using a selected set of cognitive tests at T0, T1 and T2.Referral to standard TMS therapy for non-responders:

If patients have not entered remission (i.e. a score less than 7 on HDS-17) immediately after the end of COMPACT treatment or at visit T1, they will be offered standard TMS treatment. A treatment that is approved for general clinical use in psychiatric wards and elsewhere.

Data will be collected at the participating sites in the Capital Region of Denmark (RegionH). After end of trial and final data analysis, anonymized trial-related data and methods will be made available to other researchers through public databases after publication of the main clinical outcome paper in accordance with Danish law.

Inclusion criteria:

• 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.
• Duration of the current episode must be longer than 2 months but shorter than 4 years, as judged by the investigator.

Exclusion criteria:

• 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
• Any form of compulsory admission or treatment within the past three months
• Treatment with ECT in the current depressive episode
• Non-responders to TBS treatment within the current episode
• Current harmful use or dependency of substances according to ICD-10 and interfering with outcome evaluation as judged by investigator's discretion.
• High risk of non-adherence as judged by investigators discretion
• Medical and psychiatric conditions interfering with study outcome and safety as judged by investigator's discretion.
• Female participants of childbearing age must not be pregnant or breast feeding, and they must use contraception during the trial.
• One of the prime contra-indications for MRI, including severe claustrophobia (see Appendix 08.05)
• One of the prime contra-indications for TMS and persons with electrically, magnetically, or mechanically activated implants or with metal or magnetic pieces in their head (see Appendix 08.04)
• Patients who do not wish to be informed about MRI or EEG findings, which may have clinical relevance.