Dutch-Depression Outcome Trial Comparing 5 Day Multi Daily Neuronavigated Theta Burst Sessions With 6 Weeks rTMS

Rationale: Novel therapies are crucial for patients with unipolar depression since more than 33% of these patients are medication-resistant. As a consequence, there is a high burden of illness for patients with depression, leading to increased suicide rates, inability to maintain proper work and/or social role functions, and reduced quality of life. A promising novel treatment strategy is an intensive five-day course of intermittent Theta Burst Stimulation (iTBS), a form of transcranial magnetic stimulation (rTMS), which could lead to exceptionally high remission rates (79%) in patients with treatment resistant depression. However, it remains unclear whether this novel treatment strategy is more effective in depressed patients when compared to standard 10Hz rTMS (remission 30%).

Hypothesis: 5-day multi daily neuronavigated iTBS sessions (developed by Stanford University and coined, SNT, i.e., Stanford NeuromdulaTion protocol) are more (cost-) effective than standard 10 Hz rTMS in patients with treatment resistant depression.

Objective: To determine remission of depression and cost effectiveness using the SNT protocol, in patients with treatment resistant depression who did not respond to two or more evidence-based treatments.

Study design: This study comprises a multicentre, two-phase, randomized clinical trial. Phase 1 comprises a randomized controlled trial. In Phase 1, participants will be assigned to one of the two active treatment conditions, and will receive either treatment using the SNT protocol (5 days of 10 sessions/day, resulting in 50 sessions in total 90000 pulses) or standard 10 Hz left sided rTMS, provided once daily during 6 weeks (30 sessions in total, 90000 pulses). Phase 2 comprises three follow-up measurements, one at 5 weeks, one at 10 weeks and one at 25 weeks after the last treatment with SNT or 10 Hz standard rTMS. Finally, participants who were allocated to standard 10 Hz rTMS will be offered SNT after the end of the study (e.g., 25 weeks after the last rTMS session). Patients allocated to SNT can obtain 10 Hz standard rTMS after SNT has been completed.

Study population: Adult patients with unipolar depression who did not respond to two or more evidence-based treatments for depression, in the current depressive episode, aged 18 years and over.

Sample size: Sample size calculations based on differences in remission suggest that a well-powered trial should consist of 108 patients (for a 2-sided test at alpha=0.05 and with power=0.80).

Intervention: 50 sessions using the SNT protocol in 5 days. The subregion of the left DLPFC most anticorrelated with the subgenual anterior cingulate cortex (sgACC) in each participant will be targeted based on patient-specific functional resting state magnetic resonance imaging .

Comparison: 30 standard daily 10 Hz rTMS sessions in six weeks, targeting the left DLPFC based on standard scalp-based measurement procedures.

Inclusion criteria

• 18 years of age or older;
• Sufficient level of spoken and written Dutch;
• Ability to freely provide written informed consent;
• Current DSM-5 diagnosis of a depressive episode, ascertained by the Mini International Neuropsychiatry Interview (MINI-S).
• A Hamilton depression rating score (HDRS) of >16 points: this score will be obtained from the SIGH-ADS, a depression rating scale able to determine the HDRS score and a score for atypical depression.
• have a treatment resistant depression, defined according to the criteria of Conway, that is, lack of remission for eight consecutive weeks after two different evidence-based treatments anti-depressant medication has to be adequately dosed(7,24).
• Stable anti-depressant medication 6 weeks prior to study. Benzodiazepines may be used up to a dosage equivalent of 3.0 mg lorazepam, and can be lowered over time during the study based on clinical judgement.

Exclusion criteria

• - Bipolar disorder.
• Current psychotic disorder¸ including psychotic depression, assessed by treating psychiatrist.
• Suspected dementia, assessed with a dementia screening tool, i.e., the Montreal Cognitive Assessment (MOCA)(25), with a score of less than 20 points, or a clinical suspicion of dementia, or neuroimaging indication for neurodegeneration with a Fazekas > 1 and MTA >1. These cut-offs ensure exclusion of patients with (preclinical) dementia.
• Active suicidal thoughts and intent to act on it, assessed at the baseline interview and before the start of the trial. This assessment is based on the Columbia suicide severity rating scale, i.e., question 5 is answered positive "Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan?" (26).
• Metallic devices implanted above the neck, assessed at the baseline interview.
• Patients diagnosed with epilepsy, by a neurologist, assessed at the baseline interview.
• Substance abuse 4 weeks prior to the study, including high dosage of benzodiazepine, a dosage equivalent higher than 3.0 mg lorazepam, assessed at the baseline interview.
• Inability to understand or comply with study requirements as judged by the investigators, assessed at the baseline interview.
• Pregnancy