Intermittent Theta-burst Stimulation for Major Depression: an Intensity-response Study

Depression, Unipolar Clinical Trial

Official title:

Intermittent Theta-burst Stimulation for Major Depression: an Intensity-response Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06392867
• Other study ID #: HSEARS20221101008
• Status: Recruiting
• Phase: N/A
• Start date: January 8, 2024
• Est. completion date: October 26, 2026

Study information

• Verified date: April 2024
• Source: The Hong Kong Polytechnic University
• Contact: Georg Kranz, PhD
• Phone: 27664838
• Email: georg.kranz[@]polyu.edu.hk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The United States Food and Drug Administration (FDA) approved intermittent theta-burst stimulation (iTBS) in 2018 as a form of repetitive transcranial magnetic stimulation (rTMS). Hospitals worldwide use it to treat major depressive disorder (MDD). It is safe, effective, even for depressed patients unable to respond to standard pharmacological treatment and is more efficient than standard rTMS. In accordance with the approved treatment protocol, patients experience considerable sensory discomfort at a stimulation intensity of 120% of their resting motor threshold (rMT). Antidepressant effects of iTBS are believed to be mediated by modulating prefrontal excitability. There is still a lack of evidence to support the choice of 120% rMT as the optimal stimulation intensity, and the presumed superiority of higher stimulation intensities over lower intensities has yet to be proven. This knowledge gap has clinical implications since more tolerated treatments may lead to greater adherence, resulting in improved outcomes.

The current study proposes a randomized, triple-arm, controlled trial to compare the efficacy of iTBS at 75% (iTBS75) and 120% (iTBS120) rMT with sham iTBS (SiTBS). Based on the following considerations, SiTBS was selected to be compared with iTBS75 and iTBS120: SiTBS will reveal placebo antidepressant effects and serve as a control. iTBS75 is selected because iTBS at 80% aMT exhibits significant excitatory effects on the motor cortex and corresponds to approximately 70% rMT. There is however, a distance of about 12.7mm between the coil and the motor cortex, whereas 14.4mm separates the coil from the dorsolateral prefrontal cortex (DLPFC). Accordingly, a resting motor threshold of 70% at the motor cortex corresponds to a distance-adjusted rMT of 75% at the DLPFC. Lastly, iTBS120 is chosen as the standard stimulation intensity in current iTBS depression trials.

It is our intention to investigate the potential antidepressant effects of iTBS treatment at a much lower stimulation intensity than the one currently employed by most centers in the United States and approved in these centers. Thus, our study can contribute to establishing a treatment regimen with increased adherence and lower withdrawal rates.

Description:

Introduction:

Key issues and knowledge gaps Intermittent theta-burst stimulation (iTBS), a special form of patterned repetitive transcranial magnetic stimulation (rTMS) approved by the U.S. Food and Drug Administration in 2018, is frequently used in many hospitals worldwide for the treatment of major depressive disorder (MDD). For example, at the Department of Psychiatry and Psychotherapy, Medical University of Vienna, we perform about four iTBS treatments daily, amounting to about 1000 treatments a year. iTBS is safe, effective even in depressed patients that are refractory to standard pharmacological treatments, and has the advantage of increased efficiency over standard rTMS. The approved treatment protocol involves a stimulation intensity of 120% of the individual's resting motor threshold (rMT), an intensity associated with considerable sensory discomfort for patients.

The application of a stimulation intensity of 120% rMT is common practice in many psychiatric TMS clinics, and is based on research with conventional rTMS indicating higher clinical efficacy with higher stimulation intensity . However, neuroplastic effects of iTBS of the motor cortex are generally observed at much lower intensities. Researchers have observed significant excitatory effects of iTBS when the intensity is 80% of active motor threshold (aMT), which is approximately 70% of reactive motor threshold (rMT). Moreover, the assumption that the neuromodulatory effects are greater with increasing stimulation intensity is highly debated, and recent research indicates that a linear dose-response relationship for prefrontal iTBS is unfounded. Yet, modulation of prefrontal excitability is thought to underlie the antidepressant effect of iTBS. We still lack evidence for the choice of 120% rMT as the optimal intensity and the presumed superiority of higher stimulation strengths over lower intensities is yet to be investigated. This is a knowledge gap that has important clinical implications because more tolerable treatments could result in greater adherence, and therefore ultimately better outcomes.

Here, we propose a randomized, multicentre, triple-arm, controlled clinical trial to compare the efficacy of a 4-week treatment of daily iTBS at 75% (iTBS75) and 120% (iTBS120) rMT compared to sham iTBS (SiTBS). The choice to compare SiTBS with iTBS75 and iTBS120 is based on the following considerations: SiTBS will reveal placebo antidepressant effects and serves as a control condition. iTBS75 is chosen because iTBS at 80% aMT shows significant excitatory effects of the motor cortex and equals approximately 70% rMT. However, the distance from the coil to the motor cortex is on average 12.7mm whereas the distance to the dorsolateral prefrontal cortex (DLPFC) is about 14.4 mm. Hence, a resting motor threshold of 70% at the motor cortex corresponds to a distance-adjusted rMT of approximately 75% at the DLPFC. Finally, iTBS120 is chosen as it is the standard stimulation intensity in current iTBS trials for depression.

Our proposed study will elucidate the potential antidepressant effect of iTBS treatment at a much lower stimulation intensity than that currently employed by most centres and approved in the U.S. Hence, our study has a high potential to pave the way towards establishing a treatment regimen with increased adherence and lower rates of withdrawal.

Aims and Hypotheses to be tested:

This randomized, multicentre, triple-arm, controlled clinical trial aims to compare the efficacy of SiTBS with iTBS75 and iTBS120 after four weeks of daily treatments in patients with MDD. We hypothesize that iTBS75 will be more effective in reducing depressive symptoms compared with SiTBS and iTBS120. More specifically, (1) we hypothesize that the rate of response, defined as a reduction of Montgomery-Asberg Depression Rating Scale (MADRS) score to ≤50% of baseline values after treatment is significantly higher for iTBS75, compared to sham stimulation and iTBS120 (primary hypothesis). In a secondary analysis, we will test the hypothesis that (2) the rate of remission, defined as a final MADRS score of ≤8, over the course of four weeks of treatment is significantly higher for iTBS75, compared to the other two arms. Similarly, we hypothesise that the increase of (3) subjective mood and (4) happiness, assessed using PHQ-9 and SHS, respectively, is significantly higher for iTBS75, compared to the other two arms. Finally, we hypothesize that (5) iTBS75 is more tolerable than iTBS120, as indicated by a lower reported pain sensation during iTBS75 compared to iTBS120.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 246
• Est. completion date: October 26, 2026
• Est. primary completion date: April 26, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• are aged between 18 and 70;

• have a MDD diagnosis, single or recurrent episode, diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, fifth edition criteria and confirmed by means of the Mini-International Neuropsychiatric Interview (MINI);

• have a score of at least 18 on the 17-item Hamilton Rating Scale for Depression (HDRS17) in their current episode;

• have failed to have a clinically significant response to two or more standard antidepressant treatments during their current episode;

• have received stable psychopharmacological treatment within 4 weeks prior to screening; and

• have normal thyroid function, Complete Blood Count, electrolytes, and liver enzyme levels based on pre-study blood work.

Exclusion Criteria:

• have a history of substance abuse or dependence in the past 3 months;

• have a concomitant major unstable medical illness, cardiac pacemaker or implanted medication pump;

• show active suicidal intent (MADRS item 10 score >4);

• are pregnant;

• have a lifetime MINI diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms;

• have a metal implant or any other common MRI and TMS exclusion criteria;

• take antiepileptic drugs or benzodiazepines corresponding to a dose of >1 mg lorazepam per day;

• have had initiation or dose change of any psychotropic medication in the 4 weeks prior to screening or

• have undergone TMS in the past.

Related Conditions & MeSH terms

• Depression
• Depression, Unipolar
• Depressive Disorder

Intervention

Device:
• intermittent theta-burst stimulation (iTBS)
iTBS treatment will be performed as comprising 3-pulse 50-Hz bursts, applied every 200 ms (at 5 Hz). iTBS consists of 2-second trains with an inter-train-interval of 8 seconds. Repeat trains (30 pulses; 10 bursts) 20 times to reach a total number of 600 pulses (3x10x20) which equals the standard number of pulses in a daily iTBS treatment session, as approved by the FDA. The stimulation site over the left DLPFC will be determined using the international 10-20 system for EEG electrodes corresponding to the F3 location. 20 daily treatment sessions will be performed from Mondays to Fridays for four weeks for all included patients. Treatments will be performed at the brain stimulation laboratory at the Hong Kong Polytechnic University. Stimulation will be delivered using a MagPro X100 model (details about MagPro X100: magventure.com/en_eur/products/magpro-x100/ ) and a Cool-B70 A/P Butterfly Coil, available at each participating centre.

Locations

Country	Name	City	State
Hong Kong	The Hong Kong Polytechnic University	Hong Kong

Sponsors (2)

Lead Sponsor	Collaborator
The Hong Kong Polytechnic University	Health and Medical Research Fund

Country where clinical trial is conducted

Hong Kong, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Montgomery-Asberg depression rating scale (MADRS)	The Montgomery-Åsberg Depression Rating Scale is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders. Response rate after treatment (Montgomery-Asberg depression rating scale, MADRS reduction =50% of baseline); 0 to 6: normal /symptom absent. 7 to 19: mild depression. 20 to 34: moderate depression. 35 to 60: severe depression.	through study completion, an average of 1 month
Secondary	Patient Health Questionnaire-9 (PHQ-9)	The nine-item Patient Health Questionnaire is a depressive symptom scale; PHQ-9 scores of 5, 10, 15, and 20 represented mild, moderate, moderately severe, and severe depression, respectively.	through study completion, an average of 1 month
Secondary	Subjective Happiness Scale (SHS)	The Subjective Happiness Scale seeks to conduct a global, subjective assessment of whether a person is happy or unhappy.; A final score of subjective happiness is calculated by averaging the responses to the four items, with the 4th item's response being reverse coded (i.e., 7 turns to a 1, 6 turns to a 2, etc.). The final scores range from 1.0 to 7.0. Higher scores reflect greater subjective happiness.	through study completion, an average of 1 month
Secondary	Verbal Analogue Scale (VAS) Pain level	To ensure tolerability, the stimulation intensity will be adaptively titrated upward during the initial sessions of treatment to the target intensity without exceeding pain levels of 7, rated on a verbal analogue scale (VAS) ranging from 0 (no pain) to 10 (intolerable pain).	through study completion, an average of 1 month