Depressive Disorder, Treatment-ResistantOcTOPUSNCT07758010
One-Day cTBS Over the Precuneus
A study testing Precuneus-targeted continuous theta-burst stimulation and Left dorsolateral prefrontal cortex intermittent theta-burst stimulation in people with Depressive Disorder, Treatment-Resistant and Treatment Resistant Depression (TRD), run by Mclean Hospital at 1 site in United States.
Trial summary
The goal of this clinical trial is to learn whether two forms of one-day accelerated transcranial magnetic stimulation (TMS) can reduce depressive symptoms in adults with treatment-resistant depression. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Depressive Disorder, Treatment-Resistant, Treatment Resistant Depression (TRD), Treatment Resistant Major Depression Disorder
- What is being tested?
- Precuneus-targeted continuous theta-burst stimulation and Left dorsolateral prefrontal cortex intermittent theta-burst stimulation
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 69 participants
- Where
- 1 siteUnited States
- Study dates
- 8 Sep 2026to 30 Jun 2027
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 18 years or older.
- Able to speak, read, and understand English sufficiently to complete the study assessments and provide informed consent independently.
- Diagnosis of major depressive disorder according to DSM-5-TR criteria, confirmed by a qualified physician.
- Treatment-resistant depression, defined as an inadequate response to at least two adequate trials of antidepressant pharmacotherapy.
- Patient Health Questionnaire-9 (PHQ-9) total score of 10 or higher.
Who cannot join
- Any condition identified through TMS safety screening that, in the judgment of a study physician, presents an unacceptable safety risk for TMS. Such conditions may include:
- A history of a serious adverse reaction during TMS treatment.
- A history of seizure.
- A history of stroke.
- A history of serious head injury or neurosurgery.
- Metal in the head outside the mouth, such as shrapnel, surgical clips, or metal fragments.
Show all 16Show fewer
- An implanted device, such as a cardiac pacemaker, cochlear implant, medical pump, or intracardiac line.
- Frequent or severe headaches.
- Another brain-related condition or an illness that caused brain injury.
- A family history of epilepsy.
- Permanent tattoos on the head or neck.
- Current recreational drug use.
- Current pregnancy or possible pregnancy.
- Use of a medication or combination of medications, a recent medication change, or medication withdrawal that, in the judgment of a study physician, presents an unacceptable safety risk, including a clinically significant increase in seizure risk.
- Current or lifetime diagnosis of bipolar I disorder, bipolar II disorder, a schizophrenia spectrum disorder, or another primary psychotic disorder.
- Active suicidal ideation with intent or plan requiring immediate clinical intervention, or another acute safety concern that cannot be safely managed within the study.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
McLean Hospital
Belmont, Massachusetts, 02478
Hakjoo Kim, PhD, 617-855-4203, hkim128@mclean.harvard.edu
Hakjoo Kim, PhD
About this study
Official title: One-Day cTBS Over the Precuneus (OcTOPUS)
The goal of this clinical trial is to learn whether two forms of one-day accelerated transcranial magnetic stimulation (TMS) can reduce depressive symptoms in adults with treatment-resistant depression. Treatment-resistant depression is depression that has not improved enough after at least two adequate antidepressant medication treatments. TMS is a non-invasive treatment that uses magnetic pulses to stimulate specific areas of the brain.
The main questions this study aims to answer are:
Read more
- Does continuous theta-burst stimulation (cTBS) targeting the precuneus reduce depressive symptoms 4 weeks after treatment compared with sham stimulation?
- Does intermittent theta-burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex reduce depressive symptoms 4 weeks after treatment compared with sham stimulation?
Researchers will compare precuneus cTBS, left dorsolateral prefrontal cortex iTBS, and sham stimulation to determine whether either active treatment reduces depressive symptoms more than sham stimulation. Participants will be randomly assigned to one of the three groups and will not be told which treatment they initially receive.
Participants will:
- Complete screening procedures and baseline assessments of depression, rumination, and cognitive function
- Receive 20 sessions of active or sham TMS during one in-person study day
- Complete follow-up assessments 1, 2, 3, and 4 weeks after the intervention
- Report any side effects or medical problems experienced during the study
Participants initially assigned to sham stimulation may choose to receive active TMS after completing the 4-week follow-up period. Those who choose this option will receive either precuneus cTBS or left dorsolateral prefrontal cortex iTBS and will complete additional follow-up assessments.
Read the detailed description
Treatment-resistant depression may involve dysfunction across distributed brain networks rather than a disturbance confined to a single brain region. The precuneus is a posterior hub of the default mode network and is involved in internally directed and self-referential processing. Altered interactions among the default mode, affective, and cognitive control networks have been implicated in depressive symptoms and rumination. In this study, precuneus continuous theta-burst stimulation (cTBS) is conceptualized as a hypothesis-driven network intervention that may modulate precuneus-centered network interactions implicated in depression.
A double-cone coil will be used to increase electric-field penetration toward the medial posteromedial cortex beneath the Pz scalp location of the international 10-20 electroencephalography system. Intermittent theta-burst stimulation (iTBS) of the left dorsolateral prefrontal cortex is included as an additional active treatment arm because this region is an established stimulation target for depression treatment. The three-arm design allows the novel precuneus target and the established left dorsolateral prefrontal cortex target to be evaluated within the same accelerated treatment framework and compared with sham stimulation.
Participants will be assigned to the three initial study groups using the minimal sufficient balance (MSB) randomization method, with sex and baseline depression severity, as measured by the Montgomery-Åsberg Depression Rating Scale, used as balancing factors. The target allocation ratio for the randomized, sham-controlled phase will be 1:1:1. Group allocation will be concealed from participants. Each active or sham intervention will consist of 20 stimulation sessions administered during a single day, with session onsets separated by approximately 30 minutes.
The primary efficacy analyses will use a longitudinal mixed-model framework to estimate treatment effects and evaluate the two prespecified active-versus-sham comparisons. The familywise type I error rate will be controlled across these two comparisons. The direct comparison between precuneus cTBS and left dorsolateral prefrontal cortex iTBS will be considered exploratory.
After completing the 4-week follow-up period, participants initially assigned to sham stimulation may elect to enter an open-label active TMS extension. Extension participants will be assigned to precuneus cTBS or left dorsolateral prefrontal cortex iTBS using the MSB method, with a target allocation ratio of 1:1. Sex and depression severity at the end of the sham-controlled phase, as measured by the Week 4 Montgomery-Åsberg Depression Rating Scale score, will be used as balancing factors. Because only a subset of participants assigned to sham stimulation is expected to enter the extension, extension analyses will be considered exploratory and hypothesis-generating.
- Conditions
- Depressive Disorder, Treatment-Resistant, Treatment Resistant Depression (TRD), Treatment Resistant Major Depression Disorder
- Being tested
- Precuneus-targeted continuous theta-burst stimulation, Left dorsolateral prefrontal cortex intermittent theta-burst stimulation, Sham transcranial magnetic stimulation
- Keywords
- Treatment-resistant depression, Accelerated transcranial magnetic stimulation, Precuneus, Dorsolateral prefrontal cortex, Continuous theta burst stimulation, Intermittent theta burst stimulation
- Medical subject headings
- Depressive Disorder, Treatment-Resistant
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Precuneus-targeted continuous theta-burst stimulationDevice
Also called Precuneus cTBS, Continuous theta-burst stimulation
Active continuous theta-burst stimulation is delivered to the Pz location of the international 10-20 EEG system to target the precuneus. Stimulation is administered with a double-cone coil at 80% of the participant's resting motor threshold. Each session consists of 600 pulses delivered over approximately 40 seconds. Participants receive 20 sessions during a single day, for a total of 12,000 pulses, with session onsets separated by approximately 30 minutes. If 80% of resting motor threshold is not tolerated, the intensity may be reduced to the highest tolerable level.
Left dorsolateral prefrontal cortex intermittent theta-burst stimulationDevice
Also called Left dlPFC iTBS, Intermittent theta-burst stimulation
Active intermittent theta-burst stimulation is delivered to the left dorsolateral prefrontal cortex. The stimulation target is identified using the Beam F3 method. Stimulation is administered with a figure-of-eight coil at 80% of the participant's resting motor threshold. Each session consists of 600 pulses delivered over approximately 3 minutes. Participants receive 20 sessions during a single day, for a total of 12,000 pulses, with session onsets separated by approximately 30 minutes. If 80% of resting motor threshold is not tolerated, the intensity may be reduced to the highest tolerable level.
Sham transcranial magnetic stimulationDevice
Also called Sham TMS, Sham intermittent theta-burst stimulation
Sham transcranial magnetic stimulation is administered at the left dorsolateral prefrontal cortex location identified using the Beam F3 method. A figure-of-eight coil is inverted so that the active surface faces away from the scalp. The stimulator is operated at 80% of the participant's resting motor threshold using the same intermittent theta-burst timing and approximate session duration as the active left dorsolateral prefrontal cortex intervention. Participants receive 20 sham sessions during a single day, with session onsets separated by approximately 30 minutes.
| Study group | Role | What they receive |
|---|---|---|
| Precuneus cTBS | Experimental | Participants receive 20 sessions of active continuous theta-burst stimulation (cTBS) targeting the Pz location of the international 10-20 EEG system during a single day. Stimulation is delivered using a double-cone coil at 80% of the participant's resting motor threshold. Each session consists of 600 pulses delivered over approximately 40 seconds, for a total of 12,000 pulses. Session onsets are separated by approximately 30 minutes. If stimulation at 80% of resting motor threshold is not tolerated, the intensity may be reduced to the highest tolerable level. Receives: Device: Precuneus-targeted continuous theta-burst stimulation |
| Left dlPFC iTBS | Experimental | Participants receive 20 sessions of active intermittent theta-burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex during a single day. The target is identified using the Beam F3 method, and stimulation is delivered using a figure-of-eight coil at 80% of the participant's resting motor threshold. Each session consists of 600 pulses delivered over approximately 3 minutes, for a total of 12,000 pulses. Session onsets are separated by approximately 30 minutes. If stimulation at 80% of resting motor threshold is not tolerated, the intensity may be reduced to the highest tolerable level. Receives: Device: Left dorsolateral prefrontal cortex intermittent theta-burst stimulation |
| Sham TMS | Sham comparator | Participants receive 20 sessions of sham TMS at the left dorsolateral prefrontal cortex location identified using the Beam F3 method during a single day. A figure-of-eight coil is inverted so that the active surface faces away from the scalp. The device is operated at 80% of the participant's resting motor threshold, and sham stimulation follows the same stimulation pattern and approximate 3-minute duration as active iTBS. Session onsets are separated by approximately 30 minutes. After completing the Week 4 assessment, participants may enter an optional open-label extension and are randomized to receive active precuneus cTBS or left dlPFC iTBS. Receives: Device: Sham transcranial magnetic stimulation |
What is being measured
The primary outcome is the main question the study is designed to answer.
Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 4
The MADRS is a clinician-administered 10-item scale used to assess the severity of depressive symptoms. Each item is scored from 0 to 6, yielding a total score ranging from 0 to 60. Higher scores indicate greater depressive symptom severity. MADRS total scores will be assessed at baseline and at Weeks 1, 2, 3, and 4 after the intervention. Post-intervention scores will be compared between treatment groups with adjustment for baseline MADRS total score. The primary treatment comparison will be conducted at Week 4.
Measured: Baseline and 1, 2, 3, and 4 weeks after the intervention
Secondary outcomes (5)
17-Item Hamilton Depression Rating Scale (HAM-D-17) Total Score Through Week 4
The HAM-D-17 is a clinician-administered 17-item scale used to assess the severity of depressive symptoms. The total score ranges from 0 to 52, with higher scores indicating greater depressive symptom severity. HAM-D-17 total scores will be assessed at baseline and at Weeks 1, 2, 3, and 4 after the intervention. Post-intervention scores will be compared between treatment groups with adjustment for baseline HAM-D-17 total score.
Measured: Baseline and 1, 2, 3, and 4 weeks after the intervention
Patient Health Questionnaire-9 (PHQ-9) Total Score Through Week 4
The PHQ-9 is a 9-item self-report measure used to assess depressive symptom severity. Each item is scored from 0 to 3, yielding a total score ranging from 0 to 27. Higher scores indicate greater depressive symptom severity. PHQ-9 total scores will be assessed at baseline and at Weeks 1, 2, 3, and 4 after the intervention. Post-intervention scores will be compared between treatment groups with adjustment for baseline PHQ-9 total score.
Measured: Baseline and 1, 2, 3, and 4 weeks after the intervention
Ruminative Responses Scale (RRS) Total Score Through Week 4
The RRS is a 22-item self-report measure used to assess the tendency to engage in ruminative responses. Each item is scored from 1 to 4, yielding a total score ranging from 22 to 88. Higher scores indicate greater levels of rumination. RRS total scores will be assessed at baseline and at Weeks 1, 2, 3, and 4 after the intervention. Post-intervention scores will be compared between treatment groups with adjustment for baseline RRS total score.
Measured: Baseline and 1, 2, 3, and 4 weeks after the intervention
Montreal Cognitive Assessment (MoCA) Total Score at Week 4
The MoCA is a clinician-administered cognitive screening measure that assesses multiple cognitive domains. The total score ranges from 0 to 30, with higher scores indicating better cognitive performance. MoCA total scores will be assessed at baseline and at Week 4 after the intervention. The Week 4 score will be compared between treatment groups with adjustment for baseline MoCA total score.
Measured: Baseline and 4 weeks after the intervention
MGH/McLean Objective Neurocognitive Assessment (MONA) Total Score at Week 4
The MONA is an objective neurocognitive assessment that evaluates multiple cognitive domains. The total score ranges from 0 to 30, with higher scores indicating better cognitive performance. MONA total scores will be assessed at baseline and at Week 4 after the intervention. The Week 4 score will be compared between treatment groups with adjustment for baseline MONA total score.
Measured: Baseline and 4 weeks after the intervention
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Aug 2026
- Study start8 Sep 2026
- Primary completion30 Jun 2027 (estimated)
- Study completion30 Jun 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Depressive Disorder, Treatment-ResistantStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- During the randomized, sham-controlled phase, participants are assigned in parallel in a 1:1:1 ratio to precuneus cTBS, left dlPFC iTBS, or sham stimulation. After completion of the 4-week randomized phase, participants initially assigned to sham may enter an optional open-label extension and are randomized in a 1:1 ratio to precuneus cTBS or left dlPFC iTBS.
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 69 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Mclean Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Hakjoo Kim, Mclean Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07758010
- Sponsor's protocol ID
- 2026P001989
- Acronym
- OcTOPUS
- Status last verified
- Sep 2026
- First submitted
- 6 Aug 2026
- Last updated
- 11 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
- Individual data sharing
- No: At this time, there is no plan to share individual participant data because external sharing of participant-level data is not included in the current informed consent and institutional data management plan. Aggregate study results will be disseminated through scientific presentations and publications. Any future sharing of de-identified data would require additional institutional and IRB review and approval.
Publications
Sendi M, Halko M, Traynor J, Brown J, Copersino M, Nickerson L, Harnett N, van Rooij S, Pizzagalli D, House S, Beaudoin F, An X, Neylan T, Clifford G, Jovanovic T, Linnstaedt S, Germine L, Bollen K, Rauch S, Haran J, Storrow A, Lewandowski C, Musey P Jr, Hendry P, Sheikh S, Jones C, Punches B, Swor R, Gentile N, Hudak L, Pascual J, Seamon M, Harris E, Pearson C, Peak D, Domeier R, Rathlev N, O'Neil B, Sergot P, Sanchez L, Bruce S, Sheridan J, Harte S, Kessler R, Koenen K, Phelps E, Salat D, Mayberg H, McLean S, Stevens J, Calhoun V, Ressler K, Dillon D. Comprehensive mapping of cognitive and emotion networks in stress, anxiety, and depression implicates the precuneus as a critical hub. Res Sq [Preprint]. 2025 Aug 26:rs.3.rs-7200801. doi: 10.21203/rs.3.rs-7200801/v1.
PubMed 40909772Kim H, Halko M, Copersino ML, Traynor J, Dillon D, Sendi M, Razafsha M, Uflacker A, Bharathan AV, Coyle M, Ganesh P, Nolan J, Parlikar RU, Pettibone T, Gunadeva N, Hur KH, Downar J, McGirr A, Ressler K, Brown J. 6 - Depression and Anxiety Symptom Change Following One-Day Ultra-Accelerated TMS Targeting dlPFC or Network-Guided Precuneus: Preliminary Findings. Transcranial Magnetic Stimulation. 2026;7(Suppl 1):100228. doi:10.1016/j.transm.2026.100228
Cole EJ, Phillips AL, Bentzley BS, Stimpson KH, Nejad R, Barmak F, Veerapal C, Khan N, Cherian K, Felber E, Brown R, Choi E, King S, Pankow H, Bishop JH, Azeez A, Coetzee J, Rapier R, Odenwald N, Carreon D, Hawkins J, Chang M, Keller J, Raj K, DeBattista C, Jo B, Espil FM, Schatzberg AF, Sudheimer KD, Williams NR. Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial. Am J Psychiatry. 2022 Feb;179(2):132-141. doi: 10.1176/appi.ajp.2021.20101429. Epub 2021 Oct 29.
PubMed 34711062Vaughn DA, Marino B, Engelbertson A, Dojnov A, Johnson L, Stine M, Vila-Rodriguez F, Weiss N, Nanos G, Downar J. Real-world effectiveness of a single-day regimen for transcranial magnetic stimulation using Optimized, Neuroplasticity-Enhanced techniques in Depression (ONE-D): An open-label case series. Transcranial Magnetic Stimulation. 2025;5:100200. doi:10.1016/j.transm.2025.100200
Study at a glance
From the registry record, last updated by the sponsor on 11 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- One-Day cTBS Over the Precuneus (OcTOPUS)
- ClinicalTrials.gov ID
- NCT07758010
- Acronym / sponsor ID
- OcTOPUS / 2026P001989
- Conditions
- Depressive Disorder, Treatment-Resistant, Treatment Resistant Depression (TRD), Treatment Resistant Major Depression Disorder
- Keywords
- Treatment-resistant depression, Accelerated transcranial magnetic stimulation, Precuneus, Dorsolateral prefrontal cortex, Continuous theta burst stimulation, Intermittent theta burst stimulation
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 69 participants (estimated)
- Lead sponsor
- Mclean HospitalUniversity, hospital or other
- Study start
- 8 Sep 2026 (actual)
- Primary completion
- 30 Jun 2027 (estimated)
- Study completion
- 30 Jun 2027 (estimated)
- First posted
- 11 Aug 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The goal of this clinical trial is to learn whether two forms of one-day accelerated transcranial magnetic stimulation (TMS) can reduce depressive symptoms in adults with treatment-resistant depression. Treatment-resistant depression is depression that has not improved enough after at least two adequate antidepressant medication treatments. TMS is a non-invasive treatment that uses magnetic pulses to stimulate specific areas of the brain.
The main questions this study aims to answer are:
- Does continuous theta-burst stimulation (cTBS) targeting the precuneus reduce depressive symptoms 4 weeks after treatment compared with sham stimulation?
- Does intermittent theta-burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex reduce depressive symptoms 4 weeks after treatment compared with sham stimulation?
Researchers will compare precuneus cTBS, left dorsolateral prefrontal cortex iTBS, and sham stimulation to determine whether either active treatment reduces depressive symptoms more than sham stimulation. Participants will be randomly assigned to one of the three groups and will not be told which treatment they initially receive.
Participants will:
- Complete screening procedures and baseline assessments of depression, rumination, and cognitive function
- Receive 20 sessions of active or sham TMS during one in-person study day
- Complete follow-up assessments 1, 2, 3, and 4 weeks after the intervention
- Report any side effects or medical problems experienced during the study
Participants initially assigned to sham stimulation may choose to receive active TMS after completing the 4-week follow-up period. Those who choose this option will receive either precuneus cTBS or left dorsolateral prefrontal cortex iTBS and will complete additional follow-up assessments.
Detailed description
Treatment-resistant depression may involve dysfunction across distributed brain networks rather than a disturbance confined to a single brain region. The precuneus is a posterior hub of the default mode network and is involved in internally directed and self-referential processing. Altered interactions among the default mode, affective, and cognitive control networks have been implicated in depressive symptoms and rumination. In this study, precuneus continuous theta-burst stimulation (cTBS) is conceptualized as a hypothesis-driven network intervention that may modulate precuneus-centered network interactions implicated in depression.
A double-cone coil will be used to increase electric-field penetration toward the medial posteromedial cortex beneath the Pz scalp location of the international 10-20 electroencephalography system. Intermittent theta-burst stimulation (iTBS) of the left dorsolateral prefrontal cortex is included as an additional active treatment arm because this region is an established stimulation target for depression treatment. The three-arm design allows the novel precuneus target and the established left dorsolateral prefrontal cortex target to be evaluated within the same accelerated treatment framework and compared with sham stimulation.
Participants will be assigned to the three initial study groups using the minimal sufficient balance (MSB) randomization method, with sex and baseline depression severity, as measured by the Montgomery-Åsberg Depression Rating Scale, used as balancing factors. The target allocation ratio for the randomized, sham-controlled phase will be 1:1:1. Group allocation will be concealed from participants. Each active or sham intervention will consist of 20 stimulation sessions administered during a single day, with session onsets separated by approximately 30 minutes.
The primary efficacy analyses will use a longitudinal mixed-model framework to estimate treatment effects and evaluate the two prespecified active-versus-sham comparisons. The familywise type I error rate will be controlled across these two comparisons. The direct comparison between precuneus cTBS and left dorsolateral prefrontal cortex iTBS will be considered exploratory.
After completing the 4-week follow-up period, participants initially assigned to sham stimulation may elect to enter an open-label active TMS extension. Extension participants will be assigned to precuneus cTBS or left dorsolateral prefrontal cortex iTBS using the MSB method, with a target allocation ratio of 1:1. Sex and depression severity at the end of the sham-controlled phase, as measured by the Week 4 Montgomery-Åsberg Depression Rating Scale score, will be used as balancing factors. Because only a subset of participants assigned to sham stimulation is expected to enter the extension, extension analyses will be considered exploratory and hypothesis-generating.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 3
- Model description
- During the randomized, sham-controlled phase, participants are assigned in parallel in a 1:1:1 ratio to precuneus cTBS, left dlPFC iTBS, or sham stimulation. After completion of the 4-week randomized phase, participants initially assigned to sham may enter an optional open-label extension and are randomized in a 1:1 ratio to precuneus cTBS or left dlPFC iTBS.
| Arm | Type | Receives |
|---|---|---|
| Precuneus cTBS | Experimental | Device: Precuneus-targeted continuous theta-burst stimulationParticipants receive 20 sessions of active continuous theta-burst stimulation (cTBS) targeting the Pz location of the international 10-20 EEG system during a single day. Stimulation is delivered using a double-cone coil at 80% of the participant's resting motor threshold. Each session consists of 600 pulses delivered over approximately 40 seconds, for a total of 12,000 pulses. Session onsets are separated by approximately 30 minutes. If stimulation at 80% of resting motor threshold is not tolerated, the intensity may be reduced to the highest tolerable level. |
| Left dlPFC iTBS | Experimental | Device: Left dorsolateral prefrontal cortex intermittent theta-burst stimulationParticipants receive 20 sessions of active intermittent theta-burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex during a single day. The target is identified using the Beam F3 method, and stimulation is delivered using a figure-of-eight coil at 80% of the participant's resting motor threshold. Each session consists of 600 pulses delivered over approximately 3 minutes, for a total of 12,000 pulses. Session onsets are separated by approximately 30 minutes. If stimulation at 80% of resting motor threshold is not tolerated, the intensity may be reduced to the highest tolerable level. |
| Sham TMS | Sham comparator | Device: Sham transcranial magnetic stimulationParticipants receive 20 sessions of sham TMS at the left dorsolateral prefrontal cortex location identified using the Beam F3 method during a single day. A figure-of-eight coil is inverted so that the active surface faces away from the scalp. The device is operated at 80% of the participant's resting motor threshold, and sham stimulation follows the same stimulation pattern and approximate 3-minute duration as active iTBS. Session onsets are separated by approximately 30 minutes. After completing the Week 4 assessment, participants may enter an optional open-label extension and are randomized to receive active precuneus cTBS or left dlPFC iTBS. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Age 18 years or older.
- Able to speak, read, and understand English sufficiently to complete the study assessments and provide informed consent independently.
- Diagnosis of major depressive disorder according to DSM-5-TR criteria, confirmed by a qualified physician.
- Treatment-resistant depression, defined as an inadequate response to at least two adequate trials of antidepressant pharmacotherapy.
- Patient Health Questionnaire-9 (PHQ-9) total score of 10 or higher.
Key exclusion criteria (16 listed)
- Any condition identified through TMS safety screening that, in the judgment of a study physician, presents an unacceptable safety risk for TMS. Such conditions may include:
- A history of a serious adverse reaction during TMS treatment.
- A history of seizure.
- A history of stroke.
- A history of serious head injury or neurosurgery.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Precuneus-targeted continuous theta-burst stimulationAlso: Precuneus cTBS, Continuous theta-burst stimulationActive continuous theta-burst stimulation is delivered to the Pz location of the international 10-20 EEG system to target the precuneus. Stimulation is administered with a double-cone coil at 80% of the participant's resting motor threshold. Each session consists of 600 pulses delivered over approximately 40 seconds. Participants receive 20 sessions during a single day, for a total of 12,000 pulses, with session onsets separated by approximately 30 minutes. If 80% of resting motor threshold is not tolerated, the intensity may be reduced to the highest tolerable level. | Device | Precuneus cTBS |
| Left dorsolateral prefrontal cortex intermittent theta-burst stimulationAlso: Left dlPFC iTBS, Intermittent theta-burst stimulationActive intermittent theta-burst stimulation is delivered to the left dorsolateral prefrontal cortex. The stimulation target is identified using the Beam F3 method. Stimulation is administered with a figure-of-eight coil at 80% of the participant's resting motor threshold. Each session consists of 600 pulses delivered over approximately 3 minutes. Participants receive 20 sessions during a single day, for a total of 12,000 pulses, with session onsets separated by approximately 30 minutes. If 80% of resting motor threshold is not tolerated, the intensity may be reduced to the highest tolerable level. | Device | Left dlPFC iTBS |
| Sham transcranial magnetic stimulationAlso: Sham TMS, Sham intermittent theta-burst stimulationSham transcranial magnetic stimulation is administered at the left dorsolateral prefrontal cortex location identified using the Beam F3 method. A figure-of-eight coil is inverted so that the active surface faces away from the scalp. The stimulator is operated at 80% of the participant's resting motor threshold using the same intermittent theta-burst timing and approximate session duration as the active left dorsolateral prefrontal cortex intervention. Participants receive 20 sham sessions during a single day, with session onsets separated by approximately 30 minutes. | Device | Sham TMS |
Primary outcome
Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 4
Time frame: Baseline and 1, 2, 3, and 4 weeks after the intervention
The MADRS is a clinician-administered 10-item scale used to assess the severity of depressive symptoms. Each item is scored from 0 to 6, yielding a total score ranging from 0 to 60. Higher scores indicate greater depressive symptom severity. MADRS total scores will be assessed at baseline and at Weeks 1, 2, 3, and 4 after the intervention. Post-intervention scores will be compared between treatment groups with adjustment for baseline MADRS total score. The primary treatment comparison will be conducted at Week 4.
5 secondary outcomes
17-Item Hamilton Depression Rating Scale (HAM-D-17) Total Score Through Week 4
Time frame: Baseline and 1, 2, 3, and 4 weeks after the intervention
Patient Health Questionnaire-9 (PHQ-9) Total Score Through Week 4
Time frame: Baseline and 1, 2, 3, and 4 weeks after the intervention
Ruminative Responses Scale (RRS) Total Score Through Week 4
Time frame: Baseline and 1, 2, 3, and 4 weeks after the intervention
Montreal Cognitive Assessment (MoCA) Total Score at Week 4
Time frame: Baseline and 4 weeks after the intervention
MGH/McLean Objective Neurocognitive Assessment (MONA) Total Score at Week 4
Time frame: Baseline and 4 weeks after the intervention
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Sep 2026.
- Background: PubMed 40909772Sendi M, Halko M, Traynor J, Brown J, Copersino M, Nickerson L, Harnett N, van Rooij S, Pizzagalli D, House S, Beaudoin F, An X, Neylan T, Clifford G, Jovanovic T, Linnstaedt S, Germine L, Bollen K, Rauch S, Haran J, Storrow A, Lewandowski C, Musey P Jr, Hendry P, Sheikh S, Jones C, Punches B, Swor R, Gentile N, Hudak L, Pascual J, Seamon M, Harris E, Pearson C, Peak D, Domeier R, Rathlev N, O'Neil B, Sergot P, Sanchez L, Bruce S, Sheridan J, Harte S, Kessler R, Koenen K, Phelps E, Salat D, Mayberg H, McLean S, Stevens J, Calhoun V, Ressler K, Dillon D. Comprehensive mapping of cognitive and emotion networks in stress, anxiety, and depression implicates the precuneus as a critical hub. Res Sq [Preprint]. 2025 Aug 26:rs.3.rs-7200801. doi: 10.21203/rs.3.rs-7200801/v1.
- BackgroundKim H, Halko M, Copersino ML, Traynor J, Dillon D, Sendi M, Razafsha M, Uflacker A, Bharathan AV, Coyle M, Ganesh P, Nolan J, Parlikar RU, Pettibone T, Gunadeva N, Hur KH, Downar J, McGirr A, Ressler K, Brown J. 6 - Depression and Anxiety Symptom Change Following One-Day Ultra-Accelerated TMS Targeting dlPFC or Network-Guided Precuneus: Preliminary Findings. Transcranial Magnetic Stimulation. 2026;7(Suppl 1):100228. doi:10.1016/j.transm.2026.100228
- Background: PubMed 34711062Cole EJ, Phillips AL, Bentzley BS, Stimpson KH, Nejad R, Barmak F, Veerapal C, Khan N, Cherian K, Felber E, Brown R, Choi E, King S, Pankow H, Bishop JH, Azeez A, Coetzee J, Rapier R, Odenwald N, Carreon D, Hawkins J, Chang M, Keller J, Raj K, DeBattista C, Jo B, Espil FM, Schatzberg AF, Sudheimer KD, Williams NR. Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial. Am J Psychiatry. 2022 Feb;179(2):132-141. doi: 10.1176/appi.ajp.2021.20101429. Epub 2021 Oct 29.
- BackgroundVaughn DA, Marino B, Engelbertson A, Dojnov A, Johnson L, Stine M, Vila-Rodriguez F, Weiss N, Nanos G, Downar J. Real-world effectiveness of a single-day regimen for transcranial magnetic stimulation using Optimized, Neuroplasticity-Enhanced techniques in Depression (ONE-D): An open-label case series. Transcranial Magnetic Stimulation. 2025;5:100200. doi:10.1016/j.transm.2025.100200
- Individual participant dataSharing planned: No. At this time, there is no plan to share individual participant data because external sharing of participant-level data is not included in the current informed consent and institutional data management plan. Aggregate study results will be disseminated through scientific presentations and publications. Any future sharing of de-identified data would require additional institutional and IRB review and approval.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Precuneus-targeted continuous theta-burst stimulation and Left dorsolateral prefrontal cortex intermittent theta-burst stimulation in people with Depressive Disorder, Treatment-Resistant and Treatment Resistant Depression (TRD), run by Mclean Hospital at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 11 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Hakjoo Kim Kim, Ph.D. (979-777-0679, khj213@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score at Week 4 (time frame: Baseline and 1, 2, 3, and 4 weeks after the intervention). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07758010, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Sep 2026.