An interventional study of Precuneus-targeted continuous theta-burst stimulation and Left dorsolateral prefrontal cortex intermittent theta-burst stimulation in Depressive Disorder, Treatment-Resistant, Treatment Resistant Depression (TRD) and Treatment Resistant Major Depression Disorder, sponsored by Mclean Hospital. Recruiting at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-09-11.
Sponsored by Mclean Hospital · Not applicable, Interventional, and Treatment
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:
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:
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.
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.
448 studies on the registry are indexed under Depressive Disorder, Treatment-Resistant; 147 are open to participants now.
This study's planned enrollment of 69 is above the median of 59 across 372 interventional studies indexed under Depressive Disorder, Treatment-Resistant.
Browse Depressive Disorder, Treatment-Resistant studies →Mclean Hospital is the lead sponsor of 185 studies on the registry; 32 are open to participants now.
Of its 15 completed or terminated interventional studies of FDA-regulated products, 12 (80%) have results posted.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
The American Psychiatric Association’s manual of mental health diagnoses. DSM-5 (2013, revised as DSM-5-TR in 2022) replaced DSM-IV, and some studies still name the older edition. “Meets DSM criteria for …” means diagnosed by that edition’s diagnostic criteria, usually by a clinician in an interview.
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
DSM diagnostic criteria
The American Psychiatric Association’s manual of mental health diagnoses. DSM-5 (2013, revised as DSM-5-TR in 2022) replaced DSM-IV, and some studies still name the older edition. “Meets DSM criteria for …” means diagnosed by that edition’s diagnostic criteria, usually by a clinician in an interview.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Clinically significant
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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.
Device: Precuneus-targeted continuous theta-burst stimulation
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.
Device: Left dorsolateral prefrontal cortex intermittent theta-burst stimulation
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.
Device: Sham transcranial magnetic 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.
Also known as: Precuneus cTBS, Continuous 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.
Also known as: Left dlPFC iTBS, 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.
Also known as: Sham TMS, Sham intermittent theta-burst stimulation
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.
Time frame: Baseline and 1, 2, 3, and 4 weeks after the intervention
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline and 4 weeks after the intervention
Plan to share: 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.
Started Sep 2026 (actual). Primary completion is estimated for Jun 2027, 9 months after the start.
Of 135 non-industry interventional studies with no phase under Depressive Disorder, Treatment-Resistant, half reached primary completion within 42 months of starting (the median), counting those still running; a quarter within 22 and three quarters within 79. This study's planned 9 months is below that.
Counting every sponsor, half of 139 studies reached it within 50 months; a quarter within 22 and three quarters within 88.
How these figures are worked out, and which studies are left out of them.
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Depressive Disorder, Treatment-Resistant →