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The research study is being conducted to test whether using high dose spaced theta-burst rTMS (a form of transcranial magnetic stimulation) produces a significant reduction in depressive symptoms compared with sham. This project will recruit patients aged 18-70 with symptoms of bipolar depression who have failed (or not shown signs of improvement) after at least two prior treatments.
The research study is being conducted to test whether using high dose spaced theta-burst rTMS (a form of transcranial magnetic stimulation) produces a significant reduction in depressive symptoms compared with sham. This project will recruit patients aged 18-70 with symptoms of bipolar depression who have failed (or not shown signs of improvement) after at least two prior treatments. The null hypothesis is that there will be no difference in reductions in depressive symptoms by the end of a five-day treatment period. The alternative hypothesis is that, compared with sham, active TMS will result in a greater reduction in depressive symptoms by the end of the treatment period. Participants will be randomly assigned to active or sham conditions: 50% to active and 50% to sham.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Active Transcranial Magnetic Stimulation | Active Comparator | Active Intensive iTBS involves intermittent theta-burst stimulation (iTBS), a patterned form of repetitive transcranial magnetic stimulation (rTMS) over the left dorsal lateral prefrontal cortex (L-DLPFC). |
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| Sham Transcranial Magnetic Stimulation | Sham Comparator | Sham Intensive iTBS involves using the coil's electric stimulation functionality that allows for the delivery of a brief electric pulse to the scalp simultaneous to the TMS pulse, which mimics the scalp sensation from active stimulation. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Intensive intermittent theta-burst stimulation (iTBS) | Device | Intensive iTBS is intermittent theta-burst stimulation (iTBS), a patterned form of repetitive transcranial magnetic stimulation (rTMS) over a specific brain region. |
| Measure | Description | Time Frame |
|---|---|---|
| Clinical Efficacy of High Dose Spaced Theta Burst (HDS-TBS) | The primary outcome will be based on the set of repeated Montgomery Asberg Depression scores (10 items rated on a 0-6 scale, 0-60 possible score range, with higher scores indicating greater depressive symptomology), obtained at baseline, on each of the five treatment days and post TMS. | Through study completion, approximately 1 week |
| Measure | Description | Time Frame |
|---|---|---|
| Relationship Between Change in Brain Resting State Functional Connectivity and Treatment Effects | The secondary outcome will be the change in the correlation between the dorsolateral prefrontal cortex (DLPFC) and the subgenual anterior cingulate cortex (sgACC) with the Montgomery-Åsberg Depression Rating Scale (MADRS), as assessed through MRI scans conducted at baseline and post-stimulation. Additionally, the change in the correlation within the entire Default Mode Network (DMN) intraconnectivity and MADRS will be measured for both groups (Active vs. Sham). The correlation is measured on a scale from -1 to +1, where -1 indicates the highest negative anticorrelation, +1 represents the highest positive correlation, and 0 signifies no correlation. MADRS is used to assess the clinical effect. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Yvette Sheline, MD | University of Pennsylvania | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Center for Neuromodulation in Depression and Stress, University of Pennsylvania | Philadelphia | Pennsylvania | 19104 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38985492 | Derived | Sheline YI, Makhoul W, Batzdorf AS, Nitchie FJ, Lynch KG, Cash R, Balderston NL. Accelerated Intermittent Theta-Burst Stimulation and Treatment-Refractory Bipolar Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2024 Sep 1;81(9):936-941. doi: 10.1001/jamapsychiatry.2024.1787. |
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Thirty-four participants were assessed for eligibility. Of these, eight did not meet the inclusion criteria and were excluded: three participants displayed manic symptoms at screening, four did not meet the criteria for major depression, and one did not meet the criteria for bipolar disorder.
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| ID | Title | Description |
|---|---|---|
| FG000 | Active Transcranial Magnetic Stimulation | Active Intensive iTBS involves intermittent theta-burst stimulation (iTBS), a patterned form of repetitive transcranial magnetic stimulation (rTMS) over the left dorsal lateral prefrontal cortex (L-DLPFC). Intensive intermittent theta-burst stimulation (iTBS): Intensive iTBS is intermittent theta-burst stimulation (iTBS), a patterned form of repetitive transcranial magnetic stimulation (rTMS) over a specific brain region. Active TMS was administered every day for five days over the course of nine hours. Every hour, the participant received nine minutes of TMS treatment for a total of 10 sessions a day. |
| FG001 | Sham Transcranial Magnetic Stimulation | Sham Intensive iTBS involves using the coil's electric stimulation functionality that allows for the delivery of a brief electric pulse to the scalp simultaneous to the TMS pulse, which mimics the scalp sensation from active stimulation. Intensive intermittent theta-burst stimulation (iTBS): Intensive iTBS is intermittent theta-burst stimulation (iTBS), a patterned form of repetitive transcranial magnetic stimulation (rTMS) over a specific brain region. Sham TMS was administered every day for five days over the course of nine hours. Every hour, the participant received nine minutes of sham TMS treatment and total of 10 sessions a day. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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Thirteen participants were randomized to receive active TMS, and thirteen were randomized to receive sham TMS. One participant from each group withdrew from the study due to time commitment constraints, resulting in their exclusion from the analysis. Therefore, twelve participants from each group completed the study and were included in the final analysis.
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| ID | Title | Description |
|---|---|---|
| BG000 | Active Transcranial Magnetic Stimulation | Active Intensive iTBS involves intermittent theta-burst stimulation (iTBS), a patterned form of repetitive transcranial magnetic stimulation (rTMS) over the left dorsal lateral prefrontal cortex (L-DLPFC). Intensive intermittent theta-burst stimulation (iTBS): Intensive iTBS is intermittent theta-burst stimulation (iTBS), a patterned form of repetitive transcranial magnetic stimulation (rTMS) over a specific brain region. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Thirteen participants were randomized to receive active TMS, and thirteen were randomized to receive sham TMS. One participant from each group withdrew from the study due to time commitment constraints, resulting in their exclusion from the analysis. Therefore, twelve participants from each group completed the study and were included in the final analysis |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Clinical Efficacy of High Dose Spaced Theta Burst (HDS-TBS) | The primary outcome will be based on the set of repeated Montgomery Asberg Depression scores (10 items rated on a 0-6 scale, 0-60 possible score range, with higher scores indicating greater depressive symptomology), obtained at baseline, on each of the five treatment days and post TMS. | Thirteen participants (age between 18-70)were randomized to receive active TMS, and thirteen were randomized to receive sham TMS. One participant from each group withdrew from the study due to time commitment constraints, resulting in their exclusion from the analysis. Therefore, twelve participants from each group completed the study and were included in the final analysis. | Posted | Mean | Standard Deviation | score on a scale | Through study completion, approximately 1 week |
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For each participant, adverse events were recorded from baseline to the end of participation, typically about 6 weeks. This randomized clinical trial was conducted from March 2022 to February 2024, with all adverse event data collected throughout this period.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Active Transcranial Magnetic Stimulation | Active Intensive iTBS involves intermittent theta-burst stimulation (iTBS), a patterned form of repetitive transcranial magnetic stimulation (rTMS) over the left dorsal lateral prefrontal cortex (L-DLPFC). Intensive intermittent theta-burst stimulation (iTBS): Intensive iTBS is intermittent theta-burst stimulation (iTBS), a patterned form of repetitive transcranial magnetic stimulation (rTMS) over a specific brain region. Active TMS was administered every day for five days over the course of nine hours. Every hour, the participant received nine minutes of sham TMS treatment and total of 10 sessions a day. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | Non-systematic Assessment | A mild headache occurred after the participant received TMS. It was of low intensity and resolved within a few hours without any intervention. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Walid Makhoul | University of Pennsylvania | 215-573-2409 | walid.makhoul@pennmedicine.upenn.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Sep 20, 2022 | Jan 2, 2025 | Prot_SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | Oct 10, 2023 | Jan 2, 2025 | ICF_002.pdf |
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| ID | Term |
|---|---|
| D001714 | Bipolar Disorder |
| D061218 | Depressive Disorder, Treatment-Resistant |
| ID | Term |
|---|---|
| D000068105 | Bipolar and Related Disorders |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
| D003866 | Depressive Disorder |
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| Upon study completion, approximately 1 week |
| BG001 | Sham Transcranial Magnetic Stimulation | Sham Intensive iTBS involves using the coil's electric stimulation functionality that allows for the delivery of a brief electric pulse to the scalp simultaneous to the TMS pulse, which mimics the scalp sensation from active stimulation. Intensive intermittent theta-burst stimulation (iTBS): Intensive iTBS is intermittent theta-burst stimulation (iTBS), a patterned form of repetitive transcranial magnetic stimulation (rTMS) over a specific brain region. |
| BG002 | Total | Total of all reporting groups |
| Mean |
| Standard Deviation |
| years |
|
| Sex: Female, Male | Thirteen participants were randomized to receive active TMS, and thirteen were randomized to receive sham TMS. One participant from each group withdrew from the study due to time commitment constraints, resulting in their exclusion from the analysis. Therefore, twelve participants from each group completed the study and were included in the final analysis. | Count of Participants | Participants |
|
| Race (NIH/OMB) | Thirteen participants were randomized to receive active TMS, and thirteen were randomized to receive sham TMS. One participant from each group withdrew from the study due to time commitment constraints, resulting in their exclusion from the analysis. Therefore, twelve participants from each group completed the study and were included in the final analysis | Count of Participants | Participants |
|
| OG001 | Sham Transcranial Magnetic Stimulation | Sham Intensive iTBS involves using the coil's electric stimulation functionality that allows for the delivery of a brief electric pulse to the scalp simultaneous to the TMS pulse, which mimics the scalp sensation from active stimulation. Intensive intermittent theta-burst stimulation (iTBS): Intensive iTBS is intermittent theta-burst stimulation (iTBS), a patterned form of repetitive transcranial magnetic stimulation (rTMS) over a specific brain region. Sham TMS was administered every day for five days over the course of nine hours. Every hour, the participant received nine minutes of sham TMS treatment and total of 10 sessions a day. |
|
|
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| Secondary | Relationship Between Change in Brain Resting State Functional Connectivity and Treatment Effects | The secondary outcome will be the change in the correlation between the dorsolateral prefrontal cortex (DLPFC) and the subgenual anterior cingulate cortex (sgACC) with the Montgomery-Åsberg Depression Rating Scale (MADRS), as assessed through MRI scans conducted at baseline and post-stimulation. Additionally, the change in the correlation within the entire Default Mode Network (DMN) intraconnectivity and MADRS will be measured for both groups (Active vs. Sham). The correlation is measured on a scale from -1 to +1, where -1 indicates the highest negative anticorrelation, +1 represents the highest positive correlation, and 0 signifies no correlation. MADRS is used to assess the clinical effect. | Thirteen participants (age between 18-70) were randomized to receive active TMS, and thirteen were randomized to receive sham TMS. One participant from each group withdrew from the study due to time commitment constraints, resulting in their exclusion from the analysis. Therefore, twelve participants from each group completed the study and were included in the final analysis. | Posted | Mean | Full Range | correlation coefficient | Upon study completion, approximately 1 week |
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| 0 |
| 13 |
| 0 |
| 13 |
| 6 |
| 13 |
| EG001 | Sham Transcranial Magnetic Stimulation | Sham Intensive iTBS involves using the coil's electric stimulation functionality that allows for the delivery of a brief electric pulse to the scalp simultaneous to the TMS pulse, which mimics the scalp sensation from active stimulation. Intensive intermittent theta-burst stimulation (iTBS): Intensive iTBS is intermittent theta-burst stimulation (iTBS), a patterned form of repetitive transcranial magnetic stimulation (rTMS) over a specific brain region. Sham TMS was administered every day for five days over the course of nine hours. Every hour, the participant received nine minutes of sham TMS treatment and total of 10 sessions a day. | 0 | 13 | 0 | 13 | 2 | 13 |
|
| dizziness | Nervous system disorders | Non-systematic Assessment |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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