Bipolar Depression, Treatment Resistant Depression
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DEVICEIntensive 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.
Sponsors
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Bipolar depression (BP I and BP II) by Diagnostic and Statistical Manual 5 (DSM 5) criteria * Age 18-70 * Right or left handed * All genders * Treatment resistant depression, as in they must have treatment resistant depression with 2 or more prior antidepressant trials that have failed to produce a response (\> 50% reduction in symptoms) using ATHF criteria * Able to provide informed consent to participate in the study * Must be on a stable medication regimen, requiring at least one mood stabilizer * Depression severity as represented by scoring at least 20 on Montgomery-Asberg Depression Rating Scale (MADRS)
Exclusion criteria
* No current substance abuse disorder for the past 6 months (previous substance abuse not exclusionary) * Any psychotic disorder or current active psychotic symptoms (personality disorders not exclusionary unless in the opinion of the referring psychiatrist it would jeopardize participation) * No dementia or other major neurological disorders * Not having depression as primary disorder * No major medical illness, for example metastatic cancer, end stage renal disease * Not able to verify contact information. Participants must be able to follow through with the study & must have verified contact information and at least one verified contact * Pregnancy. While there are no known risks to a fetus this is a new use of TMS, which has not been tested, thus pregnancy is exclusionary * Score on Young Mania Rating Scale (YMRS) greater than 12 (patients with mixed features have been shown not to respond well to TMS treatment) * Rapid cycling Bipolar illness (patients with \> 4 mood episodes within the past year will be excluded, as they have a higher risk of switch to mania) * Any implants, conditions, or contraindications that would be deemed unsafe for TMS or MRI * Currently using benzodiazepines (such as lorazepam) with a dose \>1 mg per day or equivalent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Efficacy of High Dose Spaced Theta Burst (HDS-TBS) | Through study completion, approximately 1 week | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relationship Between Change in Brain Resting State Functional Connectivity and Treatment Effects | Upon study completion, approximately 1 week | 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. |
Countries
United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 13 |
| 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. | 13 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Sham Transcranial Magnetic Stimulation | Total | Active Transcranial Magnetic Stimulation |
|---|---|---|---|
| Age, Continuous | 44 years STANDARD_DEVIATION 19.2 | 44.5 years STANDARD_DEVIATION 16.8 | 45 years STANDARD_DEVIATION 14.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 18 Participants | 9 Participants |
| Sex: Female, Male Female | 6 Participants | 12 Participants | 6 Participants |
| Sex: Female, Male Male | 6 Participants | 12 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 13 |
| other Total, other adverse events | 6 / 13 | 2 / 13 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 |
Outcome results
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.
Time frame: Through study completion, approximately 1 week
Population: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active Transcranial Magnetic Stimulation | Clinical Efficacy of High Dose Spaced Theta Burst (HDS-TBS) | Day 1 | 26.7 score on a scale | Standard Deviation 2.27 |
| Active Transcranial Magnetic Stimulation | Clinical Efficacy of High Dose Spaced Theta Burst (HDS-TBS) | Day 3 | 16.3 score on a scale | Standard Deviation 7.65 |
| Active Transcranial Magnetic Stimulation | Clinical Efficacy of High Dose Spaced Theta Burst (HDS-TBS) | treatment end | 10.5 score on a scale | Standard Deviation 6.76 |
| Active Transcranial Magnetic Stimulation | Clinical Efficacy of High Dose Spaced Theta Burst (HDS-TBS) | Day 4 | 11.3 score on a scale | Standard Deviation 7.23 |
| Active Transcranial Magnetic Stimulation | Clinical Efficacy of High Dose Spaced Theta Burst (HDS-TBS) | Day 2 | 20.3 score on a scale | Standard Deviation 6.27 |
| Active Transcranial Magnetic Stimulation | Clinical Efficacy of High Dose Spaced Theta Burst (HDS-TBS) | Day 5 | 10.2 score on a scale | Standard Deviation 7.56 |
| Active Transcranial Magnetic Stimulation | Clinical Efficacy of High Dose Spaced Theta Burst (HDS-TBS) | baseline | 30.4 score on a scale | Standard Deviation 4.81 |
| Sham Transcranial Magnetic Stimulation | Clinical Efficacy of High Dose Spaced Theta Burst (HDS-TBS) | Day 5 | 25.3 score on a scale | Standard Deviation 6.74 |
| Sham Transcranial Magnetic Stimulation | Clinical Efficacy of High Dose Spaced Theta Burst (HDS-TBS) | baseline | 28 score on a scale | Standard Deviation 5.41 |
| Sham Transcranial Magnetic Stimulation | Clinical Efficacy of High Dose Spaced Theta Burst (HDS-TBS) | treatment end | 25.3 score on a scale | Standard Deviation 6.74 |
| Sham Transcranial Magnetic Stimulation | Clinical Efficacy of High Dose Spaced Theta Burst (HDS-TBS) | Day 1 | 26.8 score on a scale | Standard Deviation 6.19 |
| Sham Transcranial Magnetic Stimulation | Clinical Efficacy of High Dose Spaced Theta Burst (HDS-TBS) | Day 2 | 25.7 score on a scale | Standard Deviation 5.55 |
| Sham Transcranial Magnetic Stimulation | Clinical Efficacy of High Dose Spaced Theta Burst (HDS-TBS) | Day 3 | 24.3 score on a scale | Standard Deviation 5.94 |
| Sham Transcranial Magnetic Stimulation | Clinical Efficacy of High Dose Spaced Theta Burst (HDS-TBS) | Day 4 | 24.8 score on a scale | Standard Deviation 4.81 |
p-value: <0.00195% CI: [-19.94, -9.56]t-test, 2 sided
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.
Time frame: Upon study completion, approximately 1 week
Population: 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.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Active Transcranial Magnetic Stimulation | Relationship Between Change in Brain Resting State Functional Connectivity and Treatment Effects | Correlation between connectivity between (DLPFC) vs (sgACC) and MADRS. | -0.63 correlation coefficient |
| Active Transcranial Magnetic Stimulation | Relationship Between Change in Brain Resting State Functional Connectivity and Treatment Effects | Correlation between the whole Default Mode Network (DMN) intraconnectivity and MADRS | 0.15 correlation coefficient |
| Sham Transcranial Magnetic Stimulation | Relationship Between Change in Brain Resting State Functional Connectivity and Treatment Effects | Correlation between connectivity between (DLPFC) vs (sgACC) and MADRS. | 0.33 correlation coefficient |
| Sham Transcranial Magnetic Stimulation | Relationship Between Change in Brain Resting State Functional Connectivity and Treatment Effects | Correlation between the whole Default Mode Network (DMN) intraconnectivity and MADRS | -0.43 correlation coefficient |
Comparison: Z-transformed Pearson's r values of average voxel-wise connectivity within the DMNp-value: 0.04t-test, 2 sided