Depression, Major Depressive Disorder
Conditions
Brief summary
The overarching goal of this research program is to elucidate causal and directional neural network- level abnormalities in depression, and how they are modulated by an individually-tailored, circuit-directed intervention. By using concurrent TMS and fMRI, the investigators can overcome a major limitation of neuroimaging - the inability to demonstrate causality. The investigators' findings will serve as a platform for future studies wherein TMS treatment can be directly guided by the investigators' ability to image and causally manipulate specific neural networks. Aim 1: To examine causal interactions between two major brain networks in depression. Aim 2: To examine the impact of antidepressant TMS on causal network abnormalities in depression. Hypothesis 1: Depressed subjects will show blunted responses, compared to healthy controls, in two targeted and interacting networks, using concurrent transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI). Hypothesis 2: Treatment of patients with high-frequency repetitive TMS (rTMS) will result in normalization of baseline network-level deficits, and be predicted by degree of baseline network abnormalities.
Detailed description
This study has a single primary outcome measure and other measures are exploratory. Previous versions of this study record incorrectly listed some exploratory outcome measures as secondary.
Interventions
DEVICErTMS Treatment
MRI-compatible TMS stimulator
DEVICESham rTMS Treatment
Sponsors
The Dana Foundation
National Institute of Mental Health (NIMH)
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Men and women, ages 18 to 50 * Depression assessed through phone screen * Must comprehend English well to ensure adequate comprehension of the fMRI and TMS instructions, and of clinical scales * Has failed \>1 previous adequate antidepressant medication trials * Right-handed * No current or history of neurological disorders * No seizure disorder or risk of seizures
Exclusion criteria
* Any contraindication to being scanned in the 3T scanners at the Lucas Center or CNI such as having a pacemaker or implanted device that has not been cleared for scanning at the Lucas Center or CNI * Any unstable medical condition, any significant CNS neurological condition such as stroke, seizure, tumor, hemorrhage, multiple sclerosis, etc * Current rTMS treatment or prior treatment failure with rTMS * Current electroconvulsive therapy (ECT) or prior treatment failure with ECT * Currently pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinician Administered HAM-D | Baseline; Day 10; Day 20 | The Hamilton Depression Rating Scale (HAM-D) is a 24-item clinician-administered assessment utilized as a way of determining a patient's level of depression before, during, and after treatment. It takes approximately 15-20 minutes to complete the interview and score the results. Subscale scores are 0-2 (10 questions), 0-3 (2 questions), and 0-4 (12 questions). Subscales are totaled for an overall score (range 0 -76). For the overall score and all subscales, lower scores correspond to fewer symptoms, and higher scores correspond more symptoms. |
Other
| Measure | Time frame | Description |
|---|---|---|
| fMRI/TMS Assessed Neural Network Connectivity | Up to 3 months. | From pre- to post-treatment, improvement will be based on enhanced functional connectivity. |
| Implicit Emotion Regulation | Up to 3 months | Implicit emotion regulation assessed through emotion conflict task performed during functional imaging. Performance based on reaction time and recruitment of emotion regulation regions during the task. |
| fMRI-assessed Resting Connectivity | Up to 3 months. | From pre- to post-treatment of patients with high-frequency repetitive TMS (rTMS) improvement shall be measured by normalization of baseline network-level deficits. |
Countries
United States
Participant flow
Pre-assignment details
85 participants were enrolled and 33 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| rTMS Treatment rTMS was to be delivered for 20 sessions over 4 weeks. Active 10 Hz rTMS was delivered using neuro-navigation based on participants' own fMRI images. Daily treatment regiments were to last 36.5 minutes and rTMS was delivered at 120% of the participant's motor threshold. Participants were monitored during the rTMS sessions for adverse events and/or side effects.
rTMS Treatment: MRI-compatible TMS stimulator | 20 |
| Sham Treatment Sham rTMS was to be delivered for 20 sessions over 4 weeks. Placebo 10Hz rTMS was delivered through sham stimulation electrodes. The rTMS coil was positioned using neuro-navigation based on participants' own fMRI images, mimicking active rTMS treatment. Daily treatment regiments were to 36.5minutes and sham rTMS was delivered at 120% of the participant's motor threshold. Participants were monitored during the rTMS sham sessions for adverse events and/or side effects.
Upon completing the sham 20 sessions participants are unblinded and offered 20 further treatments of guaranteed open-label treatment. The open-label treatment would follow the active rTMS treatment protocol.
rTMS Treatment: MRI-compatible TMS stimulator | 13 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Did not complete intervention | 2 | 0 |
Baseline characteristics
| Characteristic | rTMS Treatment | Sham Treatment | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 13 Participants | 33 Participants |
| Age, Continuous | 37.2 years STANDARD_DEVIATION 11.2 | 35.0 years STANDARD_DEVIATION 6.5 | 36.2 years STANDARD_DEVIATION 8.9 |
| Hamilton Depression Rating Scale (HAM-D 24) | 27.0 units on a scale STANDARD_DEVIATION 8 | 26.2 units on a scale STANDARD_DEVIATION 5.9 | 26.9 units on a scale STANDARD_DEVIATION 7.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 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 | 14 Participants | 9 Participants | 23 Participants |
| Sex: Female, Male Female | 11 Participants | 9 Participants | 20 Participants |
| Sex: Female, Male Male | 9 Participants | 4 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 13 |
| other Total, other adverse events | 1 / 20 | 1 / 13 |
| serious Total, serious adverse events | 0 / 20 | 0 / 13 |
Outcome results
Primary
Clinician Administered HAM-D
The Hamilton Depression Rating Scale (HAM-D) is a 24-item clinician-administered assessment utilized as a way of determining a patient's level of depression before, during, and after treatment. It takes approximately 15-20 minutes to complete the interview and score the results. Subscale scores are 0-2 (10 questions), 0-3 (2 questions), and 0-4 (12 questions). Subscales are totaled for an overall score (range 0 -76). For the overall score and all subscales, lower scores correspond to fewer symptoms, and higher scores correspond more symptoms.
Time frame: Baseline; Day 10; Day 20
Population: Randomized and treated
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rTMS Treatment | Clinician Administered HAM-D | Baseline | 27.0 units on a scale | Standard Deviation 8 |
| rTMS Treatment | Clinician Administered HAM-D | Day 10 | 22.0 units on a scale | Standard Deviation 9.3 |
| rTMS Treatment | Clinician Administered HAM-D | Day 20 | 17.9 units on a scale | Standard Deviation 9.9 |
| Sham Treatment | Clinician Administered HAM-D | Baseline | 26.2 units on a scale | Standard Deviation 5.9 |
| Sham Treatment | Clinician Administered HAM-D | Day 10 | 22.7 units on a scale | Standard Deviation 6.9 |
| Sham Treatment | Clinician Administered HAM-D | Day 20 | 17.6 units on a scale | Standard Deviation 9.8 |
Other Pre-specified
fMRI-assessed Resting Connectivity
From pre- to post-treatment of patients with high-frequency repetitive TMS (rTMS) improvement shall be measured by normalization of baseline network-level deficits.
Time frame: Up to 3 months.
Other Pre-specified
fMRI/TMS Assessed Neural Network Connectivity
From pre- to post-treatment, improvement will be based on enhanced functional connectivity.
Time frame: Up to 3 months.
Other Pre-specified
Implicit Emotion Regulation
Implicit emotion regulation assessed through emotion conflict task performed during functional imaging. Performance based on reaction time and recruitment of emotion regulation regions during the task.
Time frame: Up to 3 months