Major Depressive Disorder
Conditions
Keywords
Repetitive Transcranial Magnetic Stimulation, Major Depressive Disorder
Brief summary
The purpose of this study is to determine the clinical effects (if any) of connectivity-guided repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder (MDD) to provide clues about the ideal neural networks to target for more robust clinical outcomes, and to identify potential biomarkers of treatment response including changes in brain network connectivity.
Detailed description
The investigators propose a randomized, double-blind, 4-week trial of TMS to the left dorsolateral prefrontal cortex (DLPFC) for subjects with MDD all of whom at the patient's treatment clinic are concurrently receiving pharmaceutical and psychotherapeutic interventions. Arm 1 delivers active rTMS to the left DLPFC using the standard aiming strategy. Arm 2 delivers active rTMS to the left anterior DLPFC using connectivity-based, image-guided aiming. Arm 3 delivers active rTMS to the left posterior DLPFC using connectivity-based, image-guided aiming. In all three arms, rTMS is administered in an image-guided, robotically-positioned TMS (irTMS) manner to ensure therapist blinding and equivalent subject experiences across arms. In all three arms, the following stimulation protocol will be used: 10 Hz irTMS delivered in 4 sec trains with 26 sec inter-train intervals, 37.5 minutes/session (i.e. 3,000 pulses/session), 5 sessions/week, for 4 weeks. Neuroimaging will be used both for treatment planning and to characterize any TMS-induced network plasticity using resting-state functional magnetic resonance imaging (rs-fMRI) at week 4 of each treatment arm. Clinical assessments will be administered weekly throughout treatment (weeks 1-4) at the patient's treatment clinic. Additional psychological tests will be performed at UT Health-San Antonio's Research Imaging Institute (RII) at the baseline and post-treatment visits in order to track patient progress.
Interventions
DEVICErepetitive transcranial magnetic stimulation
The MagPro R30 is an advanced, high performance magnetic stimulator designed primarily for non-invasive clinical use. The non-invasive brain stimulation system will be used to deliver repetitive electromagnetic pulses in this research study's treatment of major depressive disorder.
DEVICErobotic arm
This robotic system is based on a commercially available neurosurgical robot. The robot is mounted on a mobile (i.e. retractable wheels) cart which holds the robot controller and the TMS power supply and pulse-generation computer. The robotic system will be used for TMS coil positioning/targeting.
Sponsors
IKARE Mood, Trauma, Recovery Clinic
The University of Texas Health Science Center at San Antonio
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Males or females with MDD receiving treatment at the iKare Mood Trauma Recovery Clinic between the ages of 18-65 years; 2. Meeting the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria for MDD as determined using the Mini-International Psychiatric Interview (MINI) 3. Meeting the Patient Health Questionnaire-9 (PHQ-9 \> 14) and/or the Structured Interview Guide for the Montgomery-Ashberg Depression Rating Scale (SIGMA\>18) criteria for treatment resistance in MDD despite completing at least one adequate trial of an Selective Serotonin Reuptake Inhibitor (SSRI) or Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) at an FDA-recommended dose for at least 6-8 weeks. 4. Subjects on SSRIs or other antidepressants, hypnotic medications including modulators of Gamma-Aminobutryic Acid (GABA)-A receptor function, trazodone, atypical neuroleptic or other psychotropic medications such as prazosin may enter the study if they are deemed to be on a stable dose of their medication. 5. Able to provide written informed consent. 6. Able to read and write English.
Exclusion criteria
1. Subjects with a diagnostic history of bipolar disorder, schizophrenia or schizoaffective disorder or currently exhibiting psychotic features as confirmed by MINI. 2. Serious, active suicidal risk as assessed by evaluating psychiatrist. Serious active suicidal risk is determine as imminent risk of suicide reflected in a subject having a plan and intent to end his or her life. History of suicidality in itself is not exclusion for participation in this protocol so long as the evaluating psychiatrist determines that there is an absence of serious active suicidal risk and the means to keep subjects safe. 3. Substance use disorder during the 3 months prior to screening; except for Mild or Moderate Alcohol Use Disorder according to DSM-V criteria. 4. Any history or signs of serious medical or neurological illness including seizure disorders. Except for seizures, a subject with a clinical abnormality may be included only if the study clinician considers the illness will not introduce additional risk and will not interfere with the study procedures. 5. Females will be excluded if they are pregnant (i.e. positive pregnancy test identified after their intake at the treatment clinic). 6. History of traumatic brain injury (TBI) with loss of consciousness for 20 minutes or more as determined by the Brief Traumatic Brain Injury Screen (TBI Screening Tool). 7. Any history or signs of metal objects (e.g. surgical clips, cardiac pacemakers, metal implants, etc.) in the body at the time of screening. MRI can have risks for persons with foreign bodies implanted in their body.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Depression Severity (MADRS) | Baseline to four weeks (the conclusion of rTMS treatment) | Measured by the Montgomery-Ashberg Depression Rating Scale. This is a 10-item diagnostic questionnaire with an overall score range from 0 to 60. A higher score indicates more severe depression: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression \>34 - severe depression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Depression Severity (MADRS) | Baseline to sixteen weeks (twelve weeks after the conclusion of rTMS treatment) | Measured by the Montgomery-Ashberg Depression Rating Scale. This is a 10-item diagnostic questionnaire with an overall score range from 0 to 60. A higher score indicates more severe depression: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression \>34 - severe depression. |
| Clinically Significant Response (MADRS) | Baseline to four weeks (the conclusion of rTMS treatment) | Defined as greater than or equal to a 50% decrease in the Montgomery-Ashberg Depression Rating Scale. This is a 10-item diagnostic questionnaire with an overall score range from 0 to 60. A higher score indicates more severe depression: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression \>34 - severe depression. |
| Remission From Depression (MADRS) | Baseline to four weeks (the conclusion of rTMS treatment) | Defined as Montgomery-Ashberg Depression Rating Scale score less than or equal to 10. This is a 10-item diagnostic questionnaire with an overall score range from 0 to 60. A higher score indicates more severe depression: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression \>34 - severe depression. |
| Functional Connectivity Changes of the Targeted Brain Network(s) Following rTMS Treatment | Baseline to four weeks (the conclusion of rTMS treatment) | resting-state fMRI scan will also be used to assess, network-specific functional connectivity differences between each subject's pre-treatment and post-treatment scans. The purpose of the Z score is to standardize distributions so that each has a mean of 0, and standard deviation as 1, so we can then make comparisons. Standard Score, the Z-Score: A way to make a comparison between values on two different normal curves by converting the values to the number of standard deviations above or below the mean. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Standard rTMS Aiming Active repetitive transcranial magnetic stimulation (rTMS) will be delivered to the left DLPFC using the standard aiming strategy with the rTMS coil positioned using a robotic arm. In this arm, rTMS will be delivered at 10 Hz in 4 sec trains with 26 sec inter-train intervals, 37.5 minutes/session (i.e. 3,000 pulses/session), 5 sessions/week, for 4 weeks.
repetitive transcranial magnetic stimulation: The MagPro R30 is an advanced, high performance magnetic stimulator designed primarily for non-invasive clinical use. The non-invasive brain stimulation system will be used to deliver repetitive electromagnetic pulses in this research study's treatment of major depressive disorder.
robotic arm: This robotic system is based on a commercially available neurosurgical robot. The robot is mounted on a mobile (i.e. retractable wheels) cart which holds the robot controller and the TMS power supply and pulse-generation computer. The robotic system will be used for TMS coil positioning/targeting. | 1 |
| Anterior DLPFC Targeting Active rTMS will be delivered to the left anterior DLPFC using connectivity-based, image-guided aiming with the rTMS coil positioned using a robotic arm. In this arm, rTMS will be delivered at 10 Hz in 4 sec trains with 26 sec inter-train intervals, 37.5 minutes/session (i.e. 3,000 pulses/session), 5 sessions/week, for 4 weeks.
repetitive transcranial magnetic stimulation: The MagPro R30 is an advanced, high performance magnetic stimulator designed primarily for non-invasive clinical use. The non-invasive brain stimulation system will be used to deliver repetitive electromagnetic pulses in this research study's treatment of major depressive disorder.
robotic arm: This robotic system is based on a commercially available neurosurgical robot. The robot is mounted on a mobile (i.e. retractable wheels) cart which holds the robot controller and the TMS power supply and pulse-generation computer. The robotic system will be used for TMS coil positioning/targeting. | 2 |
| Posterior DLPFC Targeting Active rTMS will be delivered to the left posterior DLPFC using connectivity-based, image-guided aiming with the rTMS coil positioned using a robotic arm. In this arm, rTMS will be delivered at 10 Hz in 4 sec trains with 26 sec inter-train intervals, 37.5 minutes/session (i.e. 3,000 pulses/session), 5 sessions/week, for 4 weeks.
repetitive transcranial magnetic stimulation: The MagPro R30 is an advanced, high performance magnetic stimulator designed primarily for non-invasive clinical use. The non-invasive brain stimulation system will be used to deliver repetitive electromagnetic pulses in this research study's treatment of major depressive disorder.
robotic arm: This robotic system is based on a commercially available neurosurgical robot. The robot is mounted on a mobile (i.e. retractable wheels) cart which holds the robot controller and the TMS power supply and pulse-generation computer. The robotic system will be used for TMS coil positioning/targeting. | 3 |
| Total | 6 |
Baseline characteristics
| Characteristic | Standard rTMS Aiming | Anterior DLPFC Targeting | Posterior DLPFC Targeting | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 1 participants | 2 participants | 3 participants | 6 participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 2 | 0 / 3 |
| other Total, other adverse events | 1 / 1 | 1 / 2 | 1 / 3 |
| serious Total, serious adverse events | 0 / 1 | 0 / 2 | 0 / 3 |
Outcome results
Primary
Change in Depression Severity (MADRS)
Measured by the Montgomery-Ashberg Depression Rating Scale. This is a 10-item diagnostic questionnaire with an overall score range from 0 to 60. A higher score indicates more severe depression: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression \>34 - severe depression.
Time frame: Baseline to four weeks (the conclusion of rTMS treatment)
Population: Discrepancies in the number of participants analyzed for this outcome measure occur because of patient withdrawals from treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Anterior DLPFC Targeting | Change in Depression Severity (MADRS) | baseline | 32 units on a scale | Standard Deviation 0 |
| Anterior DLPFC Targeting | Change in Depression Severity (MADRS) | 4 weeks | 2 units on a scale | Standard Deviation 0 |
| Posterior DLPFC Targeting | Change in Depression Severity (MADRS) | baseline | 43 units on a scale | Standard Deviation 0 |
| Posterior DLPFC Targeting | Change in Depression Severity (MADRS) | 4 weeks | 46 units on a scale | Standard Deviation 0 |
Secondary
Change in Depression Severity (MADRS)
Measured by the Montgomery-Ashberg Depression Rating Scale. This is a 10-item diagnostic questionnaire with an overall score range from 0 to 60. A higher score indicates more severe depression: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression \>34 - severe depression.
Time frame: Baseline to sixteen weeks (twelve weeks after the conclusion of rTMS treatment)
Population: Discrepancies in the number of participants analyzed for this outcome measure occur because patients did not respond to follow-up calls.
Secondary
Clinically Significant Response (MADRS)
Defined as greater than or equal to a 50% decrease in the Montgomery-Ashberg Depression Rating Scale. This is a 10-item diagnostic questionnaire with an overall score range from 0 to 60. A higher score indicates more severe depression: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression \>34 - severe depression.
Time frame: Baseline to sixteen weeks (twelve weeks after the conclusion of rTMS treatment)
Population: Discrepancies in the number of participants analyzed for this outcome measure occur because patients did not respond to follow-up calls.
Secondary
Clinically Significant Response (MADRS)
Defined as greater than or equal to a 50% decrease in the Montgomery-Ashberg Depression Rating Scale. This is a 10-item diagnostic questionnaire with an overall score range from 0 to 60. A higher score indicates more severe depression: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression \>34 - severe depression.
Time frame: Baseline to four weeks (the conclusion of rTMS treatment)
Population: Discrepancies in the number of participants analyzed for this outcome measure occur because of patient withdrawals from treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Anterior DLPFC Targeting | Clinically Significant Response (MADRS) | 1 Participants |
| Posterior DLPFC Targeting | Clinically Significant Response (MADRS) | 0 Participants |
Secondary
Functional Connectivity Changes of the Targeted Brain Network(s) Following rTMS Treatment
resting-state fMRI scan will also be used to assess, network-specific functional connectivity differences between each subject's pre-treatment and post-treatment scans. The purpose of the Z score is to standardize distributions so that each has a mean of 0, and standard deviation as 1, so we can then make comparisons. Standard Score, the Z-Score: A way to make a comparison between values on two different normal curves by converting the values to the number of standard deviations above or below the mean.
Time frame: Baseline to four weeks (the conclusion of rTMS treatment)
Population: Functional brain connectivity to the sub-genual cingulate (SGC) cortex compared between the groups (in participants with 20 treatment sessions) at baseline and 4 weeks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anterior DLPFC Targeting | Functional Connectivity Changes of the Targeted Brain Network(s) Following rTMS Treatment | -2.35 z-score |
| Posterior DLPFC Targeting | Functional Connectivity Changes of the Targeted Brain Network(s) Following rTMS Treatment | 1.86 z-score |
Secondary
Remission From Depression (MADRS)
Defined as Montgomery-Ashberg Depression Rating Scale score less than or equal to 10. This is a 10-item diagnostic questionnaire with an overall score range from 0 to 60. A higher score indicates more severe depression: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression \>34 - severe depression.
Time frame: Baseline to four weeks (the conclusion of rTMS treatment)
Population: Discrepancies in the number of participants analyzed for this outcome measure occur because of patient withdrawals from treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Anterior DLPFC Targeting | Remission From Depression (MADRS) | 1 Participants |
| Posterior DLPFC Targeting | Remission From Depression (MADRS) | 0 Participants |
Secondary
Remission From Depression (MADRS)
Defined as Montgomery-Ashberg Depression Rating Scale score less than or equal to 10. This is a 10-item diagnostic questionnaire with an overall score range from 0 to 60. A higher score indicates more severe depression: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression \>34 - severe depression.
Time frame: Baseline to sixteen weeks (twelve weeks after the conclusion of rTMS treatment)
Population: Discrepancies in the number of participants analyzed for this outcome measure occur because patients did not respond to follow-up calls.