Major Depressive Disorder
Conditions
Keywords
adolescent, biomarkers
Brief summary
The Researchers are going to gather information regarding the use of rTMS as a treatment for depression in adolescents with Major Depressive Disorder. The researchers also hope to learn if measures of brain activity (cortical excitability and inhibition) collected with transcranial magnetic stimulation (TMS) can be used to identify which patients will benefit from certain types of rTMS treatment.
Detailed description
Phase I is a double-blind, randomized, biomarker-stratified trial of 1 Hz vs. 10 Hz rTMS. Phase II is for participants who do not respond to Phase I treatment and is a biomarker guided, double-blind trial of continuous vs intermittent theta burst stimulation (TBS). Please note that transcranial magnetic stimulation (TMS) biomarkers will be collected in this protocol during the course of the proposed interventions. Participants in Phase I will be offered enrollment in a separate protocol with baseline and posttreatment 7 Tesla Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS) scans
Interventions
DEVICENeuroStar TMS Therapy® System
The NeuroStar TMS Therapy® System is a computerized electromechanical instrument that produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce electrical currents in localized regions of the cerebral cortex. It is a non-invasive tool used for the treatment of Participants with Major Depressive Disorder (MDD) who have not achieved sufficient clinical benefit from antidepressant pharmacotherapy.
DEVICENeuroStar XPLOR®
NeuroStar XPLOR® is a clinical research option for the NeuroStar TMS Therapy System that provides features necessary to conduct randomized controlled trials and other TMS research.
Sponsors
National Institute of Mental Health (NIMH)
Neuronetics
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Masking description
In both phases of the study (phase I and phase II) participants and study team members completing clinical rating scales will be blinded to treatment assignment. The study team member completing clinical rating scales and analyzing TMS neurophysiology measures will not be allowed in the treatment suite during therapeutic rTMS sessions (10 Hz, 1 Hz, iTMS, or cTBS).
Eligibility
Sex/Gender
ALL
Age
12 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Depressed adolescent participants will have a primary diagnoses of MDD based on a clinical and structured interview with the MINI * Depression symptoms severity of a 40 or greater based on evaluation with the Children's Depression Rating Scale Revised (CDRS-R) at screening and baseline visits. Further, the total score of the baseline CDRS-R score must not have had a 25% or greater decrease from the screening CDRS-R score * The duration of the current episode of depression must be 4 weeks or more but 3 years or less. * For any participant currently receiving antidepressant medication, the referring clinician must determine that insufficient benefit is being received from this treatment and it is clinically appropriate to discontinue the existing antidepressant. * Participants in psychotherapy are eligible provided that this was initiated 4 weeks prior to enrollment and that the frequency of visits will be maintained during study participation.
Exclusion criteria
* The following psychiatric comorbidities are exclusionary: psychotic disorders, bipolar disorders, anorexia nervosa, bulimia nervosa, and substance use disorders within the past year (with the exception of caffeine and tobacco) * A positive urine drug screen at baseline * Seizure history * Family history of epilepsy in a first degree relative * Head trauma with loss of consciousness for greater than 5 minutes * Any true positive findings on the rTMS safety screening form. * Any concurrent psychotropic medications (for potential participants receiving antidepressants or psychotropic medications, the referring clinician must determine that insufficient benefit is being received from the treatment and if clinically appropriate, discontinue existing antidepressants and other psychotropic medications) * Prohibited concomitant medications (See Appendix A) * Pregnancy or suspected pregnancy in female Participants (assessed with urine pregnancy test) * Conductive, ferromagnetic, or other magnetic-sensitive metals implanted in the subject's head within 30 cm of the treatment coil excluding the mouth that cannot safely be removed. Examples include cochlear implants, implanted electrodes/stimulators, aneurysm clips or coils, stents, bullet fragments, jewelry and hair barrettes. * Prior brain surgery * Risk for increased intracranial pressure such as a brain tumor * Any unstable medical condition * History of treatment with ECT or TMS Therapy for any disorder * Use of any investigational drug within 4 weeks of the baseline visit * Initiation of a new psychotherapeutic treatment within the past 4 weeks * Suicide attempt within the previous 6 months that required medical treatment or ≥ 2 attempts in the past 12 months, or has a clear cut plan for suicide and states that he/she cannot guarantee that he/she will inform a family member or call his/her psychiatrist or the investigator if the impulse to implement the plan becomes substantial during the study; or, in the investigator's opinion, is likely to attempt suicide within the next 6 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Children's Depression Rating Scale, Revised (CDRS-R) Score | 6 weeks | CDRS-R is a 17-item scale, with items ranging from 1 to 5 or 1 to 7 (possible total score from 17 to 113), rated by a clinician via interviews with the child and parent. A score of ≥40 is indicative of depression, whereas a score ≤28 is often used to define remission (minimal or no symptoms) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Intracortical Facilitation (ICF) | baseline, 6 weeks | ICF measures were collected with surface electromyography. A subthreshold conditioning stimulus (CS) was set to 80% of resting motor threshold (RMT) preceding a suprathreshold test stimulus (TS), which was calibrated to produce an average motor evoked potential (MEP) of 0.5 to 1.5 millivolt peak-to-peak amplitude in the contralateral abductor pollicis brevis (APB) muscle. Conditioning stimuli were delivered to the motor cortex prior to the TS in 15 msec interstimulus intervals. Changes in TS MEP was expressed as a percentage of the mean unconditioned MEP amplitude. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1 Hz Left Prefrontal rTMS 36 sessions of 1 Hz rTMS at 120% motor threshold were applied to the left prefrontal cortex. Each session was 2400 continuous pulses.
NeuroStar TMS Therapy® System: The NeuroStar TMS Therapy® System is a computerized electromechanical instrument that produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce electrical currents in localized regions of the cerebral cortex. It is a non-invasive tool used for the treatment of Participants with Major Depressive Disorder (MDD) who have not achieved sufficient clinical benefit from antidepressant pharmacotherapy.
NeuroStar XPLOR®: NeuroStar XPLOR® is a clinical research option for the NeuroStar TMS Therapy System that provides features necessary to conduct randomized controlled trials and other TMS research. | 22 |
| 10 Hz Left Prefrontal rTMS 36 sessions of 10 Hz rTMS at 120% motor threshold were applied to the left prefrontal cortex. Each session was 2400 pulses with 4 seconds on and 36 seconds off.
NeuroStar TMS Therapy® System: The NeuroStar TMS Therapy® System is a computerized electromechanical instrument that produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce electrical currents in localized regions of the cerebral cortex. It is a non-invasive tool used for the treatment of Participants with Major Depressive Disorder (MDD) who have not achieved sufficient clinical benefit from antidepressant pharmacotherapy.
NeuroStar XPLOR®: NeuroStar XPLOR® is a clinical research option for the NeuroStar TMS Therapy System that provides features necessary to conduct randomized controlled trials and other TMS research. | 19 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by subject - did not receive allocated intervention | 0 | 1 |
| Overall Study | Withdrawal by subject - discontinued intervention prior to week 1 | 1 | 4 |
Baseline characteristics
| Characteristic | 1 Hz Left Prefrontal rTMS | Total | 10 Hz Left Prefrontal rTMS |
|---|---|---|---|
| Age, Continuous | 15.68 years STANDARD_DEVIATION 1.83 | 15.78 years STANDARD_DEVIATION 1.51 | 15.89 years STANDARD_DEVIATION 1.05 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 5 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 36 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 5 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 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 | 17 Participants | 34 Participants | 17 Participants |
| Region of Enrollment United States | 22 participants | 41 participants | 19 participants |
| Sex: Female, Male Female | 13 Participants | 25 Participants | 12 Participants |
| Sex: Female, Male Male | 9 Participants | 16 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 24 |
| other Total, other adverse events | 20 / 23 | 21 / 24 |
| serious Total, serious adverse events | 3 / 23 | 3 / 24 |
Outcome results
Primary
Total Children's Depression Rating Scale, Revised (CDRS-R) Score
CDRS-R is a 17-item scale, with items ranging from 1 to 5 or 1 to 7 (possible total score from 17 to 113), rated by a clinician via interviews with the child and parent. A score of ≥40 is indicative of depression, whereas a score ≤28 is often used to define remission (minimal or no symptoms)
Time frame: 6 weeks
Population: Data was not collected or analyzed for one subject in the 1 Hz arm and five subjects in the 10 Hz arm
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| 1 Hz Left Prefrontal rTMS | Total Children's Depression Rating Scale, Revised (CDRS-R) Score | 41.768 score on a scale |
| 10 Hz Left Prefrontal rTMS | Total Children's Depression Rating Scale, Revised (CDRS-R) Score | 44.541 score on a scale |
Secondary
Change in Intracortical Facilitation (ICF)
ICF measures were collected with surface electromyography. A subthreshold conditioning stimulus (CS) was set to 80% of resting motor threshold (RMT) preceding a suprathreshold test stimulus (TS), which was calibrated to produce an average motor evoked potential (MEP) of 0.5 to 1.5 millivolt peak-to-peak amplitude in the contralateral abductor pollicis brevis (APB) muscle. Conditioning stimuli were delivered to the motor cortex prior to the TS in 15 msec interstimulus intervals. Changes in TS MEP was expressed as a percentage of the mean unconditioned MEP amplitude.
Time frame: baseline, 6 weeks
Population: Data was not collected or analyzed for one subject in the 1 Hz arm and five subjects in the 10 Hz arm
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 1 Hz Left Prefrontal rTMS | Change in Intracortical Facilitation (ICF) | 1.71 percentage of the mean unconditioned MEP | Standard Error 0.05 |
| 10 Hz Left Prefrontal rTMS | Change in Intracortical Facilitation (ICF) | 1.67 percentage of the mean unconditioned MEP | Standard Error 0.06 |