Treatment Resistant Depression
Conditions
Brief summary
The goal of this project is to guide rTMS using functional magnetic resonance imaging (fMRI) in individuals with depression who did not respond to standard TMS treatment to evaluate whether targeted TMS using individualized functional MRI scans produce outcome superior to that of conventional approaches. The study team also plans to scan patients with Major Depression Disorder (MDD) patients prescribed to receive standard TMS for the first time before and after which they will have resting-state Functional Magnetic Resonance Imaging (rs-FMRI) scan in order to see if we can predict their responsiveness based on the functional connectivity maps.
Detailed description
Significance: There are few therapeutic options for individuals with treatment resistant depression (TRD). One recently developed approach is rTMS over left dorsolateral prefrontal cortex. Recent studies have demonstrated overall antidepressant benefit of rTMS in patients who fail to respond to a trial of antidepressant medication (1, 2, 3). Nevertheless, for many patients the response is incomplete, suggesting the need for further optimization. One potential cause of heterogeneous response might relate to individual differences in brain anatomy and connectivity patterns. At present, the rTMS stimulation site across subjects is based upon fixed location relative to motor cortex. Potentially, however, the approach could be optimized by stimulating based upon individual brain functional connectivity pattern. The present project will collect pre- and post-treatment brain functional connectivity measures in a group of patients who will be receiving independent clinical rTMS for resistant depression, a connectivity-based targeting approach will be applied at the single-subject level to individualize therapy in those patients who do not respond to standard approaches. Patients will be divided in 2 groups. Group 1 (N=30) will be depressed patients undergoing standard TMS for the first time. Group 2 (N=30) constitutes those who have previously demonstrated that they do not respond to standard TMS. MDD patients prescribed to receive standard TMS for the first time (group 1) will have resting-state FMRI in order to see if their responsiveness based on the functional connectivity maps can be predicted. Non-responders to standard TMS approaches (Group 2) will be randomized (3:2) to either receive targeted (N=18) or standard (N=12) repetitive TMS (rTMS) treatments. A connectivity-based targeting strategy will be used on patients undergoing targeted rTMS to optimize target for focal brain stimulation. Raters and patients in group 2 will be kept blinded to the treatment assignment. All patients referred from the ongoing treatment study will be assessed by 3 tesla brain MRI, Magnetic Resonance Spectroscopy (MRS) and Cerebral Blood Flow/Volume (CBF/CBV) procedures at baseline and immediately following the final treatment.
Interventions
DEVICEtranscranial magnetic stimulation
non invasive brain stimulation approach
Sponsors
New York State Psychiatric Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
General Inclusion Criteria: 1. Male or female outpatients, 18 to 60 years of age. 2. Primary diagnosis of Major Depressive Disorder as confirmed by the Structured Clinical Interview for Diagnostic and Statistical Manual (DSM-IV-TR) Disorders (SCID-IV-TR). 3. Duration of the index episode of at least 1 month. 4. MDD symptoms, defined as a total HDRS-17 score ≥ 18 despite treatment with an adequate trial of a serotonin reuptake inhibitor (SRI). 5. Individuals who cannot tolerate medications. 6. Patients currently on medication must be at the same stable dose(s) for 1 month prior to enrollment and be willing to continue at the same dose(s) through the duration of the study. 7. Capable and willing to provide informed consent. 8. Signed HIPAA authorization. 9. Right-handed. 10. Willingness to undergo research fMRI scan (3T). 11. Willingness to undergo randomization to either treatment arm. General
Exclusion criteria
1. Investigators, and their immediate families (defined as a spouse, parent, child or sibling, whether by birth or legal adoption). 2. Individuals diagnosed by the investigators with the following conditions: Bipolar Disorder (lifetime), any Psychotic Disorder (lifetime), history of substance abuse or dependence within the past year (except nicotine and caffeine). 3. Behavior, which in the judgment of the investigator may hinder the patient in completing the procedures required by the study protocol. 4. Individuals with a clinically defined neurological disorder including, but not limited to: tics, space occupying brain lesion; any history of seizures except those therapeutically induced by electroconvulsive therapy (ECT); history of cerebrovascular accident; history of fainting; transient ischemic attack within two years; cerebral aneurysm, Dementia; Parkinson's Disease; Huntington chorea; Multiple Sclerosis. 5. Increased risk of seizure for any reason, including prior diagnosis of increased intracranial pressure (such as after large infarctions or trauma), or history of significant head trauma with loss of consciousness for ≥ 5 minutes. 6. Use of any investigational drug within 12 weeks of the randomization visit. 7. Significant acute suicide risk, defined as follow: suicide attempt within the previous 6 months that required medical treatment; or ≥ 2 suicide attempts in the past 12 months; or in the investigator's opinion, has significant risk for suicide based on the current state or recent history. 8. Cardiac pacemakers, implanted medication pumps, intracardiac lines, or acute, unstable cardiac disease. 9. Intracranial implants (e.g. aneurysms clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed. 10. Current illicit drug use (cannabinoid, phencyclidine, amphetamines, barbiturates, cocaine, methadone, and opiates), defined as drug use during the 6 months before screening. 11. Known or suspected pregnancy. Urine pregnancy test Women who are breast-feeding. 12. Women of childbearing potential not using a medically accepted form of contraception when engaging in sexual intercourse. 13. Medicinal patch, unless removed prior to the magnetic resonance (MR) scan. 14. MDD patients with very severe depression, defined as a total HDRS-17 score ≥ 23, will be excluded and referred to immediate treatment. 15. Risks related to seizures, such as substance abuse or sleep disruptions/insomnia. Specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Functional Connectivity Measured by Resting MRI | Week 1 prior to first TMS treatment and week 36 after completion of TMS treatments | Change from Baseline in Resting MRI Correlation Coefficients Between Left Dorsolateral Prefrontal Cortex and Subgenual Anterior Cingulate Change in Resting MRI is defined as post-pre |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Depressive Symptoms Measured by the Hamilton Depression Rating Scale (17-item HDRS) | Week 1 prior to first TMS treatment and week 36 after completion of TMS treatments | Patients will be classified as responders to TMS with at least 50% decrease in HDRS scores from baseline. Patients will be classified as non-responders to TMS with less than 50% decrease in HDRS scores from baseline. Change in HDRS-17 scores is defined as: \[pre-post)/pre\]x100 HDRS-17 scores range: 0-61 Levels of depression based on HDRS-17 scores: Not depressed: 0-7 Mild (subthreshold): 8-13 Moderate (mild): 14-18 Severe (moderate): 19-22 Very severe (severe): \>23 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| New Target TMS new target transcranial magnetic stimulation guided by MRI
transcranial magnetic stimulation: non invasive brain stimulation approach | 10 |
| Standard TMS standard transcranial magnetic stimulation
transcranial magnetic stimulation: non invasive brain stimulation approach | 22 |
| Total | 32 |
Baseline characteristics
| Characteristic | New Target TMS | Standard TMS | 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 | 10 Participants | 22 Participants | 32 Participants |
| Age, Continuous | 37.70 years STANDARD_DEVIATION 16.028 | 41.50 years STANDARD_DEVIATION 15.152 | 40.21 years STANDARD_DEVIATION 15.275 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 21 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 10 participants | 22 participants | 32 participants |
| Sex: Female, Male Female | 3 Participants | 12 Participants | 15 Participants |
| Sex: Female, Male Male | 7 Participants | 10 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 22 |
| other Total, other adverse events | 0 / 10 | 0 / 22 |
| serious Total, serious adverse events | 0 / 10 | 0 / 22 |
Outcome results
Primary
Change in Functional Connectivity Measured by Resting MRI
Change from Baseline in Resting MRI Correlation Coefficients Between Left Dorsolateral Prefrontal Cortex and Subgenual Anterior Cingulate Change in Resting MRI is defined as post-pre
Time frame: Week 1 prior to first TMS treatment and week 36 after completion of TMS treatments
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| New Target TMS | Change in Functional Connectivity Measured by Resting MRI | 0.103399365 correlation coefficients | Standard Deviation 0.161565183 |
| Standard TMS | Change in Functional Connectivity Measured by Resting MRI | -0.7637409 correlation coefficients | Standard Deviation 0.106948404 |
Secondary
Change in Depressive Symptoms Measured by the Hamilton Depression Rating Scale (17-item HDRS)
Patients will be classified as responders to TMS with at least 50% decrease in HDRS scores from baseline. Patients will be classified as non-responders to TMS with less than 50% decrease in HDRS scores from baseline. Change in HDRS-17 scores is defined as: \[pre-post)/pre\]x100 HDRS-17 scores range: 0-61 Levels of depression based on HDRS-17 scores: Not depressed: 0-7 Mild (subthreshold): 8-13 Moderate (mild): 14-18 Severe (moderate): 19-22 Very severe (severe): \>23
Time frame: Week 1 prior to first TMS treatment and week 36 after completion of TMS treatments
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| New Target TMS | Change in Depressive Symptoms Measured by the Hamilton Depression Rating Scale (17-item HDRS) | 64.9440 percentage change in HDRS scores | Standard Deviation 15.16426 |
| Standard TMS | Change in Depressive Symptoms Measured by the Hamilton Depression Rating Scale (17-item HDRS) | 27.7345 percentage change in HDRS scores | Standard Deviation 27.48549 |