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CompletedNCT01191333Updated Mar 9, 2018Results posted

The Effectiveness of rTMS in Depressed VA Patients

An interventional study of rTMS and Sham Device in Major Depressive Disorder, sponsored by VA Office of Research and Development. Completed at 9 sites in United States. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2018-03-09.

Sponsored by VA Office of Research and Development · Not applicable, Interventional, and Treatment

Phase
Not applicable
Study type
Interventional
Enrollment
164
Allocation
Randomized
Ages
18 Years to 80 Years
Sex
All
01

Study summary

The purpose of this multi-site trial is to determine if repetitive Transcranial Magnetic Stimulation (rTMS) helps people with depression who have not been helped by medications or who have not been helped enough by medications.

Read the detailed description

Major depression occurs in about 10% of American outpatients every year and of those, approximately 20% respond incompletely or not at all to trials of antidepressants, mood stabilizers, or psychotherapy (Kaplan and Sadock, 1996; Keller et al 1992; Thase, 2004). Treatment as usual for these cases of treatment resistant major depression (TRMD) frequently involves increased risks and increased side effects, such as those seen in monoamine oxidase inhibitors (MAOIs) and electroconvulsive therapy (ECT). New TRMD treatments are needed, preferably without major safety concerns or side effects as seen with aggressive polypharmacy or ECT.

Repetitive transcranial magnetic stimulation (rTMS) is a method of delivering brain stimulation without the seizures or risks associated with ECT, nor the potential side effects and risks of MAOI therapy. Systematic review and meta-analysis of the studies to date, which are typically of a small scale, appear to show a positive effect in TRMD (Martin et al. 2003). With a minimal side effect profile, and the rarity of untoward events and side-effects (Pascual-Leone et al. 1993; Wassermann 1997), safety concerns regarding the use of rTMS are considerably less than with ECT. Given this, rTMS has the potential to be a significant advance in care, if it were shown to be effective in TRMD in VA patients.

The trials of rTMS performed to date have not included participants with comorbid disorders, such as substance abuse and post-traumatic stress disorder (PTSD), thus the generalizability of their findings to a VA population is not clear. Further research including Veterans with possible comorbid disorders is necessary, given the high rates of co-occurring substance abuse and PTSD that is present in the Veteran population.

The present study is a randomized, controlled trial that compares active rTMS to a sham condition in Veterans with treatment resistant major depression and possible comorbid post-traumatic stress disorder (PTSD) and / or a history of substance abuse. Veterans will remain under the care of their VA primary mental health provider throughout the project. Participants will be assessed at pre-, mid- and several post-treatment time points. This is a multisite trial that will be conducted at 9 VA Medical Centers around the country.

02

Conditions studied

  • Major Depressive Disorder

Keywords

  • Mood Disorder
  • Depression
  • stress disorder, post-traumatic
  • Depressive Disorder
  • Stress Disorders, Traumatic
  • substance related disorders
  • Transcranial Magnetic Stimulation, repetitive
  • transcranial magnetic stimulation
  • Veterans
  • mental health
03

In context

Depressive Disorder

4,845 studies on the registry are indexed under Depressive Disorder; 514 are open to participants now.

This study's enrollment of 164 is above the median of 80 across 3,999 interventional studies indexed under Depressive Disorder.

Browse Depressive Disorder studies →

Lead sponsor

VA Office of Research and Development is the lead sponsor of 1,733 studies on the registry; 396 are open to participants now.

Of its 206 completed or terminated interventional studies of FDA-regulated products, 180 (87%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 80 Years
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • Between 18 and 80 years of age
  • Using the Structured Clinical Interview for Diagnostic and Statistical Manual (DSM) Disorders (SCID) for DSM-IV-TR (First et al. 2002) patients will be diagnosed Major Depressive Disorder (MDD).
  • Have a Hamilton Rating Scale for Depression (HRSD-24) score greater or equal to 20 no more than 7 days prior to randomization.
  • Exhibit moderate level of resistance to antidepressant treatment defined, using the Antidepressant Treatment History Form (ATHF) (Sackeim et al. 1990), as failure of at least two adequate medication trials.
  • Duration of current episode of less than or equal to 10 years.
  • Ability to obtain a Motor Threshold (MT) (should be determined at the end of the screening process).
  • Currently under the care of a VA psychiatrist.
  • If on a psychotropic medication regimen, that regimen will be stable for at least 4 weeks prior to randomization and patient will be willing to remain on a stable regimen during the acute treatment phase.
  • Has an adequately stable condition and environment to enable attendance at scheduled clinic visits.

  • For female participants, agrees to use one of the following acceptable methods of birth control

    • Complete abstinence (not having sexual intercourse with anyone)
    • An oral contraceptive (birth control pills)
    • Norplant
    • Depo-Provera
    • A condom with spermicide
    • A cervical cap with spermicide
    • A diaphragm with spermicide
    • An Intrauterine device
    • Surgical sterilization (having tubes tied)
  • Able to read, verbalize understanding and voluntarily sign the Informed Consent Form prior to performance of any study-specific procedures or assessments.

Exclusion criteria

Exclusion Criteria:

  • Pregnant or lactating female (This is an FDA-required exclusion. In the future, if rTMS becomes a proven treatment for major depression, its safety in the context of pregnancy should be studied separately (Nahas et al. 1999).
  • Unable to be safely withdrawn, at least two-weeks prior to treatment commencement, from medications that substantially increase the risk of having seizures. For the purpose of this study, those medications are listed in Appendix G (for example, theophylline).
  • Have a cardiac pacemaker.
  • Have an implanted device (deep brain stimulation) or metal in the brain.
  • Have a cochlear implant.
  • Have a mass lesion, cerebral infarct, increased intracranial pressure, or other active central nervous system (CNS) disease, including a seizure disorder.
  • Known current psychosis as determined by DSM-IV or SCID (axis I, psychotic disorder, schizophrenia) or a history of a non-mood psychotic disorder.
  • Known current Bipolar I disorder as determined by SCID or a History of Bipolar I disorder.
  • Current amnestic disorders, dementia, Blessed Orientation-Memory-Concentration (BOMC) greater than 10, delirium, or other cognitive disorders.
  • Current substance abuse (not including caffeine or nicotine) as determined by positive toxicology screen, or by history via SCID, within 3 months prior to screening.
  • Patients with an elevated risk of seizure due to traumatic brain injury (TBI).
  • Participation in another concurrent clinical trial.
  • Patients with prior exposure to rTMS.
  • Active current suicidal intent or plan as evidenced by a score of 4 or 5 on the suicidal ideation portion of the Columbia Suicide Severity Rating Scale (C-SSRS) or the endorsement of an actual attempt, interrupted attempt, or an aborted attempt in the past 6 months. All patients will be required to establish a written safety plan involving their primary psychiatrist and the treatment team before entering the clinical trial (See Section X.B.8).
  • Unstable cardiac disease or recent (\< 3 months previous) myocardial infarction.
  • Patient refuses to sign consent for participation in the study.
05

Study design

Phase
Not applicable
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Triple (Participant, Investigator, Outcomes assessor)
Enrollment
164 participants (actual)

Study arms

  • Experimental
    Active rTMS

    Those receiving experimental treatment will receive 20 to 30 sessions of rTMS in blocks of 5 sessions. The treatment will be delivered by trained medical personnel.

    Device: rTMS

  • Placebo comparator
    Sham rTMS

    Those receiving the sham rTMS will receive 20 to 30 sessions of sham rTMS in blocks of 5 sessions. The treatment will be delivered by trained medical personnel.

    Device: Sham Device

Interventions

  • DevicerTMS

    Repetitive Transcranial Magnetic Stimulation

  • DeviceSham Device

    Placebo Device that simulates active rTMS treatment

06

What researchers measure

Primary outcomes

  1. The Proportion of Participants Achieving Remission From Depression as Assessed by Hamilton Rating Scale for Depression

    The primary outcome is a proportion of participants achieving remission from depression based on the HRSD24 less than or equal to 10 at the end of the acute treatment phase. 24 item Instrument with overall score range from 0 - 76. High values represent a worse outcome.

    Time frame: End of acute treatment 4-6 weeks

Secondary outcomes

  1. Mean Suicidal Ideation Score as Assessed by Beck Scale for Suicide Ideation (BSS)

    To help clinicians screen psychiatric patients for suicidal ideation, the Beck Scale for Suicide Ideation was developed, and is herein referred to as the BSS. This self-report measure consists of 21 items with overall score range from 0 - 38, with the last two items not counted in scoring. A high score represents a worse outcome.

    Time frame: End of acute treatment 4-6 weeks, then end of F/U 6 months

  2. Mean Depression Score as Assessed by Beck Depression Inventory (BDI)

    This measure is a 21-item self-report test presented in a multiple choice format which measures presence and extent of depression with overall score range from 0 - 63. A higher score represents a worse outcome. Each of the 21 items addresses a specific symptom or attitude that pertains to depressed patients, and which are consistent with descriptions of the depression within the peer-reviewed literature. While generally deemed less reliable than scales score by a trained rater (for example, the HRSD), the Beck scale is easy to administer, and provides convenient means by which patients can effectively communicate their own perception of their mood state.

    Time frame: Baseline - end of acute treatment 4-6 weeks, then end of F/U 6 months

  3. Mean Mental Component Score as Assessed by VR-36 Mental Component Summary (MCS)

    The VR-36 is a self-administered survey that measures eight dimensions of health: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. It yields scale scores for each of these eight health domains, and two summary measures of physical and mental health: the Physical Component Summary (PCS) and Mental Component Summary (MCS). MCS is analyzed in this section. Standardized scoring ranging from 0-100. A higher score represents a better outcome.

    Time frame: End of acute treatment 4-6 weeks, then end of F/U 6 months

  4. Mean Physical Component Score as Assessed by VR-36 Physical Component Summary (PCS)

    The VR-36 is a self-administered survey that measures eight dimensions of health: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. It yields scale scores for each of these eight health domains, and two summary measures of physical and mental health: the Physical Component Summary (PCS) and Mental Component Summary (MCS). PCS is analyzed in this section. Standardized scoring ranging from 0-100. A higher score represents a better outcome.

    Time frame: End of acute treatment 4-6 weeks, then end of F/U 6 months

  5. Mean Depression Score as Assessed by the Montgomery Asberg Depression Rating Scale (MADRS)

    As another measure of depression, the Montgomery-Asberg Depression Rating Scale (MADRS) has been used with increasing frequency in recent years to measure outcome in antidepressant efficacy trials. It offers an alternative view of depressive illness, and may be sensitive to depressive symptoms that are not easily captured in the context of the HRSD, such as hypersomnia, increased appetite, and concentration/indecision. The MADRS is a 10-item clinician rating of depressive symptoms. Each item is scored on a 7-point scale (0 to 6) (range 0-60). A high score represents a worse outcome.

    Time frame: End of acute treatment 4-6 weeks, then end of F/U 6 months

07

Results

Posted Feb 7, 2018

Participant flow

Participant flow — Overall Study
MilestoneActive rTMSSham rTMS
Started8183
Completed6065
Not completed2118

Outcome measures

PrimaryThe Proportion of Participants Achieving Remission From Depression as Assessed by Hamilton Rating Scale for Depression

The primary outcome is a proportion of participants achieving remission from depression based on the HRSD24 less than or equal to 10 at the end of the acute treatment phase. 24 item Instrument with overall score range from 0 - 76. High values represent a worse outcome.

Time frame:
End of acute treatment 4-6 weeks
Reported as:
Count of participants · Participants
The Proportion of Participants Achieving Remission From Depression as Assessed by Hamilton Rating Scale for Depression
ParticipantsActive rTMSSham rTMS
The Proportion of Participants Achieving Remission From Depression as Assessed by Hamilton Rating Scale for Depression3331
SecondaryMean Suicidal Ideation Score as Assessed by Beck Scale for Suicide Ideation (BSS)

To help clinicians screen psychiatric patients for suicidal ideation, the Beck Scale for Suicide Ideation was developed, and is herein referred to as the BSS. This self-report measure consists of 21 items with overall score range from 0 - 38, with the last two items not counted in scoring. A high score represents a worse outcome.

Time frame:
End of acute treatment 4-6 weeks, then end of F/U 6 months
Reported as:
Mean · units on a scale
Mean Suicidal Ideation Score as Assessed by Beck Scale for Suicide Ideation (BSS)
units on a scaleActive rTMSSham rTMS
End of Acute Treatment2.0 ± 4.62.7 ± 4.9
End of F/U1.5 ± 4.22.5 ± 4.9
SecondaryMean Depression Score as Assessed by Beck Depression Inventory (BDI)

This measure is a 21-item self-report test presented in a multiple choice format which measures presence and extent of depression with overall score range from 0 - 63. A higher score represents a worse outcome. Each of the 21 items addresses a specific symptom or attitude that pertains to depressed patients, and which are consistent with descriptions of the depression within the peer-reviewed literature. While generally deemed less reliable than scales score by a trained rater (for example, the HRSD), the Beck scale is easy to administer, and provides convenient means by which patients can effectively communicate their own perception of their mood state.

Time frame:
Baseline - end of acute treatment 4-6 weeks, then end of F/U 6 months
Reported as:
Mean · units on a scale
Mean Depression Score as Assessed by Beck Depression Inventory (BDI)
units on a scaleActive rTMSSham rTMS
End of Acute Treatment14.2 ± 10.913.0 ± 9.5
End of F/U9.0 ± 8.312.8 ± 10.8
SecondaryMean Mental Component Score as Assessed by VR-36 Mental Component Summary (MCS)

The VR-36 is a self-administered survey that measures eight dimensions of health: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. It yields scale scores for each of these eight health domains, and two summary measures of physical and mental health: the Physical Component Summary (PCS) and Mental Component Summary (MCS). MCS is analyzed in this section. Standardized scoring ranging from 0-100. A higher score represents a better outcome.

Time frame:
End of acute treatment 4-6 weeks, then end of F/U 6 months
Reported as:
Mean · units on a scale
Mean Mental Component Score as Assessed by VR-36 Mental Component Summary (MCS)
units on a scaleActive rTMSSham rTMS
End of Acute Treatment35.1 ± 14.336.0 ± 14.7
End of F/U34.5 ± 12.834.8 ± 13.4
SecondaryMean Physical Component Score as Assessed by VR-36 Physical Component Summary (PCS)

The VR-36 is a self-administered survey that measures eight dimensions of health: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. It yields scale scores for each of these eight health domains, and two summary measures of physical and mental health: the Physical Component Summary (PCS) and Mental Component Summary (MCS). PCS is analyzed in this section. Standardized scoring ranging from 0-100. A higher score represents a better outcome.

Time frame:
End of acute treatment 4-6 weeks, then end of F/U 6 months
Reported as:
Mean · units on a scale
Mean Physical Component Score as Assessed by VR-36 Physical Component Summary (PCS)
units on a scaleActive rTMSSham rTMS
End of Acute Treatment41.9 ± 10.941.2 ± 11.9
End of F/U42.8 ± 10.840.1 ± 12.3
SecondaryMean Depression Score as Assessed by the Montgomery Asberg Depression Rating Scale (MADRS)

As another measure of depression, the Montgomery-Asberg Depression Rating Scale (MADRS) has been used with increasing frequency in recent years to measure outcome in antidepressant efficacy trials. It offers an alternative view of depressive illness, and may be sensitive to depressive symptoms that are not easily captured in the context of the HRSD, such as hypersomnia, increased appetite, and concentration/indecision. The MADRS is a 10-item clinician rating of depressive symptoms. Each item is scored on a 7-point scale (0 to 6) (range 0-60). A high score represents a worse outcome.

Time frame:
End of acute treatment 4-6 weeks, then end of F/U 6 months
Reported as:
Mean · units on a scale
Mean Depression Score as Assessed by the Montgomery Asberg Depression Rating Scale (MADRS)
units on a scaleActive rTMSSham rTMS
End of Acute Treatment14.3 ± 11.113.1 ± 10.5
End of F/U13.7 ± 10.215.0 ± 9.7

Adverse events

Collected over From informed consent until termination. 7-8 months.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Active rTMS0/81 (0%)22/81 (27.2%)71/81 (87.7%)
Sham rTMS0/83 (0%)18/83 (21.7%)69/83 (83.1%)
Most frequent serious events
Showing 10 of 36
Most frequent serious events
EventActive rTMSSham rTMS
Acoustic stimulation tests abnormalInvestigations4/815/83
Suicidal ideationPsychiatric disorders4/814/83
Alcohol poisoningInjury, poisoning and procedural complications2/810/83
HypoacusisEar and labyrinth disorders2/812/83
DepressionPsychiatric disorders1/812/83
Suicide attemptPsychiatric disorders1/811/83
Depressed moodPsychiatric disorders1/810/83
ManiaPsychiatric disorders1/810/83
Persistent depressive disorderPsychiatric disorders1/810/83
Road traffic accidentInjury, poisoning and procedural complications1/810/83
Most frequent other events
Showing 10 of 219
Most frequent other events
EventActive rTMSSham rTMS
Acoustic stimulation tests abnormalInvestigations16/8116/83
HeadacheNervous system disorders15/8116/83
NasopharyngitisInfections and infestations8/818/83
DepressionPsychiatric disorders6/812/83
FallInjury, poisoning and procedural complications3/816/83
Upper respiratory tract infectionInfections and infestations4/814/83
GastroenteritisInfections and infestations4/811/83
ArthralgiaMusculoskeletal and connective tissue disorders4/812/83
AnxietyPsychiatric disorders4/812/83
Muscle spasmsMusculoskeletal and connective tissue disorders2/814/83

Baseline characteristics

Age, Continuous
Age, Continuous(years)Active rTMSSham rTMSTotal
Mean55.6 ± 12.254.8 ± 12.655.2 ± 12.4
Sex: Female, Male
Sex: Female, Male(Participants)Active rTMSSham rTMSTotal
Female141832
Male6765132
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Active rTMSSham rTMSTotal
American Indian or Alaska Native202
Asian134
Native Hawaiian or Other Pacific Islander000
Black or African American121426
White6363126
More than one race325
Unknown or Not Reported011
Region of Enrollment
Region of Enrollment(Participants)Active rTMSSham rTMSTotal
United States8183164
Beck Scale for Suicide Ideation (BSI)
Beck Scale for Suicide Ideation (BSI)(units on a scale)Active rTMSSham rTMSTotal
Mean3.7 ± 6.05.6 ± 6.74.7 ± 6.5
Beck Depression Inventory (BDI)
Beck Depression Inventory (BDI)(units on a scale)Active rTMSSham rTMSTotal
Mean22.6 ± 10.326.5 ± 10.024.5 ± 10.3
VR-36 Mental Component Summary (MCS)
VR-36 Mental Component Summary (MCS)(units on a scale)Active rTMSSham rTMSTotal
Mean27.2 ± 11.625.1 ± 10.026.2 ± 10.8
VR-36 Physical Component Summary (PCS)
VR-36 Physical Component Summary (PCS)(units on a scale)Active rTMSSham rTMSTotal
Mean42.4 ± 11.540.2 ± 10.041.3 ± 10.8

1 further baseline measures are reported on the registry.

08

Study locations

9 sites
  • VA Palo Alto Health Care System, Palo Alto, CA
    Palo Alto, California 94304-1290, United States
  • San Francisco VA Medical Center, San Francisco, CA
    San Francisco, California 94121, United States
  • Cincinnati VA Medical Center, Cincinnati, OH
    Cincinnati, Ohio 45220, United States
  • Philadelphia VA Medical Center, Philadelphia, PA
    Philadelphia, Pennsylvania 19104, United States
  • VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
    Pittsburgh, Pennsylvania 15240, United States
  • Ralph H. Johnson VA Medical Center, Charleston, SC
    Charleston, South Carolina 29401-5799, United States
  • Central Texas Veterans Health Care System, Temple, TX
    Temple, Texas 76504, United States
  • VA Salt Lake City Health Care System, Salt Lake City, UT
    Salt Lake City, Utah 84148, United States
  • White River Junction VA Medical Center, White River Junction, VT
    White River Junction, Vermont 05009-0001, United States
09

References and documents

Publications

  • Mi Z, Biswas K, Fairchild JK, Davis-Karim A, Phibbs CS, Forman SD, Thase M, Georgette G, Beale T, Pittman D, McNerney MW, Rosen A, Huang GD, George M, Noda A, Yesavage JA. Repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depression (TRMD) Veteran patients: study protocol for a randomized controlled trial. Trials. 2017 Sep 2;18(1):409. doi: 10.1186/s13063-017-2125-y. PubMed 28865495 ↗
  • Yesavage JA, Fairchild JK, Mi Z, Biswas K, Davis-Karim A, Phibbs CS, Forman SD, Thase M, Williams LM, Etkin A, O'Hara R, Georgette G, Beale T, Huang GD, Noda A, George MS; VA Cooperative Studies Program Study Team. Effect of Repetitive Transcranial Magnetic Stimulation on Treatment-Resistant Major Depression in US Veterans: A Randomized Clinical Trial. JAMA Psychiatry. 2018 Sep 1;75(9):884-893. doi: 10.1001/jamapsychiatry.2018.1483. PubMed 29955803 ↗

Study documents

  • Study protocol · Feb 12, 2016
  • Statistical analysis plan · Jan 13, 2017

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Mar 9, 2018, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT01191333
Lead sponsor
VA Office of Research and Development
Responsible party
Sponsor
First posted
Aug 30, 2010
Start date
Jul 2, 2012
Primary completion
Feb 15, 2017
Completion
Mar 31, 2017
Results posted
Feb 7, 2018
Last update
Mar 9, 2018

Study contacts

Jerome A. Yesavage, MD
study chair · VA Palo Alto Health Care System, Palo Alto, CA

Oversight

Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
Yes
View the source record on ClinicalTrials.gov ↗

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