Clinical trial NCT01191333: The Effectiveness of rTMS in Depressed VA Patients
Official title: CSP #556 - The Effectiveness of rTMS in Depressed VA Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: 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
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2010-08-30
Enrollment: 164
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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:

* 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.

Primary outcomes:
measure: The Proportion of Participants Achieving Remission From Depression as Assessed by Hamilton Rating Scale for Depression
timeFrame: End of acute treatment 4-6 weeks
Secondary outcomes:
measure: Mean Suicidal Ideation Score as Assessed by Beck Scale for Suicide Ideation (BSS)
timeFrame: End of acute treatment 4-6 weeks, then end of F/U 6 months
measure: Mean Depression Score as Assessed by Beck Depression Inventory (BDI)
timeFrame: Baseline - end of acute treatment 4-6 weeks, then end of F/U 6 months
measure: Mean Mental Component Score as Assessed by VR-36 Mental Component Summary (MCS)
timeFrame: End of acute treatment 4-6 weeks, then end of F/U 6 months
measure: Mean Physical Component Score as Assessed by VR-36 Physical Component Summary (PCS)
timeFrame: End of acute treatment 4-6 weeks, then end of F/U 6 months
measure: Mean Depression Score as Assessed by the Montgomery Asberg Depression Rating Scale (MADRS)
timeFrame: End of acute treatment 4-6 weeks, then end of F/U 6 months
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System, Palo Alto, CA
state: California
city: San Francisco
country: United States
facility: San Francisco VA Medical Center, San Francisco, CA
state: California
city: Cincinnati
country: United States
facility: Cincinnati VA Medical Center, Cincinnati, OH
state: Ohio
city: Philadelphia
country: United States
facility: Philadelphia VA Medical Center, Philadelphia, PA
state: Pennsylvania
city: Pittsburgh
country: United States
facility: VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
state: Pennsylvania
city: Charleston
country: United States
facility: Ralph H. Johnson VA Medical Center, Charleston, SC
state: South Carolina
city: Temple
country: United States
facility: Central Texas Veterans Health Care System, Temple, TX
state: Texas
city: Salt Lake City
country: United States
facility: VA Salt Lake City Health Care System, Salt Lake City, UT
state: Utah
city: White River Junction
country: United States
facility: White River Junction VA Medical Center, White River Junction, VT
state: Vermont
Study officials:
affiliation: VA Palo Alto Health Care System, Palo Alto, CA
name: Jerome A. Yesavage, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.