CSP #556 - The Effectiveness of rTMS in Depressed VA Patients

• Beck Scale for Suicide Ideation (BSI) [ Time Frame: Baseline - end of active treatment 4-6 weeks, then end of F/U 6 months ] [ Designated as safety issue: No ]
• Beck Depression Inventory (BDI) [ Time Frame: Baseline - end of active treatment 4-6 weeks, then end of F/U 6 months ] [ Designated as safety issue: No ]
• VR-36 [ Time Frame: Baseline - end of active treatment 4-6 weeks, then end of F/U 6 months ] [ Designated as safety issue: No ]

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. -

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 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.

• Device: rTMS
  Repetitive Transcranial Magnetic Stimulation
• Device: Sham Device
  Placebo Device that simulates active rTMS treatment

• Experimental: Arm 1
  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.
  Intervention: Device: rTMS
• Placebo Comparator: Arm 2
  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.
  Intervention: Device: Sham Device

Inclusion Criteria:

1. Between 18 and 70 years of age; (Figiel et al. 1998; McDonald and Greenberg 2000).
2. Using the Structured Clinical Interview for DSM Disorders (SCID) for DSM-IV-TR (First et al. 2002) patients will be diagnosed MDD.
3. Have a HRSD24 20 no more than 7 days prior to randomization.
4. Exhibit moderate level of resistance to antidepressant treatment in the current episode defined, using the ATHF (Sackeim et al. 1990), as failure of at least two adequate medication trials in the current episode.
5. Duration of current episode of MDD 3 years.
6. Ability to obtain a Motor Threshold (MT) (should be determined at the end of the screening process).
7. Currently under the care of a psychiatrist.
8. If on a psychotropic medication regimen, that regimen will be stable for at least 4 weeks prior to entry to the study and patient will be willing to remain on a stable regimen during the acute treatment phase.
9. Has an adequately stable condition and environment to enable attendance at scheduled clinic visits.

10. 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 your tubes tied)
11. Able to read, verbalize understanding and voluntarily sign the Informed Consent Form prior to performance of any study-specific procedures or assessments.

Exclusion Criteria:

1. 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).
2. 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).
3. Have a cardiac pacemaker.
4. Have failed to respond clinically to an adequate trial of ECT, defined as 8 bilateral or 10 unilateral treatments, in the current episode.
5. Have an implanted device (deep brain stimulation) or metal in the brain.
6. Have a cochlear implant.
7. Have a mass lesion, cerebral infarct, increased intracranial pressure, or other active CNS disease, including a seizure disorder.
8. Known current psychosis as determined by DSM-IV or SCID (axis I, psychotic disorder, schizophrenia) or a history of a non-mood psychotic disorder.
9. Known current Bipolar I disorder as determined by SCID or a History of Bipolar I disorder.
10. Current amnestic disorders, dementia, BOMC 10 or delirium.
11. 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.
12. Patients with an elevated risk of seizure due to TBI.
13. Participation in another concurrent clinical trial.
14. Patients with prior exposure to rTMS.
15. Active current suicidal intent or plan as evidenced by a score of 4 or 5 on the suicidal ideation portion of the CSSRS 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).
16. Unstable cardiac disease or recent (< 3 months previous) myocardial infarction.
17. Patient refuses to sign consent for participation in the study.