The Effectiveness of rTMS in Depressed VA Patients

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.

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.