How Effective Will Therapy Be for Complex Mental Health Profiles?

By Annette M. Boyle

Jerome Yesavage, MD

Jerome Yesavage, MD

PALO ALTO, CA — At one point during the 20th century, the idea of using “shock treatment” on patients who failed to respond to medications or psychotherapy for their depression was considered barbaric. Over time, however, researchers realized that electroconvulsive therapy (ECT) was quite effective and, even now, remains a recommended option for those patients.

A new alternative, however, is gaining favor, because it has fewer side effects than ECT and has the advantage of not requiring sedation.

During the past two decades, the evidence supporting the use of repetitive transcranial magnetic stimulation (rTMS) in treatment of resistant major depression has steadily built. But will it work for veterans, who have more complex medical and mental health profiles?

That’s the question Jerome Yesavage, MD, associate chief of staff for Mental Health and director of the Mental Illness Research Education and Clinical Center at the VA Palo Alto Health Care System and colleagues at nine VA facilities are trying to answer with a multicenter, randomized clinical trial that started in June 2012 and enrolled its last participants in April.

The VA study will compare active rTMS to sham rTMS in approximately 160 veterans with treatment resistant major depression. Participants will be randomized to one of two arms to receive either 20 to 30 sessions of rTMS in blocks of five sessions or the same number of sham treatments.

In addition to Palo Alto, the participating facilities are the San Francisco VAMC; Cincinnati VAMC; Philadelphia VAMC; Pittsburgh Health System; Ralph H. Johnson VAMC in Charleston, SC; Central Texas Veterans Health Care System in Temple, TX; VA Salt Lake City Health Care System; and the White River Junction VAMC in White River, VT.

VA Pittsburgh researchers prepare a study participant for repetitive transcranial magnetic stimulation (rTMS). Photo from Pittsburgh VAMC

VA Pittsburgh researchers prepare a study participant for repetitive transcranial magnetic stimulation (rTMS). Photo from Pittsburgh VAMC

Finding a new and effective therapy for major depression could benefit thousands of veterans. About 14% of veterans of the OEF/OIF conflicts met the criteria for major depression, according to a RAND study, and the VA reports that 10% of older veterans have been diagnosed with the disorder.

About 10% of Americans suffer from major depression each year, but, for more than 20% of them antidepressants, mood stabilizers, or psychotherapy fail to provide enough relief.

Some of those who do not respond to either of these therapies find relief with ECT. Despite studies demonstrating its efficacy, many patients and psychiatrists remain uncomfortable with the seizures, risks, and popular perceptions associated with the treatment.

Repetitive transcranial magnetic stimulation might offer another option for treatment. In rTMS, an electrical current is pulsed through an insulated coil placed on the patient’s scalp. The pulse generates a brief dynamic magnetic field that induces an electrical current in the brain’s neural circuitry.

“Compared to ECT, it does not require anesthesia and may have fewer side effects,” Yesavage told U.S. Medicine. Like ECT, it stimulates the brain, but it does not provoke seizures or cause memory loss or confusion.

Currently, one rTMS device has Food and Drug Administration approval for delivery of rTMD in patients with major depression who have failed to respond to at least one antidepressant. The Food and Drug Administration clearance was based on a large, multisite, sham-controlled randomized study that found that 15% of patients who had failed to respond to an average of 1.6 medications achieved remission within six weeks and 23% within nine weeks, as measured by the 17-question Hamilton Depression Rating Scale criteria.1

Large studies of rTMS in clinical practice have found response rates of 50% to 60% and remission rates of 25% to 35% in patients who have failed multiple trials of antidepressants. A recent trial that continued to follow participants for a year found that less than 30% of those who responded to treatment or achieved remission relapsed during the 12 months.2,3,4

The applicability to veterans, however, is unclear. “Veterans are very complex patients with many comorbidities,” Yesavage said. “Other psychiatric treatments that have worked in civilians have not worked in veteran populations.”

Yesavage noted two particular comorbidities that might lead to different outcomes from rTMS, compared with other patients: post-traumatic stress disorder (PTSD) and substance abuse. Previous clinical trials of rTMS for depression have excluded participants with these conditions, which affect a significant percentage of depressed veterans. A study conducted by researchers at the Syracuse VAMC found that 47% of depressed OEF/OIF veterans also had PTSD and 14% had PTSD and a substance use disorder.5

The VA study does not exclude veterans with these comorbidities.

Veterans will remain under the care of their VA primary mental health provider throughout the study. Participants will be assessed using the Beck Scale for Suicide Ideation, the Beck Depression Inventory and Veterans RAND 36-Item Health Survey at the end of the four- to six-week treatment period and again at the end of the six-month follow-up period.

The estimated completion date for the study is June 2017. A positive outcome could expand the choices available to VA clinicians. As Yesavage observed, “both in veterans and civilians, there is always the need for better treatments for depression.”


  1. O’Reardon JP, Solvason HB, Janicak PG, Sampson S, Isenberg KE, Nahas Z, McDonald WM, Avery D, Fitzgerald PB, Loo C, Demitrack MA, George MS, Sackeim HA. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007 Dec 1;62(11):1208-16.
  2. Carpenter LL, Janicak PG, Aaronson ST, et al. Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice. Depress Anxiety 2012; 29:587–596.
  3. Connolly RK, Helmer A, Cristancho MA, et al. Effectiveness of transcranial magnetic stimulation in clinical practice post-FDA approval in the United States: results observed with the first 100 consecutive cases of depression at an academic medical center. J Clin Psychiatry 2012; 73:e567–e573.
  4. Dunner DL, Aaronson ST, Sackeim HA, Janicak PG, Carpenter LL, Boyadis T, Brock DG, Bonneh-Barkay D, Cook IA, Lanocha K, Solvason B, Demitrack MA., A multisite, naturalistic, observational study of transcranial magnetic stimulation for patients with pharmacoresistant major depressive disorder: durability of benefit over a 1-year follow-up period. J Clin Psychiatry 2014;75(12):1394–1401.
  5. Possemato K, Wade M, Andersen J, Ouimette P. The impact of PTSD, depression, and substance use disorders on disease burden and health care utilization among OEF/OIF veterans. Psychological Trauma: Theory, Research, Practice, and Policy, Vol 2(3), Sep 2010, 218-223.