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A Sham-Controlled Randomized Trial

Mark S. George, MD; Sarah H. Lisanby, MD; David Avery, MD; William M. McDonald, MD; Valerie Durkalski, PhD; Martina Pavlicova, PhD; Berry Anderson, PhD, RN; Ziad Nahas, MD; Peter Bulow, MD; Paul Zarkowski, MD; Paul E. Holtzheimer III, MD; Theresa Schwartz, MS; Harold A. Sackeim, PhD

Arch Gen Psychiatry. 2010;67(5):507-516.

Context  Daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) has been studied as a potential treatment for depression, but previous work had mixed outcomes and did not adequately mask sham conditions.

Objective  To test whether daily left prefrontal rTMS safely and effectively treats major depressive disorder.

Design  Prospective, multisite, randomized, active sham-controlled (1:1 randomization), duration-adaptive design with 3 weeks of daily weekday treatment (fixed-dose phase) followed by continued blinded treatment for up to another 3 weeks in improvers.

Setting  Four US university hospital clinics.

Patients  Approximately 860 outpatients were screened, yielding 199 antidepressant drug–free patients with unipolar nonpsychotic major depressive disorder.

Intervention  We delivered rTMS to the left prefrontal cortex at 120% motor threshold (10 Hz, 4-second train duration, and 26-second intertrain interval) for 37.5 minutes (3000 pulses per session) using a figure-eight solid-core coil. Sham rTMS used a similar coil with a metal insert blocking the magnetic field and scalp electrodes that delivered matched somatosensory sensations.

Main Outcome Measure  In the intention-to-treat sample (n = 190), remission rates were compared for the 2 treatment arms using logistic regression and controlling for site, treatment resistance, age, and duration of the current depressive episode.

Results  Patients, treaters, and raters were effectively masked. Minimal adverse effects did not differ by treatment arm, with an 88% retention rate (90% sham and 86% active). Primary efficacy analysis revealed a significant effect of treatment on the proportion of remitters (14.1% active rTMS and 5.1% sham) (P = .02). The odds of attaining remission were 4.2 times greater with active rTMS than with sham (95% confidence interval, 1.32-13.24). The number needed to treat was 12. Most remitters had low antidepressant treatment resistance. Almost 30% of patients remitted in the open-label follow-up (30.2% originally active and 29.6% sham).

Conclusion  Daily left prefrontal rTMS as monotherapy produced statistically significant and clinically meaningful antidepressant therapeutic effects greater than sham.

Trial Registration  clinicaltrials.gov Identifier: NCT00149838

Author Affiliations: Brain Stimulation Division, Department of Psychiatry (Drs George, Anderson, and Nahas), and Department of Biometry (Dr Durkalski), Medical University of South Carolina, Charleston; Ralph H. Johnson Veterans Affairs Medical Center, Charleston (Dr George); the Division of Brain Stimulation and Therapeutic Modulation, Columbia University/New York State Psychiatric Institute, New York, New York (Drs Lisanby and Bulow); Department of Psychiatry, University of Washington, Seattle (Drs Avery and Zarkowski); Department of Psychiatry, Emory University, Atlanta, Georgia (Drs McDonald and Holtzheimer); and Departments of Biostatistics (Drs Pavlicova and Ms Schwartz) and Psychiatry (Dr Sackeim), Columbia University College of Physicians and Surgeons, New York.

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