Daily Left Prefrontal Transcranial Magnetic Stimulation Therapy for Major Depressive Disorder: A Sham-Controlled Randomized Trial | Depressive Disorders | JAMA Psychiatry | JAMA Network
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    1 Comment for this article
    TMS: Does it Really Work?
    Jeffrey A. Mattes, M.D. | Psychopharmacology Research Association of Princeton
    No relevant conflicts of interest.
    Letter to the Editor:
    I’m writing regarding the article by George et al. on TMS in the May 2010 issue (Volume 67, No. 5, pages 507-516).
    I’ve always been skeptical regarding the efficacy of TMS, partly because it affects primarily the superficial layers of the cortex, while moods like depression are thought to involve deeper structures in the brain (e.g. the limbic lobe). So I may be overly critical, but I question whether this study is, as the authors state, a “relatively unambiguous demonstration of a treatment effect in the absence of
    Several issues deserve clarification. In their “Concomitant Treatments” section, the authors indicate that remission was defined as a Ham-D score of 3 or less; was this a misprint? “3” is unusually low; if they really used 3 to define remitters, was this chosen a priori, before seeing the data.
    The percentage of responders was quite low, only 15% in the active group and 5% in the sham group. It’s true that these were relatively refractory patients, but one still might have expected a higher response rate. Somewhat paradoxically, perhaps, the response rate in Phase II, which provided open TMS treatment, yielded a much higher response rate, about 30%, whether patients received active or sham treatment during Phase I. This is hard to explain, and suggests that patients were not so very refractory.
    While the authors present a number of analyses, they don’t present what I think would still be considered the most standard analysis, including all data, last observation carried forward, on an intent to treat basis. Their footnote “a” on Table 5 indicates that scores missing at the end of Phase I were considered as missing observations, rather than using LOCF. This resulted in the loss of about 10% of patients, in data analyses. There are pros and cons to different statistical approaches, but I think the standard analyses should be presented, even if other analyses were stated a priori to be primary and were therefore given more weight.
    The authors report under “Site Differences” that 15 of the 18 remitters came from only two of the four sites. They relate this to those two sites also having less treatment resistant individuals, but since the response to Phase II was so much better than to Phase I, I think that they should also indicate whether most of the remitters at the end of Phase II also came from those two sites. I think too that the authors should state which sites had the large number of remitters; clearly one of the sites (MUSC) has been most involved with the development of TMS, and might have the most conflict of interest (even if this conflict is not financial). The authors made a valiant attempt to preserve the blind, but treaters, as they indicate, were able to guess whether patients were receiving active treatment or sham, better than chance. This may also occur in medication studies, but I think it’s especially relevant when trying to document efficacy with novel treatments.
    Jeffrey A. Mattes, M.D.
    Original Article
    May 2010

    Daily Left Prefrontal Transcranial Magnetic Stimulation Therapy for Major Depressive Disorder: A Sham-Controlled Randomized Trial

    Author Affiliations

    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.

    Arch Gen Psychiatry. 2010;67(5):507-516. doi:10.1001/archgenpsychiatry.2010.46

    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