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Original Article:
Mark S. George; Sarah H. Lisanby; David Avery; William M. McDonald; Valerie Durkalski; Martina Pavlicova; Berry Anderson; Ziad Nahas; Peter Bulow; Paul Zarkowski; Paul E. Holtzheimer III; Theresa Schwartz; Harold A. Sackeim
Daily Left Prefrontal Transcranial Magnetic Stimulation Therapy for Major Depressive Disorder: A Sham-Controlled Randomized Trial
Arch Gen Psychiatry 2010; 67: 507-516 [Abstract] [Full text] [PDF]
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Electronic letters published:

[Read Readers Reply] TMS: Does it Really Work?
Jeffrey A. Mattes   (June 29, 2010)

TMS: Does it Really Work? June 29, 2010
Jeffrey A. Mattes,
Psychopharmacology Research Association of Princeton

Send reply to journal:
Re: TMS: Does it Really Work?

jmattesmd{at} Jeffrey A. Mattes

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 unblinding”.

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.

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