At last some good news about rTMS?
A large study to the efficacy and safety of rTMS is recently published. The primary outcome criterion for rTMS for treatment of depression was the difference between the mean MADRS score before minus the score at week 4 of treatment. The difference between rTMS and sham TMS was not significant (p=0.057)at week 4. There was a baseline imbalance between groups. Six patients had a MADRS baseline score between 14 and 19 which is in the mild range. They were unevenly randomized across the two groups (i.e., 4 to the active and 2 to the sham). Excluding these six from the analysis finally resulted in a significant difference between groups (p=0.038), favoring active treatment. At week 6 the baseline to endpoint change on the MADRS was not significant with or without the six afore mentioned patients.
With the Hamilton Ratings Scale for Depression 17 and 24 item version (HAMD-17, HAMD-24), the difference of the mean change at week 4 was significant for both rating scales in favor of the active treatment. This advantage was sustained at week 6.
Mean differences of scores of depression severity scales are very sensitive measures. They easily lead to significant differences but are these differences not only significant but also clinically relevant.
For comparison clinician rated global illness severity showed significant greater improvement with the active treatment already at week 2 continuing to week 6.
Response rates, that is a reduction of 50% or more on the severity scale from baseline until week 4 and 6 was significantly higher for the active treatment compared to the sham treatment for all three rating scales.
Remission rates were not significantly higher for the active treatment except for the MADRS at week 6 and HAMD-24 at week 6. Remission is what you should seek in the treatment of depression. Remission rate at week 6 defined as a score on the HAMD-17 lower than 7 was 15.5%.
Patient reported mood change and global improvement were not significantly higher for the active treatment compared to sham rTMS.
Side effects of rTMS
There was more scalp discomfort and pain with the active treatment. There were no seizures. 16 serious were reported, 9 in the active treatment and 7 in the sham treatment, mostly due to disease related exacerbation.
This is the first large (n=301), multi site (23 US, 2 Australia, 1 Canada), placebo controlled trial on medication free depressed patients. Patients were required to have failed at least one but no more than four adequate antidepressant treatments. Patients with lack of response to ECT were excluded.
Dr Shock’s opinion
This is a trial very well done. Due to its design only the scores on time point of week 4 are truly double-blind. They introduced a new method for sham treatment: the sham coil had a embedded magnetic shield. This study also shows that longer treatment with rTMS is well tolerated. The use of pharmacotherapy treatment failure as an inclusion criterion every time amazes Dr Shock. There are far better treatment options e.g. plasma level controlled TCAs, lithium addition and ECT to name a few.
Considering the outcome on the time point at week 4, Dr Shock is not very impressed by the results. For significant difference with the primary outcome 6 patients had to be excluded from the analysis. The mean difference between active and sham on the severity scales is in the range of 2-3 points, significant but hardly clinical relevant. Absolute figures on response and remission at week 4 are not given in this article. Remission rate at 6 weeks on the HAMD-17 was 15.5% increasing to 22.6% at week 9 with open labeled therapy. Not very impressive.
Article discussed:
Biol Psychiatry. 2007 Dec 1;62(11):1208-16. Epub 2007 Jun 14.
Efficacy and safety of transcranial magnetic stimulation in the acute treatment
of major depression: a multisite randomized controlled trial.
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.
PMID: 17573044 [PubMed – in process]
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November 17, 2007 @ 3:56 am
Hi Doc,
I owe you several thanks. First thanks for opening the door on Flickr. Apparently I didn’t pay much attention to the sidebar on your site. Those are wonderful photos that you’ve taken and then I spent an evening perusing some of the other work.
Most importantly, thanks for expressing your viewpoint as it relates to your reading of the study results. I’ve come to learn even you professionals differ over the interpretation of the same study results making it even more difficult for me as a lay-person and care giver to make the best possible decision(s) for my charge.
Of note also from my perspective was the apparent lowering of the bar as to the acceptability of study subjects when compared to the VNS study.
Once again, thank you and thanks for taking the time to share with me.
Warmly,
Herb
VNSdepression.com
November 27, 2007 @ 1:20 am
Hi Doc,
I thought you might have interest in reading the following press release.
http://www.eurekalert.org/pub_releases/2007-11/uops-prs112607.php#
Since I’ve already read your thoughts relating to the study would you care to comment about this press release?
Warmly,
Herb
VNSdepression.com
November 27, 2007 @ 8:13 pm
Dear Herb,
I’ve seen articles like this one by the dozens in my RSS reader, what is puzzling me is why does this article, one of many about depression treatment and rTMS get so much attention?
It only strengthens my opinion expressed in the post.
Regards Dr Shock
November 27, 2007 @ 8:56 pm
Doc,
Media or sponsor hype? I don’t know.
Maybe it is paid professional hype along the lines of Dr. Carlat’s recent expose or contrition in the New York Times if you happened not to read the piece or the various commentaries on the subject.
http://carlatpsychiatry.blogspot.com/2007/11/dr-drug-rep.html#links
Warmly,
Herb
VNSdepression.com
Transcranial Magnetic Stimulation Gains approval of the FDA for Depression | Dr Shock MD PhD
October 17, 2008 @ 6:27 am
[…] In another trial was very well done but results with rTMS for depression were not very impressive. […]
December 28, 2008 @ 11:13 pm
A recent multicentre trial was published in Neuropsychopharmacology (2009)34,522-534 http://www.neuropsychopharmacology.com (http://www.nature.com/npp/journal/v34/n2/full/npp2008118a.html)
RCT study. > 300 patients included. LOCF design.
In patients that failed to respond to one adequate trial with antidepressants the effect size was 0.83. Not to bad , I guess.
What is Your comment on this study ?
Sincerely,
Dr. G. Otte
December 29, 2008 @ 2:38 pm
This study is only a study for clinical predictors to rTMS. This study is done following a RCT and an openlabel follow up study.
You can read a discussion about those two studies here: RCT:http://tinyurl.com/9lw6j9
Follow up open label study here: http://tinyurl.com/726u8b
I didn’t discus this study for obvious reasons, it’s a analysis of data available from an good RCT and a worse openlabel study. It doesn’t add much to the knowledge already provided. These hypothesis generating trials should be followed up by prospective trials with their hypothesis to test. Waiting for those trials. Not another “look what I have found this time…” By the way I don’t believe rTMS should be tested with therapy resistant depression, whatever that is ( see:http://tinyurl.com/8q62qs). It should be tried by outpatients with depressive disorders.
Kind regards Dr Shock
Kind regards Dr Shock
December 29, 2008 @ 3:03 pm
Good lord !!! Thanks for claryfing things out. As the authors were different I did not immediately realise that this is just a post hoc analysis of identifying so called predictive variables on data of two previous older and already separately published studies “lumped” together: one good (RCT) and one bad (open label). As in the movie it gives me a bit of an “ugly” end feeling. OK It is not really deceptive for he or she who reads attentively but a casual reader could think of it as “new” evidence. I agree with You completely that methodologically it would have been much better to skip this and get to a real prospective (new data) study instead. I am a bit baffled that nature reviewers allowed this to pass so easily. Making it public could be dangerous as it will enhance picking the low fruit for those doing a survey on rTMS efficacy. Thanks again for Your critical and vigilant EBM attitude !!
Dr. G. Otte