Apparently, the FDA will approve just about anything as an antidepressant. Despite patients indicating that they don't perceive Abilify to work as an antidepressant, the FDA approved it, likely leading to tens of thousands of Americans being able to enjoy a taste of akathisia while getting all the psychological benefits of a placebo. Good work, FDA. The shift of antipsychotics into antidepressants has been documented in many places and is, ironically, very depressing (1, 2, 3, 4).
The FDA's "anything goes" attitude regarding antidepressants apparently extends to mediocre medical devices. In 2007, a paper in Biological Psychiatry presented results from a large trial comparing TMS to sham TMS. The article concluded that the treatment was a fantastic option for depression. Well, close to that anyway. That actually wrote that "Transcranial magnetic stimulation was effective in treating major depression with minimal side effects reported. It offers clinicians a novel alternative for the treatment of this disorder."
Before all of us poor depressed souls get in line for some sweet magnetic stimulation, maybe we should, like, look at the evidence. On the primary measure of outcome, the Montgomery-Asberg Depression Rating Scale, the results weren't quite statistically significant. So the sponsor tried to convince the FDA Neurological Devices Panel that the secondary measures showed super-impressive results. The problem: They didn't. The FDA review panel thought a few things (as can be seen in its entirety here):
- The Panel’s consensus was that the efficacy was not established; some stated that the device’s effectiveness was “small,” “borderline,” “marginal” and “of questionable clinical significance.” The Study 01 endpoint with a p value of 0.057 per se was not considered a fatal flaw in the study analysis. The Panel did not believe that clinical significance was demonstrated with these results.
- In general, the panel believed that the analyses of the secondary effectiveness endpoints did not contribute significant information to help establish the effectiveness of the device.
- The Panel agreed that unblinding was greater in the active group, and considering the magnitude of the effect size, it may have influenced the study results. (35.8% of people receiving TMS reported pain at the application site compared to only 3.8% in the sham TMS group. This is a quick way to make a study unblind, as people experiencing pain could logically surmise that they were receiving TMS).
- The Panel stated that there were too many non-random dropouts to reliably interpret these results. The Panel’s consensus was that the Week 6 data was of limited value and did not provide supportive data for establishing effectiveness. (After week 4, patients who did not show adequate improvement were given the option to quit the double-blind study; over half of patients departed the study after week 4).
The authors note that some patient outcome measures were collected in the trial but omitted from the article. Of the 15 secondary end points the authors included in the paper, 11 were statistically significant. Of 11 secondary end points not included, 2 were statistically significant. Thus, the published end points were three times more likely to be statistically significant than the unpublished ones.TMS was denied FDA-approval in January, 2007. But in October 2008, the FDA had a change of heart, approving the device. I'm not quite sure what changed the mind of the FDA.
The following disclaimer on the device's website is a bit funny:
NeuroStar TMS Therapy has not been studied in patients who have not received prior antidepressant treatment. Its effectiveness has also not been established in patients who have failed to receive benefit from two or more prior antidepressant medications at minimal effective dose and duration in the current episode.So it's only demonstrated (weak) efficacy in people who have failed one (not zero, not more than one) antidepressant trial. Impressive, eh? To summarize, the sponsor and its affiliated academics wrote a paper in a major psychiatry journal in which positive outcomes were three times as likely to be reported as negative outcomes. The efficacy data were unimpressive according to an FDA panel -- and these panels are not known for being particularly choosy about efficacy data. It seemed that TMS was dead in the water, only to be resurrected in the form of a surprising FDA approval. And if being resurrected from the grave doesn't make for a great Halloween post, then what does?
Offending Study:
O’Reardon, J., Solvason, H., Janicak, P., Sampson, S., Isenberg, K., Nahas, Z., McDonald, W., Avery, D., Fitzgerald, P., & Loo, C. (2007). Efficacy and Safety of Transcranial Magnetic Stimulation in the Acute Treatment of Major Depression: A Multisite Randomized Controlled Trial Biological Psychiatry, 62 (11), 1208-1216 DOI: 10.1016/j.biopsych.2007.01.018
Letter to Editor:
Yu, E., & Lurie, P. (2009). Transcranial Magnetic Stimulation Not Proven Effective Biological Psychiatry DOI: 10.1016/j.biopsych.2009.03.026
