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
15 comments:
This is indeed bizarre. Did the FDA make any attempt to explain themselves?
I tried to find an explanation and was unsuccessful. If people want to dig deeper, they could conceivably find something. Weird.
TMS does not harm a person to my knowledge so its only problem is in its expense and competition to regular Pharma antidepressant chemicals.
People flopping about as a puppet does during real TMS versus fake TMS where nothing happens is hard to make a double blind efficacy test .
How could the FDA make a serous attempt to explain themselves -- short of admitting the obvious? People got paid off!
In 2008 FDA also approved the antipsychotics Saphris (asenapine Merck) and Fanapt (iloperidone -Vanda). It you look at the reviews you find that in both cases reviewers said the drug should not be approved. The reviewers then disappear and FDA management in one case ignores safety and efficacy concerns (with the help of the advisory committee) and in the over case does a complete 180 on their own assessment of the lack of efficacy.
Salmon
Thank you for a timely post. I am getting introductory cards in the mail from a local psychiatric office inviting me to send clients with "treatment resistant depression." I so appreciate you doing my homework for me.
I just need to say thank you for your work. This post, like all of your pieces, answers a desperate need for someone to tell the truth. You're doing us all a tremendous service.
Mike: Thanks for your comment. Responses follow...
"If they had performed TMS on people without a history of treatment resistant depression they would have likely gotten much better results."
Maybe -- let them conduct such a study and let's see what happens.
"It’s really better to compare the outcomes of the TMS trial to the STAR*D trial on medication resistant patients."
How about a study comparing TMS, medication switching, and placebo for treatment-resistant depression...
I'm fine with researchers using a bunch of secondary measures. However, selectively presenting the positive results and burying the negative results is not acceptable.
I'm not saying TMS is necessarily a bad treatment. Maybe future research will show it is utterly amazing. But the evidence base on which the FDA approval was generated is unimpressive.
if this medicine is not effective to depression, why FDA still approve it.
First, please allow me to introduce myself. My name is Karl Lanocha. I am a psychiatrist specializing in treatment resistant depression. For 20 years I was the medical director for psychiatric services at Concord Hospital in Concord New Hampshire. For most of my career, the most effective treatment for treatment resistant depression has been electroconvulsive therapy. Contrary to popular belief, ECT is safe and extremely effective. Unfortunately however, it does cause certain well known side effects, chief among them temporary, but sometimes severe memory problems.
In January 2009, I became one of the first doctors in the country to begin using the newly approved Neurostar TMS therapy device and, within 3 months, I was so impressed with the efficacy of TMS that I decided to leave my position of 20 years in order to devote myself exclusively to this new treatment.
I have thus far treated more than two dozen patients, all but one of whom have had either very good or excellent responses. Nearly all are in complete remission after decades of chronic and debilitating depression.
I too have been unimpressed with the efficacy of atypical antipsychotics (eg. Abilify, Saphris, et al.) either as stand-alone treatments or as adjuncts in the treatment of depression. Not only is TMS effective, but it causes no side effects. Contrary to the statement made by Mark p.s.2, people are not "flopping around like puppets".
Indeed, the only sensation associated with TMS is a mild tingling or tapping sensation on the scalp. Most people adapt to this quickly and it's not unusual for patients to fall asleep during during a treatment. Currently, my youngest patient is a 16 year old girl and my oldest patient is an 87 year old woman (with a cardiac pacemaker). Both of them sleep through their sessions.
Most of the comments on this blog are, unfortunately, either incorrect, misinformed, or both. Without specifically trying to refute each of them, I would point out that TMS has been in continuous worldwide use since 1985. It has been approved for research use in the United States since 1986. The technology itself is not new.
The usefulness of TMS in the treatment of depression was discovered accidentally in the mid-1990s while investigating its use in the treatment of Parkinson's disease. It has been in routine clinical use for depression in many European countries, Canada, and Australia-New Zealand for over a decade.
The issues with FDA approval had nothing to do with safety and very little to do with efficacy. The FDA did not approve TMS-they had already done that in 1986. What they approved was a specific device for the specific use of TMS in treatment resistant depression. This device has a number of features that make it very different from existing research devices. That information can be readily found elsewhere.
In summary, I would encourage all readers of this blog to obtain information from reliable and knowledgeable sources only. (The information here pertaining to the FDA approval process, for example, was outdated and incomplete). In fact, TMS is not only safe and effective, it is truly a revolutionary treatment that may be effective for a range of neuropsychiatric conditions other than depression. Third party insurance coverage is expected to be routine by late 2010.
Karl Lanocha, MD
The TMS Center of New England
www.tmsnewengland.com
Karl: Thanks for your lengthy comment.
"The issues with FDA approval had nothing to do with safety and very little to do with efficacy." According to the FDA, the issues had a lot to do with efficacy. This is stated rather clearly and documented in my post, and by Yu and Lurie.
You mention that people should be getting their information from "reliable and knowledgeable sources" - I'm wondering what those sources are. The sources cited in my post seem pretty reliable.
Sounds like the good doctor, Lanocha has a very vested interest in this therapy. I won't say more.
I am currently on my 12th session of TMS. I have been depressed to some extent my entire life, more or less housebound by it for 10 yrs. I have been on all meds/combos, had 13 ECT treatments which made me a whole lot worse and cognitively I am still paying for 5 years later. TMS is working. It is incredible. Small changes at this point but sig to do with daily functioning, leaving the house, GOING TO GET MY HAIR DONE (huge. I have been unable to tolerate looking at myself or have others for yrs)enjoyment sometimes of just reg things, and the best so far - the glimmer of a sense of self. This is the future first choice for severe depression instead of ECT.
Yes Dr. Lanocha does sound like he has a vested interest in this, but that is probably because HE IS TRYING TO HELP PEOPLE!!! Not all people are only interested in money.
I don't have a lot of experience with TMS, but I am a psychotherapist who works in conjunction with medical doctors and psychiatrists. I was thrilled when a couple of my clients began telling me that the psychiatrist was treating them with something other than drugs. I only have one client who completed the whole 6 week treatment and was consistent with showing up for her therapy, and she had very good results. By week 4 she said she noticed a change, and after week 6 she said she just wasn't sad anymore and had more motivation, and stressful things were not bothering her the way they used to. The only side effect was a little bit of a headache on some of the days she received the treatment. Doctors are SO eager to push drugs onto people that it is refreshing for them to be trying something like this. If it doesn't work- well at least your kidneys and liver aren't suffering now too.
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