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A new form of brain stimulation relieved severe depression in a small study

430 points| doener | 6 years ago |med.stanford.edu | reply

253 comments

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[+] PragmaticPulp|6 years ago|reply
Actual paper is available here: https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2019.1...

n=21, no control group, zero blinding. Placebo response is notoriously high in depression studies, so it's unacceptable that they didn't include a control group.

This technique is a variant of rTMS, which has been around for a long time. We've had years of positive rTMS study results that failed to replicate in real-world conditions. There's some early evidence that it might do something positive, but it's not clear that it's a viable treatment option. In most major cities you can usually find at least one obscure rTMS clinic somewhere, but they won't offer the exact rTMS technique studied here. They also won't give you 50 sessions across 5 days as used in this study.

It's very disappointing, even suspicious, that they didn't include a control group. It's trivially easy to include a sham rTMS treatment because the patients can't see the magnetic field. At minimum, they could have split the group into low-dose and high-dose to demonstrate a dose-response relationship. Yet they deliberately chose to avoid any control group or dose-response measurements.

I can't access the full text, so I don't know when they measured the patients' depressive symptoms. If they scored the depression inventory on the final day of the 5-day treatment, this wouldn't be very promising as a long-term treatment. The real test would be how the depression remission holds up after the rTMS treatment is discontinued. If the remission persists for months, that would be truly impressive. On the other hand, if this only works with 50 in-office rTMS sessions per week, it's not a practical outpatient treatment.

I would love to be wrong and for this to be the holy grail of depression treatment, but given the circumstances I think it's best interpreted as an outlier study unless/until someone else reproduces it. I don't think we'll all be going in for 50 sessions of rTMS across 5 days any time soon.

[+] jdm2212|6 years ago|reply
Either this will win the Nobel Prize, or it won't hold up. (Guess which one is more likely.)

A few reasons I don't think it will hold up: - this is a university press release - N = 21 - no control group - no blinding - university press release doesn't even claim it's a new approach, just incremental improvement on an existing approach - the paper (link below) is about evaluating safety, feasibility, and "preliminary efficacy" (i.e., they're not advertising this as a robust result)

Paper available here:

https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2019.1...

https://www.biorxiv.org/content/10.1101/581280v3.full

[+] jimmyswimmy|6 years ago|reply
Indeed.

>With SAINT, study participants underwent 10 sessions per day of 10-minute treatments, with 50-minute breaks in between. After a day of therapy, Lehman’s mood score indicated she was no longer depressed; it took up to five days for other participants. On average, three days of the therapy were enough for participants to have relief from depression.

One imagines that three to five 10 hour (!) days of a presumably highly-trained professional spending time and attention and focus on a patient serves as no less than an incredibly strong placebo. It would be interesting to see a blinded study where the transducer functionality was replaced by a small heater (or whatever is needed to make the system act, feel and sound the same for all involved).

It would be lovely if this held up. Depression and other psychological issues are insidious.

[+] riyadparvez|6 years ago|reply
As someone who is in therapy for quite some time and read quite a lot about psychology, I can please take any claims of "evidence"-based short-term therapy approach with gain of salt. Particularly, if it's a very short term manualized approach of therapy eg, CBT style therapy.

Lots of research in CBT is plagued with abuse of statistics, manipulation of randomized controlled trials, sensalization, and over-hype. For the vast majority of time CBT is good for symptomp reduction and patients relapse frequently. Frankly, the depressed people I know in real life, I don't know how many of them would be benefitted by CBT style therapy.

My own experience is it took me almost a year of therapy, reading psychology and philosophy, lots of self-relfection and going to dark places in my mind to see marked improvement in my depression. If you are suffering from depression, please give psychotherapy a try. It'd be hard, but it's worth it!

[+] MelioRatio|6 years ago|reply
I very much agree, we have to be cautious with our optimism.

Concerning the approach, this study looked into a fairly new form of rTMS, namely iTBS. Here is paper detailing how it differs from 10Hz rTMS, with a specific focus on potential cost savings: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742475/

We certainly need more data on iTBS effectiveness and I hope that a properly controlled, double-blind study can yield some information on whether this is actually effective on a larger scale and in the long term. A sample size of 21 is simply to small to make any judgement on that.

[+] JamesBarney|6 years ago|reply
I'm more hopeful. The remission rate probably won't hold up in subsequent studies, but the current remission rate is enormous. I think there is a very good chance that some effect holds up.

Also I don't think your analysis that it's all or nothing, i.e. that it has a true effect size of "Nobel prize winning" or nothing is true. I think it's very likely that there is some effect size it's just not world changing.

[+] _bxg1|6 years ago|reply
No blinding on a study of a psychological condition just seems doubly bad
[+] c3534l|6 years ago|reply
Transcranial Magnetic Stimulation has had poor results in the past, failing to live up to its previous hype. So I want to know what they did that's fundamentally different from past results. If what they did differently was do a poor job in their experimental setup, then that is enough to explain it.
[+] _prototype_|6 years ago|reply
I'm not a scientist, but I'm curious if any of you know: why do these important studies use such small N? I think its pretty obvious that a small N is not statistically significant, yet for this study, or the myriad of COVID-19 studies, the N is usually < 20.

It's just so frustrating that professional scientists just completely ignore this statistical fact. Why not use use N >= 100 or not at all. It just confuses things in my opinion.

[+] solinent|6 years ago|reply
The criteria for what "depression" is has changed over time, no wonder our results are changing. Almost everyone has depression given the current criteria [1].

Most people have 2,4,5,6,7.

The criteria is so vague your study would have to control for each item on the list. Here, they're not even using that criteria, and instead just using a simple test which involves self-reports. Placebo could be a huge factor here.

[1] https://www.psycom.net/depression-definition-dsm-5-diagnosti...

[+] greendestiny_re|6 years ago|reply
If you're feeling depressed, you might be helped by a—warm bath.

A 2017 Freiburg study [1] took 36 moderately clinically depressed patients and assigned 17 to 30-minute, 40 °C hyperthermic baths, with 19 as control.

After bathing twice a week for four weeks, the study claims the 17 patients had a "moderate but significant improvement".

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371197/

[+] hn_throwaway_99|6 years ago|reply
I think a lot of things these studies have in common is someone else is making you do self care.

As someone who has suffered severe depression on more than one occasion, in those times I know I should practice good hygiene, nutrition, exercise, sleep habits, etc., but the very nature of depression is that it takes away the motivation to do those things. If I were in a study where someone actually prepared the bath for me at a spa center, I bet I would also improve.

IMO, "fixing" depression really means fixing fundamental self-motivation, not just a transitory "oh this feels a little better".

[+] saltyfever|6 years ago|reply
People must not want to hear the truth, hence your downvotes. Most forms of depression can be cured with self-care.

"In health care, self-care is any necessary human regulatory function which is under individual control, deliberate and self-initiated."

[+] cjensen|6 years ago|reply
"Take a warm bath" suffers from a lot of the same problems as this study. You can't actually have a blind control group, so there is effectively no control group.

So this is really just 17 people assigned to take a warm bath. The thing about mental illness is that it's really really hard to be sure if something helped. You're brain is the thing that is broken, and your brain knows you are being treated.

I have depression. I've lost count of the things I've tried, and when asked, I have to say "I don't know if this actually helped or if it's just my brain thinking it should have helped."

With depression, studies which are not double-blind are garbage.

[+] kyuudou|6 years ago|reply
Add moderate exercise 2-3 times a week and there'd probably be even more improvement. I wouldn't discount the importance of good nutrition, either.
[+] 0xcde4c3db|6 years ago|reply
One thing to note is that the study population consisted entirely of severely depressed people. As far as I've read about it, the current consensus seems to be that the more severe the depression is, the more likely it is to respond to medical interventions as opposed to psychological/behavioral ones. This ties in to a broader understanding that depressive disorders are considerably heterogeneous and no single theory or treatment target is relevant to all cases.

So while this may be a genuine breakthrough, I hope people don't get the idea that it's the cure for depression generally.

[+] yboris|6 years ago|reply
> the more severe [a problem] is, the more likely it is to respond to [some shock]

I think there's a generalizable pattern - regression to the mean.

In psychiatry, ECT (Electroconvulsive therapy) seems to be very effective in some severe cases: https://www.mayoclinic.org/tests-procedures/electroconvulsiv...

I'm hopeful that the Stanford technique becomes yet another tool we have to address some of the hardest-to-treat problems.

[+] starpilot|6 years ago|reply
> As far as I've read about it, the current consensus seems to be that the more severe the depression is, the more likely it is to respond to medical interventions as opposed to psychological/behavioral ones.

I've never heard this in my life, can you link? These test subjects were people with treatment-resistant depression though, which I have as well. My experience, along with others I've known with it, is that we're more likely to deal with nocebo effects. HN is tossing heaps of cynicism on this report but even for unblinded testing these results are remarkable.

> “There’s never been a therapy for treatment-resistant depression that’s broken 55% remission rates in open-label testing,” said Nolan Williams, MD, assistant professor of psychiatry and behavioral sciences and a senior author of the study

[+] curiousgal|6 years ago|reply
I hold the prejudiced opinion that most, if not all, psychology research is bogus. It's the one field with the most abuse of statistics and a crisis of reproducibility that dates back to the last century.
[+] threatofrain|6 years ago|reply
This is psychiatry. Psychiatry certainly respects its sister field but takes an independent look at the brain. We could always go back to the wild wild west with no psychologists or psychiatrists.

I mean, does depression even exist, or is it a psychiatric scam?

[+] throwaway5752|6 years ago|reply
I think that is grossly unfair, and honestly a really condescending thing to say about a legitimate area of research.

It is a messy area of work. Brains work differently between people, they work differently over time, among different groups of people, and they can rarely (outside of functional MRIs where you have structural factors) have anything but self reported outcomes. You have the privilege of saying that because people post their research and their numbers, which is all you can ask from any field of science.

[+] solinent|6 years ago|reply
It's all based on self-reports, it's very hard to account for individual differences in how people answer the questions and to control for those factors. I agree wholeheartedly.

However, certain types of severe depression seem to have a biological basis. Inflammatory cytokines may play a role. The "leaky gut" theory seems to be what's helped me personally.

[+] blablabla123|6 years ago|reply
I don't think there is such a thing as abuse of statistics as long as the methodology is published.

In this case, N=21 and no control group shows that there isn't much useful data present in the first place...

[+] riyadparvez|6 years ago|reply
Not to mention lots of psychology research has been done using affluent white college undergrads as research population. If you take lots of these therapy approaches outside of this demographic, they simply don't hold upto the claims made in original research papers.
[+] mindfulplay|6 years ago|reply
Agreed! Asking people how they feel and jotting that down on a piece of paper isn't science. Similar to social and nutrition "sciences" that gear more toward PR angle and "number of news outlets talking about my paper" than legit science.

They should all be relegated back to the arts and crafts.

[+] wolco|6 years ago|reply
Most if not all? That's an interesting statement. If you said all I would assume you do not swe pjsychology as a testable science. What kind of studies do you approve?
[+] m_a_g|6 years ago|reply
90% is really high. Like actually scary high. All the previous treatments were lower than 60%.

I hope everything goes well with this treatment, and there will be no serious side effects. It can save many people's lives.

[+] penagwin|6 years ago|reply
It looks to be a form of TMS which has already shown a lot of promise for several mental disorders. I wasn't able to look at what they changed specifically, but TMS itself is rather safe.
[+] GenericThrow123|6 years ago|reply
A 90% response rate is in-line with ECT on non-medication resistant patients, actually, and it's not historically out of place that TMS performs so effectively. [1] [2]

Historically, TMS has had lower response rates than ECT, though this trial seems to offer a less invasive treatment with a comparable response rate. The measured response rates of the initial trials tend to drop after testing in a larger population, but it's great to see TMS progressing with improvements identified regularly.

1: https://www.nejm.org/doi/full/10.1056/NEJM199303253281204

2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361049/

[+] slothtrop|6 years ago|reply
As soon as I saw "magnetic stimulation" I was a tad skeptical as they've already achieved this with brain electrodes in the past. The difference is it could actually be practical, on psych visits. I see it as a stand-in for medication with all sorts of side-effects. Not a solution mind-you, just a way to bridge the gap to recover, which is what medication is meant to be.

EDIT: a stand-out line: "One month after the therapy, 60% of participants were still in remission from depression. Follow-up studies are underway to determine the duration of the antidepressant effects."

[+] markroseman|6 years ago|reply
Reading some of the comments is a good reminder that solid and meaningful mental health research is very tough and expensive, just based on the sheer variability, which can't be meaningfully captured by 99.9% of studies. Each needs to be seen as one piece in a much, much larger puzzle.

I wrote up some of the problems with doing/interpreting mental health research here: https://mhnav.com/lies-and-evidence/

[+] TheLegace|6 years ago|reply
> Intermittent theta-burst stimulation (iTBS) is a noninvasive brain stimulation treatment that has been approved by the U.S. Food and Drug Administration for treatment-resistant depression.

If this is anything like Neurofeedback treatment, it wouldn't surprise me that it is effective. Neurofeedback treats 3 major frequency ranges of the brain, Delta, Theta and Alpha. Although this treatment seems passive whereas Neurofeedback treatment requires active modulation and stimulation by the person getting the treatment.

Going through Neurofeedback treatment myself and seeing the incredible life changes because of it and now seeing the similarity of the affected brain regions in this study shows that there might be some consensus reached on treating these conditions without medication one day.

[+] starpilot|6 years ago|reply
This is some of the worst HN commentary I've seen. Boundless cynicism on an early study which is actually showing unusually high success rate. What's noteworthy is that the these results are good among unblinded studies on depression treatment. They are doing a double-blind study right now, mentioned in the second sentence. These were patients with treatment-resistant depression, which is defined as people who have undergone multiple treatments without success and are rife with nocebo tendencies. These are not people who are hopeful about their nth medication or round of talk therapy. They are tough nuts to crack. That the treatment is showing any success with this group is worth doing further studies.
[+] MelioRatio|6 years ago|reply
Here is the published study including an abstract, for those interested: https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2019.1...

This new form of rTMS appears to have truly incredible potential to help people whose depression is otherwise resistant to treatment, which is sorely needed.

Having over 85% of participants meet remission criteria is, to put it mildly, incredible, though with only 21 participants, sample size is too small to make conclusions regarding large scale effectiveness.

As the paper notes, we now need double-blind trials. I very much hope that this treatment will be able to help people on a larger scale.

[+] Ididntdothis|6 years ago|reply
Sounds interesting. I wonder what’s the best way to try such a treatment without first spending tons of money and energy dealing with insurance and doctors.
[+] taurath|6 years ago|reply
Individual TMS is really interesting. My understanding was that most large-scale TMS was untargeted and not really that effective.

I was about to write something about a side effect I had read, which was about people losing the ability to swim, but that apparently a DBS (deep brain stimulation) side effect for tremors from parkinsons.

[+] jnaddef|6 years ago|reply
> The researchers are conducting a larger, double-blinded trial in which half the participants are receiving fake treatment.

This second sentence from the article is enough: let us not comment on an experiment that had no control group. I will be interested in the results from the second trial though.

[+] yewenjie|6 years ago|reply
Important note: this result is not from a randomized controlled trial, and have been done on small number of subjects. The article mentions that the researcher are designing a larger and proper trial.
[+] cpeterso|6 years ago|reply
Here is a short interview with comedian Neal Brennan about his personal experiences with (40 30-minute sessions) of Transcranial Magnetic Stimulation. He says it was more effective and longer lasting than Ketamine Therapy or Zoloft. He was able to stop taking Zoloft.

https://youtu.be/vB9DHMOiojE

This is an excerpt from a longer interview about his depression:

https://youtu.be/FfsUxrGmbdU

[+] awaythrower|6 years ago|reply
Assuming, on the off chance, that this isn't some sort of quack treatment ploy, anything that works significantly would be a plus.

I'm on my 13th antidepressant now that is yet-again not working well and I'm starting to wonder if my condition is inflammation-mediated rather than receptor- or neurotransmitter-caused as only mirtazapine (also a powerful antihistamine) ever helped me significantly, but only for a limited time.

[+] 1_player|6 years ago|reply
Obvious disclaimer that every depression is different.

My depressive symptoms have never been medicated yet I'm pretty sure are inflammation-based: changes in my diet drastically affect my mental and physical well-being.

Exercise, lifestyle changes help, but diet seems to be the primary cause and solution in my case.

[+] sneak|6 years ago|reply
Is there further documentation about this, or other papers I can read? This part in particular seemed counterintuitive to me:

> “The less treatment-resistant participants are, the longer the treatment lasts,” said postdoctoral scholar Eleanor Cole, PhD, a lead author of the study.

[+] skat20phys|6 years ago|reply
In the context of the press release it was a little confusing to me because the published paper doesn't really report on anything that would be considered long-term. I assume she meant something like "the less treatment resistant, the more pronounced the effect"?

Treatment resistance probably refers to prior treatments, which is a sort of indicator of severity or, well, resistance to treatment. So it makes sense to me that people who were less resistant to prior treatments would show more immediate longer-lasting effects.

But it's confusing.

This is impressive but it's not a randomized controlled trial at all, and it's a fairly select group of patients, so it's hard to know what to make of it. TMS treatment of depression has kind of been plagued with publication bias effects -- not to say there's no effect but more rigorous meta-analyses have suggested that publication bias is significant in the area.

Sometimes with very severe patients you see more regression to the mean, in that they have bigger apparent improvements in control conditions just because they can only stay the same or get better.

[+] mattkrause|6 years ago|reply
I think she means "the less treatment-resistant the participants are, the longer the treatment remains effective" (not that the session drags on longer).

The results of this study are pretty exciting, but the idea of using various forms of TMS to treat depression has been kicking around for a while, and several groups have been trying to optimize the stimulation in different ways.

Here's a decent review of its effectiveness https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582998/

and here's another group that's trying something similar: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344760/

[+] stupidcar|6 years ago|reply
I interpreted this as “The less treatment-resistant participants are, the longer the [effects of the] treatment lasts,” which would make more sense.
[+] derefr|6 years ago|reply
I'm not sure exactly why, but common sense would state that, with treatment-resistant participants, you already know "1000 things that don't work", and so you've narrowed the search space.

If the way they're doing this treatment involves hitting the subject with magnetic stimulation in "all possible parts of the search space" that might potentially solve the problem, then if you've already half-treated a subject (stimulated one entire side of their brain, say) and it didn't work, that means both that they're "treatment-resistant" and that the second treatment should only focus on the other half of the brain.

[+] fallingfrog|6 years ago|reply
If stimulating some part of the brain can increase neural activity in a lasting way, could you use this to, say, make yourself better at math? Or, could you use it to suppress unrest by making everyone happy? If this works there are a lot of larger implications.