New therapy for depression

[member2721]

http://well.blogs.nytimes.com/2013/02/11/promising-depression-therapy/

"The experimental therapy, known as transcranial direct current stimulation, or tDCS, involves a low-level charge about one-400th of that used in electroshock treatment. Unlike electroshock (also called electroconvulsive therapy or ECT), which is administered for a few seconds to patients under anesthesia, tDCS is given for 20 to 30 minutes continuously while patients are conscious.

While doctors do not see it replacing electroshock, considered the most effective approach for major depression that has been treatment-resistant and requires urgent attention, tDCS does not appear to cause memory loss as electroshock can. Because it is inexpensive and easily administered, scientists say it might become an alternative or additional treatment for people whose depression is not completely helped by medication."


....Fingers crossed that, with more trials, it will turn out more efficacious than rTMS.

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[vistaril]

"The study, involving 120 patients, found that tDCS appeared to work about as well as a low dose of Zoloft"

well that tells me a lot....and not in a way to make me believe this is super promising.

 

[member2721]

http://archpsyc.jamanetwork.com/article.aspx?articleid=1568955

Results At the main end point, there was a significant difference in Montgomery-Asberg Depression Rating Scale scores when comparing the combined treatment group (sertraline/active tDCS) vs sertraline only (mean difference, 8.5 points; 95% CI, 2.96 to 14.03; P = .002), tDCS only (mean difference, 5.9 points; 95% CI, 0.36 to 11.43; P = .03), and placebo/sham tDCS (mean difference, 11.5 points; 95% CI, 6.03 to 17.10; P < .001). Analysis of tDCS only vs sertraline only presented comparable efficacies (mean difference, 2.6 points; 95% CI, &#8722;2.90 to 8.13; P = .35). Use of tDCS only (but not sertraline only) was superior to placebo/sham tDCS. Common adverse effects did not differ between interventions, except for skin redness on the scalp in active tDCS (P = .03). There were 7 episodes of treatment-emergent mania or hypomania, 5 occurring in the combined treatment group.

 

[Salpingo]

Have to wait and read the article, but can someone explain how this treatment could be comparable to Zoloft as monotherapy and better than placebo/sham, even though Zoloft monotherapy wasn't significantly different from placebo/sham?

In other words zoloft = tDCS > placebo, but somehow zoloft = placebo. It also seems strange they didn't have a tDCS+placebo pill.

 

[billypilgrim37]

In other words zoloft = tDCS > placebo, but somehow zoloft = placebo. It also seems strange they didn't have a tDCS+placebo pill.

Basically, you fell asleep during stats class. That explains it.

Imagine you're in New York. How far is it to San Diego? How far is it to Los Angeles? It's basically the same, right? It's not THE SAME, but it's pretty much the same.

Now imagine you're in Bakersfield. How far is San Diego? How far is Los Angeles? Depending on the traffic on the 5, San Diego is a lot further away.

If your brain hurts, it's okay. Mine does too.

It's not strange at all they didn't have a combo arm. This stuff is expensive to do. If they split it into 4 arms, they lose a lot of power, and they need all the help they can get. The combo answers a question you care about, but not a question they care about in order to make money off this thing! Plus, if they show it's no better than combo treatment, who is going to use it besides maybe pregnant people? Nobody!

I'm not super smart about non-ECT psychosomatic tx, but my understanding is that DBS is really going to be the only thing that ever makes any real difference. rTMS seems like a really expensive joke, VNS doesn't have great data, etc. I'd personally rather have the paddles than have a neurosurgeon cutting me open, but that's just me.

 

[splik]

I'm not super smart about non-ECT psychosomatic tx, but my understanding is that DBS is really going to be the only thing that ever makes any real difference. rTMS seems like a really expensive joke, VNS doesn't have great data, etc. I'd personally rather have the paddles than have a neurosurgeon cutting me open, but that's just me.

and even the data for DBS is pretty disappointing. it's remarkable how excited people get about it when most people don't benefit from it. i suppose you're dealing with a treatment-resistant population in the first place, but i find it remarkable that even stimulating the emotional centers of the brain wont bring people out of their depression.

 

[BobA]

and even the data for DBS is pretty disappointing. it's remarkable how excited people get about it when most people don't benefit from it. i suppose you're dealing with a treatment-resistant population in the first place, but i find it remarkable that even stimulating the emotional centers of the brain wont bring people out of their depression.

First of all, DBS works OK - depending on where you stimulate you might have 50% of people acheive FULL REMISSION, and these are people who've often failed multiple medications and ECT.

But why doesn't it work better?
1) We don't know where exactly where to stimulate. It seems the field is pretty much in a process of trial and error looking for the optimal simulation site.

2) "Depression" as it's currently defined is probably too broad. If you take depressed mood +/- anhedonia and then the various combinations of the 9 DSM symptoms of depression you could come up with over 100 varieties of depression. Would all of these have the same treatment?

3) My gut tells me there's probably numerous causes of even severe depression - inflammatory, intracellular, monoamine deficiency, and others causes we don't yet understand- and so I wouldn't expect one treatment to be the optimal treatment for all sub-types of depression.

 

[Armadillos]

Are TMS outcomes really that bad in the scheme of things? I remember seeing a citation on a powerpoint lecture slide of a couple trials with a NNT of like 8 for getting treatment resistant depression into remission. Considering that over time TMS is going to get exponentially cheaper than it is now, seems like it is something that could have a place in the treatment of resistant depression.

 

[notdeadyet]

i suppose you're dealing with a treatment-resistant population in the first place, but i find it remarkable that even stimulating the emotional centers of the brain wont bring people out of their depression.

Well, keep in mind what we're saying here. We have this rough idea about where some kind of "emotional widget" of the brain lives and we're basically jump starting it. This is the very first steps in the technology. It's promising so far.

 

[BobA]

Are TMS outcomes really that bad in the scheme of things? I remember seeing a citation on a powerpoint lecture slide of a couple trials with a NNT of like 8 for getting treatment resistant depression into remission. Considering that over time TMS is going to get exponentially cheaper than it is now, seems like it is something that could have a place in the treatment of resistant depression.

TMS barely separates from placebo

 

[vistaril]

TMS barely separates from placebo

it's also a fact that placebo itself barely separates from placebo.....if I were an academic who also wrote for the onion, I would have two arms- placebo and placebo.....then I would measure mood and mood symptoms, and the placebos likely wouldnt get the *exact* same scores on whatever rating scale I use....thus I claim the placebo with the better scores slightly better response than the other placebo is somewhat effective and shows promise......

 

[member2721]

TMS barely separates from placebo

http://summaries.cochrane.org/CD003493/transcranial-magnetic-stimulation-tms-for-depression

Cochrane review:
"Authors' conclusions:
The information in this review suggests that there is no strong evidence for benefit from using transcranial magnetic stimulation to treat depression, although the small sample sizes do not exclude the possibility of benefit."

I remember seeing a citation on a powerpoint lecture slide of a couple trials with a NNT of like 8 for getting treatment resistant depression into remission.

You may be thinking of antidepressants.

http://www.ncbi.nlm.nih.gov/pubmed/19588448

Cochrane Review:
"Both TCAs and SSRIs are effective for depression treated in primary care."
"The numbers needed to treat (NNT) for TCAs ranged from 7 to 16 {median NNT 9} patient expected event rate ranged from 63% to 26% respectively) and for SSRIs from 7 to 8 {median NNT 7} (patient expected event rate ranged from 48% to 42% respectively) ."

 

[OldPsychDoc]

it's also a fact that placebo itself barely separates from placebo.....if I were an academic who also wrote for the onion, I would have two arms- placebo and placebo.....then I would measure mood and mood symptoms, and the placebos likely wouldnt get the *exact* same scores on whatever rating scale I use....thus I claim the placebo with the better scores slightly better response than the other placebo is somewhat effective and shows promise......

"Pacifex is the only placebo that's green and shaped like a triangle. Pacifex: A doctor gave it to you."

 

[hamstergang]

it's also a fact that placebo itself barely separates from placebo.....if I were an academic who also wrote for the onion, I would have two arms- placebo and placebo.....then I would measure mood and mood symptoms, and the placebos likely wouldnt get the *exact* same scores on whatever rating scale I use....thus I claim the placebo with the better scores slightly better response than the other placebo is somewhat effective and shows promise......

Is your claim that TMS doesn't have a statistically significant separation from placebo, or that in your experiment the placebo would show a statistically significant separation from the placebo?

 

[billypilgrim37]

Are TMS outcomes really that bad in the scheme of things? I remember seeing a citation on a powerpoint lecture slide of a couple trials with a NNT of like 8 for getting treatment resistant depression into remission. Considering that over time TMS is going to get exponentially cheaper than it is now, seems like it is something that could have a place in the treatment of resistant depression.

Well, TMS studies have small Ns. They might show relatively large absolute differences in response rates (a NNT of 8 would imply about 12-13% absolute improvement over placebo), but if it's barely significant, it's probably not a good estimate of an actual NNT. Sometimes people avoid publishing a confidence interval for a NNT, which is absolutely necessary for these psychosomatic treatments with poorly powered studies.

 

[billypilgrim37]

1) We don't know where exactly where to stimulate. It seems the field is pretty much in a process of trial and error looking for the optimal simulation site.

I thought the sub cingulate cortex (broca 25?) was the identified spot. Is there still debate? (genuine question, I'm just learning about this stuff, as I've never really had a reason to care)

2) "Depression" as it's currently defined is probably too broad. If you take depressed mood +/- anhedonia and then the various combinations of the 9 DSM symptoms of depression you could come up with over 100 varieties of depression. Would all of these have the same treatment?

I think the response rates in melancholics, just like in ECT, is really high with DBS, whereas more atypical depressions do not respond well. But, yeah, your point is definite.

 

[shan564]

and even the data for DBS is pretty disappointing. it's remarkable how excited people get about it when most people don't benefit from it. i suppose you're dealing with a treatment-resistant population in the first place, but i find it remarkable that even stimulating the emotional centers of the brain wont bring people out of their depression.

I don't have much real clinical experience, so I'm probably just misinterpreting the literature, but my impression was that the DBS has only really been studied in people who have failed pretty much every other treatment. From my limited reading, it seems like it has been shown to provide clinical improvement in a reasonable number of these patients, although it's still not a miracle cure. I think its efficacy has been quite variable depending on the particular emotional center that's stimulated, so the results of different studies can vary from "very disappointing" to "reasonably promising" depending on the techniques that they used.

I thought that this was a great paper that outlined the differences between DBS studies targeting different regions of the brain:
http://www.ncbi.nlm.nih.gov/pubmed/22721950

 

[Salpingo]

Basically, you fell asleep during stats class. That explains it.

I get the statistics, even though I don't know where Bakersfield is (there can be a 6% chance that the difference between A and B is not real, a 4% chance the difference between B and C is not real, while still being a >5% chance that the difference between A and C is not real). I just thought the language used in the abstract was funny. I could be sitting in my office with a depressed patient, tell him I could either zap his brain, give him a pill or do nothing. I'd then tell him that zapping and the pill would be the same, according to the literature, but it would be better to zap than to do nothing, and it would be better to do nothing than to give a pill (since the pill has side effects).

tl;dr, its a little crazy we put so much faith in a random number, 0.05. And here's a good cartoon:

 

[Salpingo]

http://archpsyc.jamanetwork.com/article.aspx?articleid=1568955

Results At the main end point, there was a significant difference in Montgomery-Asberg Depression Rating Scale scores when comparing the combined treatment group (sertraline/active tDCS) vs sertraline only (mean difference, 8.5 points; 95% CI, 2.96 to 14.03; P = .002), tDCS only (mean difference, 5.9 points; 95% CI, 0.36 to 11.43; P = .03), and placebo/sham tDCS (mean difference, 11.5 points; 95% CI, 6.03 to 17.10; P < .001). Analysis of tDCS only vs sertraline only presented comparable efficacies (mean difference, 2.6 points; 95% CI, &#8722;2.90 to 8.13; P = .35). Use of tDCS only (but not sertraline only) was superior to placebo/sham tDCS. Common adverse effects did not differ between interventions, except for skin redness on the scalp in active tDCS (P = .03). There were 7 episodes of treatment-emergent mania or hypomania, 5 occurring in the combined treatment group.

That was a pretty good study.

1. They actually had every possible arm for the study (including shock + placebo and sham + sertraline)
2. They made a point of proving that there was an additive effect between electrical stimulation and pharm
3. They had a couple of tables to see how often people were able to guess if they were on placebo or not. Not surprisingly, the sertraline arm did better predicting if they were on placebo or not, but the study actually acknowledged they didn't control perfectly.

Anyway, if you buy that ECT is a legitimate treatment, it makes sense that you could gradually narrow down what exactly is being targeted for specific types of depression. This study actually made a point of distinguishing melancholic vs. atypical depression. Look at chemotherapy, which started off as carpet-bombing all folate production and hitting people with chemical mustard gas before they even knew cancer was a genetic malfunction, and now we're using antigen-specific, genetically modified HIV vectors. I think the biggest hold-ups are our dependence on fMRI, which has some serious inherent flaws, and our current categorization of depression/psychosis.

Edit: forgot to mention, all the shocks were administered by clinical nurses.

 

[BobA]

I thought the sub cingulate cortex (broca 25?) was the identified spot. Is there still debate? (genuine question, I'm just learning about this stuff, as I've never really had a reason to care)

My understanding is that broca 25 has had the best results, but other groups are stimulating other areas as well.

http://www.annualreviews.org/doi/pdf/10.1146/annurev-neuro-061010-113638

 

[OldPsychDoc]

...
Edit: forgot to mention, all the shocks were administered by clinical nurses.

Well played.

 

[vistaril]

I get the statistics, even though I don't know where Bakersfield is (there can be a 6% chance that the difference between A and B is not real, a 4% chance the difference between B and C is not real, while still being a >5% chance that the difference between A and C is not real). I just thought the language used in the abstract was funny. I could be sitting in my office with a depressed patient, tell him I could either zap his brain, give him a pill or do nothing. I'd then tell him that zapping and the pill would be the same, according to the literature, but it would be better to zap than to do nothing, and it would be better to do nothing than to give a pill (since the pill has side effects).

tl;dr, its a little crazy we put so much faith in a random number, 0.05. And here's a good cartoon:

this is very funny(and captures some of my frustrations as well)....

 

[vistaril]

Is your claim that TMS doesn't have a statistically significant separation from placebo, or that in your experiment the placebo would show a statistically significant separation from the placebo?

Given the large number of studies started and thrown together(many never published), I have a good bit of skepticism as to what 'statistically significant separation from placebo' really is....and yes I am comfortable with stats.

 

[billypilgrim37]

I get the statistics, even though I don't know where Bakersfield is (there can be a 6% chance that the difference between A and B is not real, a 4% chance the difference between B and C is not real, while still being a >5% chance that the difference between A and C is not real).

I think we're agreeing, but if you'd said that a result was "not real" in my epid classes, my professor would have swatted you with a ruler! Because the idea that something is "not real" or that it "could have happened by chance" are dramatically different ideas, not just synonymous statements. The results are real. They measured things. At least, unless they made numbers up.

The lithium, depakote, lithium+depakote for prevention of mania recurrence study is a classic example.

Lithium is better than placebo, depakote is better than placebo.

Lithium+depakote is better than placebo and depakote alone.

Lithium+depakote was also better than lithium alone. But because this difference was not "statistically significant," people wrongly go around saying that lithium+depakote was not better than lithium alone. Whoever decided this was the way to teach medical students about statistics should be smacked, because that's not correct. If you look at the probability distributions, there's a really good chance that lithium+depakote really was better than lithium not by chance, though the probability of it being by chance was greater than our beloved alpha of 0.05. And where we agree is that alpha of 0.05 is a very blunt instrument that makes people very stupid if they don't think.

So, there aren't any true paradoxes in these things. We just use these confidence intervals to tell us how much we might trust these results as being something that would happen in an infinite universe of practice. The results are the results. They're never "real" or "unreal". But we may or may not feel like it makes sense to believe that they would apply in another study or in the patient we have in front of us.

 

[member2721]

Anyway, if you buy that ECT is a legitimate treatment.

ECT is the most effective treatment for depression and and mania in my limited experience. I think The problem was that ECT was so effective, that it was established really early the 60s and 70s, before stringent RCTs became the norm in research, and folks recently challenged the FDA for approval before double blinded RCTs became the standard in clinical research, and now there is very little financial incentive from industry to sponsor these studies. But ECT definitively works if you ever get the chance to see it first hand. Here are some pubs to consider.


Efficacy of ECT in Depression: A Meta-Analytic Review:
Data analyzed suggest that ECT is a valid therapeutic tool for treatment of depression, including severe and resistant forms.


The efficacy of electroconvulsive therapy and antidepressants in depression.
(PMID:889984)
Avery D, Winokur G
Biological Psychiatry [1977, 12(4):507-523]

Electroconvulsive therapy (ECT), antidepressants, and neither treatment were compared by reviewing 609 hospitalizations for depression from 1959 to 1969. The groups receiving ECT had a significantly (p less than 0.001) greater percentage of patient who had marked improvement or a complete response (49%) than either adequate or inadequate antidepressant therapy groups (27%) or the group which received neither ECT nor antidepressants (25%). If antidepressant failures who require ECT are included in the evaluation, the percentage total improvement with ECT (90%) is significantly (p less than 0.001) greater than the adequate (74%) or inadequate (60%) antidepressant groups, or neither treatment (60%). At the end of 7 weeks of hospitalization, 74% of the ECT group had been discharged, significantly more (p less than 0.001) than the adequate antidepressant group, 54%. Delusional depressed patients responded much mor frequently to ECT.