Electroconvulsive therapy (ECT) is a crude but effective treatment for depression. It consists of applying a brief alternating current to the brain in order to induce a generalized seizure, which usually lasts for less than half a minute. It looks nothing like the picture to the left.ECT is typically given three times per week, and a dozen sessions are enough to produce a dramatic improvement in depression in most cases. However, how it works is entirely mysterious. There are plenty of theories. An important little study from Duke University psychiatrists Cassidy et al (including Bernard Carroll) has just ruled out one of them.
Monoamines are a class of neurotransmitters: serotonin, dopamine and noradrenaline. They're involved in various aspects of mood, although the picture is very complicated, and almost all antidepressant drugs target one or more monoamines. Could ECT act by increasing monoamine levels? It's as good a theory as any, and there's some evidence for it.
However, Cassidy et al's data suggest it's not the case. They took 9 volunteers who had been severely depressed, but had recently responded well to a course of ECT. They gave them combined serotonin depletion, with the tryptophan depletion method, and dopamine/noradrenaline depletion with the drug AMPT. As a placebo comparison, they used diphenhydramine, aka Benadryl, a mildly sedative antihistamine; this is because AMPT is a sedative, and they wanted to control for active placebo effects. Few psychopharmacology studies are so well controlled.
These depletion techniques, given separately, are known to cause temporary relapses in about 50% of people who've responded to antidepressants targeting the corresponding monoamine, and also in some people who used to be depressed but are no longer taking medication. If monoamines are involved in the response to ECT, depleting all of them at once should definitely cause relapse.
What happened? Nothing. No-one experienced even a partial return of their depression with either the real or the placebo treatments. These depletions don't put levels of the neurotransmitters down to zero, but Cassidy et al. used the same doses that have caused dramatic relapses in susceptible people.
This strongly suggests that monoamines are not required for the clinical response to ECT, at least not in any straightforward more-is-better way. Given that ECT works faster than antidepressants and more often (the controversial side effects are the main reason it's used only as a last resort), this is a blow for the monoamine hypothesis of depression... like I said, it is complicated.
And how does ECT work? We still don't know. This study narrows down the possibilities.
Cassidy, F., Weiner, R., Cooper, T., & Carroll, B. (2010). Combined catecholamine and indoleamine depletion following response to ECT The British Journal of Psychiatry, 196 (6), 493-494 DOI: 10.1192/bjp.bp.109.070573
12 comments:
If no-one knows how it works, it's surely remarkable that it was discovered in the first place?
Awesome post, clear and informative. Thanks!
It's the brute kicking the flickering tv scenario....
Perhaps violence is the key.
This is interesting. It is particularly interesting that monoamine depletion does cause depression in those that respond to antidepressants, but not in those who don't but respond to ECT. Does this suggest that different factors might cause depression in these individuals?
There is no mystery about how ECT works. It works in the same way you "cure" a frozen computer. You basically turn the computer ("brain") off and restart (e.g. "re-charge") it.
As a conceptual point, diphenydramine may not be the best control, as it's known to affect (at least) serotonin levels in the brain (ie. http://meeting.chestpubs.org/cgi/content/abstract/134/4/c4002 ).
It's also neat to me that the study subjects didn't even show a normal reaction to monoamine depletion - they did better than normals would, as if ECT somehow insulated them against sensitivity to monoamine levels. I don't have access to the full text of the paper, but I'd like to see how the authors explain that.
how they get this study past the IRBs? Taking severely depressed people who had a beneficial response to ECT and attempting to make them depressed again?
@ Anonymous:
Thank you for raising that issue of IRB approval.
In clinical research like this, the patients are true collaborators, and it isn’t for everybody. If you declined to consent to the protocol then your preference would be respected, with no negative effect on the care we provided to you. Some patients, however, are motivated to participate in advancing clinical science, and they do give informed consent.
As investigators, our responsibility is to ensure that the research question is significant enough to justify any anticipated risk. This one was. We also had good reason from prior work to expect that any symptomatic relapse would be transient. As it happens, we saw no relapse at all.
The sensitivities around such research also demand, rightly, that the investigators have no conflict of interest.
Astrid: That's a really good point (that I missed entirely) - people don't get ECT unless they've failed to respond to multiple antidepressants; most people will respond to one eventually so the minority who don't are probably quite unusual.
Having said that though, there is good evidence that antidepressants do prevent relapse after successful ECT and even that giving antidepressants alongside ECT works, so ECT patients are not completely different.
Re: the ethical issues, the same dilemma faces everyone doing monoamine depletion studies (although it's especially bad with ECT patients because their depression was so severe).
However a lot of patients are willing to go through with it, often they say that they want to help other sufferers by providing a better understanding of depression.
The relapses are usually only a few hours long because eating some food provides protein which replenishes the monoamines. I've not read or heard of any prolonged relapses. Some patients say that it's a positive experience because it helps them to accept that their depression is "biological".
Thank you for a good post.
One question to your conclusion. Shouldn't we distinguish between the mechanism of action of ECT in two settings, one being the acute therapeutic response and the other the maintenance effect?
The article seems only to draw its conclusion from the latter and not the former as you write? Is it unreasonable to distinguish between these two mechanisms?
Good point; I've always assumed that the mechanism is the same, as so do most people I guess, but they could be different.
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