This article was published in Scientific American’s former blog network and reflects the views of the author, not necessarily those of Scientific American
Most people have heard of ECT: Electroconvulsive Therapy. A lot of people will immediately think of the scene during One Flew Over the Cuckoo's Nest, which doesn't give you a very good picture. People think of ECT and think of horrible seizures, something terribly dangerous.
But it's not like that anymore. Now, ECT is usually done during a light anesthesia as well as a muscle relaxant. The huge seizures don't happen anymore, though it's still uncomfortable to watch (that's a warning for the video below).
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So while ECT is no longer horrifying, it's not something to be taken lightly. Aside from the fact that you're getting an induced seizure, there are side effects, often people have deficits in working memory for a while afterward. But for people with severe depression who are truly desperate, it's sometimes their best hope.
But while we know that, in many patients, ECT does work, we still don't know HOW.
Lanzenberger et al. "Global decrease of serotonin-1A receptor binding after electroconvulsive therapy in major depression measured by PET" Molecular Psychiatry, 2013.
There are lots of antidepressants on the market today. All of them currently act on neurotransmitters, chemical messengers in the brain, and most of them act, at least in part, on serotonin.
But the problem is, antidepressants don't work for everyone. In fact, about 60% of patients being treated for depression won't respond to the first drug they are given, and require trials of several different different drugs. And, sadly, 20% of patients don't respond to all of the drugs tried. That's a lot of people. And those people, who have often exhausted all of the drug options, sometimes turn to ECT.
Despite the way it looks, ECT is pretty effective in these patients, at least for a while (most of the patients will relapse). Some studies have shown that about 50% of the patients who undergo the treatment respond to ECT.
But we still don't know WHY it's effective. Some people hypothesize that it "resets" the neurotransmitters in the brain (though really, what does THAT mean?). Others suggest that it helps with neurogenesis and plasticity, strengthening neuronal connections. But why? How does it do this?
The authors of this study turned to the 5-HT1A receptor. And they've got good reason. The 5-HT1A receptor plays an important role in the serotonin system. It's primarily an autoreceptor, a receptor that sits on the cell bodies of neurons that make serotonin. When it is hit by serotonin, it tends to reduce the action of the cells it is on. So 5-HT1A receptors on serotonin neurons generally reduce the release of serotonin when they are activated. But in issues like major depression, we want to increase the amount of serotonin, so shutting down serotonin-making neurons is no good. In this case, you'd want to reduce the amount of 5-HT1A receptors. If these receptors are reduced, they will have weaker effects on the neurons they are on, and may help increase the amount of serotonin. 5-HT1A receptors can also exist on non-serotonergic neurons (we call these heteroreceptors), and reducing these can also help with symptoms of depression.
There are a number of drugs that have been approved for treatment of depression (either on their own, or in conjunction with other therapies) that are partial agonists of the 5-HT1A receptor, and which can help reduce 5-HT1A receptor concentrations. For example, Vilazodone (Viibryd, currently approved in Europe) is both a selective serotonin reuptake inhibitor AND a partial agonist at 5-HT1A. The hypothesis is that the partial agonists can help decrease 5-HT1A receptors faster than an SSRI might do on its own. If a decrease in 5-HT1A autoreceptors is involved in an eventual antidepressant response, the sooner you can get the levels down, the better. It's possible that decreasing these levels of 5-HT1A receptors could have antidepressant effects, or at least help other antidepressants work faster. There are other drugs that are also tending this direction, Buspar, Deprax, Abilify, and others.
So for a treatment that is effective as quickly at ECT is, it might be a good idea to look at the 5-HT1A receptor. So the authors of this study looked at patients getting ECT, and use positron emission tomography (PET) to look at the 5-HT1A receptors before and after.
PET imaging uses a radioactive tracer (in very low amounts), which binds to the receptors you are interested in. You can then see the concentrations available. The authors took 12 patients (they started with 18, but several dropped out due to things like fear of the scanner or worries about the procedure), who had never had a drug that targeted 5-HT1A before (an important control), and did PET for 5-HT1A receptors before and after ECT. The ECT was a series of sessions, between 4 and 13 total (depending on the patient).
(Figure 1)
10 of their patients responded to the ECT, but ALL of them showed decreases in 5-HT1A receptors after the treatment. In the figure above you can see three scans, representing the average from all the patients. The top and middle scans are before the ECT, the bottom is after. The color intensity (red being the highest) indicates the concentration of the 5-HT1A receptors. You can see that the bottom picture has far lower color intensity, the authors found that the ECT treatment significantly decreased 5-HT1A concentration, between about 20-30% in various areas throughout the brain.
There's a lot of variability here, as there is with most human studies. The subjects (and there aren't very many, ECT subjects are hard to get) got very variable amounts of ECT, between 4 and 13 sessions. Not only that, but the original scans were done while the subjects were on medication, which may have affected the baseline. Of course, you don't want to take severely depressed patients OFF their medication, so you can't blame them for going with it.
But they still got a significant effect, and it makes me wonder what role the 5-HT1A receptor is playing here, and HOW ECT makes the concentrations decrease. It's also interesting that even the people who did not become less depressed after ECT still had the decreases in 5-HT1A. So is the 5-HT1A enough for an antidepressant effect? It doesn't look like it. What else needs to take place? Is the reduced 5-HT1A receptor concentration part of a mechanism? Or is it a symptom of an alteration in something else? There are ECT studies in animal models of depression, so we may have to turn back to those to find out what role 5-HT1A plays in this treatment. But it's an interesting finding, from a treatment that is still so mysterious.
Lanzenberger, R., Baldinger, P., Hahn, A., Ungersboeck, J., Mitterhauser, M., Winkler, D., Micskei, Z., Stein, P., Karanikas, G., Wadsak, W., Kasper, S., & Frey, R. (2012). Global decrease of serotonin-1A receptor binding after electroconvulsive therapy in major depression measured by PET Molecular Psychiatry, 18 (1), 93-100 DOI: 10.1038/mp.2012.93