A new book, Shock Therapy, has recently been published, which offers a contrarian take on the history of electroconvulsive therapy, or ECT. I haven't read the book, but Barron Lerner reviews it in Slate:
The authors believe that electroconvulsive therapy is incredibly effective. And yet for decades, a severely depressed patient--even one on the brink of suicide--might not have been offered the therapy, or if her doctors had proposed it, she or her family might well have declined it. In explaining why, the authors demonstrate that though we may assume medical treatments get adopted or rejected based on objective statistics, in fact data are often misinterpreted and manipulated by outside influences that end up overpowering them.
Scientists are finally beginning to understand the precise mechanisms that make ECT such an effective treatment for severe psychiatric disorders. For the most part, it seems that ECT relies on the same cellular mechanisms as typical anti-depressants, like Prozac. All of these treatments work by increasing the production of a class of proteins known as trophic factors. (The serotonin story is vastly oversimplified, if not flat out wrong.) Trophic factors make neurons grow. What water and sun do for trees, trophic factors do for brain cells.
What does an up-regulation of trophic factors have to do with mood disorders? The simple answer is that nobody quite knows. But there's some suggestive if preliminary evidence that trophic factors ease depression by increasing neurogenesis, or the birth of new cells, in the hippocampus. Here's how I described the research in a 2006 article:
In December 2000, Ronald Duman's lab published a paper in the Journal of Neuroscience demonstrating that antidepressants increased neurogenesis in the adult rat brain. In fact, the two most effective treatments they looked at--electroconvulsive therapy and fluoxetine, the chemical name for Prozac--increased neurogenesis in the hippocampus by 75% and 50%, respectively. Subsequent studies did this by increasing the exact same molecules, especially trophic factors, that are suppressed by stress.Duman was surprised by his own data. Fluoxetine, after all, had been invented by accident. (It was originally studied as an antihistamine.) "The idea that Prozac triggers all these different trophic factors that ultimately lead to increased neurogenesis is just totally serendipitous," Duman says. "Pure luck."
But demonstrating a connection between antidepressants and increased neurogenesis was the easy part. It is much more difficult to prove that increased neurogenesis causes the relief provided by antidepressants, and is not just another of the drugs many side-effects. To answer this question, Duman partnered with the lab of René Hen at Columbia.
The research team, led by post-doc Luca Santarelli, effectively erased neurogenesis with low doses of radiation. All other cellular processes remained intact. If the relief from depression was due to changes in serotonin, then halting neurogenesis with radiation should have had no effect.
But it did. Hen and Duman's data was unambiguous. If there is no increase in neurogenesis, then antidepressants don't work in rodents. They stay "depressed."
Duman and Hen's work was greeted, as expected, by a howl of criticism. Mice aren't people. The experiment was flawed. The radiation wasn't specific enough. Robert Sapolsky, whose work on stress paved the way for much of Duman's own research, is one of the most incisive skeptics. He argues that neurogenesis researchers have no plausible model for how decreased neurogenesis might cause the symptoms of depression. Why would having a handful fewer new cells in the hippocampus have such an effect? "The more expertise someone has about the hippocampus," Sapolsky wrote in a review in Biological Psychiatry, "the less plausible they find this novel role."
Since then, Duman has gone on to show that one trophic factor in particular, VEGF, seems to play a large role in increasing neurogenesis. (Although BDNF also seems to be important.)
Update: Vaughan has a typically superb summary of ECT's history over at Mind Hacks.
In a nutshell, it [ECT] seems to be the most effective treatment for severe depression, seems to impair memory, is disliked and stigmatised, and is difficult to research. Most notably, as a patient, your mileage may vary. Some people have no benefit, some have huge improvement; some have no side-effects, some have ongoing difficulties. Most have some of each.
Brain & Behavior
Comments (7)
This is, randomly enough, exactly my line of research.
"by increasing the production of a class of proteins known as trophic factors."
The neurotrophin story can be quickly complicated. The (four) behavioral studies that have looked at exogenous neurotrophic factor application have conflicting results, and the genetic models are all over the place. A small cohort of researchers have published some rather convincing studies showing that neurotrophin delivery will desensitize neurons in a manner that is dose and time-course dependent. So, boosting neurotrophic factor alone might not guarantee increased plasticity, but this work is not readily cited in the molecular psychiatry field and it is unclear how often behaviorists are aware of this complication. In my current studies I am observing a convincing pro-depressive effect following particular kinds of exogenous neurotrophin delivery to the hippocampus. I couldn't speak for Ron Duman's viewpoint, but we have talked about the my experimental results and he seemed to find them consistent. Perhaps (and this is my own speculation here) increased neurotrophin production is merely a side effect that occurs when cells are in a neurogenesis-ready state. It could be more effective to achieve this state in a manner other than artificially boosting neurotrophin levels, which would be back to square one (chancing upon effective drugs rather than discovering them )
Anyway, I don't disagree with what you wrote at all. Just entering my own soapbox about what the role of neurotrophic signaling could be. From my perspective, boosting neurotrophic factor production might very well be a dead end from a therapeutic perspective, though neurogenesis still seems to be key.
Here's a paper by Carl Diesseroth's group in Stanford that searches for better metrics to explain pro and anti depressive like behaviors. They observed changes in regional hippocampal activity that could account for behavior regardless of whether the actual behavior was pro- or anti- depressive. This is very, very cool research.
Sorry this was so long... I can't help the soapbox!
Posted by: Rachael | January 4, 2008 12:47 PM