Over at Neurophilosophy, Mo has an excellent summary of a drug in Phase II clinical trials that tries to treat depression by up-regulating neurogenesis. In other words, it wants to ease your sadness by giving you more new brain cells. What these new brain cells do, exactly, remains a mystery, but numerous studies have found a connection between reduced neurogenesis and rodent models of depression. This research strongly suggests that the most effective treatments for severe depression (Prozac and ECT) work by increasing the rate of neurogenesis in the hippocampus. For instance, if you effectively erase neurogenesis with low doses of radiation (but leave other cellular processes intact), then these antidepressants don't seem to work their magic. The rats stay "depressed".
According to the Technology Review, the company is also working on a neurogenic drug that will make you think better, although that strikes me as a real long-shot, since the cognitive function of all these new cells is still totally unclear.
But I do think there is a growing body of evidence suggesting some sort of convoluted connection between the effectiveness of anti-depressants and neural plasticity, of which neurogenesis is an extreme example. Consider this recent paper in Science, which found that fluoxetine (Prozac) restores plasticity in the adult visual cortex of the rat:
We found that chronic administration of fluoxetine reinstates ocular dominance plasticity in adulthood and promotes the recovery of visual functions in adult amblyopic animals, as tested electrophysiologically and behaviorally. These effects were accompanied by reduced intracortical inhibition and increased expression of brain-derived neurotrophic factor in the visual cortex. Cortical administration of diazepam prevented the effects induced by fluoxetine, indicating that the reduction of intracortical inhibition promotes visual cortical plasticity in the adult. Our results suggest a potential clinical application for fluoxetine in amblyopia as well as new mechanisms for the therapeutic effects of antidepressants and for the pathophysiology of mood disorders.
The question, of course, is what plastic cells have to do with mood disorders. Why does having more malleable neurons (and newly born neurons are incredibly malleable) seem to treat the torpor of depression? I have yet to hear any convincing hypothesis that explains how or why these two phenomenon are related.
If you're interested in learning more about neurogenesis, or why the serotonin hypothesis isn't right, check out my old Seed article.
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On a cognitive level, many psychological treatments for depression focus explicitly on trying new ways of behaving and reacting. You don't think it would be helpful to have a bunch of new high-plasicity neurons to do that?
Sure, it's not a *molecular* connection- yet. But I think it makes a lot of intutive sense that more plasticity in neurons is good for depression.
Yes, you're absolutely right: there is certainly an "intuitive" connection. But since these new neurons don't seem to migrate into the neocortex, it's hard to even know how this "intuitive" connection might be translated on a cellular level.
Thanks Jonah - I'm flattered.
One thing I should have mentioned in the post is the evidence that physical exercise also induces neurogenesis in the hippocampus, and can alleviate the symptoms of depression.
Assuming that antidepressants are effective because of their neurogenic effects, complementing the medication with exercise could possibly stimulate neurogenesis and also promote the promote survival of the newly-generated cells.
The paper you point to warrants an investigation of whether or not fluoxetine also affects plasticity in the hippocampus. It seems quite obvious to me that at least some degree of hippocampal plasticity would be required for integration of newborn cells into the pre-existing circuitry.
However, as far as I know, the role of newly-generated cells in the adult brain is not at all clear, although I do seem to remember a recent study which suggested that cells born in the adult olfactory bulb are somehow involved in the formation of olfactory memories.
Are you saying that all cognitive behavoral therapy effects will be on the neocortex? I understand why they'd be mediated *through* the neocortex, but it's not like the brain consists of isolated regions- their neurons, they communicate, it's what they do. There are obviously ways in which concious thought (originated in the neocortex) alters short term memory (presumably dependent on the hipocampus, where all those lovely new neurons would be).
Now, I gather from your Seed article (which is fantastic, btw!) that the new neurons don't exactly hook up to the network. But forgeting neuron-specific electrical activity, what about paracrine signaling to other hippocampal neurons? I have a hard time believing they don't have some effects on the other cells they are around.
As an aside- what is sNN0031 used to treat?
You're very handsome.
I'm more interested in the amblyopia part of this, does the drug somehow help the brain start using the "weak" eye?
Haven't some 2nd generation selective serotonin reuptake inhibitors (such as the black-label drug brandnamed Serzone) been clinically shown to induce human neurogensis?
I don't know if it has any relation to generation of brain cells, but when I was taking Prozac in my 20's I was able to bowl well at a company team building event, even though I'd bowled only 4 or 5 times in my life and have no innate athletic ability. I went off the Prozac only because it made me anorexic and have never found another antidepressant that helped my mood as much.
Have you read Eero Castren's 2005 article 'Is mood chemistry?' in Nature Reviews Neuroscience?
He outlines the 'network hypothesis' of depression which basically states that there are neural networks for mood modulation, and depression is the result of them being thrown out of wack. There can be different causes, but the result is essentially the same. Similarly different treatments can restore the network to normal function, although it seems neurogenesis is a key element in the equation.
As far as I know the current thinking on this implicates a ventral hippocampus-pfc circuit and perhaps the meso-cortico-limbic system. I recommend checking out both Thomas Insel's perspective piece (doi:10.1126/science.1147565) and the article it highlights (doi:10.1126/science.1144400) in Science for more info.
Two relatively successful deep brain stimulation trials for treatment resistant depression target, via Cg 25 and the nucleus accumbens, these neural networks.
Hi Jonah,
you may like to check my earlier article on neurogenisis and depression , where I advance a theory for the underlying effect based on an inability to learn that the situation has changed (from a previous worse situation). I prefer calling my model of depression 'learning helplessness.
The article URL is http://the-mouse-trap.blogspot.com/2006/12/history-in-making-neurogenei…