Everyone once in a while, someone sends Sci email. Often it's silly. This one, however, was very good in that it asked for some clarification on a series of posts that I've been working on looking at clinical depression and possible causes and treatments, including neurogenesis in the hippocampus, cell cycle controls, and CREB.
And luckily, the guy who sent it gave Sci permission to repost, which is good, because it allows me to clarify some stuff. Here goes:
Hi Sci: I read your blog about how antidepressants stimulate neurogenesis in the hippocampus. Since the CREB deficient mice had robust neurogenesis and normal serotonin I wasn't sure why they were anxious. Apparently they did benefit from antidepressants right away on the tail suspension and forced swim tests so the neurogenesis hypothesis took a bit of a whack. To add to the complexities I just read about MIF (macrophage migration inhibitory factor). Apparently reducing the amount of MIF in the rat hippocampus dramatically reduces neurogenesis and increases anxiety. Do you understand how CREB and MIF are related? I'm trying to get a handle on this whole complex area. Thanks.
All right, I'm going to try this before my first cup of coffee and we'll see how it goes:
1) One of the things that a lot of people really don't realize is that neurogenesis probably is not all there is to depression. This happened when the serotonin theory was hot, too (well, the serotonin theory is still hot, really). Serotonin levels may be a symptom of the problem, or they may be part of one of the solutions (due to the effectiveness of SSRIs), BUT they are not the problem itself. Similarly, neurogenesis may help the solution, but it may not be the problem in all patients (though it might in some of them.
2) Anxiety and depression are linked, but they are not the same thing. It is very possible to be high anxiety and not depressed, and there are many mouse models that include this. However, there is probably a link between many cases of anxiety and depression, but we're still working out how that works.
3) Animals and their reactions in the forced swim test: What a lot of people don't realize about the forced swim test and the tail suspension (heck, a lot of scientists don't realize this and give us flak for it) is that these tests have NOTHING to do with depression. They have a LOT to do with antidepressant efficacy. Basically, the only thing these tests are is predictive, they can tell you whether a given drug is going to be a good antidepressant. They can tell you whether a drug increases serotonin or norepinephrine. But they don't tell you anything about how depression works or whether the mice themselves are "depressed". Unfortunately, a lot of scientists want to see those kinds of behavioral tests in our studies, and since there is nothing better, we have to do them. Other tests are coming along (including one called novelty induced hypophagia) that may end up performing better, that only respond to long term clinical treatment.
4) The real problem with this is that depression is WAY more complicated than most people think it is. For example, what causes MIF growth? What causes MIF reduction? Do those things ALSO cause changes in neurogenesis in the hippocampus? Probably. And if I understood how CREB and MIF are related and how this relates to neurogenesis in the hippocampus, I would probably be VERY famous. Sci isn't very famous. 🙂
So here's the breakdown: We know that drugs that chronically increase the neurotransmitters serotonin and norepinephrine will help people with depression. We know that this isn't a result of immediate increases in these neurotransmitters (though we can detect that with the forced swim test and tail suspension test). We think that it may have something to do with increases in neurogenesis caused by these drugs. HOWEVER, that is not to say that people with depression have necessarily decreased neurogenesis, the neurogenesis may be a sign of something else. Additionally, keep in mind that not all antidepressants work in all people, and many people do not respond. Many MOUSE strains also do not respond, and a lot of people are currently investigating the differences between these mice strains, to see why they respond differently and what this may mean about humans who respond differently to antidepressants.
I hope that helps! I know, it probably just made it more confusing. Welcome to the brain, where we who study it are confused a good 99.9999999% of the time.