How Trophic Factors Affect Depression
This chapter was originally written in 2002. At that time, this was big news. Now, it is very well accepted science, and the “news” comes in later chapters. This was so exciting at the time, though, you’ll see my style is a little different, a bit more run-on, perhaps. You can skim if you like because the main molecules shown here, BDNF and Bcl-2, will appear again in the next chapter. The main point: fluoxetine/Prozac and other antidepressants work by stimulating cell growth factors.
You’ve heard the story: fluoxetine/Prozac increases serotonin levels. But what difference does that make? What happens after serotonin increases? That’s a good question. Here’s the current working answer: it looks like antidepressants, and exercise, and other antidepressant approaches including even ECT (electroconvulsive therapy), all cause brain cells to start to feed themselves again. Huh? That’s right, these effective treatments all cause the brain to make a protein that helps cells grow and make connections to neighbors.
OK, here we go. We’ll start pretty basic. If you already understand about synapses, and how neurotransmitters bind to the receptors, skip to How Antidepressants Affect Neurotransmitters . If you already understand how antidepressants increase neurotransmitters, skip to What Happens After the Increase.
For those of you who haven’t heard about any of this, here’s a quick version.
How Nerve Cells Communicate
Brain cells (“neurons”) talk to each other over the space between them, using a chemical message. The message chemicals are called “neurotransmitters”. Serotonin is one of those. If Cell A needs to tell Cell B about something, it releases a neurotransmitter across the gap. The gap is called a synapse.
Cell B has special proteins on its surface that can receive a neurotransmitter, just like a keyhole can receive a key. Of course this is all so small we can’t really “see” what this looks like, except with the most powerful microscopes. But from years of research, the basic model of a synapse is thought to look something like this:
There’s Cell A on top with the green things (we’ll get to those in a minute). And Cell B is on the bottom: you can only see part of it because we’re so close. The blue things are the receivers, each like a little keyhole. They’re called receptors. And the red crosses are the neurotransmitters. Cell A can release these neurotransmitters into the space between the cells (the synapse), when it wants to “talk” to Cell B.
When the neurotransmitter floats around in the gap, some of it will bind to the receptor on the other side. The fit is very precise, very much like a key and lock. It has to be precise, because there are a lot of other keys floating around in the brain fluids! Each key sends one type of message. Most cells can only “hear” a few of these chemical messages because they only have a few receptor types on their surface. In our model above, there is only one receptor type shown — blue. On a real cell there would be green receptors and yellow ones too; but not purple or gray, other cells would have those.
You may have already guessed that there must be some way to get those red guys out of the synapse quickly. After all, Cell A is “talking” by releasing bursts of neurotransmitter. If that transmitter didn’t get cleared out quickly, Cell B could never tell when A was talking and when it wasn’t. So, you’re right: there are several ways that neurotransmitter is removed. You’ll see more about that in a moment.
And what happens when the neurotransmitter fits into the receptor on Cell B? Ah, that’s the whole point, right? Cell B is directly affected by this. Sometimes when the neurotransmitter binds to the receptor, Cell B becomes more active, sending its own messages on to other cells. Sometimes, binding a neurotransmitter can decrease the activity of the receiving cell. It depends on the type of neurotransmitter. There are nearly 100 known neurotransmitters. I hope you’re guessing that means there must be at least 100 different receptors too; each key has a matching lock. (In fact, it’s far more complicated: there are many different receptor types for most neurotransmitters. One of the most extreme examples is serotonin, which has seven families of receptors, most of which have several subtypes, e.g. 1A, 1C; 2A, 2B, and so forth.)
Ok, so now you know about neurotransmitters, their receptors, and how they are organized in synapses. This is where antidepressants have their effects. We’ll show you now what those effects are. But remember, the story we’re after is what happens after that, inside the cell. We’ll get to that soon.
How Antidepressants Affect Neurotransmitters
For years we have known that most antidepressants work by increasing the amount of neurotransmitter in the synapse. The receiving cells thus “see” more neurotransmitter out there. How do antidepressants cause this increase? Well, you can imagine that there are basically two ways to do this: increase the amount released, or decrease the amount disappearing!
It turns out that most antidepressants decrease the amount of neurotransmitter being cleared away. This leaves more of it floating around in the synapse, where it can bind to the receptors of the next
cell. Some antidepressants block the enzyme that chews up neurotransmitter. But most of the ones you’ve heard about, like Prozac, work a different way: they block a recycling device!
Most cells re-use a lot of their neurotransmitter. They have a recycling device that pulls the neurotransmitter out of the synapse and prepares it to be released again. In our synapse model, this is shown as a green molecule on the pre-synaptic cell (Cell A, in our discussion above):
So, if we block the recycling device, you would expect to see more neurotransmitter in the synapse. We can show that in our model like this, using Prozac (P):
This is what you hear all the time, right? — “Prozac increases serotonin”. True. Ok, then what happens? How does increasing serotonin lead to a decrease in depression? Ah, good: that’s what we’re here to try to understand.
What happens after the increase in serotonin?
For many years, the answer has been known — at least the first thing that happens. In fact, it’s been part of the puzzle. You see, antidepressants usually take at least days and sometimes weeks to become effective, if they work. They don’t work the first day (actually, in some people they do work that fast. Those people are either getting a great placebo response; or, they may have “bipolar disorder”, which can react very quickly to an antidepressant with manic” symptoms. For more about bipolar disorder variations, see the section on Mood Swings But Not Manic).
But the increase in serotonin does happen the first day. Thus, for years it has been known that simply increasing serotonin is not the way antidepressants have their effects on mood. It must be something that happens later, and something that takes days to weeks to happen.
Yet many of the next changes have also been known for years. For example, it has been known that both antidepressant medications and ECT (electroconvulsive therapy), decrease the number of receptors on the post-synaptic cell:
Notice that in our model there are now fewer blue receptors. There’s Prozac blocking the re-uptake site, and there’s the increase in serotonin. Now we’re seeing what happens within 24 hours after someone takes an antidepressant.
What happens next? Finally we’re getting to the “new news”, although much of this has been worked out over the last 10 years. We’ll examine the so-called “second messenger” system inside cells. Where the neurotransmitter was the “first messenger”, there are other molecules inside the cell that carry the message further. That makes sense, doesn’t it? Surely there must be some effect inside the post-synaptic cell (Cell B, in our original model)?
Changes inside the cell
Well, here’s what happens:
The decrease in receptor number on the outside of the cell, is associated with an increase inside the cell of “cyclic AMP” (cAMP). That’s just the first in a string of these “second messengers”. Just what each one is or does is not as important as seeing what happens when they all work together to reach the nucleus of the cell — that yellow oval up there. Here they are:
Finally we have arrived at the new “discovery” of the last several years of research: brain derived neurotrophic factor” (BDNF). Although there are probably other important molecules in the story of depression, this molecule appears to be a probably “final common pathway” — a way that they all work eventually, even when they start very differently — for several different antidepressant approaches. These include antidepressants like Prozac, but also other effective antidepressants like lithiumRicken, ECTDuman, exerciseOliff, and transcranial magnetic stimulation (TMS)Muller. All of these treatments increase BDNF ( at least in rats, and likely in humans, as supported by multiple threads of evidence, e.g. direct measures of BDNF in the bloodstreamShimuzu and indirect measures through the immune systemChen). What is this molecule and what does it do?
As it sounds, this is a molecule that “trophs” neurons. What do “trophs” do? This term comes from the Greek word trophe, which means nourishment. A trophic factor is a molecule that causes neurons to grow, and to flourish. Without such factors neurons decrease in activity and decrease their connections to other cells. Both lithium and valproate, mood stabilizers used in bipolar disorder, increase another neurotrophic factor called bcl-2. Estrogen is another neurotrophic factor! (Unfortunately, we don’t know exactly what to do with that fact, but as we learn, I’ll keep you posted on the Hormones and Mood page).
So, we just learned that the end effect of taking an antidepressant — or regular exercise, or ECT, or rTMS — is to increase BDNF; and that when the cell nucleus makes more BDNF, it helps nourish the neuron. The neuron becomes more active and makes more connections to other cells.
Here’s an irony for you: one study in rats showed that eating a diet high in fat and sugar lowered BDNF levelsMolteni — a result which if shown again in humans has some really stunning implications, don’t you think?
Does psychotherapy, which also definitely works in depression, increase BDNF too? That hasn’t been tested yet. There are several recent powerful studies of brain changes from effective psychotherapy, though, at which you might want to look.
If you want to see some nifty pictures of BDNF itself, and see Prozac maintaining BDNF levels under stress, read more on BDNF.