Ok, the serotonin theory of depression may not be wrong. But it is definitely incomplete. One might ask why we use serotonergic drugs to treat depression if the theory behind it is wrong. A good question, but to this I say: because it worked.
(I love the Zoloft depressed marshmallow. He’s so cute!)
This is post four of my series on depression. For previous posts on the etiology of depression, the pharmacotherapies for depression, and how depression is evaulated in the lab, please play link hopscotch! I’ve also got a very recent post on the serotonin system which can give you some more background.
The original antidepressants, the monoamine oxidase inhibitors and tricyclic antidepressants, were originally used to treat other diseases, such as tuberculosis and psychosis, and found to be effective for depression as a sideline. Did people know how they worked? Nope, but they appeared to work (though only in a subset of the population), and so they came into use. Some people might get up in arms about this, and yell about how we shouldn’t use drugs unless we know how they work. But if we spent our lives doing that, no one would have ever made asprin. Or morphine. Heck, no one would have patented Ritalin. We know THAT Ritalin works, and we know what Ritalin does in the brain, but do we know why Ritalin calms down people with ADHD when it’s really a stimulant? Not really, no. But it’s still out there, because it works.
And the serotonin-based antidepressants do work in some people. Only in about 60% of patients at best, and at their best, they only perform 30% better than placebo. But the modern selective serotonin reuptake inhibitors (SSRIs) still work in a set of depressed patients, and they do so with far fewer side effects than pre-existing drugs. And what can I say, we haven’t really got anything better yet. Except cocaine. That’s a GREAT antidepressant, but it obviously has some issues.
So where did this serotonin theory of depression come from? And why is it flawed?
To start off with, the serotonin theory of depression actually began as the norepinephrine theory of depression. This idea came from Dr. Schildkraut in 1965, who came up the with theory based on the pharmacotherapies current at the time. Antidepressant drugs were really new stuff then, and the original drugs, the tricyclic antidepressants, inhibited the reuptake of both serotonin and norepinephrine. So the norepinephrine theory wasn’t that out there. The serotonin theory followed from Dr. Coppen in 1967, who hypothesized that serotonin, not norepinephrine, was the cause of antidepressant effectiveness. And as more drugs were discovered, he appeared to be right. First came the tricyclics, then the MAOIs, both of which had effects on serotonin. Then came the SSRIs, which had effects on almost nothing BUT serotonin, and were still effective as antidepressants. And yet, they’re not THAT effective.
So what is the serotonin theory of depression? It’s pretty simple, that depression is caused by low levels of serotonin in your brain. Studies have been done in humans which show that depleting tryptophan, the amino acid required for serotonin production, can result in decreased mood and increased irritability in humans (though I don’t know if that was just the serotonin, apparently the special drink they had to take to deplete serotonin was so nasty many of them couldn’t keep it down. That would make me irritable). If it really was serotonin, then all you’d have to do to relieve depression would be to increase serotonin levels in your brain. As for how this happens, I’m going to use the most well-known antidepressant in the world: Prozac.
Prozac, which we sciencetists like to call by its chemical name fluoxetine, is an SSRI, a selective serotonin reuptake inhibitor. As you may have gathered from my previous post on serotonin, when serotonin is in the synapse and has stimulated the post-synaptic receptors, it has two options. It can be broken down in the synapse by monoamine oxidase A into the metabolite 5-HIAA (which is an important way to measure serotonin levels), or it can be recycled back up into the pre-synaptic neuron. The recycler is called the serotonin transporter, or SERT (some people like to call it the 5-HTT, but that doesn’t sound any good when you say it aloud). SERT sits in the membrane and scoops up serotonin, flipping it back into the pre-synaptic neuron so that it can be packaged in vesicles and used again.
The SERT is a great target for drugs if you want to increase serotonin levels in the brain. All you have to do is clog it up with an inhibitor (like Prozac), and serotonin can’t be recycled! The serotonin is stuck around the synapse, and as the pre-synaptic neuron continues the fire, will build up, constantly sitmulating the post-synaptic neuron, and thus causing a net increase in serotonin effects in the brain. And it’s been found that some drugs that increase serotonin in the brain, such as Prozac, can help relieve depression.
So depression MUST be caused by low levels of serotonin in the brain, right? Wrong! Just because a drug relieves the symptoms of something, does not mean that the lack of that drug was the cause of the symptoms. In the most common example, it’s a well known fact that headaches are not caused by a lack of asprin.
But of course, science wasn’t just going to sit on this drug and say the serotonin theory was right without testing it. There have been many tests performed testing the serotonin theory of depression. Unfortunately, almost all of them have been conflicting or inconclusive. Scientists have tried measuring the serotonin metabolites of depressed patients to see if they have different levels from healthy controls, but the samples are incredibly small and human data has tons of variables (such as what drugs they had been treated with, how long the patient has been depressed, if they have other disorders as well, etc, etc). Researchers have also tried depleting serotonin levels (give people drinks with TONS of other amino acids, and your cells will set to work making protein, which will use up your tryptophan and end up decreasing your serotonin), but results were inconsistent and mostly made people irritable. They even tried increasing tryptophan in the diets of depressed patients, but got no results.
Finally, new drugs have come on to the market recently which can relieve symptoms of depression, and these drugs don’t even touch the serotonin system. For example, the very popular drug Welbutrin (chemical name buproprion) is capable of relieving depression just as well as Prozac, but instead of acting on the serotonin system, it acts on the dopamine, norepinephrine, and cholinergic systems. Other drugs which act only on the norepinephrine system have also been shown to relieve depression
So basically, there aren’t large numbers of studies out there saying “serotonin theory of depression totally works!”, and there are other drugs which work for depression, and yet exclude the serotonin system all together. But Prozac still works in a significant number of patients. So what does this mean? Is the serotonin theory of depression totally wrong? Well, probably not entirely. The brain is a complicated place, and it’s most likely that depression is a combination of factors, such as changes in neuronal growth and death, changes in neuronal connections, and changes in the biochemistry of neurotransmitters such as serotonin. Additionally, it is very possible that all of these changes feed back and influence each other. So serotonin may still play a role in depression, but it is probably not the main cause, and in fact there may not be one main cause of depression.
Now this sounds like bad news to people who suffer from depression, and it’s true that the traditional serotonin-based antidepressants don’t work in many patients. But the news isn’t that bad. This means that other drugs, such as those that affect dopamine or norepinephrine, may have effects in patients that don’t respond to serotonin drugs. Additionally, this also means that, with more research, we may be able to come up with more effective drugs based on what we have learned from work with serotonin. So don’t get all depressed. We may not know the answer, but the answer is out there, and learning about serotonin and the drugs that work now, can help us find the answer in the future.