Some people write off antidepressants as being useless because the serotonin hypothesis was wrong, while others insist they need antidepressants because they don’t have enough serotonin. There’s a lot of confusion about what the serotonin hypothesis was and what it meant, so this post will try to clear up some of that.
A bit of background
How did serotonin and depression get linked in the first place? The very first antidepressant, iproniazid, was originally developed to treat tuberculosis, and it was discovered by accident that it helped with mood. This was in 1952.
Okay, so how did it work as an antidepressant? That was the next thing to try to figure out. What was known at the time was that it inhibited the enzyme monoamine oxidase (i.e. it was a monoamine oxidase inhibitor, or MAOI). MAO hangs out in neurons and recycles the monoamine neurotransmitters (serotonin, norepinephrine, and dopamine).
Okay great, but so what? The serotonin hypothesis (or, more generally, the monoamine hypothesis) was a possible explanation for that.
A bit of science
At this point, we’ll do a quick detour to talk about the scientific method. Georgia State University explains it nicely in the context of figuring out why the sky is blue. Basically, you start with an observation. You come up with a hypothesis, which is a potential explanation for that observation. Next, you design an experiment to test your hypothesis. If you’ve designed your experiment well, your data will tell you whether or not you’re barking up the right tree (i.e. they support your hypothesis) or the wrong tree. Then you do more experimentation to confirm and build your results. Your observations lead you to new hypotheses that perhaps get more detailed or refined. You do more experiments.
A hypothesis doesn’t say that something is a certain way; it’s not a fact. It’s an idea that could be a possible explanation for facts, so let’s experiment and see if it’s a good fit. However, the technology may not exist yet to be able to do an experiment that properly tests your hypothesis. You can keep it around as a hypothesis, but you have to wait until it’s testable before it can start telling you anything about facts.
The serotonin hypothesis
Researchers started with the observation that iproniazid helped depression. They knew iproniazid was an MAOI.
Based on that observation and background knowledge, they came up with this hypothesis: People who have major depressive disorder have lower levels of monoamines like serotonin than people who do not. To actually be a testable hypothesis, you’d have to specify where those lower levels of serotonin are.
Okey dokey, so they’ve got themselves a hypothesis, but how do they test it? At the time, they didn’t have the technology to be able to measure serotonin in the brain. However, the hypothesis was consistent with what was known and observed, so the idea hung around but remained untested.
Along come PET scanners
Positron emission tomography (PET) scan technology finally made it possible to start doing some form of measurement of neurotransmitters using radiotracers. This technology is still evolving, and likely lots more progress will be made as it evolves further.
With this technology, it was possible to finally start doing some testing of the serotonin hypothesis. And, lo and behold, the data hasn’t clearly supported the hypothesis. Researchers didn’t see a consistent link between a deficit in the absolute amount of serotonin. Does that change anything? Not really, except that researchers need to continue generating new hypotheses to explain the relationship between what’s known and the effects that are observed.
What it means
We’re left with the observation that meds that affect signalling via monoamine neurotransmitters help with depression (not everyone, by any means, but they do better than placebo when tested in large groups of people). The fact that one possible explanation is not the actual explanation for why that works doesn’t change the observation that the meds work, which has been reproduced repeatedly in experiments.
So, why do these meds that act in a certain way work for depression?
That remains to be seen. Serotonin is probably involved somehow, but it’s not a simple matter of not having enough. Researchers will continue hypothesizing and experimenting, but they’re probably not going to figure it out until the technology gets better.
For now, we know these meds help. We know that the meds affect these neurotransmitters, so that’s got to be involved somehow. We just don’t know what that somehow is yet. And a deficit in the absolute amount of serotonin is certainly not the only possible way that communication via serotonin can be screwed up.
Why does the serotonin hypothesis still get brought up?
If the serotonin hypothesis hasn’t been empirically supported, why does it keep getting trotted out? Probably because the idea of a chemical imbalance makes for a simplified explanation that people without background knowledge of psychopharmacology can wrap their heads around. That doesn’t mean it’s what people who do have the background are being taught. I graduated from pharmacy school in 2002, and at that point, they were teaching us that depression didn’t come from a deficit in the amount of serotonin.
I think it’s a more general issue than just the serotonin hypothesis that oversimplified explanations given to the general public can sacrifice accuracy for simplicity. Vaccines are one example where a lack of background knowledge combined with simplified public explanations can facilitate the development of some weird ideas. I’m not sure what the solution is, though, because giving detailed scientific explanations isn’t likely to be helpful either. As a non-coder, it doesn’t help my life at all for WordPress to explain the code behind the assorted gremlins; I just need it to work.
Is the serotonin hypothesis something that you’ve come across? Was it presented as a fact?
For more info and MH@H posts on psychiatric medications, visit the Psych Meds Made Simple page. There’s also a Psych Meds 101 series covering: