Clearing Up the Serotonin Hypothesis/Depression Confusion

Depression and the serotonin hypothesis - illustration of a neural synapse

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. Perhaps it relates to changes in serotonin receptors, downstream effects of changes in serotonergic neurotransmission, or effects on brain-derived neurotrophic factor (BDNF). 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. Just as science hasn’t figured out why exactly it is that lithium has a mood stabilizing effect in bipolar disorder, the “how’ is ultimately less important than the fact that these meds do have a therapeutic effect.

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?


Since this post was first published, this issue made the news following the publication of an article in the journal Nature in July 2022 titled The Serotonin Theory of Depression: A Systematic Umbrella Review of the Evidence. While it’s not really new information, news outlets don’t necessarily recognize that. A CBC News article discussing the results was titled Have We Been Treating Depression the Wrong Way for Decades? Despite the fact that the study did not review antidepressant efficacy, subheadings in that CBC article include “Are antidepressants effective against depression?” and “Research calls antidepressants into question.”

The comments on the article (which I’ve written more about in the post A Display of Public Ignorance About Depression) were full of people saying antidepressants are useless and depression has nothing to do with the brain and is all about lifestyle and societal factors. Given the article’s framing, that’s not surprising, and I think it’s really unfortunate when journalists present things in a way that provides food for ignorance.

32 thoughts on “Clearing Up the Serotonin Hypothesis/Depression Confusion”

  1. Just awesome and beautiful affirmation of the information that seem to be the truth of the scientific community about this dilemma and observation. And where do we go from here? And what are your thoughts about genetic testing of patients for a possibly more personalized medication recommendation?

    1. Really interesting article. I know I’m tired of medication not helping much. It helps but I always slowly get depressed again. And I dunno what to do. And I don’t think I’d actually be eligible for ECT and I just…I just am tired of having dysthymia and double depression episodes

  2. It’s eye-opening when you see just how many meds are currently being used to treat a condition, that started out as being designed for something completely different, wildly different in some cases. Plenty of scientific advancements have come from accidents and coincidental findings. It’s interesting how you’ve described this, in showing how they came about developing the hypothesis.

    If I recall correctly, my old Psych materials presented serotonin as being linked pretty much as fact to neurological function and depression. But there was also emphasis on individual differences. There’s still plenty of general theorising and understanding in society at large I think that low serotonin can be a cause of depression, and that “serotonin boosters” will lift your mood. I think it can have an impact on mood, sure, but the issues around the medication and clinical depression aren’t as cut and dried. Good point on the hypothesis enabling people to get a simplified construct to wrap their heads around.

    It also shows that confirming hypotheses, or just diagnoses themselves, often hinge on things that can be seen through scans or blood tests. Not everything can be evidenced that way, or perhaps our understanding our or technology just isn’t quite there yet. It’ll be interesting to see what happens next with the research around serotonin.

    Another fab post, Ashley! xx

  3. I take Wellbutrin, which works differently (I believe) than the kinds of antidepressants you are discussing. How then can depression be treated with two different approaches? And, just how different are they?

    1. Wellbutrin is a norepinephrine and dopamine reuptake inhibitor, so it works in the same type of way as SSRIs, but affects different neurotransmitters. Depressive symptoms involve a number of different brain circuits, and certain symptoms may respond better to to tweaking different neurotransmitter signalling systems. Some people respond better if they take a combination of Wellbutrin plus an SSRI to target all three monoamine neurotransmitters. It does seem to suggest, though, that disrupted signalling via those neurotransmitters is part of the problem but not the source of the problem.

      1. Interesting. I am on both amitrypline and vortioxetine, which I believe works like you say. But drug interaction websites probably might simplify it? If I plug my meds in, I get told its a risk for “serotonin syndrome”.

        1. Being on multiple drugs that affect serotonin will have the potential risk of causing serotonin syndrome, but in a lot of cases, the combination is still appropriate. I’m on a combo of mirtazapine and venlafaxine, which has the risk of causing serotonin syndrome, but it’s well-established as a useful combination.

          1. Ooh, thanks for explaining! 💜 Last night I found some 2014 depression practice guidelines for GPs in my country and finally understood “combination” and “adjunct” treatment with regards to medication. Can’t find psychiatrist guidelines but going by that guide for GPs, I better understand my psychiatrist’s decisions.

  4. People in my family frustrate my younger brother a lot (because he understands science) because they have ridiculous ideas.

    Which they say as facts… like microwaves having radiation therefore you can get cancer from them.

    Wonder how that kind of education problem can be solved.

  5. Definitely presented as a fact. This was when I was in the Bay Area in the 90’s and early 2000’s and had a Kaiser psychiatrist. She also prescribed me Prozak at one point (which I thought was bizarre). She asked how I liked it the next time she saw me and I was like: “I didn’t. It was horrible. Why on earth are you giving me an SSRI?”

    The only other experience I’ve had with an SSRI was a girlfriend I had who insisted I take some Zoloft. I acquiesced, lost my center completely, and she apologized a couple weeks later. If there’s a chemical imbalance related to depression and insufficient serotonin, I sure don’t have it.

      1. I was going to Kaiser for therapy and psychiatry since 1993 and they did not diagnose me bipolar till 2004. I believe this was around 2001. I asked my psychiatrist later what diagnosis they were using before the bipolarized me and she said “schizo affective disorder.” I don’t believe I am schizo affective (not in the least) though I have had a friend who was schizo affective and they had him on Prozac and Lexapro. Fwiw

      1. The Kaiser dynamic was such that I saw my psychiatrist for a half hour every three months, and I think she assumed that every patient coming in was interested primarily in getting a scrip to begin with. I often told her I didn’t really think the pills were helping, but for some reason I did not know I had the personal authority to deny them. Looking back, it’s hard for me to believe how naive I was.

  6. I am always unsure whether to like that common meme of “if you can’t make your own neurotransmitters, store bought are fine.” I love the concept, and I love how the cute art and simple phrasing gets a point across in a very PR-friendly way for the willfully ignorant- er the ‘less clinically savvy’ who always talk the loudest online. But, neurodiverse ‘likes things to be properly precise’ me also gets vaguely discomfited by the fact it implicitly perpetuates the most basic, unsupported version of the serotonin hypothesis. I…try to tell myself to shut up. Because strict scientific accuracy is worth far less than a message that reduces stigma. (Research how accurately naming ‘global warming’ as ‘global warming’ at first – even though more extreme winters *are a logical consequence- and Inhofe’s famous “I’m holding a snowball, how can be ‘global warming’ if still snow?” idiocy on the U.S. Congress floor if you ever need a lesson in why ‘the truth’ needs PR far more than the misinformation. We’re trying to rename it ‘climate change’ now. It’s…too late…)

    1. Yeah, I remember the orange monster saying global warming couldn’t be real because it was snowing. It sucks that messaging has to be tweaked so it’s not misinterpreted by the scads of idiots populating this world.

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