Depression Post 4: The Serotonin Theory (and why it's probably wrong)

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.
zoloft.png
(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.
SSRI.jpg
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.

60 responses so far

  • Donna B. says:

    I can't tell you how much I appreciate these informative articles you do. Not only do I learn something new with every one, I also have "aha!" moments where I finally understand something I'd read somewhere else.
    You have a talent for making science accessible.

  • BAllanJ says:

    Could it be that we need to characterize people with depression better, to be able to tell which ones have too little serotonin and which ones don't? Depression may be 10 different diseases with the same set of mood symptoms. (By the way, I'm one of the lucky ones that SSRIs worked well for.)

  • Sveta says:

    This is great! "headaches are not caused by a lack of aspirin".
    May I add these other possible/probable factors to the discussion?
    Mother's depression affects fetus/neonate (this is one study of many): "Relative right versus left frontal EEG in neonates."
    Mothers and newborns have low serotonin, high cortisol, greater right frontal EEG, lower vagal tone.
    and this, "Depression: Beyond Serotonin, Much more than a chemical imbalance, depression is a disorder of mind, brain, and body." Hara Estroff Marano
    This article is really well written and broad and on the hypothalamus-pituitary-adrenal axis, high levels of cortisol and connection to heart disease and osteoporosis.
    I've also been thinking about the group who become manic on SSRI's. Maybe connected with early morning insomnia, OCD like racing/repetitive thought symptoms, but where depression is the norm. High cortisol? The DSM boxes may be way too restrictive on our hypothesizing.

  • Andy says:

    That is really interesting. Are people who respond to buproprion usually insensitive to fluoxetine, and vice-versa? I mean, does it appear that depression is caused by some perturbation very specifically in different systems in different people?

  • Scicurious says:

    BAllanJ and Sveta: yes, I do think that depression can probably be divided up into several diagnoses, once we know enough about the causes. But right now, we still diagnose based on subjective symptoms, rather than evidence of neurochemical or neurological imbalance. So I think multiple kinds of depression diagnosis may be some distance in the future.
    Andy: you know, I don't actually know if there's data on that. Mostly what I've seen is that there are some people who respond to SSRIs, and some who don't. There are even some people who will respond to certain SSRIs and not others. But I do think that some people could have different factors that contribute in different ways to their depression. It'd be interesting to see what DOES work for people who don't respond to SSRIs.

  • catgirl says:

    BAllenJ,
    I think your idea is the most probable. There may be several causes of depression, just like there are several causes of headaches.

  • arvind says:

    You have a real gift for explaining complex ideas to laypeople using very accessible language, while not dumbing it down at all. I'm enjoying these posts!

  • eNeMeE says:

    Thanks for this series of posts.
    Very helpful and interesting.

  • Sylvia S says:

    Andy,
    I can only offer myself up as one ancedote: I respond to Welbutrin. I tried it because my sister said it worked for her. At one point, I also tried Effexor. All it did was make me sleepy and slow. So, I appear to be one of those for whom buproprion works. According to Wikipedia, Effexor is actually a SNRI, so I would probably have to try several other things before I could say that SSRIs don't work for me. But that's unlikely to happen.

  • Zach says:

    I responded reasonably well to Wellbutrin after Prozac made me a bit of a lunatic. In general, I find that most people I know who have depressive tendencies fall to either one side or the other: they're either serotonin-deprived or dopamine-deprived (with the serotonin-lacking sorts comprising a majority, accounting for Prozac's wide initial appeal and success rate).
    With all of these drugs, I highly recommend listening very closely to your body, mind and emotional states to gauge what the drug is doing to you -- because these drugs are potent, and a drug might be *good* but not *great* for you. I kept a detailed "depression journal" that made me realize how sensitive I was to these medications, and allowed my psychiatrist and me to more carefully tailor my treatment toward *me.* Because nothing here is a one-size-fits-all. And another thing: after four years of psychotherapy, two years on supervised medication and two more years on unsupervised medication, I will say unequivocally -- taking anti-depression medication without psychiatric or psychotherapeutic assistance is really not a good idea.

  • Sara says:

    I think it is also interesting to think about depression from a network dynamic perspective. SSRIs keep serotonin in the synapse longer, making transmission fuzzy. SSREs (the only one I know of is tianeptine) enhances reuptake of serotonin, making transmission sharper. I'm going into computational neuroscience in grad school, and I hope to be able to make predictions from comparing models of fuzzy versus sharp transmission.
    As a personal anecdote, I have responded very poorly to fluoxetine, citalopram, and paroxetine (all SSRIs), but I respond very well to tianeptine (an SSRE). Mostly, I find that the tianeptine reduces incidence of negative mental loops (feeling down on myself) without causing physical or mental fatigue. The SSRIs caused me mental and physical fatigue, and difficulty with breathing.
    I, too, would be interested to see the different types of depression categorized, and clinical data about the effectiveness of different types of drugs on each group.

  • Merely a "readability/accessibility" suggestion for when blogging on one topic but as a series of posts:
    Start each post with links to the previous installments in the series, so those who discover the series through a middle or late post don't have to search or scroll, but can click right to the first installment. This assumes that the topic is covered in a handful of posts.
    If the topic is covered in many posts, it's better to link each post to a single post that acts like a table of contents, a single list of the direct links to previous installments. You then add a link to the list each time you publish a new installment.

  • JLK says:

    I think the neurotransmitter theories of depression need to take into account the different social and personal factors that lead to depression. There are missing links between the outside of the brain and the inside of the brain that need to be discovered before we can account for why different people respond to different medications (and some respond to none at all).
    For example, take me - right now. All this rejection is definitely getting to me, and that combined with the impending departure of my husband for the next 6 months makes me want to lie in bed and not wake up until this is all over. It's possible that the firings (or lack of) that are happening in my brain right now are being affected by those things, altering levels of NTs at the synapses. Maybe I would respond well to wellbutrin because it deals with the chemicals that are being affected by these specific events. But perhaps if several family members of friends died, my brain would be affected differently, with different NTs altering their levels, and I would respond to a DIFFERENT medication that deals with those chemicals instead.
    This is totally not my area (except for the social stuff) but I would look at similarities and differences in case histories leading up to the depressive episode, and look for correlations with the medications that were affected.
    But maybe someone already that, I have no clue.

  • AK says:

    I found this article interesting:
    Modulation of the Activity of Pyramidal Neurons in Rat Prefrontal Cortex by Raphe Stimulation In Vivo: Involvement of Serotonin and GABA by M. Victoria Puig, Francesc Artigas and Pau Celada Cerebral Cortex 2005 15(1):1-14; doi:10.1093/cercor/bhh104
    From the Introduction:

    In vitro and in vivo studies suggest that 5-HT1A and 5-HT2A receptors are key players that exert opposite effects on the excitability and firing activity of pyramidal neurons in the medial PFC (mPFC) ([ref's]). The activation of 5-HT1A receptors in PFC hyperpolarizes pyramidal neurons, whereas that of 5-HT2A receptors results in neuronal depolarization, reduction of the afterhyperpolarization, and increase of excitatory postsynaptic currents (EPSCs) and of discharge rate ([ref's]). 5-HT can also activate excitatory receptors (5-HT2A and 5-HT3) in gamma aminobutyric acid (GABA) interneurons ([ref's]) to increase a synaptic GABA input onto pyramidal neurons ([ref's]).

    From the Conclusions:

    Despite the presence of excitatory 5-HT2A receptors in a large percentage of PFC neurons and their co-expression with 5-HT1A receptors, the present study shows that the main effect of physiologically released 5-HT in PFC is inhibitory, perhaps due to a suggested localization of 5-HT1A receptors in the axon hillock of pyramidal neurons. [...] Lastly, inhibitory responses evoked in mPFC involve 5-HT1A receptor- and GABAA receptor-mediated components, whereas in MOs only the serotonergic component appears to be present. Various sources of GABA may account for the inhibitions in mPFC, yet the very short latency of the DR/MnR-evoked inhibitions suggests the presence of a GABAergic projection from the DR/MnR to the cingulate and prelimbic areas of mPFC.

    If I understand correctly, then, a single source of Serotonin in the dorsal and median raphe nuclei is feeding two types of receptors (probably in the same cells) with roughly opposite effects. It seems to me that, if there is an "imbalance" in this system, it's probably between the different receptor levels, rather than the overall supply of serotonin. There also seems to be a GABA-ergic feed directly from these nuclei, which might sometimes be involved in the problem(s).

  • DuWayne says:

    Andy -
    Not necessarily. A friend of mine was on Paxil, which worked well for his depression, but like me, he had the side effect of sexual dysfunction. This was not a problem in and of itself, but like I experienced, it was pretty extreme and caused actual genital discomfort. So it was doing what it was supposed to, but he had to switch to something else. He went on to use Welbutrin and it worked about the same, minus the discomfort.

  • Becca says:

    How deranged am I that the Zoloft Marshmallow is making me hungry?

  • Sueblimely says:

    You explain things so clearly and I now understand some aspects of SSRI's that were a mystery to me. After trying a variety of SSRI's for anxiety and depression, with either no result or negative effects, Effexor started working almost immediately for me. The tricyclic antidepressant I was on for a while years ago was better for me than the plain SSRI's. It makes sense now considering they also worked on norepinephrine.

  • Scicurious says:

    blogfordarwin: oops. Yeah, I actually usually do that, unfortunately I forgot to this time. I will edit those in, thanks for pointing that out.
    AK: Artigas (the author of that paper) is THE MAN. And yeah, the hypothesis that 1A and 2A are having opposing actions is not a new one. It certainly could be different levels of receptors having different effects. The question would then become for each person which receptor imbalance was causing which set of problems, and how to correctly medicate for it. Thanks for the reference.
    JLK: Depression is definitely caused by multitudes of factors. There's obvious environmental factors, as well as issues arising from genetic predispositions, and I'm sure there are more. Of course, the real problem right now is parsing how each of these can contribute to depression, and then, once you know that, to parse it out for each individual person, because depression is such an individual disease. We definitely have a long way to go.
    Becca: I know! He's so cute, but all I can think of right now are s'mores...

  • Bioephemera says:

    Becca, you are sick! My maternal instincts are kicking in to defend the Zoloft Marshmallow from you because it's so neonatally round and therefore endearing.

  • Nonny Mouse says:

    Another anecdotal data point: my own depression responded brilliantly to tricyclics. Like turning a switch; it was incredible. No psychotherapy, either, it was literally "take pills for a couple of weeks and bammo! all fine!"
    A decade later, when I relapsed after years unmedicated, they were off the standard first line agenda. I ran through several SSRIs and therapy, but with a much smaller improvement. Finally I'm back on the old Prothiaden to much greater effect. I did find the cognitive behaviour therapy helpful; I half suspect that the partial improvement on SSRIs was therapy rather than drug-related.
    So, heh, maybe I have a problem with my norepinephrine not my serotonin. Who knows? Is it actually possible to research this clinically? It does make you wonder - I see from other comments I'm not alone with this thought.

  • Anonymonyton says:

    I too enjoy the simplicity of your explanations.
    I very much suspect there are many different forms of depression.
    I'd also be interested to hear a neuroscientist's take on NeuroAnalysis and Clinical Brain Profiling as promulgated by Avi Peled.

  • Pinus says:

    I would say that the 5HT theory of depression has lost some ground to the neurogenesis theory and the role that neurotrophic factors play in 'recovery'.

  • PeterS says:

    There seems to be some anecdotal evidence that a regular programme of intensive physical exercise can be more effective than drugs in relieving depression.
    This certainly seems to be true in my case.
    What if anything does this say about the serotonin theory and the nature of depression?

  • chemdude says:

    "Prozac, which we sciencetists like to call by its chemical name fluoxetine, is an SSRI, a selective serotonin reuptake inhibitor."
    Ha, real chemists calls it N-methyl-3-phenyl-3-[4- (trifluoromethyl)phenoxy]propan-1-amine

  • Megan says:

    hahaha--"so don't get all depressed"
    i think that guy who considers himself a "real chemist" is actually a real dick

  • Scicurious says:

    Megan: Easy, there. I hold a policy of "innocent until proven troll" around here. He's probably joking. And he is correct in his use of the chemical name for fluoxetine. On the other hand, if he were to use it in his daily conversation, I think he'd have a rough time getting anywhere.
    To all those who wrote about the norepinephrine: you know, I don't really know. I'm sure there's got to be some norepi depression lit out there. I'll do some digging. I do know that there's a norepi theory of ADHD brewing the background of the scientific world, but depression I'm not sure.
    Pinus: I was going to cover BDNF next. It was holding sway for a while, but now people are saying THAT can't explain it all, either. And BDNF levels can be influenced by changes in serotonin levels. As well as changes in other things. I would be hesitant to ascribe depression to any one overall cause.

  • Epictetus says:

    As for a simple 1:1 correlation between serotonin and depression, in India, a commonly used anti-depressant is reserpine, a serotonin *depletor.*

  • Andrea G. says:

    Scicurious: Among people whose daily life includes many chemists, that's pretty common. But thanks to the fact that in conversation participants quickly establish a domain of chemicals of interest, you're much more likely to hear parts of an IUPAC name floating around. Specifically, just the parts that distinguish between chemicals in the set under consideration.
    But yes, even the pharmacist would probably boggle at a request for N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine. 🙂

  • becca says:

    Bioephemera- yes, yes I am. Don't click my name.
    "There seems to be some anecdotal evidence that a regular programme of intensive physical exercise can be more effective than drugs in relieving depression.
    This certainly seems to be true in my case.
    What if anything does this say about the serotonin theory and the nature of depression?"

    Well, guess what I learned this week? If you kill your dopamine manufacturing neurons (in rat models they can do this with 6-hydroxydopamine, and I think also with cocaine), which they do to create models of Parkinson's disease (which is now understood as a disease of dopamine malfunction that is very frequently, and totally unsuprisingly, acompanied by depression) you can revamp the system with exercise!
    This also works with BDNF. Apparently BDNF is ERK dependent... so I'm especially eagerly awaiting your post on that one, Sci!
    (note- I learned about the above research from Michael Zigmond. Neuro people who don't know him should go PubMed him. Right Now. I'll wait. He's also just an incredibly cool guy. Except CPP would hate him. He's darn near a CareBear. Except with more social conscience)

  • bioephemera says:

    @ becca - ROTFLMeow.

  • JOHN says:

    when will you ppl realize that ssri's fry your serotonin neurons leaving your entire nervous system rewired. google it. also theres lab stduies to confirm this which have been ignored by the media.

  • lostmymind says:

    I should have googled this long ago.
    Lost job and husband through uncharacteristic aggression and severe memory loss after birth of our twins who then didnt sleep through the night for three and a half years. We have gone into debt since the twins, also, with me not working, a temporary layoff for my husband a few years back, and house that wouldnt sell, that we left behind in another city(paying two mortgages basically). So, we havent been able to afford to buy enough food in general, or get high quality protein in our diet.
    I was misdiagnosed by a doctor when the twins were two, told I was just very tired, not depressed. Then, this past summer, when the twins were nearly six and a half, one of them asked me how many days there were in a year, and I couldnt remember. Screaming when someone made a loud noise near me. Aggressive with husband. "Losing" my car regularly in the parking lot, at age 42. Bouncing checks weekly, because it was too much effort to balance the checkbook.
    He decided I was a nutcase, and proceeded to divorce me. Doctor and psychologist team have me taking Cymbalta, after Zoloft kept me up all night, and Lexipro had me sleeping all day. 5HTP didnt seem to do anything, but after the Lexipro, I was afraid to take it very long, because I thought anything tryptophan related would make me sleepy. Being tired might seem like a minor side effect to some, but after the first years with the twins, I am allergic to being tired. Also, I dont care about anything or anyone when I am tired, now,whether kids or job. I get in bed. Sometimes I wonder if the sleepiness on some of these antidepressants isnt just the chemical reaction of, say, tryptophan added to the brain, but the body literally trying to rehab itself from the severe fatigue that I feel caused my brain to fall apart and personality deteriorate in the first place. I asked my doctor if she thought that much of the depression she diagnoses is caused by the fatigue just brought on by the ratrace...the pace of modern society. She said, undoubtedly, yes. Would the body, if the brain chemistry righted itself, either naturally or via a drug, just shut itself down to catch up for lost sleep. In other words, does sleeping all day when recovering from depression, really signify a negative side effect? Or is it what needs to happen to get well?
    My meds "stop working" when I have a stressful event, and dont seem to work all the time anyway, but there arent any side effects,at least, with the Cymbalta, and I look better, so my doctor thinks its working. I tend to think it isnt, because most days it is still a chore to do the basic minimum to survive.
    My psychologist says there should be better results if it is really working. She wants to try other things. My hesitation is that dealing with another set of new side effects, while randomly trying other meds, could make keeping it together during the divorce even harder than with my current level of depression. I feel I need to appear to be a good parent, and not have my kids telling dad I slept all day, or freaked out. (I have about another six months to get through before we are officially divorced.)
    I feel much better, almost my old self, after a few days to a week of repeated excercise. But if I cant go for a week or two to the gym because something comes up, kids are sick, etc., then I lose motivation,can hardly get out of bed again. MY psychologist says, if I cant get myself to the gym, what good does the excercise cure do me? Though I am wholistically minded, and avoid meds in general, I tend to agree with her, at this point.
    After reading this blog, I am wondering if should try something like Wellbutrin. Also, I have those symptoms that someone suggestd could be caused by high cortisol.
    What would be really helpful to me would be a grid or list which shows which meds affect which brain chemicals, up or down, to potentially relieve which symptoms. (Including common potential side effects would be good, too) This would be helpful for the patient, as well as doctors and psychologists trying to recommend and prescribe these meds or predict whether lifestyle changes without meds could be more helpful for a particular patient, at a particular time, due to potential side effects.
    After reading the discussion here, I understand now why my psychologist wants me to try something else, but I am now a little disappointed with my doctor. She said since I had negative side effects with some meds, I seem to be sensitive to meds, and she doesnt want to keep trying things and put me through more reactions. Kind of her, but this seems uneducated, in light of what I have read on this site.

  • ichay says:

    GREAT!!!!
    Helps me lot!! thaks ^^

  • Willis says:

    A bit late, but I have a question related to the earlier post on serotonin. I've been puzzling over the enteric nervous system for a while now with Gershon, and I wanted to check a point of fact that differs with the "Serotonin System" post.
    In writing the history of his work on the ENS (prior to serotonin being accepted as a nuerotransmitter in the ENS), he writes: "Even in 1981, the gut was known to manufacture nearly all of the body's serotonin. Since only 1 percent or so of the body's serotonin is made in the brain, the brain's output can thus be thought of a as a minor supplement (Gershon 1998, The Second Brain, p. 48)." Is there a distinction between the serotonin produced in the gut (restricted in distribution to those tissues only?) and that which is produced in the brain, and therefore you do not mention it in this post, or is Gershon incorrect? Can serotonin produced in the ENS affect the CNS and vice versa? If so, what are the mechanisms for this? I've just found your blog here, so perhaps you have written on this before. I appreciate your guidance.
    -a layman

  • allergen says:

    Great stuff in article and comments. As a chronic sufferer of depression, mostly now alleviated by psychotherapy and anti-depressants (SSRIs) I recently discovered that allergies could make my depression worse. I'm not as scientfically minded as some of you so I don't rmemember the details but the short story is that they can deplete one's serotonin. This recently happenned to me. I felt like a switch had been turned on. I was yelling and screaming at home, crying at work. I had thoughts of suicide. (I would never do it.) I aaid to myself, what the hey? Of course, there were stressors, there always are but I felt that my reactions were way out of proportion to the events that were stressing me out. Finally, I thought, could this be allergies? I did a little research and discovered there was, indeed, a connection. After a few days of allergy medication I was back to my normal self with my normal ups and downs. So, I guess I am in that category of person for whom Serotonin levels make a big difference. A long time ago I took a small dose of Wellbutrin for 2 days and I thought someone had given me a syringe of caffeine; it was so unpleasant. So, we are all different.

  • chemdude says:

    Yeah, I was pretty much joking. In fact I am not a chemist. And neither does Sci claim to be, real or otherwise, (as far as I am aware) so no need to be insulted.
    The tiny amount of seriousness in my statement is that I react when people say that "the scientific name for substance X is Y" like there was only one scientific name.

  • BioloBri says:

    I'm wondering if the problem lies in metabolism. Could the brain be in need of L-tryptophan and not 5-HTP (since it is metabolized so quickly)? Giving someone oral tryptophan is less predictable to gauge the effects of it in the brain than say, intracranial injection since it will begin to be metabolized before it crosses the BBB. I'm wondering if the theory is wrong or if our experiments are flawed.

  • Sarita says:

    I quite by accident discovered this wonderful blog (thanks to google) and loved the topic, discussions and comments. Congratulations, Andy ! I got a question that often bugs me : if serotonin can not be measured, if there is not tangible individual evidence of its existence, isn't it merely a theoretical construct? Aren't we just guinea pigs when we take the so-called antidepressant drugs, and if they work -- great ! and if they don´t -- oppps, sorry my bad! -- something like that ? When one goes to a lab, there are thousands of tests that can be accurately performed on an individual basis for almost every cell and hormone in or body. Why not for dopamine, serotonin and other brain biochem?

  • Alexander says:

    Good little artictle.
    The Serotonin hypothesis is completely flawed. Fx the antidepressant Tianpine(stablon) is a Serotonin releaser, thus leaving less serotonin in the synaptis. True SSRI's are not antidepressants. They are emotional anthesiacts. Dopamine is the true antideressant neurostransmitter which causes motivation, bright mood and strength and what not. Noradrenalin also causes heightened attention and energy. Increased noradrenalin also is protective of noradrenalin.
    Most SSRI's aren't very selective at all. The only selective SSRI is lexapro. Thus having a bad reputation for depression but a good one for anxiety.
    hormones also have huge role in depression and changing neurotransmitters will change the hormone balance and the hormone balance will change the neurotransmitters. This is nearly always overlooked by Gp's and psychiatrists. You can't really distinguish between hormones and neurotransmitters.

  • Scicurious says:

    oooookay ok ok. Sarita: we CAN measure 5-HT. We measure it in animals all the time. The issue is that it involves a VERY invasive procedure (brain probe), and so measuring it in humans just isn't done very often. We can in fact conduct tests for all the brain transmitters you could ever want. The issue is getting the brains to do it. We often use post-mortem tissue for this, or animal research to look at models of the disease.
    Alexander: This might require a post to clear this one up. Let's talk for a moment about the difference between an SSRI, a releaser, and a receptor agonist.
    SSRI: selective serotonin reuptake inhibitor: These drugs block the serotonin transporter, causing serotonin to build up in the synapse.
    Release: for serotonin, this releases serotonin INTO the synapse. Not into the blood or randomly. The end result is the same as with an SSRI; increased serotonin in the synapse.
    A receptor agonist: you are referring to a "selective SSRI" but I think what you're really referring to is a specific receptor agonist. These stimulate specific serotonin receptors, and have their effects that way. This is good because they are more specific and can have fewer side effects, but the general effect is still one you could get with general increases in serotonin.
    And while some neurotransmitters are also hormones, others are not, and most hormones are not also neurotransmitters. It is true that dopamine and norepinephrine also have big roles in depression, but keep in mind that a global increase will have other effects, like anxiety, as well. The serotonin hypothesis isn't completely flawed, but it probably isn't the whole story. Still, we're not throwing it out until we have something better. We need something to base treatments on until we can develop better ones.

  • flow says:

    Well, MDMA certainly worked well as an anti depressant for me - for 7 years i was just great, consuming only 2-4 hundred milligrams a weekend, plus jumping up and down.
    the only problem was coming off the stuff.
    years of intensive work later it is clear - the only cure for depression is to not take the world seriously, since its just impossibly horrible.
    more psychedelics, please doctor.
    oh. that's me. thank god.

  • Carlos Daniel Llosa says:

    Just correcting a small mistake:
    MAO is an intracellular enzyme, it doesn't degrade 5-HT in the synapse, only in the cytoplasm.

  • Carlos Daniel Llosa says:

    And the drink to deplete serotonin works by giving them lots of amino acids but not tryptophan. Those amino acids compete with tryptophan for transport across the BBB (I think leucine and valine use the same transporter than tryptophan). I don't think it has much to do with protein synthesis, maybe it has to do with that as well but I've never heard of it.

  • Sarita says:

    Scicurious : Thanks for your answer. Feelings bettter now that you explained that it was not just a mad-scientist fantasy coming out of the blue!!! Another small curiosity. I know one cannot keep probing someone else's brain, but what about the liquor ? Aren't there any residual traces of serotonin that could be measurable? The reason for my question is that the pharmaceutical industry keeps pouring mass-produced antidepressants, which have severe adverse effects, regardless of individual constitution. My major daydream is a custom-made antidepressant. For someone who is on meds for over a decade, that would be so goood !!! Thanks again.

  • Scicurious says:

    Sarita: The "liquor" that you are referring to is known as cerebrospinal fluid, we call it CSF. This fluid surrounds and cradles the brain and spinal cord, to help prevent injury. You can indeed detect things like serotonin in the CSF, but it's a relatively invasive procedure (inserting a needle into the spine is pretty delicate). Additionally, you have to understand that the measures you get wouldn't be very accurate. Serotonin is not just floating around the brain all the time, and the global levels of serotonin may not really mean much in the grand scheme of things. What probably makes a difference is differences in serotonin, dopamine, norepinephrine, or other factors such as BDNF, in particular, specific areas of the brain. Low levels of serotonin in your spine or cerebellum, for example, may not mean a lot, but it may make a big difference in an area like your hippocampus or amygdala. So just measuring global levels of serotonin isn't going to be specific enough, though it may give us some idea of correlations.
    I agree that custom-made drugs of any kind, with side effects reduced to low levels for every person, would be a wonderful thing, but that's a long way down the line. Right now, the "mass-produced" antidepressants have some unfun side effects, but they are still the best thing we have. Until we know much more about depression (we think that genes and environment interact, but this appears to be different for different people), how it acts, and what can prevent the symptoms with the fewest side effects, we're stuck with what we have.

  • Glenn says:

    "And what can I say, we haven't really got anything better yet. Except cocaine."
    Um...don't forget psychotherapy. Even fewer side effects than AD meds and just as effective. For severe depression, there's ECT.

  • DingedUp says:

    Good article, wonder if you could comment on the theories offered in this article; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1855049/
    How these findings relate to references to omega 3 use in treating depression.
    Thanks

  • Lynn Finley says:

    I am wondering why readers are blindly accepting everything you post as truth. It is really quite curious. Since we all have different brain chemistry, some do well on SSRIs because of their lack of serotonin while others receive no benefit but do well on Wellbutrin because of an imbalance of norepinephrine and dopamine.
    The important thing is lives have been saved by depressed people taking SSRIs and that is proof enough for them. And for me. And remember, studies show that the most effective treatment for depression is medication and psychotherapy rather than either by itself.

  • RCR says:

    What can you tell us about the down-regulation of 5-HT receptor sites after a patient has been on an SSRI, for example, for several weeks? How does that down-regulation ameliorate the symptoms of depression? This has been a difficult concept for me to grasp.

  • Anna says:

    Has anyone seen "the Marketing of Madness" on the Citizen's Commission on Human Rights web site?
    Looking for sincere responses to that documentary from professionals who AREN'T receiving any money from drug companies.
    thanks a lot.

  • Anonymous says:

    Are you sure MAOs live in the synapse? I thought they live membrane-bound in the mitochondrias of the presynaptic neuron.
    Oh, commenter #44 already pointed that out.
    I'm not an expert or anything, btw, so I'm not sure of anything I write.

  • [...] antidepressants (like fluoxetine, used above) which target monoamine neurotransmitter systems (like serotonin, norepinephrine, and dopamine). While these drugs do work in some people, something like 40% of [...]

  • Mark says:

    Very nice, accurate history of antidepressants. However, in the largest, independent analysis of antidepressants, they have been shown to be of no more benefit than a placebo. These drugs were all developed on the chemical imbalance theory, and with no actual proof that they worked or how they worked on some people, if they did at all. The drop-out rates, in part due to side effects are not taken into account when the OWN manufacturer performs clinical trials. Only the people who make it to the end. And the results are almost entirely, not statistical significant. How does one give someone a drug that affects their brain, conduct their own skewed research, and then manufacturer an explanation as to how they work. Serotinin, NE, etc, are simple amino acids that are used to communicate between neurons across synapses. If serotinin was the cause, then one should expect an increase in mood in nearly everyone, and since they are reported to raise levels immefiately, it should happen in less than three-eight weeks. Also, the changes should be felt, not just looking back three months later and noticing some symptoms have abated, equal to those taking a sugar pill. It's important we start to look at working images of depressed people to see areas where there is less brain activity and brain atrophy in depressed patients rather than just saying it works, when a sugar pill also works.

  • Mark says:

    Scicurious, we can not indeed measure working serotonin directly, in all areas of the brain. In alive animals or humans. We can pick-up receptors for serotonin and other neurotransmitters and neuropeptides, but not trace the chemical itself througjout regions of the brain while in real time. We can due post mortum studies of serotinin levels in the brain. We do not have the technology to do so at this time, and it will be a long way off. In humans we can only measure the breakdown products produced by seerotonin, and that's only in the spine via a spinal tap.

  • Mark says:

    Lastly, if any of the antidepressants actual do work in a subset of people, attributing it to soley serotonin, is far fetched. It is the downdtream affects, affects on certain known pathways, and actual structur as l changes that occur for patients depressed for a long-time. If SSRI's do truly help some by some action, we should try and find out the changes thay take place. And, since there are antidepressants that have nothing to do with serotonin, and some that actually decrease it, much more empirical, which means brain region activity, increase in atrophied brain structures, etc. needs to be pursued equal to that of cancer or any other debilitating disease. As well as gene study. Most sources site depression as lasting only six months without treatment (Mayo Clinic, etc), but re-occuring usually. Well, I think those statistics need to be looked at as well.....

  • Mark says:

    sorry, you say thst it is the best thing we have so far. Well if they due work in someway, which nobody on Earth can say by what means (and numerous studies have shown placebos and excercise to be as effective for those who respond), what about the other 50% of the population that suffer. An aside, are you aware that the individual responsible for writing the DSM

  • Mark says:

    What about the other 50% of people who don't respond to excercise, antipressants of questionable theaurepeutic value, sugar pills, talk or cognitive therapy. More scientific study, gene and otherwise needs to be done. An aside, are you aware that the person in charge of writing the mental health bible, DSM IV, before the current 5, regrets it? Largely because he believes there are illnesses listed by symptoms, that aren't illnesses in reality, and others that are illnesses but are really variations of one type. Because of lack of knowledge, and symptom based illnesses, he says the manual is currently mainly important for insurance companies to pay, patients to feel they have found their illness, and to give worth to Psychiatrists.

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