11 ms·

Will this make the "chemical imbalance" (i.e. low-serotonin) theory of depression obsolete once and for all?

pid_0 6y ago
Isn't it already though? Besides for those self-diagnosed tumbrlinas complaining about "no serotonin". It's pretty well established that Dopamine, Norepinephrine, etc play a huge role in depression. Serotonin is a small part of it. And anyway, I would bet almost all cases of depression ultimately stem from ineffective behaviors and thoughts, not some fundamental chemical imbalance.
- toiletfuneral 6y ago
  wow, super constructive comment. You seem very proud of yourself
- loceng 6y ago
  Arguably it's life experiences and environmental stimuli that actually play a role in depression et al - it's just these neurotransmitters you speak of are the communicators. E.g. Self-protective mechanism from trauma (physical and/or emotional) to "close ones heart" or develop defensive behaviours - and then being locked into that state, indoctrinated into it - without the ability to disconnect from that pattern until say dramatically changing the chemical supply of transmitters - say either MDMA flooding the brain with serotonin, more than the brain naturally can at once, or say through ketamine or Ayahuasca or other psychedelics that give the opportunity for a perception change outside of the indoctrinated state(s) and behaviours. I imagine the vast majority of people who's circumstances aren't due to a chemical issue, more so the lack of adequate support for them and/or any element of Maslow's Hierarchy of Needs not being met during rapid and crucial childhood development.
  - johncolanduoni 6y ago
    Mood disorders found to be are significantly heritable in twin studies so I don’t think one can say the “vast majority” aren’t due to a chemical issue here. It’s also worth noting that BDNF is not a neurotransmitter, and so having a direct connection with thoughts and personality seems unlikely, though there is reason to believe it may be downstream of long term psychological stresses.
    - loceng 6y ago
      Fair enough, however I'd want to review those studies to see what similarities do exist - even if in different households/environments. Studies that aren't taking into account the relative general lack of health of people in many parts of the world needs to be addressed, accounted for, in research as well. I do understand how some makeups could allow a large amount of people to certainly to be prone to environmental stresses, have a more fragile-sensitive system - and if those factors are allowed to continue say for decades, there will be a hardening.
omegaworks 6y ago
We have new insight now into how antidepressants interface with specific signaling molecules, making them more effectively permeate the neuron cell membrane. It's still about chemical balance. It's a highly complex system involving more than serotonin, though. He mentions serotonin reuptake inhibitors once, but it looks like this finding applies to other substances identified as anti-depressants that aren't necessarily serotonin targeting.
vegannet 6y ago
I’ve always understood the chemical imbalance description of depression (and other mental health conditions) to be a casual way of describing the conditions as being part of the person rather than a choice — and not a way to describe the internal mechanics of the conditions. I’ve found it effective when having conversations about mental health conditions: how would you describe depression without using that phrase, based on what this paper reveals?
- anaphor 6y ago
  I'm not saying there isn't a biochemical component to depression (or any other mood disorders). The specific theory that I'm talking about is "low serotonin causes depression" (as in the proximate cause, not the ultimate cause). When SSRIs were first discovered to be useful for treating depression, one of the theories about why they worked was that they boosted levels of serotonin, but we know now that's not true. It doesn't mean it can't be explained in other ways (like the one this article discusses). Also, if there is a behavioral component to depression as well, then it doesn't necessarily mean someone is to blame for their disorder. You don't control the environment you grow up in, which has an enormous impact even on traits that are highly heritable (the whole subject of heritability is very misunderstood anyway). So basically if I were going to describe depression's cause, I'd say it's a mixture of biochemical reactions, behavioural traits, and environmental stresses that cause it.
  - sjg007 6y ago
    In the article they discuss that known SSRIs weakly bind a different receptor which may be why they have an antidepressant effect. It would explain why more specific SSRIs that are thought to target serotonin receptors selectively do not work. That they see a bunch of them doing the same thing is pretty convincing. to quote: "Now to the BDNF hypothesis. I used the phrase “unknown mechanism” above, and that’s exactly what this work may have cleared up. The authors show that when the TrkB protein forms a dimer in the cell membrane, a binding site for small molecules is formed at the interface. A whole list of known antidepressants (fluoxetine, imipramine, venlafaxine, moclobemide, ketamine, esketamine, and R,R-hydroxynorketamine) bind to this site at about 1 micromolar levels (and can displace each other in binding assays(, while a set of control CNS compounds like chlorpromazine, diphenhydramine, and indeed S,S-hydroxynorketamine do not. It will not be lost on those who’ve done research in the field that the antidepressant compounds listed above have been thought to work through completely different mechanisms. "
danielovichdk 6y ago
I am not a neuro anything, but has that been the a big debate in the antidepressant discussion long? The low level of serotonin? Is that a fallacy or an i missing something?
- anaphor 6y ago
  It's been a persistent myth perpetuated in the media/journalism/society/etc for a few decades, but there is a lot of scientific evidence showing that it doesn't really explain how depression works, and the fact that SSRIs boost serotonin doesn't explain why they work as a treatment. See https://sci-hub.st/https://www.sciencedirect.com/science/article/abs/pii/S0149763415000287 https://sci-hub.st/https://www.sciencedirect.com/science/art... for example.
hammock 6y ago
How antidepressants work (this article) and what causes depression (your postulate) are two completely different things.
sekh60 6y ago
Forgive my ignorance, but what alternative is there to a chemical imbalance of some sort? Structural differences? I have schizoaffective bipolar subtype, and wouldn't mind some links to more current literature, I'm obviously very behind.
- aantix 6y ago
  Have you ever tried Niacin/magnesium approach for treatment?
- anaphor 6y ago
  It used to be the case that the theory for why people have depression was "people who are depressed don't have enough serotonin" (in very simple terms), and the reason why SSRIs work was supposed to be that they increase levels of serotonin, but scientists have found that boosting levels of serotonin alone does not help with depression. Here's a good journal article on the subject https://sci-hub.st/https://www.sciencedirect.com/science/article/abs/pii/S0149763415000287 https://sci-hub.st/https://www.sciencedirect.com/science/art...
  - corin_ 6y ago
    If that theory is definitely wrong, it hasn't yet worked its way out of common use. Examples: NHS current website "This type of medication [SSRIs] works by increasing the level of a chemical called serotonin in your brain." https://www.nhs.uk/conditions/generalised-anxiety-disorder/treatment/ https://www.nhs.uk/conditions/generalised-anxiety-disorder/t... Wikipedia "It is believed to work by blocking the re-uptake of the chemical serotonin by neurons in the brain." https://en.wikipedia.org/wiki/Paroxetine https://en.wikipedia.org/wiki/Paroxetine etc.
    - Delk 6y ago
      I'm not sure that the reason why some (e.g. official) health information sources keep repeating that isn't just a combination of having an easy explanation and making a (benign) attempt to induce a placebo effect in unknowledgeable patients. If you either get massively technical about complex things that would make most laymen's heads spin, or shrugged your shoulders and said that we don't really know, you might miss on the potential psychological effects that you can get by projecting some kind of confidence.
johncolanduoni 6y ago
Not really, it’s just proposing a different chemical imbalance than the “monoamine hypothesis” (i.e. serotonin, etc.). That one has already been disfavored for the past few decades, due to a lot of findings that it has trouble explaining. In particular the discovery of effective antidepressants that don’t affect the monoamine receptors enough or in sufficiently similar ways.
konjin 6y ago
That theory makes as much sense as the theory that "chemical imbalances" (i.e. low-alcohol) cause social anxiety. Alcohols are produced in your brain naturally and adding more changes behavior. Clinical trials show that more alcohol increases sociability compared to placebos (but with side effects). There are some concerns about giving alcohol to three year olds, but it is better that they become socialized at a young age than deal with the consequences for life. In short: science + tons of money = not science.
- vinger 6y ago
  Are you a bot?
- imwillofficial 6y ago
  I don’t know, tons of alcohol makes me very social ;)
johnisgood 6y ago
"The monoamine hypothesis, like the neurotrophic hypothesis, is at best incomplete. Many studies have not found an alteration in function or levels of monoamines in depressed patients. In addition, some candidate antidepressant agents under study do not act directly on the monoamine system. In addition to the monoamines, the excitatory neurotransmitter glutamate appears to be important in the pathophysiology of depression. A number of studies of depressed patients have found elevated glutamate content in the cerebrospinal fluid of depressed patients and decreased glutamine/glutamate ratios in their plasma. In addition, postmortem studies have revealed significant increases in the frontal and dorsolateral prefrontal cortex of depressed patients. Likewise, structural neuroimaging studies have consistently found volumetric changes in the brain areas of depressed patients in which glutamate neurons and their connections are most abundant, including the amygdala and hippocampus." "Given the effect of antidepressants on the glutamate system, there has been a growing interest in the development of pharmaceutical agents that might modulate the glutamate system. Ketamine is a potent, high-affinity, noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist that has long been used in anesthesia and is a common drug of abuse in some parts of the world." Novel antidepressants now are NMDA receptor antagonists, or take a look at tianeptine which works just as well, yet it only affects your opioid receptors. None of which have to do with the monoamine hypothesis.
meowface 6y ago
This topic is often a red herring and source of conflation. I strongly recommend this series of articles from a psychiatrist about it: https://slatestarcodex.com/2015/04/05/chemical-imbalance/ https://slatestarcodex.com/2015/04/05/chemical-imbalance/, https://slatestarcodex.com/2015/04/18/polemical-imbalance/ https://slatestarcodex.com/2015/04/18/polemical-imbalance/
- anaphor 6y ago
  I linked to a paper published and written by several psychiatrists and psychologists that explains the history of the monoamine hypothesis, and why it's not a good theory. Why would they spend so much time debunking a theory nobody believes? Quoting directly from the article > Despite decades of research, the role serotonin plays in depressive phenotypes has not been conclusively determined. The original clue that monoamines (serotonin, norepinephrine, and dopamine) were involved in depression came from two serendipitous discoveries (Baumeister et al., 2003; Valenstein, 1998). First, during the investigations of iproniazid as a treatment for tuberculosis and imipramine as a treatment for schizophrenia, clinicians reported that these drugs could reduce depressive symptoms. An effort was then made to find a common pharmacological property that could explain their antidepressant effect. Eventually, researchers found that iproniazid inhibits the enzymes that break down the monoamines, while imipramine blocks the serotonin transporter (SERT) and the norepinephrine transporter (NET). Second, clinical observations suggested that reserpine, a drug known to deplete monoamines, increased depressive symptoms. These findings appeared to solve the puzzle. By preventing the breakdown of norepinephrine and serotonin, or preventing their clearance from the synapse, iproniazid and imipramine appeared to increase forebrain monoamine levels. > The monoamine-enhancing effect of antidepressant medications (ADMs), coupled with the depression-inducing effects of reserpine, suggested that depression was caused by reduced monoamine neurotransmission (Everett and Toman, 1959; Jacobsen, 1964; Schildkraut, 1965) https://sci-hub.st/https://www.sciencedirect.com/science/article/abs/pii/S0149763415000287 https://sci-hub.st/https://www.sciencedirect.com/science/art... Additionaly, this is something that lots of undergraduate psychology textbooks still mention as a potential explanation (one of mine did ~6 or 7 years ago, although at least they said that it was an implausible theory).
ravi-delia 6y ago
To my knowledge the idea that depression is a result of low serotonin has not been accepted by the scientific community at any time; immediately after SSRIs were shown to have an effect lots of people assumed that serotonin was important, but reuptake inhibition wouldn't even treat low levels overall, let alone matching the super weird timing effects.

Isn't it already though? Besides for those self-diagnosed tumbrlinas complaining about "no serotonin". It's pretty well established that Dopamine, Norepinephrine, etc play a huge role in depression. Serotonin is a small part of it. And anyway, I would bet almost all cases of depression ultimately stem from ineffective behaviors and thoughts, not some fundamental chemical imbalance.

toiletfuneral 6y ago
wow, super constructive comment. You seem very proud of yourself
loceng 6y ago
Arguably it's life experiences and environmental stimuli that actually play a role in depression et al - it's just these neurotransmitters you speak of are the communicators. E.g. Self-protective mechanism from trauma (physical and/or emotional) to "close ones heart" or develop defensive behaviours - and then being locked into that state, indoctrinated into it - without the ability to disconnect from that pattern until say dramatically changing the chemical supply of transmitters - say either MDMA flooding the brain with serotonin, more than the brain naturally can at once, or say through ketamine or Ayahuasca or other psychedelics that give the opportunity for a perception change outside of the indoctrinated state(s) and behaviours. I imagine the vast majority of people who's circumstances aren't due to a chemical issue, more so the lack of adequate support for them and/or any element of Maslow's Hierarchy of Needs not being met during rapid and crucial childhood development.
- johncolanduoni 6y ago
  Mood disorders found to be are significantly heritable in twin studies so I don’t think one can say the “vast majority” aren’t due to a chemical issue here. It’s also worth noting that BDNF is not a neurotransmitter, and so having a direct connection with thoughts and personality seems unlikely, though there is reason to believe it may be downstream of long term psychological stresses.
  - loceng 6y ago
    Fair enough, however I'd want to review those studies to see what similarities do exist - even if in different households/environments. Studies that aren't taking into account the relative general lack of health of people in many parts of the world needs to be addressed, accounted for, in research as well. I do understand how some makeups could allow a large amount of people to certainly to be prone to environmental stresses, have a more fragile-sensitive system - and if those factors are allowed to continue say for decades, there will be a hardening.

omegaworks 6y ago

We have new insight now into how antidepressants interface with specific signaling molecules, making them more effectively permeate the neuron cell membrane. It's still about chemical balance. It's a highly complex system involving more than serotonin, though. He mentions serotonin reuptake inhibitors once, but it looks like this finding applies to other substances identified as anti-depressants that aren't necessarily serotonin targeting.

vegannet 6y ago

I’ve always understood the chemical imbalance description of depression (and other mental health conditions) to be a casual way of describing the conditions as being part of the person rather than a choice — and not a way to describe the internal mechanics of the conditions. I’ve found it effective when having conversations about mental health conditions: how would you describe depression without using that phrase, based on what this paper reveals?

anaphor 6y ago
I'm not saying there isn't a biochemical component to depression (or any other mood disorders). The specific theory that I'm talking about is "low serotonin causes depression" (as in the proximate cause, not the ultimate cause). When SSRIs were first discovered to be useful for treating depression, one of the theories about why they worked was that they boosted levels of serotonin, but we know now that's not true. It doesn't mean it can't be explained in other ways (like the one this article discusses). Also, if there is a behavioral component to depression as well, then it doesn't necessarily mean someone is to blame for their disorder. You don't control the environment you grow up in, which has an enormous impact even on traits that are highly heritable (the whole subject of heritability is very misunderstood anyway). So basically if I were going to describe depression's cause, I'd say it's a mixture of biochemical reactions, behavioural traits, and environmental stresses that cause it.
- sjg007 6y ago
  In the article they discuss that known SSRIs weakly bind a different receptor which may be why they have an antidepressant effect. It would explain why more specific SSRIs that are thought to target serotonin receptors selectively do not work. That they see a bunch of them doing the same thing is pretty convincing. to quote: "Now to the BDNF hypothesis. I used the phrase “unknown mechanism” above, and that’s exactly what this work may have cleared up. The authors show that when the TrkB protein forms a dimer in the cell membrane, a binding site for small molecules is formed at the interface. A whole list of known antidepressants (fluoxetine, imipramine, venlafaxine, moclobemide, ketamine, esketamine, and R,R-hydroxynorketamine) bind to this site at about 1 micromolar levels (and can displace each other in binding assays(, while a set of control CNS compounds like chlorpromazine, diphenhydramine, and indeed S,S-hydroxynorketamine do not. It will not be lost on those who’ve done research in the field that the antidepressant compounds listed above have been thought to work through completely different mechanisms. "

danielovichdk 6y ago

I am not a neuro anything, but has that been the a big debate in the antidepressant discussion long? The low level of serotonin? Is that a fallacy or an i missing something?

anaphor 6y ago
It's been a persistent myth perpetuated in the media/journalism/society/etc for a few decades, but there is a lot of scientific evidence showing that it doesn't really explain how depression works, and the fact that SSRIs boost serotonin doesn't explain why they work as a treatment. See https://sci-hub.st/https://www.sciencedirect.com/science/article/abs/pii/S0149763415000287 https://sci-hub.st/https://www.sciencedirect.com/science/art... for example.

hammock 6y ago

How antidepressants work (this article) and what causes depression (your postulate) are two completely different things.

sekh60 6y ago

Forgive my ignorance, but what alternative is there to a chemical imbalance of some sort? Structural differences? I have schizoaffective bipolar subtype, and wouldn't mind some links to more current literature, I'm obviously very behind.

aantix 6y ago
Have you ever tried Niacin/magnesium approach for treatment?
anaphor 6y ago
It used to be the case that the theory for why people have depression was "people who are depressed don't have enough serotonin" (in very simple terms), and the reason why SSRIs work was supposed to be that they increase levels of serotonin, but scientists have found that boosting levels of serotonin alone does not help with depression. Here's a good journal article on the subject https://sci-hub.st/https://www.sciencedirect.com/science/article/abs/pii/S0149763415000287 https://sci-hub.st/https://www.sciencedirect.com/science/art...
- corin_ 6y ago
  If that theory is definitely wrong, it hasn't yet worked its way out of common use. Examples: NHS current website "This type of medication [SSRIs] works by increasing the level of a chemical called serotonin in your brain." https://www.nhs.uk/conditions/generalised-anxiety-disorder/treatment/ https://www.nhs.uk/conditions/generalised-anxiety-disorder/t... Wikipedia "It is believed to work by blocking the re-uptake of the chemical serotonin by neurons in the brain." https://en.wikipedia.org/wiki/Paroxetine https://en.wikipedia.org/wiki/Paroxetine etc.
  - Delk 6y ago
    I'm not sure that the reason why some (e.g. official) health information sources keep repeating that isn't just a combination of having an easy explanation and making a (benign) attempt to induce a placebo effect in unknowledgeable patients. If you either get massively technical about complex things that would make most laymen's heads spin, or shrugged your shoulders and said that we don't really know, you might miss on the potential psychological effects that you can get by projecting some kind of confidence.

johncolanduoni 6y ago

Not really, it’s just proposing a different chemical imbalance than the “monoamine hypothesis” (i.e. serotonin, etc.). That one has already been disfavored for the past few decades, due to a lot of findings that it has trouble explaining. In particular the discovery of effective antidepressants that don’t affect the monoamine receptors enough or in sufficiently similar ways.

konjin 6y ago

That theory makes as much sense as the theory that "chemical imbalances" (i.e. low-alcohol) cause social anxiety. Alcohols are produced in your brain naturally and adding more changes behavior. Clinical trials show that more alcohol increases sociability compared to placebos (but with side effects). There are some concerns about giving alcohol to three year olds, but it is better that they become socialized at a young age than deal with the consequences for life. In short: science + tons of money = not science.

vinger 6y ago
Are you a bot?
imwillofficial 6y ago
I don’t know, tons of alcohol makes me very social ;)

johnisgood 6y ago

"The monoamine hypothesis, like the neurotrophic hypothesis, is at best incomplete. Many studies have not found an alteration in function or levels of monoamines in depressed patients. In addition, some candidate antidepressant agents under study do not act directly on the monoamine system. In addition to the monoamines, the excitatory neurotransmitter glutamate appears to be important in the pathophysiology of depression. A number of studies of depressed patients have found elevated glutamate content in the cerebrospinal fluid of depressed patients and decreased glutamine/glutamate ratios in their plasma. In addition, postmortem studies have revealed significant increases in the frontal and dorsolateral prefrontal cortex of depressed patients. Likewise, structural neuroimaging studies have consistently found volumetric changes in the brain areas of depressed patients in which glutamate neurons and their connections are most abundant, including the amygdala and hippocampus." "Given the effect of antidepressants on the glutamate system, there has been a growing interest in the development of pharmaceutical agents that might modulate the glutamate system. Ketamine is a potent, high-affinity, noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist that has long been used in anesthesia and is a common drug of abuse in some parts of the world." Novel antidepressants now are NMDA receptor antagonists, or take a look at tianeptine which works just as well, yet it only affects your opioid receptors. None of which have to do with the monoamine hypothesis.

meowface 6y ago

This topic is often a red herring and source of conflation. I strongly recommend this series of articles from a psychiatrist about it: https://slatestarcodex.com/2015/04/05/chemical-imbalance/ https://slatestarcodex.com/2015/04/05/chemical-imbalance/, https://slatestarcodex.com/2015/04/18/polemical-imbalance/ https://slatestarcodex.com/2015/04/18/polemical-imbalance/

anaphor 6y ago
I linked to a paper published and written by several psychiatrists and psychologists that explains the history of the monoamine hypothesis, and why it's not a good theory. Why would they spend so much time debunking a theory nobody believes? Quoting directly from the article > Despite decades of research, the role serotonin plays in depressive phenotypes has not been conclusively determined. The original clue that monoamines (serotonin, norepinephrine, and dopamine) were involved in depression came from two serendipitous discoveries (Baumeister et al., 2003; Valenstein, 1998). First, during the investigations of iproniazid as a treatment for tuberculosis and imipramine as a treatment for schizophrenia, clinicians reported that these drugs could reduce depressive symptoms. An effort was then made to find a common pharmacological property that could explain their antidepressant effect. Eventually, researchers found that iproniazid inhibits the enzymes that break down the monoamines, while imipramine blocks the serotonin transporter (SERT) and the norepinephrine transporter (NET). Second, clinical observations suggested that reserpine, a drug known to deplete monoamines, increased depressive symptoms. These findings appeared to solve the puzzle. By preventing the breakdown of norepinephrine and serotonin, or preventing their clearance from the synapse, iproniazid and imipramine appeared to increase forebrain monoamine levels. > The monoamine-enhancing effect of antidepressant medications (ADMs), coupled with the depression-inducing effects of reserpine, suggested that depression was caused by reduced monoamine neurotransmission (Everett and Toman, 1959; Jacobsen, 1964; Schildkraut, 1965) https://sci-hub.st/https://www.sciencedirect.com/science/article/abs/pii/S0149763415000287 https://sci-hub.st/https://www.sciencedirect.com/science/art... Additionaly, this is something that lots of undergraduate psychology textbooks still mention as a potential explanation (one of mine did ~6 or 7 years ago, although at least they said that it was an implausible theory).

ravi-delia 6y ago

To my knowledge the idea that depression is a result of low serotonin has not been accepted by the scientific community at any time; immediately after SSRIs were shown to have an effect lots of people assumed that serotonin was important, but reuptake inhibition wouldn't even treat low levels overall, let alone matching the super weird timing effects.