<p>Haha, yep. We don't know how depression or SSRIs work. We have hypotheses for both schizophrenia and depression - <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669582/" rel="nofollow noreferrer">the dopamine hypothesis</a> and <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405681/" rel="nofollow noreferrer">the serotonin hypothesis</a>.</p>

<p>While I was conducting my research, I too was faced with this conundrum. And <a href="https://davidhealy.org/switch-on-anti-depression-today/" rel="nofollow noreferrer">Dr. David Healy</a> is one of the trailblazers of the side which says that it's all clever pharma marketing.</p>

<p>As in the post you sent, norepinephrine was considered to be the monoamine that was linked to depression. Soon the notion changed from this to serotonin deficiency being the culprit. Back then a class of drugs known as "Monoamine Oxidase Inhibitors (MAOIs)" were administered which worked selectively to suppress the effect of the enzyme MAO which was responsible for the breakdown of the monoamines (da, ht, ne).</p>

<p>SSRIs were revolutionary because these targeted the serotonin reuptake (popular speculation). Since it's more targeted towards ht, it's clear why they're more popular than MAOIs now.</p>

<p>Find a brief comparison between MAOIs and SSRIs here : <a href="https://www.verywellmind.com/how-do-ssris-compare-to-maois-1066856" rel="nofollow noreferrer">https://www.verywellmind.com/how-do-ssris-compare-to-maois-1066856</a></p>

<p>But just like any drug, they've got their own drawbacks. And since there's a big question mark on their functioning, it's clear that there's a need to carry out rigorous and definitive research into this area to know how depression and SSRIs work for certainty. </p>

CC BY-SA 4.0
2019-06-24T18:09:30.480Z
2019-06-25T21:32:58.913Z
2019-06-25T21:32:58.913Z
Opp3nh31m3r
<p>This question may be seen as an extension of my <a href="https://psychology.stackexchange.com/questions/14082/can-the-effectiveness-of-antidepressants-be-explained-by-a-placebo-effect">previous question</a>, here. I was talking to a person online where s/he mentioned that psychiatrists themselves don't have an idea as to how SSRIs work. Upon searching YouTube, I found <a href="https://youtu.be/Ugcq6FWmNI8" rel="nofollow noreferrer">this video</a> where the narrator goes on to make many statements referencing various journals, doctors, researchers, etc. </p>

<p>Here are some points in particular that have been bothering me a bit from the video;</p>

<blockquote>
  <ul>
  <li><p>[...] in 1965 he said that "some, if not all depressions are associated with an absolute or relative deficiency of catecholamines, particularly norepinephrine." After that researchers quickly turned much of their attention to serotonin, guessing a deficiency in serotonin to be a root cause of depression. So, in this case, researchers first understood how a drug worked, then assumed the cause of depression based on the way the drug works. [...] The American Psychiatric Association's own 1999 textbook explains that assuming depression is caused by low serotonin because a drug that seems to prevent depression raises serotonin "...is similar to concluding that because aspirin causes gastrointestinal bleeding, headaches are caused by too much blood loss and the <em>therapeutic action of aspirin in headaches involves blood loss.</em> So, in 1999 the APA is making fun of how the chemical imbalance idea came to be.</p></li>
  <li><p>Going back to antidepressants again, we’d want to know the context in which you introduce this medication. A genetic test, for example, would be helpful, but before you introduce a drug that increases serotonin signalling, we would at least want to verify that the person actually has low serotonin levels. Especially because antidepressants are known to have a very high risk for complications including the potentially life-threatening serotonin syndrome and a black box warning for “suicidal thoughts and behaviours.”. But as researchers at McMaster University explain, “It is currently impossible to measure exactly how the [living] brain is releasing and using serotonin..." [...] In 1971, investigators at McGill University failed to find a “statistically significant” difference between the 5-HIAA levels of depressed patients and normal controls and there was no correlation whatsoever between depression severity and levels of 5-HIAA. Then in 1974, two researchers at the University of Pennsylvania found that a serotonin depleting drug didn’t reliably induce depression at all. Then, in 1975, investigators at the Karolinska Institute in Stockholm found that 30% of the depressed patients they tested indeed suffered from low levels of the serotonin metabolite 5-HIAA. But, they also found that 25% of the “normal” group also had low cerebrospinal levels of these metabolites. Finally, in 1984, NIMH investigators wanted to see whether those depressed patients with low serotonin would be the best responders to an antidepressant. Unfortunately for the chemical imbalance theory, lead investigator James Maas wrote, “contrary to expectations, no relationships between cerebrospinal 5-HIAA and response to [the antidepressant] amitriptyline were found.” Simply put, researchers assumed that antidepressants were working their magic in a certain context based on what the antidepressant does, not based on proper evidence for that context.</p></li>
  <li><p>[...] Have a listen to Psychiatrist Daniel Carlat’s comment on this: "But on the other hand, what we don't is we don't know how the medications actually work in the brain... when patients ask me about these medications, I'll often say something like, well, the way Zoloft works is it increases the levels of serotonin in your brain... and presumably the reason you're depressed or anxious is that you have some sort of deficiency. ... I say that because patients ... certainly don't want to hear that a psychiatrist essentially has no idea how these medications work." So with antidepressants, we don’t actually know why they would work, and there’s doubt about whether they actually do work. [...] But what happens in people who just don’t take medication? In Robert Whitaker’s book “Anatomy of an Epidemic,” he explains that before the age of antidepressants, people’s depression would usually resolve by itself eventually. A 1931 long term study of 2,700 depressed patients reported that more than half of those admitted for depression only had one depressive episode and no relapse. [...] At the end of 6 years, the people who received the medication were more than 3 times as likely to have stopped functioning in their usual societal roles.</p></li>
  </ul>
</blockquote>

<p>And there are many points he said in the video (that I didn't quote so as to not make the post long enough to read, but keep it succinct as well) that I am totally unable to accept as hardcore facts/pieces of evidence against anti-depressants and that doctors, as well as researchers, don't know what they are doing. This is totally against what I have seen <a href="https://youtu.be/tLntiP5Msxw" rel="nofollow noreferrer">here</a> and <a href="https://youtu.be/Yy8e4sw70ow" rel="nofollow noreferrer">here</a>. The video craftily puts a disclaimer before that if someone is on medication, they should first take the advice of their physician/psychiatrist, but goes on to plant the seeds of doubt. And as I am a novice in this field, this video has managed to boggle my mind as well has irked me a bit. I'd really appreciate it if I get some clear explanations as to what is going on here. Regards! </p>

CC BY-SA 4.0
2019-06-24T18:20:54.207Z
There is a difference between "don't know how it works" and "doesn't know what they are doing" - other drug classes are similarly mysterious but no more casually used (anesthetics for example: we still don't know how/why general anesthesia works but it's really effective). It makes it more difficult to develop novel drugs, but all the evidence for a drug is based on outcomes, not based on mechanism.
Bryan Krause
CC BY-SA 4.0
2019-06-24T18:24:28.803Z
That hit home. Thank you!
Janus Boffin
CC BY-SA 4.0
2019-06-25T09:28:41.797Z
Another thing to think about is YouTube videos are not always a good source of reliable information unless you are following a reputable channel. Anyone can cite a spurious study from 1989 say, but without a reference list or full citation in the video, you cannot assess the validity of what they are saying. As @AliceD said in his answer to your previous question, don’t believe everything you listen to or read in websites. Question it’s validity until you can guarantee the truth is being told. I don’t know how reputable they are but there is no reference list in the text below the video.
Chris Rogers
<neuroscience><psychiatry><depression><neuro-transmitters><medication>
Do psychiatrists and researchers themselves don't have an idea how antidepressants work?
Janus Boffin
# Do psychiatrists and researchers themselves don't have an idea how antidepressants work?

(Asked by: username_0 on 2019-06-24)

This question may be seen as an extension of my [previous question](https://psychology.stackexchange.com/questions/14082/can-the-effectiveness-of-antidepressants-be-explained-by-a-placebo-effect), here. I was talking to a person online where s/he mentioned that psychiatrists themselves don't have an idea as to how SSRIs work. Upon searching YouTube, I found [this video](https://youtu.be/Ugcq6FWmNI8) where the narrator goes on to make many statements referencing various journals, doctors, researchers, etc.

Here are some points in particular that have been bothering me a bit from the video;

> * [...] in 1965 he said that "some, if not all depressions are associated with an absolute or relative deficiency of catecholamines, particularly norepinephrine." After that researchers quickly turned much of their attention to serotonin, guessing a deficiency in serotonin to be a root cause of depression. So, in this case, researchers first understood how a drug worked, then assumed the cause of depression based on the way the drug works. [...] The American Psychiatric Association's own 1999 textbook explains that assuming depression is caused by low serotonin because a drug that seems to prevent depression raises serotonin "...is similar to concluding that because aspirin causes gastrointestinal bleeding, headaches are caused by too much blood loss and the *therapeutic action of aspirin in headaches involves blood loss.* So, in 1999 the APA is making fun of how the chemical imbalance idea came to be.
> * Going back to antidepressants again, we’d want to know the context in which you introduce this medication. A genetic test, for example, would be helpful, but before you introduce a drug that increases serotonin signalling, we would at least want to verify that the person actually has low serotonin levels. Especially because antidepressants are known to have a very high risk for complications including the potentially life-threatening serotonin syndrome and a black box warning for “suicidal thoughts and behaviours.”. But as researchers at McMaster University explain, “It is currently impossible to measure exactly how the [living] brain is releasing and using serotonin..." [...] In 1971, investigators at McGill University failed to find a “statistically significant” difference between the 5-HIAA levels of depressed patients and normal controls and there was no correlation whatsoever between depression severity and levels of 5-HIAA. Then in 1974, two researchers at the University of Pennsylvania found that a serotonin depleting drug didn’t reliably induce depression at all. Then, in 1975, investigators at the Karolinska Institute in Stockholm found that 30% of the depressed patients they tested indeed suffered from low levels of the serotonin metabolite 5-HIAA. But, they also found that 25% of the “normal” group also had low cerebrospinal levels of these metabolites. Finally, in 1984, NIMH investigators wanted to see whether those depressed patients with low serotonin would be the best responders to an antidepressant. Unfortunately for the chemical imbalance theory, lead investigator James Maas wrote, “contrary to expectations, no relationships between cerebrospinal 5-HIAA and response to [the antidepressant] amitriptyline were found.” Simply put, researchers assumed that antidepressants were working their magic in a certain context based on what the antidepressant does, not based on proper evidence for that context.
> * [...] Have a listen to Psychiatrist Daniel Carlat’s comment on this: "But on the other hand, what we don't is we don't know how the medications actually work in the brain... when patients ask me about these medications, I'll often say something like, well, the way Zoloft works is it increases the levels of serotonin in your brain... and presumably the reason you're depressed or anxious is that you have some sort of deficiency. ... I say that because patients ... certainly don't want to hear that a psychiatrist essentially has no idea how these medications work." So with antidepressants, we don’t actually know why they would work, and there’s doubt about whether they actually do work. [...] But what happens in people who just don’t take medication? In Robert Whitaker’s book “Anatomy of an Epidemic,” he explains that before the age of antidepressants, people’s depression would usually resolve by itself eventually. A 1931 long term study of 2,700 depressed patients reported that more than half of those admitted for depression only had one depressive episode and no relapse. [...] At the end of 6 years, the people who received the medication were more than 3 times as likely to have stopped functioning in their usual societal roles.

And there are many points he said in the video (that I didn't quote so as to not make the post long enough to read, but keep it succinct as well) that I am totally unable to accept as hardcore facts/pieces of evidence against anti-depressants and that doctors, as well as researchers, don't know what they are doing. This is totally against what I have seen [here](https://youtu.be/tLntiP5Msxw) and [here](https://youtu.be/Yy8e4sw70ow). The video craftily puts a disclaimer before that if someone is on medication, they should first take the advice of their physician/psychiatrist, but goes on to plant the seeds of doubt. And as I am a novice in this field, this video has managed to boggle my mind as well has irked me a bit. I'd really appreciate it if I get some clear explanations as to what is going on here. Regards!

**Tags:** neuroscience, psychiatry, depression, neuro-transmitters, medication

> **Comments:**
> **username_1**: There is a difference between "don't know how it works" and "doesn't know what they are doing" - other drug classes are similarly mysterious but no more casually used (anesthetics for example: we still don't know how/why general anesthesia works but it's really effective). It makes it more difficult to develop novel drugs, but all the evidence for a drug is based on outcomes, not based on mechanism.  
> **username_0**: That hit home. Thank you!  
> **username_2**: Another thing to think about is YouTube videos are not always a good source of reliable information unless you are following a reputable channel. Anyone can cite a spurious study from 1989 say, but without a reference list or full citation in the video, you cannot assess the validity of what they are saying. As @AliceD said in his answer to your previous question, don’t believe everything you listen to or read in websites. Question it’s validity until you can guarantee the truth is being told. I don’t know how reputable they are but there is no reference list in the text below the video.  

---

## 1 answers

### Answer by username_3 on 2019-06-24. Score: 2

Haha, yep. We don't know how depression or SSRIs work. We have hypotheses for both schizophrenia and depression - [the dopamine hypothesis](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669582/) and [the serotonin hypothesis](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405681/).

While I was conducting my research, I too was faced with this conundrum. And [Dr. David Healy](https://davidhealy.org/switch-on-anti-depression-today/) is one of the trailblazers of the side which says that it's all clever pharma marketing.

As in the post you sent, norepinephrine was considered to be the monoamine that was linked to depression. Soon the notion changed from this to serotonin deficiency being the culprit. Back then a class of drugs known as "Monoamine Oxidase Inhibitors (MAOIs)" were administered which worked selectively to suppress the effect of the enzyme MAO which was responsible for the breakdown of the monoamines (da, ht, ne).

SSRIs were revolutionary because these targeted the serotonin reuptake (popular speculation). Since it's more targeted towards ht, it's clear why they're more popular than MAOIs now.

Find a brief comparison between MAOIs and SSRIs here : <https://www.verywellmind.com/how-do-ssris-compare-to-maois-1066856>

But just like any drug, they've got their own drawbacks. And since there's a big question mark on their functioning, it's clear that there's a need to carry out rigorous and definitive research into this area to know how depression and SSRIs work for certainty.


---

