The serotonin theory of depression: a systematic umbrella review of the evidence.. Thoughts?

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ccool

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Hi, anyone seen this recent Molecular Psychiatry paper also published in Nature?


From their review of systematic reviews and meta-analyses published through 2020, authors conclude that, “it is time to acknowledge that the serotonin theory of depression is not empirically substantiated.”

I am personally open to considering this possibility, particularly given that “depression” does not have a singular cause. But the limitations of their review, some of which they acknowledge, are major. And I’m not sure how they can be so unequivocal in the conclusion that there is no support for the serotonin theory of depression given these major limitations - most of the studies in their review were low quality and had low power, and most of the studies did not account for the effects of antidepressant use.

In their words, “Most of the included studies were rated as low quality on the AMSTAR-2, but the GRADE approach suggested some findings were reasonably robust. Most of the non-genetic studies did not reliably exclude the potential effects of previous antidepressant use and were based on relatively small numbers of participants.”

I’m also curious how “depression” was defined across included studies and the impact of that on their findings. Depression in quotes given that the disorder (MDD) is not a single biological reality or construct.

Anyway, curious about others’ thoughts, implications, etc.

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Well, we know serotonin is not the *cause* of depression. Serotonin in the brain changes rapidly upon taking these medications. However, the antidepressent, anxiolytic, antiPtSD, etc effects are not seen for 4-6 weeks typically. This points to some other reason we are seeing the treatment effect besides serotonin.

Regardless, the ‘chemical soup’ hypothesis brought us many useful drugs we use daily. So even if it only partially explained the underlying pathology, it shot the field forward and gave us a model.

The new age model is that our meds are actually causing neuron/dentritic growth , the so called ‘neuroplastogen’ hypothesis. This is bringing us new meds as well. Im sure this will not fully explain the above syndromes either, however it will hopefully bring more treatment options and some more insight into the brain. It has already given us ketamine, brexanolone, etc - and more are in the pipeline.
 
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The lead investigator Joanna Moncrieff is a psychiatrist with a history of views against psychiatric medications. Her website lists her books including titles such as:

The Bitterest Pills: the troubling story of antipsychotic drugs

The Myth of the Chemical Cure: A Critique of Psychiatric Drug Treatment

A Straight Talking Introduction to Psychiatric Drugs: The truth about how they work and how to come off them.


So it's possible she entered into this study with an expected outcome in mind.

The idea that serotonin is not low in depression isn't a new idea. I've personally never heard a psychiatrist who believes low serotonin or chemical imbalance is the cause of depression. The source the study uses to support professionals believing in a chemical imbalance theory is based on a survey of UK primary care doctors, not psychiatrists.

However, the study acts like it's some bombshell. The serotonin chemical imbalance theory is refuted, and all psychiatrists are just plain wrong. Well that's obviously dramatic nonsense. But it's sure a catchy claim and probably is what helps her sell books.

I'm not a researcher, but we have studies showing antidepressants do work, somewhat at least, and separate from placebo in RCTs. The delay for antidepressant response certainly suggests that increasing low serotonin levels, or driving normal levels higher, is not directly how antidepressants affect depression. If it was, you'd have more immediate results (we see an immediate serotonin action in overdose sometimes: if someone ingests a month of Prozac with a 2D6 inhibitor, and skyrockets their Prozac levels, you can see serotonin syndrome right away).

There is likely a complicated cascade of subsequent effects that take time (weeks) and with variable effect among individuals, which is why some meds, even from the same class, may work for one person, but not another. Like someone takes Prozac and feels more depressed, then tries Lexapro and it works for them. I think this is just really hard to study.

The article makes a point of saying the studies looking at levels of serotonin use 5-HIAA as a marker, and plasma levels are easier to test so there is more data for that, and relatively limited data for CSF 5-HIAA. But to me it seems the CSF studies would be most relevant, and with limited data are they even useful? And why even include plasma levels if we're talking about a brain process.

Also, when I read through the article sections on SERT, Depletion of serotonin by reducing dietary tryptophan, and SERT gene variation, it gets very confusing. It sounds like the study is dismissing evidence readily that doesn't support their conclusion, and makes assumptions about synaptic serotonin concentrations based on SERT gene that I'm not sure are actually backed up by research. These three sections are suspect to me.

The author I think is being dishonest by suggesting low serotonin levels is the accepted theory for why serotonergic antidepressants work, when that is not true. And the study results don't show antidepressants are not effective, that's not what it was looking for.

This quote from the discussion section is most troublesome to me:

The idea that depression is the result of a chemical imbalance also influences decisions about whether to take or continue antidepressant medication and may discourage people from discontinuing treatment, potentially leading to lifelong dependence on these drugs

because it's subtle, but now the article is implying that people are taking medications that DO NOT WORK and cause "lifelong dependence". Which the study was not designed to test and does not prove or disprove in any way. I think this line is why all the news outlets are running with the story that SSRIs don't work. Which is likely just what the author wanted.
 
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There was a time when the "chemical imbalance" nonsense was oversold, particularly in the 90s and 00s.
There's a difference between saying 'antidepressants work and it's probably somehow related to serotonin' vs the elaborate hypotheses that were at times taken like they were substantiated when they were absolutely not. And this definitely did 'help' sell the field as more 'biological' and more 'scientific' when we're nowhere near, despite the very obvious oversimplifications. I mean, Stahl is still treated like a God in many residencies.

I always get a chuckle when people start hypothesizing what would work better based on this and that receptor when the evidence in the literature is very scant.

The reality is that MDD as defined in the DSM is a very amorphous and imprecise concept. We don't even have good evidence why 4/9 and which symptoms are supposed to do the trick for the diagnosis. It's essentially guess work and 'expert opinion'. Maybe if we start from there and acknowledge how unscientific our field is, instead of selling snake oil to the public.

Psychiatry has been trying to sell itself for something it isn't, right from the time of Freud, going through the DSM till now.
 
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The monoamine theory of depression has been proved insufficient at best and plain wrong at worst around 10-15 years ago

This is oooooold news i m not sure what the fuzz is about really

"We need to stop telling patients they lack serotonin in their brain" well no ****

The paper as a whole is embarassing and propably better refered to as "psych 101 for general practice"
 
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I don't know any colleagues who believe in the idea that low serotonin means depression.
 
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The lead investigator Joanna Moncrieff is a psychiatrist with a history of views against psychiatric medications.

I don't think the Critical Psychiatry Network ever had much impact outside of the UK, and even there the number of members is relatively small.
 
The idea that serotonin is not low in depression isn't a new idea. I've personally never heard a psychiatrist who believes low serotonin or chemical imbalance is the cause of depression. The source the study uses to support professionals believing in a chemical imbalance theory is based on a survey of UK primary care doctors, not psychiatrists...

The author I think is being dishonest by suggesting low serotonin levels is the accepted theory for why serotonergic antidepressants work, when that is not true. And the study results don't show antidepressants are not effective, that's not what it was looking for.
Exactly. Yawn. How did this make it into Molecular Psychiatry??
 
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It's all because of their relationship with their mother, silly!
 
Mm, thanks all for your perspectives.

These were my general inclinations but with it being such (public) news, I wasn’t sure if I was missing something. I’ll have to do more reading about SSRIs regardless. Cheers.
 
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Lately there seems to be another anti-psychiatry push by the media. I’m thinking also of recent article in NY Times about treatment of psychotic disorders with medication. I’m not sure which is more harmful to my patients, the deceptions of big pharma or the misleading narrative of the anti-pharma folk. It is also kind of interesting that no matter how much much push back there is against the overreliance of medications as a sole treatment for mental illness, the pharmaceutical companies continue to make back off it and there market just keeps growing. In other words, in a month no one will remember this article and the ads for new medications will still be everywhere.
 
Lately there seems to be another anti-psychiatry push by the media. I’m thinking also of recent article in NY Times about treatment of psychotic disorders with medication. I’m not sure which is more harmful to my patients, the deceptions of big pharma or the misleading narrative of the anti-pharma folk. It is also kind of interesting that no matter how much much push back there is against the overreliance of medications as a sole treatment for mental illness, the pharmaceutical companies continue to make back off it and there market just keeps growing. In other words, in a month no one will remember this article and the ads for new medications will still be everywhere.

Not sure if it was that article or another one, but it was discussing the very real issue of patients essentially being given medication straightjackets by snowing the **** out of them because it's cheaper and easier to deal with people that way. Also that this practice was disproportionately used on BIPOC individuals despite simialr levels of symptomatology. This isn't some boogeyman that the media dreamed up, many of us who have worked in inpatient units, particularly those in hospitals that see a large medicare/aid base have seen this personally. Not sure what was misleading about that. Did the NYT article discuss something different?
 
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Because people are misguided and still live in a world where toughing it out is what works.

The reason why psychiatry appears to be so first world is because the human mind is designed to be protective in survival situations, so it's easy for those who aren't faced with these stressors to think so arrogantly about their affect on the psyche.

It's equally easy to assign mental illness as an umbrella term to minimize the need to act on something. If it's all in your mind then the world doesn't need to change, just your mind.

I still come across new doctors, mostly foreign ones, who think psychiatry isn't real medicine and utilize psychiatrists as ways to pass liability on patients they don't want to take care of.

It's important to address gross overdiagnosis and over medication of patients, especially those who don't actually have psychiatric illness, as much as it is important to diminish the stigma of the existence of mental illness in general.
 
Not sure if it was that article or another one, but it was discussing the very real issue of patients essentially being given medication straightjackets by snowing the **** out of them because it's cheaper and easier to deal with people that way. Also that this practice was disproportionately used on BIPOC individuals despite simialr levels of symptomatology. This isn't some boogeyman that the media dreamed up, many of us who have worked in inpatient units, particularly those in hospitals that see a large medicare/aid base. Not sure what was misleading about that. Did the NYT article discuss something different?
This was a different one, I believe, as I recall it was more about antipsychotics being unnecessarily prescribed or mandated in community settings which I also agree can be a problem. The flip side of that is not mandating treatment and medication can also be a problem. Just saying that it is more nuanced than the media is able to portray well. Also working in these units, I always advocated for less restrictive treatment for my patients against a system that was designed to guard against risk. Managing risk is counter therapeutic and it makes sense that people who are different from the staff would be seen as riskier and thus treated with more restrictive measures and I have seen that very clearly when I was working in those settings. I would love to see those settings be more therapeutic and less of an example of unhealthy group dynamics of race and stereotypes played out, but when I worked there I felt like pushing against that was like Sisyphus and the boulder.
Final point, I am glad that the media is covering these issues and the NY Times has always been one of the better sources for reporting on our field from my perspective. Often by the time it gets disseminated the nuance is lost and the agendas are all that’s left.
 
Not sure if it was that article or another one, but it was discussing the very real issue of patients essentially being given medication straightjackets by snowing the **** out of them because it's cheaper and easier to deal with people that way. Also that this practice was disproportionately used on BIPOC individuals despite simialr levels of symptomatology. This isn't some boogeyman that the media dreamed up, many of us who have worked in inpatient units, particularly those in hospitals that see a large medicare/aid base have seen this personally. Not sure what was misleading about that. Did the NYT article discuss something different?

Yes, yes it did.
Short version: Central character was basically someone with actually probably a trauma history and borderline personality disorder who started "hearing voices in daycare", was talking about all the meds she had been put on, all the side effects from this, then stopped them all after college and solved her problems by doing roller derby. She then started leading the Hearing Voices Network Support Program and it talks about how all these people are doing fine there on minimal/no doses of antipsychotics. The article then used this as a central premise for why lots of people don't need antipsychotics but keeps using relatively mild or even likely non-psychotic disorder cases of people with AH/VH to explain this.

Doesn't talk about all the people who deterioriate as soon as they're unable to come in for their Invega LAI or clozapine followups. Doesn't talk about the hordes of homeless schizophrenic/bipolar patients who get fired or are unable to hold down a job due to their disconnect from reality or erratic behavior. Doesn't talk about what it looks like when someone is actually psychotic and won't bathe/eat and are totally disconnected from reality until they're treated. Doesn't talk about all the people whose lives had been substantially improved by continuing an antipsychotic.

Do I think antipsychotics are overprescribed? Sure. But pretty one sided and not necessarily even representative of what severe mental illness outcomes actually look like.

If you don't have access to NYT its probably behind a paywall:

I too have noticed the recent anti-psychiatry bent from the NYT. In fact there was a recent article about the lack of child psychiatrists which quoted a pediatrician as saying "if I’ve got this child and they’re cutting and saying they’re going to kill themselves, I’ll say, ‘Well, I’ll see them today.’ If I call a child psychiatrist, they say, ‘I’ll see them in a month"....of course assuming that every kid cutting is some emergency that needs to be seen today by a specialist.
This same pediatrician is then quoted as telling a teenage trauma victim whose parents were drug users, taken in by grandparents then raped at 9yo by her grandfather so now lives with aunt that she needs to stop cutting because "You’re such a cute girl. You have so much going for you. I wish we could make you see that." Instead of, I don't know, validating the fact that her life sucks ass and self destructive behavior is not an unusual choice but lets work together to think about other ways to redirect stress?

Also going wild prescribing (in two days mind you) "Abilify for mood disorders; Zoloft, Trazodone and Clonidine for sleep issues; Ritalin, Adderall, Qelbree and Vyvanse for A.D.H.D.; and Remeron for major depressive disorder."

 
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Yes, yes it did.
Short version: Central character was basically someone with actually probably a trauma history and borderline personality disorder who started "hearing voices in daycare", was talking about all the meds she had been put on, all the side effects from this, then stopped them all after college and solved her problems by doing roller derby. She then started leading the Hearing Voices Network Support Program and it talks about how all these people are doing fine there on minimal/no doses of antipsychotics. The article then used this as a central premise for why lots of people don't need antipsychotics but keeps using relatively mild or even likely non-psychotic disorder cases of people with AH/VH to explain this.

Doesn't talk about all the people who deterioriate as soon as they're unable to come in for their Invega LAI or clozapine followups. Doesn't talk about the hordes of homeless schizophrenic/bipolar patients who get fired or are unable to hold down a job due to their disconnect from reality or erratic behavior. Doesn't talk about what it looks like when someone is actually psychotic and won't bathe/eat and are totally disconnected from reality until they're treated. Doesn't talk about all the people whose lives had been substantially improved by continuing an antipsychotic.

Do I think antipsychotics are overprescribed? Sure. But pretty one sided and not necessarily even representative of what severe mental illness outcomes actually look like.

If you don't have access to NYT its probably behind a paywall:

I too have noticed the recent anti-psychiatry bent from the NYT. In fact there was a recent article about the lack of child psychiatrists which quoted a pediatrician as saying "if I’ve got this child and they’re cutting and saying they’re going to kill themselves, I’ll say, ‘Well, I’ll see them today.’ If I call a child psychiatrist, they say, ‘I’ll see them in a month"....of course assuming that every kid cutting is some emergency that needs to be seen today by a specialist.
This same pediatrician is then quoted as telling a teenage trauma victim whose parents were drug users, taken in by grandparents then raped at 9yo by her grandfather so now lives with aunt that she needs to stop cutting because "You’re such a cute girl. You have so much going for you. I wish we could make you see that." Instead of, I don't know, validating the fact that her life sucks ass and self destructive behavior is not an unusual choice but lets work together to think about other ways to redirect stress?

Also going wild prescribing (in two days mind you) "Abilify for mood disorders; Zoloft, Trazodone and Clonidine for sleep issues; Ritalin, Adderall, Qelbree and Vyvanse for A.D.H.D.; and Remeron for major depressive disorder."


Just read it, didn't get the same feel. Seems to be more focused on validating and fostering connections with individuals with AV/VH. The article was very clear, at one point stating "there is little research that looks at the approach favored by the alliance" when talking about alternatives to involuntary hospitalization, and also relays anecdotes about people who committed suicide while in the alternative housing situations. It doesn't paint it as rosy as you make it sound, it seems to fairly clearly state that this is an approach we do not know a lot about. I also disagree that the central premise is that people don't need antipsychotics, just that we haven't made a huge amount of progress there, and our long-term outcome literature is not promising in the area, which is very much true. Overall, while, of course this article could have talked about the most severe cases, which isn't really the point, it hardly seems like the hit piece that its being made out as.
 
Just read it, didn't get the same feel. Seems to be more focused on validating and fostering connections with individuals with AV/VH. The article was very clear, at one point stating "there is little research that looks at the approach favored by the alliance" when talking about alternatives to involuntary hospitalization, and also relays anecdotes about people who committed suicide while in the alternative housing situations. It doesn't paint it as rosy as you make it sound, it seems to fairly clearly state that this is an approach we do not know a lot about. I also disagree that the central premise is that people don't need antipsychotics, just that we haven't made a huge amount of progress there, and our long-term outcome literature is not promising in the area, which is very much true. Overall, while, of course this article could have talked about the most severe cases, which isn't really the point, it hardly seems like the hit piece that its being made out as.

These are stories and when your central character is someone who I'd bet good money likely does not have an actual psychotic disorder but then you try to extrapolate this story to the general population of people with these disorders, it certainly paints an interesting picture. The article also essentially gives no detailed stories of people whose lived were improved significantly by these medications. It's not like they turned around and did another followup piece about the benefits of antipsychotics.

I also don't get where you're pulling info that we "haven't made a huge amount of progress" in terms of antipsychotics. Development? Sure, possibly because it's difficult to develop new ones after the first couple iterations. But overall? We've gone from literally people being indefinitely confined to psychiatric hospitals for life to a significant proportion of these people being able to function day to day independently because of our ability to utilize these medications.
 
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The lead author had some very, very serious bias going into the review. I'm more concerned that it was published in the journal it was published in than that it was written. It's an okay review, but there are extreme limitations and I don't understand why the journal editors felt it deserved the wide audience it got in their journal with those limitations.
 
These are stories and when your central character is someone who I'd bet good money likely does not have an actual psychotic disorder but then you try to extrapolate this story to the general population of people with these disorders, it certainly paints an interesting picture. The article also essentially gives no detailed stories of people whose lived were improved significantly by these medications. It's not like they turned around and did another followup piece about the benefits of antipsychotics.

I also don't get where you're pulling info that we "haven't made a huge amount of progress" in terms of antipsychotics. Development? Sure, possibly because it's difficult to develop new ones after the first couple iterations. But overall? We've gone from literally people being indefinitely confined to psychiatric hospitals for life to a significant proportion of these people being able to function day to day independently because of our ability to utilize these medications.

I won't debate whether or not she has a psychotic disorder, definitely some symptoms consistent, though likely some comorbidities.

As for the "pulling info" part, we really haven't made a lot of progress. Long-term outcomes on meds in this population are still not great, particularly in the severe group, who are for all intents and purposes still largely institutionalized, just not in the hospital. As for the milder cases, some would definitely be better off not on meds for the most part, especially long-term. The middle group is probably the most debatable.

As for presenting "all views" in an article, that's not always the purpose of a piece. It's not a systematic review, it's a character piece.
 
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Yes, yes it did.
Short version: Central character was basically someone with actually probably a trauma history and borderline personality disorder who started "hearing voices in daycare", was talking about all the meds she had been put on, all the side effects from this, then stopped them all after college and solved her problems by doing roller derby. She then started leading the Hearing Voices Network Support Program and it talks about how all these people are doing fine there on minimal/no doses of antipsychotics. The article then used this as a central premise for why lots of people don't need antipsychotics but keeps using relatively mild or even likely non-psychotic disorder cases of people with AH/VH to explain this.

Doesn't talk about all the people who deterioriate as soon as they're unable to come in for their Invega LAI or clozapine followups. Doesn't talk about the hordes of homeless schizophrenic/bipolar patients who get fired or are unable to hold down a job due to their disconnect from reality or erratic behavior. Doesn't talk about what it looks like when someone is actually psychotic and won't bathe/eat and are totally disconnected from reality until they're treated. Doesn't talk about all the people whose lives had been substantially improved by continuing an antipsychotic.

Do I think antipsychotics are overprescribed? Sure. But pretty one sided and not necessarily even representative of what severe mental illness outcomes actually look like.

If you don't have access to NYT its probably behind a paywall:

I too have noticed the recent anti-psychiatry bent from the NYT. In fact there was a recent article about the lack of child psychiatrists which quoted a pediatrician as saying "if I’ve got this child and they’re cutting and saying they’re going to kill themselves, I’ll say, ‘Well, I’ll see them today.’ If I call a child psychiatrist, they say, ‘I’ll see them in a month"....of course assuming that every kid cutting is some emergency that needs to be seen today by a specialist.
This same pediatrician is then quoted as telling a teenage trauma victim whose parents were drug users, taken in by grandparents then raped at 9yo by her grandfather so now lives with aunt that she needs to stop cutting because "You’re such a cute girl. You have so much going for you. I wish we could make you see that." Instead of, I don't know, validating the fact that her life sucks ass and self destructive behavior is not an unusual choice but lets work together to think about other ways to redirect stress?

Also going wild prescribing (in two days mind you) "Abilify for mood disorders; Zoloft, Trazodone and Clonidine for sleep issues; Ritalin, Adderall, Qelbree and Vyvanse for A.D.H.D.; and Remeron for major depressive disorder."

Yep I’ve heard from patients so many dumb comments made to them by other specialties. I will say particularly OBGYNs (look at your baby, he is so cute, you should be happy)

The media also needs to make up their mind whether we are not doing enough or too much to treat mental health issues. Regardless, we are doomed if we do, doomed if we don’t
 
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We've gone from literally people being indefinitely confined to psychiatric hospitals for life
The community mental health clinic system doesn't seem to be working too well in keeping people out of emergency situations in my state. We had a state senator whose son attacked him and then died by suicide. The community mental health clinic he went to beforehand let him go of his own recognizance after being unable to find a bed for him before the attacks. We have a huge staffing shortage at state hospitals, and that's for acute stabilization, which the state hospitals claim they are unable to even do (they claim the cases are too complex--I'm not sure where they are supposed to go then). I think long-term residential care is a non-starter, sort of like waiting lists of public housing. Texas is even worse keeping mentally ill defendants in prison for extremely long periods because they don't have beds to have them go to to get well enough to even stand trial. So they just linger in prison.

I would agree that the days are gone of psychiatric hospital availability for extended periods or even on an emergent basis, but I am not sure based on what I've read how good that is for people with SMI or the general public. I don't know the practicalities of it, and this might just be fanciful thinking, but I don't understand why prisons can't be converted into long-term care facilities since they seem to often serve the same purpose and are still very expensive to taxpayers but focus on being punitive rather than humanistic.
 
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The community mental health clinic system doesn't seem to be working too well in keeping people out of emergency situations in my state. We had a state senator whose son attacked him and then died by suicide. The community mental health clinic he went to beforehand let him go of his own recognizance after being unable to find a bed for him before the attacks. We have a huge staffing shortage at state hospitals, and that's for acute stabilization, which the state hospitals claim they are unable to even do (they claim the cases are too complex--I'm not sure where they are supposed to go then). I think long-term residential care is a non-starter, sort of like waiting lists of public housing. Texas is even worse keeping mentally ill defendants in prison for extremely long periods because they don't have beds to have them go to to get well enough to even stand trial. So they just linger in prison.

I would agree that the days are gone of psychiatric hospital availability for extended periods or even on an emergent basis, but I am not sure based on what I've read how good that is for people with SMI or the general public. I don't know the practicalities of it, and this might just be fanciful thinking, but I don't understand why prisons can't be converted into long-term care facilities since they seem to often serve the same purpose and are still very expensive to taxpayers but focus on being punitive rather than humanistic.
Fun fact: prisons are the largest providers of inpatient psychiatric care in this country. I just can’t wait to see all the dementia patients ending up in psych facilities as the population of this country ages.. now that will be a real crisis
 
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Yep I’ve heard from patients so many dumb comments made to them by other specialties. I will say particularly OBGYNs (look at your baby, he is so cute, you should be happy)

The media also needs to make up their mind whether we are not doing enough or too much to treat mental health issues. Regardless, we are doomed if we do, doomed if we don’t
These same providers will page you at 3 in the morning to come see a patient who "looks like a psych patient" and thank you profusely for saving their night shift followed by joking to the other providers "lol psych isn't a real specialty".
 
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Yep I’ve heard from patients so many dumb comments made to them by other specialties. I will say particularly OBGYNs (look at your baby, he is so cute, you should be happy)

The media also needs to make up their mind whether we are not doing enough or too much to treat mental health issues. Regardless, we are doomed if we do, doomed if we don’t

I also think we should own up to the current status of the field.

I agree antipsychotics are probably one of the few bright spots, but there are so many scams in the history of this specialty, that I feel a little (a lot) of skpeticism is warranted.
 
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Well, we know serotonin is not the *cause* of depression. Serotonin in the brain changes rapidly upon taking these medications. However, the antidepressent, anxiolytic, antiPtSD, etc effects are not seen for 4-6 weeks typically. This points to some other reason we are seeing the treatment effect besides serotonin.

Regardless, the ‘chemical soup’ hypothesis brought us many useful drugs we use daily. So even if it only partially explained the underlying pathology, it shot the field forward and gave us a model.

The new age model is that our meds are actually causing neuron/dentritic growth , the so called ‘neuroplastogen’ hypothesis. This is bringing us new meds as well. Im sure this will not fully explain the above syndromes either, however it will hopefully bring more treatment options and some more insight into the brain. It has already given us ketamine, brexanolone, etc - and more are in the pipeline.
Ketamine was not the result of a neuroplasticity model of depression. It was incidentally noted to improve depression symptoms when used in experimental models of inducing psychosis. Once found to be effective, the neuroscience was at hand but nobody predicted it would be a good antidepressant before it was clinical found to be one.
 
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Hi, anyone seen this recent Molecular Psychiatry paper also published in Nature?


From their review of systematic reviews and meta-analyses published through 2020, authors conclude that, “it is time to acknowledge that the serotonin theory of depression is not empirically substantiated.”

I am personally open to considering this possibility, particularly given that “depression” does not have a singular cause. But the limitations of their review, some of which they acknowledge, are major. And I’m not sure how they can be so unequivocal in the conclusion that there is no support for the serotonin theory of depression given these major limitations - most of the studies in their review were low quality and had low power, and most of the studies did not account for the effects of antidepressant use.

In their words, “Most of the included studies were rated as low quality on the AMSTAR-2, but the GRADE approach suggested some findings were reasonably robust. Most of the non-genetic studies did not reliably exclude the potential effects of previous antidepressant use and were based on relatively small numbers of participants.”

I’m also curious how “depression” was defined across included studies and the impact of that on their findings. Depression in quotes given that the disorder (MDD) is not a single biological reality or construct.

Anyway, curious about others’ thoughts, implications, etc.
This article is incredibly frustrating to read, as almost everything is imprecise. First is the idea that there is a current consensus as to depression being a 'serotonin' illness (what does that even mean?). The state of our understanding of depression pathophysiology implicates factors from genes through circuits to environment, and there is no valid school of thought that tries to explain depression as a problem with levels of a single neurotransmitter. There are the clear fingerprints of a reviewer who pushed back against some of this, with some statements being softened to the point of not meaning anything (the serotonin hypothesis is called 'influential' - to whom? how? Like Pokémon is influential? What does that matter?).

Citing work by Ronald Duman as evidence that leaders in the field are attached to the serotonin hypothesis is RIDICULOUS. He literally wrote a paper describing a complex model of depression that relies on diverse mechanisms - it has been cited 2000 times.(Google Scholar).

I insist that they provide evidence that the serotonin hypothesis is being taught anywhere as a reason to prescribe antidepressants. Given that ACGME mandates that residencies teach evidence based medicine, I am sure that most of us our recommending treatments based on empirical research rather than isolated components of old mechanistic hypotheses.

The take home from this paper is that if everyone was an idiot, the way they think about depression would be wrong. Since none of us are, there is really nobody who needs to worry about this nonsense. Otherwise framed, I guess there could be value for evaluating evidence for any type of association between serotonin levels and depression but even that is not something that has been much of an open question and my medical school textbook which was written by our own faculty stated as much more than 15 years ago.
 
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This article is incredibly frustrating to read, as almost everything is imprecise. First is the idea that there is a current consensus as to depression being a 'serotonin' illness (what does that even mean?). The state of our understanding of depression pathophysiology implicates factors from genes through circuits to environment, and there is no valid school of thought that tries to explain depression as a problem with levels of a single neurotransmitter. There are the clear fingerprints of a reviewer who pushed back against some of this, with some statements being softened to the point of not meaning anything (the serotonin hypothesis is called 'influential' - to whom? how? Like Pokémon is influential? What does that matter?).

Citing work by Ronald Duman as evidence that leaders in the field are attached to the serotonin hypothesis is RIDICULOUS. He literally wrote a paper describing a complex model of depression that relies on diverse mechanisms - it has been cited 2000 times.(Google Scholar).

I insist that they provide evidence that the serotonin hypothesis is being taught anywhere as a reason to prescribe antidepressants. Given that ACGME mandates that residencies teach evidence based medicine, I am sure that most of us our recommending treatments based on empirical research rather than isolated components of old mechanistic hypotheses.

The take home from this paper is that if everyone was an idiot, the way they think about depression would be wrong. Since none of us are, there is really nobody who needs to worry about this nonsense. Otherwise framed, I guess there could be value for evaluating evidence for any type of association between serotonin levels and depression but even that is not something that has been much of an open question and my medical school textbook which was written by our own faculty stated as much more than 15 years ago.
That last paragraph clearly describes what I understand as the classic straw man argument. Making up a potential argument that is easy to knock down. Maybe if they said that drug companies were pushing this idea back in the 90s and some docs even bought into it and many people still believe it because it was such an effective and misleading campaign that continues to promote selling these drugs to people who don’t need them as well as those who do benefit from them because if they only sold to the people who could really benefit then they wouldn’t make as much money. That might be a bit more accurate.
 
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It's by Moncrieff, that should be all that's needed to know what the article will say. She seems like a fairly smart individual who is pretty anti-medication and has spoken out about numerous meds including SSRIs, Lithium, antipsychotics, and stimulants, and frequently expresses views that data should be more than conclusive in regards to treatment efficacy. By her standards, we shouldn't be prescribing any medications for insomnia due to the lack of convincing evidence for their efficacy. It's just another much ado nothing piece by her that the media seems to have latched onto for some reason. I also echo the disappointment that it was published in what I consider a pretty reputable journal, I really don't understand why it was accepted or even seriously considered.
 
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This article is incredibly frustrating to read, as almost everything is imprecise. First is the idea that there is a current consensus as to depression being a 'serotonin' illness (what does that even mean?). The state of our understanding of depression pathophysiology implicates factors from genes through circuits to environment, and there is no valid school of thought that tries to explain depression as a problem with levels of a single neurotransmitter. There are the clear fingerprints of a reviewer who pushed back against some of this, with some statements being softened to the point of not meaning anything (the serotonin hypothesis is called 'influential' - to whom? how? Like Pokémon is influential? What does that matter?).

Citing work by Ronald Duman as evidence that leaders in the field are attached to the serotonin hypothesis is RIDICULOUS. He literally wrote a paper describing a complex model of depression that relies on diverse mechanisms - it has been cited 2000 times.(Google Scholar).

I insist that they provide evidence that the serotonin hypothesis is being taught anywhere as a reason to prescribe antidepressants. Given that ACGME mandates that residencies teach evidence based medicine, I am sure that most of us our recommending treatments based on empirical research rather than isolated components of old mechanistic hypotheses.

The take home from this paper is that if everyone was an idiot, the way they think about depression would be wrong. Since none of us are, there is really nobody who needs to worry about this nonsense. Otherwise framed, I guess there could be value for evaluating evidence for any type of association between serotonin levels and depression but even that is not something that has been much of an open question and my medical school textbook which was written by our own faculty stated as much more than 15 years ago.

They did not just look at the levels of serotonin, but also at genetic and receptor studies, and they found no evidence of a pathophysiological link between serotonin and depression.

I do not think this study is anahronistic or meaningless. I think it's telling that they cite studies involving the general public and the GPs, and not psychiatrists, to show the influence of the 'serotonin theory of depression'. Perhaps most psychiatrists moved on because the evidence is simply not there, but others haven't and that was largely due to the campaigns of pharma and psychiatrists themselves. There was a time in the 90s when depression was popularized as a 'chemical imbalance'. Maybe it is time to fix that perception, and I think that is the point of the paper.

I also do think SSRIs will take a hit even if the 'empirical research shows they work' if one cannot find a link between how they supposedly work and the 'pathophysiology of depression'. Is it placebo? Emotional blunting? (with all of its associated side effects). What are we missing? If this it, then they really aren't such an appealing choice.
 
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I already get enough patients from PCPs who are started on Xanax for depression. We really don’t need more anti-SSRI sentiment
 
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I also do think SSRIs will take a hit even if the 'empirical research shows they work' if one cannot find a link between how they supposedly work and the 'pathophysiology of depression'
Medical science/practice does what "works" (now and a hundred years before), because...it is what works. Or.... it seems to anyway. If you are in true denial about this then don't be psychologist or physician and maybe just resign yourself to a smelly home for the clinically goofy right now???
 
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Medical science/practice does what "works" (now and a hundred years before), because...it is what works. Or.... it seems to anyway. If you are in true denial about this then don't be psychologist or physician and maybe just resign yourself to a smelly home for the clinically goofy right now???

Right. That's why we learn about diagnosis, etiology and pathophysiology.
I can't really bother to respond to that ridiculously trollish response any further.
 
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I am glad the medications are taking a hit. Way too much reliance and misconceptions of them by the public. Now if I can just get the public to understand that we don’t have patients lie on the couch and do some mumbo jumbo Freudian psychoanalysis thing anymore or that EMDR is some wild new cure all. If I had a dollar for every person in the last couple of years that has asked me about EMDR…
 
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I think it is telling that so many people are getting their knickers in a twist about this paper. This is the typical response anytime a paper is published where the findings are somewhat critical of conventional psychiatry. Psychiatry has a massive chip on its shoulder and many psychiatrists seem to take any criticism as a personal affront. While I agree this paper is not the best, nor particular novel in its findings, and I don't think it would have been published in this journal if it wasn't open access (i.e. they paid for it to be published), some of the criticisms are ridiculous. You cannot say the field hasn't been interested in the role of serotonin in depression when the paper is literally a systematic review of very recent studies that have looked at serotonin in depression. The paper is not looking at whether depression is caused by serotonin dysfunction but at the association. The fact that studies have continued to be published on this theory are evidence that the idea continues to have some influence, even if there are other competing theories which are more fashionable today. The fact that this paper has been picked up by various news outlets is also evidence that the theorized serotonin-depression connection is one that is well known to the public.

Regardless, the ‘chemical soup’ hypothesis brought us many useful drugs we use daily. So even if it only partially explained the underlying pathology, it shot the field forward and gave us a model.
This is false. It is the drugs that brought us the monoamine theory and not the other way round. Indeed, the lead author's main arguments elsewhere have been that for a long time psychiatry's model of psychopathology has been "drug centered" rather than "disease centered", relying on backward logic that because x drug affects y neurotransmitter, that this must be involved in the pathophysiology of z psychiatric disorder. Most of the important developments in psychopharmacology have been the result of serendipity rather than science, and the rest of what we have is a bunch of "me too" drugs.
 
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relying on backward logic that because x drug affects y neurotransmitter, that this must be involved in the pathophysiology of z psychiatric disorder.
Reminds me of what I wrote back in 2013 (from a different thread) which was writing about what I knew at 14 that my doctor didn't seem to get:

A newer article on the subject:

The Psychiatric Drug Crisis

It makes me a bit upset that I saw through the chemical imbalance line I was told by a psychiatrist when I was 14 years old, only to be told there indeed is such a thing. If I were allowed to tell my story, you would know there is no vindication now.

But even back then, it didn't make sense on face value. I remember telling my psychiatrist that his logic was the same as if me feeling better while watching the Golden Girls was proof that I had a Golden Girls deficiency.

How did something that is now admitted to be a myth ever come to be doctrine? Was it always just folksy wisdom or was there ever science behind it?
 
Reminds me of what I wrote back in 2013 (from a different thread) which was writing about what I knew at 14 that my doctor didn't seem to get:
I never really bought into it myself either as I am notoriously skeptical in my outlook. There is some science behind the theory though. Serotonin is a real thing and so is the brain and so is Prozac. A medication that effects serotonin in the brain can reduce depression. Maybe there is a link. Not a bad hypothesis. I am still not going to say there isn’t a relationship between these, but I was pretty sure then and am almost as sure now that it is not a serotonin deficit that causes depression. Neurobiology is just not that simplistic.

At the time this theory was being promoted I was learning about the fallacies or challenges around the dopamine hypothesis of schizophrenia. it seemed pretty similar. One aspect that I find interesting is that dopamine is related to psychosis and movement and when my dad with his Parkinson’s developed dopamine induced psychosis from the medications that made sense and when meth addicts flood their brain with dopamine they get psychotic too and medications that treat schizophrenia also induce Parkinson’s like symptoms. It all seems interrelated and straightforward as I lay it out, but it’s not so easy as that. I’m at the edge of my a little better than layman’s knowledge of psychopharmacology so will let the experts elaborate further or correct me If they care too.
 
I never really bought into it myself either as I am notoriously skeptical in my outlook. There is some science behind the theory though. Serotonin is a real thing and so is the brain and so is Prozac. A medication that effects serotonin in the brain can reduce depression. Maybe there is a link. Not a bad hypothesis. I am still not going to say there isn’t a relationship between these, but I was pretty sure then and am almost as sure now that it is not a serotonin deficit that causes depression. Neurobiology is just not that simplistic.

At the time this theory was being promoted I was learning about the fallacies or challenges around the dopamine hypothesis of schizophrenia. it seemed pretty similar. One aspect that I find interesting is that dopamine is related to psychosis and movement and when my dad with his Parkinson’s developed dopamine induced psychosis from the medications that made sense and when meth addicts flood their brain with dopamine they get psychotic too and medications that treat schizophrenia also induce Parkinson’s like symptoms. It all seems interrelated and straightforward as I lay it out, but it’s not so easy as that. I’m at the edge of my a little better than layman’s knowledge of psychopharmacology so will let the experts elaborate further or correct me If they care too.

I think the evidence for the dopamine-psychosis link is much stronger. There have been pharmacological and imaging studies showing in a causal link that dopamine release particularly in the striatum is associated with psychotic experiences.
Of course it's more complicated than dopamine-->striatum = psychosis, but there's evidence that this is an important factor in the pathophysiology.
 
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This is false. It is the drugs that brought us the monoamine theory and not the other way round. Indeed, the lead author's main arguments elsewhere have been that for a long time psychiatry's model of psychopathology has been "drug centered" rather than "disease centered"
Important point. Makes you wonder how the emphasis on monoamines at the outset vis a vis drug-related observations “poisoned the well” and gave everyone blinders.

Obviously monoamines (really any neurotransmitter) don’t map singularly onto disease constructs (themselves not entirely reality based).

Also makes you question why there hasn’t been more “start from zero” approaches to depression research.

I think the solution is to work backwards. Find only the most apparently severely depressed patients who offer the largest “signal to noise” ratio of “depression.” Then analyze every metric of their brain structure/function you can. Spend way more money on finding objective signs of depression. Define depression more clearly. You can’t find an effect by a variable on a variable if your groups aren’t dissimilar enough.

Another solution would be a massive study enlisting anyone with depression and any comorbidity. Find the people who get better compared to those who don’t and analyze what factors might have caused this (and unify a theory of what links the factors?). For instance, what’s the common denominator between being part of a social club AND good response to sertraline?
 
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