The serotonin theory of depression: a systematic umbrella review of the evidence
ucl.ac.uk
ucl.ac.uk
- https://news.ycombinator.com/item?id=32160703
- https://news.ycombinator.com/item?id=32191728
- https://news.ycombinator.com/item?id=32176401
Link to actual paper:
https://www.nature.com/articles/s41380-022-01661-0
See expert responses here:
https://www.sciencemediacentre.org/expert-reaction-to-a-revi...
I don't usually say this, but pay attention to conflict of interest statements:
>All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author). SA declares no conflicts of interest. MAH reports being co-founder of a company in April 2022, aiming to help people safely stop antidepressants in Canada. MPH reports royalties from Palgrave Macmillan, London, UK for his book published in December, 2021, called “Evidence-biased Antidepressant Prescription.” JM receives royalties for books about psychiatric drugs, reports grants from the National Institute of Health Research outside the submitted work, that she is co-chairperson of the Critical Psychiatry Network (an informal group of psychiatrists) and a board member of the unfunded organisation, the Council for Evidence-based Psychiatry. Both are unpaid positions. TS is co-chairperson of the Critical Psychiatry Network. RC is an unpaid board member of the International Institute for Psychiatric Drug Withdrawal.
There's also a background debate here over whether depression should be seen as biological/chemical or environmental. This comes up in the article toward the end:
> Although viewing depression as a biological disorder may seem like it would reduce stigma, in fact, research has shown the opposite, and also that people who believe their own depression is due to a chemical imbalance are more pessimistic about their chances of recovery.
The thing is, if you're not a dualist, there's no reason depression can't be chemical and environmental. Clearly life circumstances can lead to depression and making changes (diet, exercise, leaving a job, leaving a relationship, undertaking therapy) can be a way out. Most doctors understand this and that doesn't discredit medication as a potential option.
I was given Cipralex temporarily in my early 20s for anxiety w/ a very positive experience (lack of sex drive is a major downside and why everyone I know doesn't use them or stopped): https://en.wikipedia.org/wiki/Escitalopram
I'm curious if anxiety is similarly being targeted here? (didnt read the paper)
One angle I've seen in certain circles is that people who are against gun legislation in the US are claiming that SSRI use is the real root cause for all the gun violence.
https://www.sciencedirect.com/science/article/pii/S0924977X2...
We don't know whether this is a significant factor in gun violence.
Agreed it doesn't do these things, but there is value in publicizing the fact that "the idea that depression results from a 'chemical imbalance' is hypothetical." Anecdotally, most people I've encountered that are depressed view the chemical imbalance theory as fact. This has consequences in how they approach treatment (medication-centric) and in how they view their situation (inalterable).
If anything (in my experience) people are too biased against medicine. And as others pointed out, this isn't at all evidence that medicines don't work - their efficacy is based on double-blind studies, not on chemical imbalance hypotheses.
There are many other possible mechanisms that aren't related to the environment. Publicizing studies like this beyond academia is only likely to cause confusion and unfounded anti-medicine sentiment.
Not everything needs to be constructive. You sound like you don't appreciate this kind of work. I don't see a problem about this "not being new" nor being "just a meta review".
Should scientists "shut up unless they have new or good things to say"?
https://link.springer.com/book/10.1007/978-0-230-58944-5
Obviously I have not read every line of the new paper and I have no idea if it has any new research.
I’m not proposing this, I honestly don’t know the answer since the latter has been put forth as a kind of miracle drug for depression.
I believe this comes from the religious culture in the USA and the core tenet of religion being that God is all powerful and you must relinquish your problems to God while acknowledging your lack of power and remaining in submission. That line of thinking gives a sense of relief, but ultimately causes people to avoid dealing with things directly due to not realizing how powerful their minds really are (as far as being able to make changes on their own without “magic pills” that often leave you feeling worse).
Ironically, religion also helps a bit because people often “find God” and turn their lives around for the better due to the benefits of prayer which are often described as peace or serenity. However, prayer is LITERALLY just forgiveness/open heart meditation. That sense of relief people feel after praying and releasing all of their problems to God for 15 minutes? That can be achieved without identifying as powerless without the help of a supreme deity.
Sorry about the rant, but this has been on my mind for a while now.
"We conclude that it is impossible to say that taking SSRI antidepressants is worthwhile, or even completely safe. People need all this information to make informed decisions about whether or not to take antidepressants."
Seems like an attempt to deflect from much more likely issues.
Usually depression is treated with a mix of drugs—such as SSRIs—and psychotherapy. I think health officials are completely aware of the long term effects, and that is why the treatment is most often multi-faceted.
I feel many people who comment on meds like SSRI never really needed them so much so for them the long term safety is a big issue, but when these pills have a huge positive impact on your life then you are more willing to accept it.
I find this kind of messaging completely irresponsible and it just contributes to the stigma around mental health and medications.
If the golden standard were to hit yourself in the head with a hammer, it is very useful to point out that it doesn't seem to help and is not safe. Even if you don't have a better alternative.
Heck. Just watch how the treatment was portrait in a Hollywood blockbuster in the 1970s. There is no way One Flew Over the Cuckoo’s Nest would frame lobotomy so badly if it was consider a “golden standard”.
Comparing SSRI to lobotomy is a historic revisionism at best.
The individualization of mental health problem misses that there are very likely systemic causes of depression.
I've gone through several severe periods of depression, and at the time it all seemed like something was wrong with me and this is the prevailing narrative. In retrospect all of these were caused by a very real external problem in my life that I didn't see (depressing job, emotionally abusive parents, unhealthy marriage etc).
I have no doubt that had I sought medication in any of these cases I would have been given it. But that would have prevented me from being forced to realize the very real problems in my life.
In a broader perspective there are plenty of wide spread social issues that are very likely legitimately causes depression. The idea of simply medicating this away is akin to simply giving Tylenol to someone who has a abscessed tooth. I'm horrified at the wide adoption of medications (often with adverse side effects) to mask what are very real and legitimate sources of depression.
A better alternative is to openly discuss and challenge the prevailing social issues leading to a mental health crisis.
This is a popular idea, and I have no idea where this corruption of the scientific process came from.
It's not true.
It is completely viable, legal, moral, and all the things to simply scientifically point at something and say "That doesn't work." No obligation to produce something that does work is incurred.
If the "golden standard" is in fact the placebo effect, that's good to know.
Mental health is too important to leave to superstition.
You don't have to be a tailor with a ready new suit to point out that the Emperor is naked.
If you're cherry-picking negative examples that's the very definition of stigma.
I do disagree with your cherry-picking assessment, I am relaying my lived experience. The people I know of that take SSRIs are either in an unhealthy environment or are masking trauma. Or a bit of both.
And speaking from personal experience: I was never suicidal, more like burnt out and depressed. What helped me was an exceptional therapist that assisted me in making sense of what I am feeling and gently worked with me to build a framework to cope. That involved a spiritual component and helped me regain my creativity.
My point being: I can not imagine that SSRIs would have enabled me to do that. I am glad they helped your friends. Out of curiosity I would be interested in what they had going on at that time. I also do understand that this is deeply personal and none of my business.
It’s not the responsibility of one study to resolve depression. That would be nice and convenient, but it’s a scientific community driven solution space exploration. And determining a path is ineffective leads to more time and money spent on alternate paths to find something which is effective.
Imagine this.
A teenaged boy and his mother show up at the doctor's. The boy is in tears, and says his arm hurts. The doctor comes out, and is terribly busy, and prescribes a cast without X-Rays, an examination, or even asking a history.
The family is terribly busy, and doesn't get back to the doctor. The boy says his arm still hurts, and isn't getting better. The parents are firm, the cast must stay on, because the doctor prescribed it.
Later, the arm becomes deeply infected, and the boy goes to intensive care when his body becomes septic. While they decide to treat this as a laceration and infection instead of a break, there is still no assessment or feedback. Just more medication. (They were right this time, but by chance. The cast still stays on after this, by the way.)
This is exactly what I saw happen -- except replace the cast with amphetamines, sepsis with a mental breakdown, and intensive care with involuntary commitment. The doctor literally walked into the waiting room, prescribed amphetamines, and scheduled a follow up later.
The doctors don't have a clue what they're doing when they say "chemical imbalance". They're guessing and using the medication shotgun.
I'm manic-depressive/bipolar and there's a clear behavioral marker that doesn't happen as a result of despondency over negative life situations: mania. Clinical trials for manic depression are much better, and the gold standard -- lithium -- is known to work for most people. If you go back into the history of psychiatry, the touchpoint where it starts to sort of look like medicine is when Kraepelin develops a differential diagnostic method to sort out manic-depression from schizophrenia. It's very hard to see something like that for depression.
To compound: American psychiatry is especially bad because it fell for psychoanalysis hard, to the point that it seemed like NYC had higher rates of psychosis than London because Americans had deviated from the standard definition of psychosis to use Freud's. Who knows what passes for "depression" in the US.
We're doing that with adderal/ritalin/speed now.. (Netherlands)
I think I assume that it is not "as" intense and people are relatively more in-tune with their bodies.
All these behaviors seem to me to be tied with the height we assign to science to tell us how to live our lives.
Serotonin rises beginning on the first dose, but BDNF takes longer, which is why you have to take them for at least 4-6 weeks, sometimes longer, before noticing benefits. It's also one of the reasons why exercise is antidepressive, and many other things. But antidepressants increase BDNF more consistently than exercise, so for some, exercise is not enough.
Antidepressants are effective for lots of people. Those saying otherwise in the article...I have no clue where their comments came from...do they have any clinical experience?
Also worth noting: psylocibin and LSD are microdosed to give an antidepressant effect, and they both do two similar things: activate serotonin receptors (psylocibin and LSD I think mainly activate 5HT3, and probably other serotonin receptors) as well as increase neuronal rewiring/growth (one through BDNF, the others through a change in perspective and other mechanisms I'm not versed in).
I will say that depression meds have helped me in the past from going too low. But it never fixed depression, more like a safety net.
hmmm....
The problem is that there is a mis-alignment between the reality of daily life and the software my brain has constructed for handling and processing daily life. The software doesn't give good results on the inputs: for instance, not having a good script for what to do with time to feel happy or like myself, or not knowing how to navigate social situations to get positive and fulfilling results. The result is the brain gives up on the software and stops trying because it's become aware it's not working but doesn't have any better ideas.
If I was programming my brain, a better strategy would obviously be to switch to "explore" mode and start rapidly iterating on the software to try to find something that works better. But evidently the brain doesn't work that way, and the negative feedback from real life causes it to slip into depression and torpor.
So there's a chemical imbalance, yeah, but it's not the root cause. If a "chemical disposition to depression" is anything, it's this tendency to give up on the software instead of iterating on it.
(IRL, "iterating on the software" looks like a person making big changes in their life: quitting jobs, moving, leaving relationships, picking up new hobbies.. you know, all of the stuff people advise you to do to get out of a funk. "Changing variables until something works".)
SSRIs, at least the ones I've taken, seem to work by reducing the severity of the (bad results from software) -> (downregulate energy levels) step; in particular, the reduce the amount of fixation my brain gives on the bad results and makes me not worry so much about them, which -- presumably -- reduces the amount of the downregulation that results, which prevents slipping into the extreme-depressive state where you have no willpower to try anything new that might help.
In particular I observe that my natural tendency is for negative social interactions to trigger a negative feedback loop of self-doubt and frustration that spirals out of control, and Lexapro seems to reduce the coefficient on the feedback loop so that it dissipates instead of amplifies.
(I'm not all that confident in this model but it's my best guess so far. I'll also add that a lot of my depressive states seem to have social anxiety as the main trigger, so it might be that this is phenomenologically quite different from sorts of depression that are, I guess, "intrinsic", rather than caused by something else.)
(Also, there is another node in the system worth mentioning: the tendency for "vortexing" ie addictive/obsessive behavior that turns off the brain's analysis / awareness, used as an escape mechanism to avoid contending with a hostile reality. In my case, video game addiction. Vortexing fixes one in the anxious-avoidant state, and realizing one is vortexing, aka, operating in a very small subspace of thought-space, can break out of a depressive spiral. It's a whole thing that I don't know exactly how to put into words, but I feel like I've made lots of progress on it and have the tools to solve it the rest of the way now.)
As I understand your comment, it proposes a feedback-loop model a bit like this, where the brain observes reality and makes decisions about it. Those decisions affect reality -- which in turn affects the brain's state, it's ability to make decisions, and the very decisions it makes:
|----------->-----------|
| |
reality brain
| |
|-----------<-----------|
One notion I'm toying with is to decouple the right side of the diagram further. In this sense, I think "psychological resilience" means essentially the brain's ability to maintain its own internal state independent of reality -- in more practical terms, the brain can remain confident of its own ability to operate in reality, even as reality throws curveballs and does all kinds of wacky stuff (like, say, a job that becomes unfulfilling while the world is going through global pandemics and a volatile stock market).
|----------->----------->-----------|
| | |
reality internal decision-making
| emotional state brain
| | |
|-----------<-----------<-----------|
> External goods are of trivial importance and without much influence in either direction: prosperity does not elevate the sage and adversity does not depress him. For he has always made the effort to rely as much as possible on himself and to derive all delight from himself.
It's all still way easier said than done. I have no illusions that I'm even close to being a "sage," in Seneca's definition. But remembering that there are more pieces to the puzzle -- more variables to toy with, more factors to optimize, smaller steps I can take -- helps, sometimes, at least for me.
[1]: https://www.themarginalian.org/2017/05/02/seneca-consolation...
> I think "psychological resilience" means essentially the brain's ability to maintain its own internal state independent of reality -- in more practical terms, the brain can remain confident of its own ability to operate in reality, even as reality throws curveballs and does all kinds of wacky stuff
In particular, I think one of the big differences between depressive people and non-depressive people is whether their upbringing/community/learned value system is one that is "sturdy" ie resilient to damage.
A socially vulnerable person who has never had a strong foundation for their social legitimacy goes into every social interaction looking for evidence of being accepted. A person who has grown up with their acceptance never in doubt doesn't need anything from each new interaction. So the former person is susceptible to trauma from every interaction, whereas it would take the latter person a long time be worn down by negative responses to the point where it would affect them psychologically.
I suspect that the mechanism by which modern life causes such an epidemic of depression is that people grow up less integrated into communities and family units that provide this stability-of-identity by the time they get to adulthood. If you reach adolescence with no model of what a legitimate person looks like or how to be one, it makes sense that you will flounder, and being a social being that craves acceptance by society, you can end up obsessively trying to find that legitimacy in every interaction.
(Another mechanism for this is when someone grows up with an abusive or otherwise psychologically damaging home life, such as never being validated by their parents and always criticized -- so even if they are by all metrics very good at life or very good at socializing, they're programmed to never perceive themselves as good enough, so they never get to that state of imperviousness to slightly-negative reality.)
I agree that tie-in to developmental psychology makes a ton of sense. The patterns of thought get set early in life, when neuroplasticity is high. Refactoring them later on becomes more and more difficult with the passage of time.
Even nowadays, it seems like there's a general lack of strong male role models (in a true, healthy sense of the word "strong"). One puts it all together piecemeal and -- eventually, hopefully -- gets to the point of being able to self-validate.
It sounds like you've made a ton of progress yourself. I'm curious if you're up for sharing -- what was most helpful for you?
As someone who once had depression that did not respond to any medication, which was completely resolved within 1-2 weeks of making a big but well planned life change, in retrospect I consider what was done to me borderline malpractice, considering some of the sude effects.
This sounds reasonable, until you think that you are saying something isn't true because you can't explain it, which is also true of a 3 year old when asked how planes fly. Them not being able to explain it doesn't make the plane fall from the sky.
To be fair, the title of the article and the general gist of the theory are not what is being refuted in the article, but the article is the one saying SSRIs probably aren't worth it. It seems likely there is not a good explanation for their effectiveness but sure looks effective.
Here's a couple things I found from searching "strength of placebo vs ssri":
https://www.ncbi.nlm.nih.gov/books/NBK555852/table/ch4.tab29...
https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12... https://jamanetwork.com/journals/jama/article-abstract/18515...
The last one has a nice summary:
> Antidepressant medications represent the best established treatment for major depressive disorder, but there is little evidence that they have a specific pharmacological effect relative to pill placebo for patients with less severe depression.
Basically "they're the best tool we have but we don't have evidence that it actually has an effect". I remember a while ago I had a teacher that said "we laugh about rain dances today, but at the time there was a lot of evidence - you dance and you don't stop until it rains or you die, it's almost a 100% success rate". I feel like we see something similar here - we think what we're doing is helping but we don't have any causal evidence to support that. The evidence seems to suggest you could tell someone they're getting an SSRI, not give them any, and get the same outcome - suggesting the SSRI has little to no effect and what's actually causing the issue is something else, and could maybe be better addressed some other way.
There's another famous story about "the anti-depressant cow" which seems very relevant here
> https://antidepressantcow.org/2020/02/the-story-of-the-antid...
The TLDR is that a doctor tried to sell antidepressant meds in Cambodia and they basically told him "we don't need those - if someone is upset we get together as a community and make it better instead of trying to tell them it's their own problem to deal with"
I think that's the point: depression is not independent of circumstances (in the wider sense).
It's not necessarily likely that a single chemical is the cause (as is suggested in the serotonin hypothesis).
I know there are people who are chronically depressed but I don't know how to untangle them from the context in which their disease exists. The only way to really know would be to try adapting them to wholly different circumstances and see whether or not the way the brain responded changed as a result.
Also, many psychiatrists prescribe them out like M&Ms, stating that they "believe" in them. Meanwhile - and this is the point of the article which you seem to have missed despite it being right there in the headline - we have no idea how they "work", just some very iffy guesses.
After a while, the high's not enough, so they need to either up the dose, start mixing alcohol, or turn to other drugs.
No, they do not.
Edit: you do not see patients surreptitiously increasing their own doses, nor do you see patients buying these medications on the street.
While I'm sure there's someone out there selling illicit SSRIs on the street, it's quite rare. That's not the case with drugs that "get people high".
Alternatively, that there is more than one cause of what we call "depression", and that SSRIs are only effective against some (but not all) of those causes.
"Little more effective than a placebo" conflicts with the large number of patients who claim SSRIs have been a life-changing treatment for them.
One way to reconcile this is by observing that if (just making up numbers here) 50% of people have no effect and 50% have a good effect, the overall effect is going to probably appear small, despite the fact that 50% of the patients had a very real positive effect.
That statement only makes sense if tested against placebos. A lot of folk on placebos make identical claims.
The notion that it's not much better than a placebo is partially true. Short term; placebos and SSRI's aren't that dramatically different. Also, for unknown reasons, the effectiveness of SSRI's is diminishing somewhat (not due to tolerance - diminishing in results given to new patients). This makes it all a bit muddled.
If you pop out a much further distance though - placebos lose their effeciveness faster than SSRI's (and some people on both never lose effectiveness).
The SSRI's are definitely doing something, often something useful. Maybe for some people they are the long-term solution. I'm generally as suspicious of over-generalization in any direction. People are all different so blanket statements aren't likely the most correct.
Something I've heard a lot of clinicians repeat (though I don't know where the statement originates) is something to the effect of: "If you have someone who is terrible depressed - get them on SSRI's because you can't help them if they're dead; and then begin the work of addressing the issues that lead to the depressive states."
Again - a bit of a blanket statement - but probably the best general course of action. Start with staving off the immediate threat, then see if you can work on a solution that doesn't involve medication forever. If you can't you can't and shouldn't get hung up on that, but if you can, you probably should.
Can you attack the root cause by means other than serotonin levels? Possibly, but that's the best we have for now.
Here's an interesting article laying out the issue at hand: https://connect.springerpub.com/content/sgrehpp/17/1/60
He isn't, and you don't.
Statement B: you have a point
According to you, A => B.
However, you claiming (-A) does not necessarily mean -A => -B.
He isn't. Not by many millions. "Anecdotal evidence" refers to one (or at least only a small number) of people claiming something.
If your ft4 is very high or you have low levels of hgh, there is a cause. What theories to they have for these issues with serotonin?
When psychiatric problems become testable, they move to the neurology department. Psychiatry, like economics, is "problematic", but it's a pragmatic answer to problems that may have no fundamental solution.
Everyone who felt depressed knows it is caused by life conditions. Of course, chemicals can help. Chemicals can make you very happy. Under a dose. But implying that happiness is just a state of chemicals in the brain is a path to existential void.
It's like "headache", maybe you took too much coffee today, or maybe you have stage IV brain cancer
Thanks, WebMD.
We go through a bunch of these during our lives, especially as children and adolescents, but society and culture have incorporated mechanisms to help young minds build new, more accurate, world models so it usually isn't much of a problem. However, we're at a point in our societal development where more and more minds are seeing the failures of their world model that society has no answer for.
Read more here: https://blogs.scientificamerican.com/mind-guest-blog/why-we-...
Look, maybe a chemical imbalance is the main factor in some or much of depression cases but that still leave a lot of cases when it isn’t, and something else is the main factor.
We should be able to freely talk about what it is, and investigate it, without being squaelched, downvoted and shamed into stopping. The same when it comes to systemic racism being the main factor for PoC in various statistics or systemic sexism being the main factor for women in tech. There are other, very serious, perspectives that should be allowed to be discussed and explored, like this one for instance: https://magarshak.com/blog/?p=286
Personally, I think that much of actual depression comes from external forces. In the north it has to do with lack of sunlight and warmth causing Seasonal Affective Disorder, through a variety of mechanisms. But in the USA, there has been a huge uptick in depression and its treatment over the last 20-30 years.
A major problem is that the anglophone world as a society are too medication-happy instead of looking at the underlying cause. One in four middle-aged women is on antisepressants! An epidemic of kids getting prescribed amphetamines for ADD and ADHD! Now surely, the hormonal imbalances haven’t reached such epidemic proportions… could it be our attitude towards pills and medical interventions rather than social?
The book Bowling Alone by Robert Putnam came out circa 2000 to describe the already-rapid decline of American social life. We live alone, then both parents work, stick their kids in a glorified daycare center and their parents in a nursing home (which medicates them too). Meanwhile traditional societies have less but are happier. They live together, have less depression, etc.
Look, in Finland the school day is far shorter and the kids can climb trees. Their prevalence of ADHD is an order of magnitude less than in the USA, isn’t it? How is that possible? Because a lot of the things we try to throw pills at, are things we created with our society. One that has the government put high fructose corn syrup into everything, overuses antibiotics on factory farms, produces massive amounts of obesity and diabetes (even in kids!) and btw those are risk factors for serious coronavirus cases. That is the reL epidemic.
Telling everyone to “lean in” and work corporate jobs robs them of their time to spend with each other and raising their kids. Rather than give everyone universal health insurance like other countries (and maybe a UBI) we tie it to employment and tell them to come to work as soon as they can after they have kids. And so on. Things are STARTING to change, but still the culture (including on HN) is to discourage serious discussion of societal change because it will distract from medical interventions. The pendulum has swung too far and we should consider societal structure. And that is also true for the autism spectrum and other things for which there is also an uptick.
(If you are about to downvote this and not even respond with any substance, consider that you’re doing exactly what I described. You’re “part of the problem”, making your diagnoses of a problem win not by argument or data but simply by burying any attempts at conversation, respectful or not, that propose other major factors and solutions.)