10 ms·

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

92 points by agomez314 4y ago

sidcool 4y ago
The article mentions Serotonin, but is it possible some other chemical is responsible? Coz i can't think of any other reason apart from a biochemical one for some types of depression that aren't caused by circumstances.
- dariusj18 4y ago
  I've always suspected that (sometimes) it doesn't have to be a consistent chemical imbalance, but one that triggers creation of negative feedback loops in the brain.
  - onlyrealcuzzo 4y ago
    What powers feedback loops? I imagined chemicals.
    - dariusj18 4y ago
      Pathways that were established when those chemical imbalances were active.
- pmoriarty 4y ago
  "can't think of any other reason apart from a biochemical one for some types of depression that aren't caused by circumstances." I think that's the point: depression is not independent of circumstances (in the wider sense).
  - WalterSear 4y ago
    Strictly speaking, that's exactly what clinical depression is, as opposed to 'distress'.
- nicoburns 4y ago
  I think this is true, but only the vapid sense that absolutely everything in the body and mind is biochemical (and if you believe that the mind has non-biological aspects then it ceases to be true). It's not necessarily likely that a single chemical is the cause (as is suggested in the serotonin hypothesis).
- Induane 4y ago
  How our brains respond to circumstances is essentially chemical. Perhaps some peoples brains don't do well without a particular cultural or social context and we ultimately see that at the physical level with the chemical changes that result from it. Maybe the brain is really saying "change the circumstances" and we're interpreting it as "chemical proportions are off and/or chemical receptors are responding differently" and seek to correct the physical component. 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.
sillyquiet 4y ago
Wow. "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."
- tinyhouse 4y ago
  This is indeed a wow statement. Not from the field and completely anecdotal. I know 5 people in my family taking Lexapro for anxiety and all with significantly improved results after a month or two of use. I know it's not depression but still.
  - starkd 4y ago
    There's no doubt there's a short term efficacy. The real issue is the waning efficacy over long term with risk of dependence.
    - zionic 4y ago
      I worry about long-term users skipping a day and going deep down a blackhole. Some correlate mass shootings and heavy antidepressant use (then rapid cessation).
      - starkd 4y ago
        That's a very real risk. Do not suddenly stop these meds.
      - ttpphd 4y ago
        That is a moral panic whipped up by pro-gun crusaders who want to blame everything but the easy availability of guns for America's domestic terrorist problem
      - bigbillheck 4y ago
        > Some correlate mass shootings and heavy antidepressant use (then rapid cessation). Seems like an attempt to deflect from much more likely issues.
binbag 4y ago
What's the alternative explanation?
- lm28469 4y ago
  "depression" is a big word behind which dozens if not hundreds of causes hide. It's like "headache", maybe you took too much coffee today, or maybe you have stage IV brain cancer
  - jaywalk 4y ago
    > maybe you took too much coffee today, or maybe you have stage IV brain cancer Thanks, WebMD.
- lexapro 4y ago
  Genetics, behavioral and thinking patterns, lifestyle, life circumstances, ...
  - amthna 4y ago
    society, culture, capitalism
- frankus 4y ago
  I wonder if it's related to the broader trend of lowered resting metabolic rate in humans. Not necessarily that the latter causes the former, but that some mechanism is driving both: an adaptation that tells the organism that it's time to hunker down, avoid unnecessary activity/risk, and save up calories.
- pantalaimon 4y ago
  Might be a software issue, not a hardware issue
- artificialLimbs 4y ago
  Part of it (all of it?) SEEMS to be a lack of purpose/meaning and connection to nature. Total anecdata from my own friends/family that are/were depressed including myself.
justsomeguy33 4y ago
ortusdux 4y ago
Direct publication link: https://www.nature.com/articles/s41380-022-01661-0 https://www.nature.com/articles/s41380-022-01661-0
jkukul 4y ago
Related discussion from 2 days ago: https://news.ycombinator.com/item?id=32160703 https://news.ycombinator.com/item?id=32160703
- das_keyboard 4y ago
  It is even about the same publication[1]. So is there any reason why it should be discussed here again? 1: https://www.nature.com/articles/s41380-022-01661-0 https://www.nature.com/articles/s41380-022-01661-0
tokai 4y ago
Problematizing the serotonin hypothesis is nothing new. I'm disappointed that this is not a new study but just a meta review. It does nothing to resolve the issue with serotonin levels not causing depression while antidepressants have a proven (slight) positive effect on depressive symptoms. It also doesn't do anything for explaining the effects from antidepressants that affect other things than serotonin. Like sertraline with its dopaminergic effect.
- dmix 4y ago
  Yeah this type of anti-SSRI stuff is definitely not new but this has been getting major viral traction for some reason. 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 https://en.wikipedia.org/wiki/Escitalopram I'm curious if anxiety is similarly being targeted here? (didnt read the paper)
  - Goronmon 4y ago
    Yeah this type of anti-SSRI stuff is definitely not new but this has been getting major viral traction for some reason. 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.
    - nradov 4y ago
      There is some fairly strong evidence that SSRI use can make certain people more violent. And there appears to be a real causal effect: it's not just that people who already have violent tendencies are more likely to take SSRIs. https://www.sciencedirect.com/science/article/pii/S0924977X20301048 https://www.sciencedirect.com/science/article/pii/S0924977X2... We don't know whether this is a significant factor in gun violence.
      - EddieRingle 4y ago
        I'm not sure the study you linked supports that. They found an association between SSRIs and violent crimes, but specifically state they cannot claim a causal link without further study.
htk 4y ago
My uninformed opinion is that this smells of a hidden agenda. Is anyone here more educated on the subject to comment on this new study and the articles that are being based on it?
ramesh31 4y ago
I think the overprescribing of SSRIs to the millenial generation is one of the least talked about public health issues today. We have an entire generation of kids who were force fed these things from as young as 4 years old. I know because I was one of them. They literally made a Prozac "syrup" for young children, and I was taking it in kindergarten. God knows what all those chemicals did to my developing brain.
- boesboes 4y ago
  USA I presume? We're doing that with adderal/ritalin/speed now.. (Netherlands)
  - oldsklgdfth 4y ago
    My perception (which I would like to correct) is that such trends are mostly isolated to the US and not prevalent in Europe. Ex. over-prescribing based on some recent finding, new diet, new exercise trend, new [insert habit/lifestyle]. Is that the case? 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.
aaaaaaaaaaab 4y ago
Bullshit. It has been known for decades that it's not the serotonin levels that matter, rather, the various down/upregulation cascades that follows after elevating serotonin levels for a few weeks. We don't know the specifics, but SSRIs work for a large chunk of people. That's beyond questioning at this point. Can you attack the root cause by means other than serotonin levels? Possibly, but that's the best we have for now.
- digdugdirk 4y ago
  The difference between SSRI's and placebo is surprisingly minimal. Here's an interesting article laying out the issue at hand: https://connect.springerpub.com/content/sgrehpp/17/1/60 https://connect.springerpub.com/content/sgrehpp/17/1/60
  - aaaaaaaaaaab 4y ago
    I know from first hand that SSRIs work.
    - abmackenzie 4y ago
      Ah yes, anecdotal evidence, the bedrock of any sound scientific analysis.
      - fffffffa 4y ago
        The article posted that is being replied to isn't an intellectually honest attempt either.
      - Turing_Machine 4y ago
        You might have a point if the OP was the only one claiming this. He isn't, and you don't.
        2143 4y ago
        Statement A: OP was the only one claiming this. Statement B: you have a point According to you, A => B. However, you claiming (-A) does not necessarily mean -A => -B.
daniel-cussen 4y ago
Neurons can only function with chemical inbalances.
EGreg 4y ago
On HN, a lot of people react badly to this thesis, that there may be additional causes to depression and that they may be addressable, to prevent or mitigate it. 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 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.)
thepasswordis 4y ago
Ridiculous. SSRIs are literally life saving medication. Millions of people have seen themselves and their family members go from suicidally depressed to normally functioning due to SSRIs.
- ajkjk 4y ago
  That's undoubtedly true but has little to do with the veracity of the claim in the parent article either way.
- mandmandam 4y ago
  Let's keep some perspective here: They're mildly better over an inactive placebo, come with many very serious side effects, and are dangerous to withdraw from. Plus, "normally functioning" is a very questionable term to use. 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.
  - linuxftw 4y ago
    We know how they work. They get people high, and people like to be high. Does it correct any issue? No, but being high masks feeling down. After a while, the high's not enough, so they need to either up the dose, start mixing alcohol, or turn to other drugs.
    - Turing_Machine 4y ago
      > They get people high, 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".
- fellow_human 4y ago
  Your appeal to reductio ad absurdum here fails because it's not established that SSRIs work by restoring an imbalance. SSRIs are only little more effective than a placebo, suggesting there's something deeper at play with regards to depression. Yes they may be an effective measure in serious cases of depression but they certainly are not a cure and many people do not just turn "normal functioning" after SSRI treatments like you're suggesting. The disease model of depression simply is not true.
ajkjk 4y ago
I've experienced a lot of depression in my life and it feels fairly obvious that the chemical imbalance state -- the feeling of extreme torpor, lack of motivation to do things, negativity about future prospects, and inability to enjoy anything -- is well downstream of the root cause, which is a sort of "software problem" that looks like this: 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.)
- 4y ago
thanatropism 4y ago
"Listening to Prozac" was already popularizing this idea in the mid-90s. 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.
bjt2n3904 4y ago
The "chemical imbalance" model is a strange way to go about treatment. There's no objective assessment, and no feedback path to confirm it's working. 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.
dmtroyer 4y ago
"Mark Horowitz is co-founder of a company aiming to help people safely stop unnecessary antidepressants in Canada" hmmm....
slibhb 4y ago
The evidence for antidepressants is not based on the serotonin theory of depression. It's based on blinded placebo studies. The serotonin theory was posited after MAOI antidepressants were discovered. It's been argued that antidepressants aren't significantly better than placebo. There's a good discussion of that here: https://lorienpsych.com/2020/10/25/ssris/#3_How_effective_are_SSRIs https://lorienpsych.com/2020/10/25/ssris/#3_How_effective_ar... 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.
- HardlyCurious 4y ago
  It doesn't discredit medication as an option, which is a really open ended statement, but it does redefine the role medication plays. It moves medication from a necessary status to a non-necessary status. Where it's role is to provide a mental break for the patient so they can make other necessary changes more easily. The medication could probably be fully replaced with a wellness retreat, but the medication is a lot more feasible for most people.
rtpg 4y ago
I don't know how you square this review with the fact that SSRIs seem to work. This feels a hell of a lot like "we can't find a good explanations for why this work, therefore it doesn't work." 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.
- e_i_pi_2 4y ago
  I don't think the argument is "they don't work", moreso that they only work because the person thinks it will work and gets a placebo effect - not that the drug actually works to fix a chemical issue in the brain. 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://www.ncbi.nlm.nih.gov/books/NBK555852/table/ch4.tab29... https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-016-1173-2 https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12... https://jamanetwork.com/journals/jama/article-abstract/185157 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-antidepressant-cow 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"
thanatropism 4y ago
I wonder whether clinical trials can even select correctly candidates who are "depressed". 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.
xivzgrev 4y ago
Having had depression for over half of my life, I’ve never believed it was a chemical imbalance. For me, it’s a complicated function of thoughts and feelings that lead to depressive mood. Some I’ve been able to address and get better, some I have not. 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.
752963e64 4y ago
nothatscool 4y ago
I have never understood the chemical imbalance theory anyway. Surely there needs to be a cause of a chemical imbalance like an auto-immune illness or something. Why hasn’t the focus been on the cause? 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?
jonnycomputer 4y ago
Has already been discussed on HN: - https://news.ycombinator.com/item?id=32160703 https://news.ycombinator.com/item?id=32160703 - https://news.ycombinator.com/item?id=32191728 https://news.ycombinator.com/item?id=32191728 - https://news.ycombinator.com/item?id=32176401 https://news.ycombinator.com/item?id=32176401 Link to actual paper: https://www.nature.com/articles/s41380-022-01661-0 https://www.nature.com/articles/s41380-022-01661-0 See expert responses here: https://www.sciencemediacentre.org/expert-reaction-to-a-review-paper-on-the-serotonin-theory-of-depression/ 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 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.
dandanua 4y ago
Why it was a theory in the first place? 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.
lr4444lr 4y ago
Has any study ever been able to induce depression reliably by reducing neurotransmitters? 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.
hereme888 4y ago
The biggest antidepressant effect of SSRIs and SNRIs comes from the upregulation of BDNF, not serotonin. 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).

92 points by agomez314 4y ago

The article mentions Serotonin, but is it possible some other chemical is responsible? Coz i can't think of any other reason apart from a biochemical one for some types of depression that aren't caused by circumstances.

dariusj18 4y ago
I've always suspected that (sometimes) it doesn't have to be a consistent chemical imbalance, but one that triggers creation of negative feedback loops in the brain.
- onlyrealcuzzo 4y ago
  What powers feedback loops? I imagined chemicals.
  - dariusj18 4y ago
    Pathways that were established when those chemical imbalances were active.
pmoriarty 4y ago
"can't think of any other reason apart from a biochemical one for some types of depression that aren't caused by circumstances." I think that's the point: depression is not independent of circumstances (in the wider sense).
- WalterSear 4y ago
  Strictly speaking, that's exactly what clinical depression is, as opposed to 'distress'.
nicoburns 4y ago
I think this is true, but only the vapid sense that absolutely everything in the body and mind is biochemical (and if you believe that the mind has non-biological aspects then it ceases to be true). It's not necessarily likely that a single chemical is the cause (as is suggested in the serotonin hypothesis).
Induane 4y ago
How our brains respond to circumstances is essentially chemical. Perhaps some peoples brains don't do well without a particular cultural or social context and we ultimately see that at the physical level with the chemical changes that result from it. Maybe the brain is really saying "change the circumstances" and we're interpreting it as "chemical proportions are off and/or chemical receptors are responding differently" and seek to correct the physical component. 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.

sillyquiet 4y ago

Wow. "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."

tinyhouse 4y ago
This is indeed a wow statement. Not from the field and completely anecdotal. I know 5 people in my family taking Lexapro for anxiety and all with significantly improved results after a month or two of use. I know it's not depression but still.
- starkd 4y ago
  There's no doubt there's a short term efficacy. The real issue is the waning efficacy over long term with risk of dependence.
  - zionic 4y ago
    I worry about long-term users skipping a day and going deep down a blackhole. Some correlate mass shootings and heavy antidepressant use (then rapid cessation).
    - starkd 4y ago
      That's a very real risk. Do not suddenly stop these meds.
    - ttpphd 4y ago
      That is a moral panic whipped up by pro-gun crusaders who want to blame everything but the easy availability of guns for America's domestic terrorist problem
    - bigbillheck 4y ago
      > Some correlate mass shootings and heavy antidepressant use (then rapid cessation). Seems like an attempt to deflect from much more likely issues.

binbag 4y ago

What's the alternative explanation?

lm28469 4y ago
"depression" is a big word behind which dozens if not hundreds of causes hide. It's like "headache", maybe you took too much coffee today, or maybe you have stage IV brain cancer
- jaywalk 4y ago
  > maybe you took too much coffee today, or maybe you have stage IV brain cancer Thanks, WebMD.
lexapro 4y ago
Genetics, behavioral and thinking patterns, lifestyle, life circumstances, ...
- amthna 4y ago
  society, culture, capitalism
frankus 4y ago
I wonder if it's related to the broader trend of lowered resting metabolic rate in humans. Not necessarily that the latter causes the former, but that some mechanism is driving both: an adaptation that tells the organism that it's time to hunker down, avoid unnecessary activity/risk, and save up calories.
pantalaimon 4y ago
Might be a software issue, not a hardware issue
artificialLimbs 4y ago
Part of it (all of it?) SEEMS to be a lack of purpose/meaning and connection to nature. Total anecdata from my own friends/family that are/were depressed including myself.

justsomeguy33 4y ago

ortusdux 4y ago

Direct publication link: https://www.nature.com/articles/s41380-022-01661-0 https://www.nature.com/articles/s41380-022-01661-0

jkukul 4y ago

Related discussion from 2 days ago: https://news.ycombinator.com/item?id=32160703 https://news.ycombinator.com/item?id=32160703

das_keyboard 4y ago
It is even about the same publication[1]. So is there any reason why it should be discussed here again? 1: https://www.nature.com/articles/s41380-022-01661-0 https://www.nature.com/articles/s41380-022-01661-0

tokai 4y ago

Problematizing the serotonin hypothesis is nothing new. I'm disappointed that this is not a new study but just a meta review. It does nothing to resolve the issue with serotonin levels not causing depression while antidepressants have a proven (slight) positive effect on depressive symptoms. It also doesn't do anything for explaining the effects from antidepressants that affect other things than serotonin. Like sertraline with its dopaminergic effect.

dmix 4y ago
Yeah this type of anti-SSRI stuff is definitely not new but this has been getting major viral traction for some reason. 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 https://en.wikipedia.org/wiki/Escitalopram I'm curious if anxiety is similarly being targeted here? (didnt read the paper)
- Goronmon 4y ago
  Yeah this type of anti-SSRI stuff is definitely not new but this has been getting major viral traction for some reason. 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.
  - nradov 4y ago
    There is some fairly strong evidence that SSRI use can make certain people more violent. And there appears to be a real causal effect: it's not just that people who already have violent tendencies are more likely to take SSRIs. https://www.sciencedirect.com/science/article/pii/S0924977X20301048 https://www.sciencedirect.com/science/article/pii/S0924977X2... We don't know whether this is a significant factor in gun violence.
    - EddieRingle 4y ago
      I'm not sure the study you linked supports that. They found an association between SSRIs and violent crimes, but specifically state they cannot claim a causal link without further study.

htk 4y ago

My uninformed opinion is that this smells of a hidden agenda. Is anyone here more educated on the subject to comment on this new study and the articles that are being based on it?

ramesh31 4y ago

I think the overprescribing of SSRIs to the millenial generation is one of the least talked about public health issues today. We have an entire generation of kids who were force fed these things from as young as 4 years old. I know because I was one of them. They literally made a Prozac "syrup" for young children, and I was taking it in kindergarten. God knows what all those chemicals did to my developing brain.

boesboes 4y ago
USA I presume? We're doing that with adderal/ritalin/speed now.. (Netherlands)
- oldsklgdfth 4y ago
  My perception (which I would like to correct) is that such trends are mostly isolated to the US and not prevalent in Europe. Ex. over-prescribing based on some recent finding, new diet, new exercise trend, new [insert habit/lifestyle]. Is that the case? 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.

aaaaaaaaaaab 4y ago

Bullshit. It has been known for decades that it's not the serotonin levels that matter, rather, the various down/upregulation cascades that follows after elevating serotonin levels for a few weeks. We don't know the specifics, but SSRIs work for a large chunk of people. That's beyond questioning at this point. Can you attack the root cause by means other than serotonin levels? Possibly, but that's the best we have for now.

digdugdirk 4y ago
The difference between SSRI's and placebo is surprisingly minimal. Here's an interesting article laying out the issue at hand: https://connect.springerpub.com/content/sgrehpp/17/1/60 https://connect.springerpub.com/content/sgrehpp/17/1/60
- aaaaaaaaaaab 4y ago
  I know from first hand that SSRIs work.
  - abmackenzie 4y ago
    Ah yes, anecdotal evidence, the bedrock of any sound scientific analysis.
    - fffffffa 4y ago
      The article posted that is being replied to isn't an intellectually honest attempt either.
    - Turing_Machine 4y ago
      You might have a point if the OP was the only one claiming this. He isn't, and you don't.
      - 2143 4y ago
        Statement A: OP was the only one claiming this. Statement B: you have a point According to you, A => B. However, you claiming (-A) does not necessarily mean -A => -B.

daniel-cussen 4y ago

Neurons can only function with chemical inbalances.

EGreg 4y ago

On HN, a lot of people react badly to this thesis, that there may be additional causes to depression and that they may be addressable, to prevent or mitigate it. 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 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.)

thepasswordis 4y ago

Ridiculous. SSRIs are literally life saving medication. Millions of people have seen themselves and their family members go from suicidally depressed to normally functioning due to SSRIs.

ajkjk 4y ago
That's undoubtedly true but has little to do with the veracity of the claim in the parent article either way.
mandmandam 4y ago
Let's keep some perspective here: They're mildly better over an inactive placebo, come with many very serious side effects, and are dangerous to withdraw from. Plus, "normally functioning" is a very questionable term to use. 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.
- linuxftw 4y ago
  We know how they work. They get people high, and people like to be high. Does it correct any issue? No, but being high masks feeling down. After a while, the high's not enough, so they need to either up the dose, start mixing alcohol, or turn to other drugs.
  - Turing_Machine 4y ago
    > They get people high, 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".
fellow_human 4y ago
Your appeal to reductio ad absurdum here fails because it's not established that SSRIs work by restoring an imbalance. SSRIs are only little more effective than a placebo, suggesting there's something deeper at play with regards to depression. Yes they may be an effective measure in serious cases of depression but they certainly are not a cure and many people do not just turn "normal functioning" after SSRI treatments like you're suggesting. The disease model of depression simply is not true.

ajkjk 4y ago

I've experienced a lot of depression in my life and it feels fairly obvious that the chemical imbalance state -- the feeling of extreme torpor, lack of motivation to do things, negativity about future prospects, and inability to enjoy anything -- is well downstream of the root cause, which is a sort of "software problem" that looks like this: 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.)

4y ago

thanatropism 4y ago

"Listening to Prozac" was already popularizing this idea in the mid-90s. 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.

bjt2n3904 4y ago

The "chemical imbalance" model is a strange way to go about treatment. There's no objective assessment, and no feedback path to confirm it's working. 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.

dmtroyer 4y ago

"Mark Horowitz is co-founder of a company aiming to help people safely stop unnecessary antidepressants in Canada" hmmm....

slibhb 4y ago

The evidence for antidepressants is not based on the serotonin theory of depression. It's based on blinded placebo studies. The serotonin theory was posited after MAOI antidepressants were discovered. It's been argued that antidepressants aren't significantly better than placebo. There's a good discussion of that here: https://lorienpsych.com/2020/10/25/ssris/#3_How_effective_are_SSRIs https://lorienpsych.com/2020/10/25/ssris/#3_How_effective_ar... 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.

HardlyCurious 4y ago
It doesn't discredit medication as an option, which is a really open ended statement, but it does redefine the role medication plays. It moves medication from a necessary status to a non-necessary status. Where it's role is to provide a mental break for the patient so they can make other necessary changes more easily. The medication could probably be fully replaced with a wellness retreat, but the medication is a lot more feasible for most people.

rtpg 4y ago

I don't know how you square this review with the fact that SSRIs seem to work. This feels a hell of a lot like "we can't find a good explanations for why this work, therefore it doesn't work." 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.

e_i_pi_2 4y ago
I don't think the argument is "they don't work", moreso that they only work because the person thinks it will work and gets a placebo effect - not that the drug actually works to fix a chemical issue in the brain. 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://www.ncbi.nlm.nih.gov/books/NBK555852/table/ch4.tab29... https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-016-1173-2 https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12... https://jamanetwork.com/journals/jama/article-abstract/185157 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-antidepressant-cow 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"

thanatropism 4y ago

I wonder whether clinical trials can even select correctly candidates who are "depressed". 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.

xivzgrev 4y ago

Having had depression for over half of my life, I’ve never believed it was a chemical imbalance. For me, it’s a complicated function of thoughts and feelings that lead to depressive mood. Some I’ve been able to address and get better, some I have not. 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.

752963e64 4y ago

nothatscool 4y ago

I have never understood the chemical imbalance theory anyway. Surely there needs to be a cause of a chemical imbalance like an auto-immune illness or something. Why hasn’t the focus been on the cause? 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?

jonnycomputer 4y ago

Has already been discussed on HN: - https://news.ycombinator.com/item?id=32160703 https://news.ycombinator.com/item?id=32160703 - https://news.ycombinator.com/item?id=32191728 https://news.ycombinator.com/item?id=32191728 - https://news.ycombinator.com/item?id=32176401 https://news.ycombinator.com/item?id=32176401 Link to actual paper: https://www.nature.com/articles/s41380-022-01661-0 https://www.nature.com/articles/s41380-022-01661-0 See expert responses here: https://www.sciencemediacentre.org/expert-reaction-to-a-review-paper-on-the-serotonin-theory-of-depression/ 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 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.

dandanua 4y ago

Why it was a theory in the first place? 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.

lr4444lr 4y ago

Has any study ever been able to induce depression reliably by reducing neurotransmitters? 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.

hereme888 4y ago

The biggest antidepressant effect of SSRIs and SNRIs comes from the upregulation of BDNF, not serotonin. 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).