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How Antidepressants Work, at Last?
- mastrsushi 6y agoI'm sure the people of Hacker News will find this article relatable.
- anaphor 6y agoWill this make the "chemical imbalance" (i.e. low-serotonin) theory of depression obsolete once and for all?
- pid_0 6y agoIsn't it already though? Besides for those self-diagnosed tumbrlinas complaining about "no serotonin". It's pretty well established that Dopamine, Norepinephrine, etc play a huge role in depression. Serotonin is a small part of it. And anyway, I would bet almost all cases of depression ultimately stem from ineffective behaviors and thoughts, not some fundamental chemical imbalance.
- toiletfuneral 6y agowow, super constructive comment. You seem very proud of yourself
- loceng 6y agoArguably it's life experiences and environmental stimuli that actually play a role in depression et al - it's just these neurotransmitters you speak of are the communicators. E.g. Self-protective mechanism from trauma (physical and/or emotional) to "close ones heart" or develop defensive behaviours - and then being locked into that state, indoctrinated into it - without the ability to disconnect from that pattern until say dramatically changing the chemical supply of transmitters - say either MDMA flooding the brain with serotonin, more than the brain naturally can at once, or say through ketamine or Ayahuasca or other psychedelics that give the opportunity for a perception change outside of the indoctrinated state(s) and behaviours. I imagine the vast majority of people who's circumstances aren't due to a chemical issue, more so the lack of adequate support for them and/or any element of Maslow's Hierarchy of Needs not being met during rapid and crucial childhood development.
- johncolanduoni 6y agoMood disorders found to be are significantly heritable in twin studies so I don’t think one can say the “vast majority” aren’t due to a chemical issue here. It’s also worth noting that BDNF is not a neurotransmitter, and so having a direct connection with thoughts and personality seems unlikely, though there is reason to believe it may be downstream of long term psychological stresses.
- loceng 6y agoFair enough, however I'd want to review those studies to see what similarities do exist - even if in different households/environments. Studies that aren't taking into account the relative general lack of health of people in many parts of the world needs to be addressed, accounted for, in research as well. I do understand how some makeups could allow a large amount of people to certainly to be prone to environmental stresses, have a more fragile-sensitive system - and if those factors are allowed to continue say for decades, there will be a hardening.
- omegaworks 6y agoWe have new insight now into how antidepressants interface with specific signaling molecules, making them more effectively permeate the neuron cell membrane. It's still about chemical balance. It's a highly complex system involving more than serotonin, though. He mentions serotonin reuptake inhibitors once, but it looks like this finding applies to other substances identified as anti-depressants that aren't necessarily serotonin targeting.
- vegannet 6y agoI’ve always understood the chemical imbalance description of depression (and other mental health conditions) to be a casual way of describing the conditions as being part of the person rather than a choice — and not a way to describe the internal mechanics of the conditions. I’ve found it effective when having conversations about mental health conditions: how would you describe depression without using that phrase, based on what this paper reveals?
- anaphor 6y agoI'm not saying there isn't a biochemical component to depression (or any other mood disorders). The specific theory that I'm talking about is "low serotonin causes depression" (as in the proximate cause, not the ultimate cause). When SSRIs were first discovered to be useful for treating depression, one of the theories about why they worked was that they boosted levels of serotonin, but we know now that's not true. It doesn't mean it can't be explained in other ways (like the one this article discusses). Also, if there is a behavioral component to depression as well, then it doesn't necessarily mean someone is to blame for their disorder. You don't control the environment you grow up in, which has an enormous impact even on traits that are highly heritable (the whole subject of heritability is very misunderstood anyway). So basically if I were going to describe depression's cause, I'd say it's a mixture of biochemical reactions, behavioural traits, and environmental stresses that cause it.
- sjg007 6y agoIn the article they discuss that known SSRIs weakly bind a different receptor which may be why they have an antidepressant effect. It would explain why more specific SSRIs that are thought to target serotonin receptors selectively do not work. That they see a bunch of them doing the same thing is pretty convincing. to quote: "Now to the BDNF hypothesis. I used the phrase “unknown mechanism” above, and that’s exactly what this work may have cleared up. The authors show that when the TrkB protein forms a dimer in the cell membrane, a binding site for small molecules is formed at the interface. A whole list of known antidepressants (fluoxetine, imipramine, venlafaxine, moclobemide, ketamine, esketamine, and R,R-hydroxynorketamine) bind to this site at about 1 micromolar levels (and can displace each other in binding assays(, while a set of control CNS compounds like chlorpromazine, diphenhydramine, and indeed S,S-hydroxynorketamine do not. It will not be lost on those who’ve done research in the field that the antidepressant compounds listed above have been thought to work through completely different mechanisms. "
- danielovichdk 6y agoI am not a neuro anything, but has that been the a big debate in the antidepressant discussion long? The low level of serotonin? Is that a fallacy or an i missing something?
- anaphor 6y agoIt's been a persistent myth perpetuated in the media/journalism/society/etc for a few decades, but there is a lot of scientific evidence showing that it doesn't really explain how depression works, and the fact that SSRIs boost serotonin doesn't explain why they work as a treatment. See https://sci-hub.st/https://www.sciencedirect.com/science/article/abs/pii/S0149763415000287 https://sci-hub.st/https://www.sciencedirect.com/science/art... for example.
- hammock 6y agoHow antidepressants work (this article) and what causes depression (your postulate) are two completely different things.
- sekh60 6y agoForgive my ignorance, but what alternative is there to a chemical imbalance of some sort? Structural differences? I have schizoaffective bipolar subtype, and wouldn't mind some links to more current literature, I'm obviously very behind.
- aantix 6y agoHave you ever tried Niacin/magnesium approach for treatment?
- anaphor 6y agoIt used to be the case that the theory for why people have depression was "people who are depressed don't have enough serotonin" (in very simple terms), and the reason why SSRIs work was supposed to be that they increase levels of serotonin, but scientists have found that boosting levels of serotonin alone does not help with depression. Here's a good journal article on the subject https://sci-hub.st/https://www.sciencedirect.com/science/article/abs/pii/S0149763415000287 https://sci-hub.st/https://www.sciencedirect.com/science/art...
- corin_ 6y agoIf that theory is definitely wrong, it hasn't yet worked its way out of common use. Examples: NHS current website "This type of medication [SSRIs] works by increasing the level of a chemical called serotonin in your brain." https://www.nhs.uk/conditions/generalised-anxiety-disorder/treatment/ https://www.nhs.uk/conditions/generalised-anxiety-disorder/t... Wikipedia "It is believed to work by blocking the re-uptake of the chemical serotonin by neurons in the brain." https://en.wikipedia.org/wiki/Paroxetine https://en.wikipedia.org/wiki/Paroxetine etc.
- Delk 6y agoI'm not sure that the reason why some (e.g. official) health information sources keep repeating that isn't just a combination of having an easy explanation and making a (benign) attempt to induce a placebo effect in unknowledgeable patients. If you either get massively technical about complex things that would make most laymen's heads spin, or shrugged your shoulders and said that we don't really know, you might miss on the potential psychological effects that you can get by projecting some kind of confidence.
- johncolanduoni 6y agoNot really, it’s just proposing a different chemical imbalance than the “monoamine hypothesis” (i.e. serotonin, etc.). That one has already been disfavored for the past few decades, due to a lot of findings that it has trouble explaining. In particular the discovery of effective antidepressants that don’t affect the monoamine receptors enough or in sufficiently similar ways.
- konjin 6y agoThat theory makes as much sense as the theory that "chemical imbalances" (i.e. low-alcohol) cause social anxiety. Alcohols are produced in your brain naturally and adding more changes behavior. Clinical trials show that more alcohol increases sociability compared to placebos (but with side effects). There are some concerns about giving alcohol to three year olds, but it is better that they become socialized at a young age than deal with the consequences for life. In short: science + tons of money = not science.
- vinger 6y agoAre you a bot?
- imwillofficial 6y agoI don’t know, tons of alcohol makes me very social ;)
- johnisgood 6y ago"The monoamine hypothesis, like the neurotrophic hypothesis, is at best incomplete. Many studies have not found an alteration in function or levels of monoamines in depressed patients. In addition, some candidate antidepressant agents under study do not act directly on the monoamine system. In addition to the monoamines, the excitatory neurotransmitter glutamate appears to be important in the pathophysiology of depression. A number of studies of depressed patients have found elevated glutamate content in the cerebrospinal fluid of depressed patients and decreased glutamine/glutamate ratios in their plasma. In addition, postmortem studies have revealed significant increases in the frontal and dorsolateral prefrontal cortex of depressed patients. Likewise, structural neuroimaging studies have consistently found volumetric changes in the brain areas of depressed patients in which glutamate neurons and their connections are most abundant, including the amygdala and hippocampus." "Given the effect of antidepressants on the glutamate system, there has been a growing interest in the development of pharmaceutical agents that might modulate the glutamate system. Ketamine is a potent, high-affinity, noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist that has long been used in anesthesia and is a common drug of abuse in some parts of the world." Novel antidepressants now are NMDA receptor antagonists, or take a look at tianeptine which works just as well, yet it only affects your opioid receptors. None of which have to do with the monoamine hypothesis.
- meowface 6y agoThis topic is often a red herring and source of conflation. I strongly recommend this series of articles from a psychiatrist about it: https://slatestarcodex.com/2015/04/05/chemical-imbalance/ https://slatestarcodex.com/2015/04/05/chemical-imbalance/, https://slatestarcodex.com/2015/04/18/polemical-imbalance/ https://slatestarcodex.com/2015/04/18/polemical-imbalance/
- anaphor 6y agoI linked to a paper published and written by several psychiatrists and psychologists that explains the history of the monoamine hypothesis, and why it's not a good theory. Why would they spend so much time debunking a theory nobody believes? Quoting directly from the article > Despite decades of research, the role serotonin plays in depressive phenotypes has not been conclusively determined. The original clue that monoamines (serotonin, norepinephrine, and dopamine) were involved in depression came from two serendipitous discoveries (Baumeister et al., 2003; Valenstein, 1998). First, during the investigations of iproniazid as a treatment for tuberculosis and imipramine as a treatment for schizophrenia, clinicians reported that these drugs could reduce depressive symptoms. An effort was then made to find a common pharmacological property that could explain their antidepressant effect. Eventually, researchers found that iproniazid inhibits the enzymes that break down the monoamines, while imipramine blocks the serotonin transporter (SERT) and the norepinephrine transporter (NET). Second, clinical observations suggested that reserpine, a drug known to deplete monoamines, increased depressive symptoms. These findings appeared to solve the puzzle. By preventing the breakdown of norepinephrine and serotonin, or preventing their clearance from the synapse, iproniazid and imipramine appeared to increase forebrain monoamine levels. > The monoamine-enhancing effect of antidepressant medications (ADMs), coupled with the depression-inducing effects of reserpine, suggested that depression was caused by reduced monoamine neurotransmission (Everett and Toman, 1959; Jacobsen, 1964; Schildkraut, 1965) https://sci-hub.st/https://www.sciencedirect.com/science/article/abs/pii/S0149763415000287 https://sci-hub.st/https://www.sciencedirect.com/science/art... Additionaly, this is something that lots of undergraduate psychology textbooks still mention as a potential explanation (one of mine did ~6 or 7 years ago, although at least they said that it was an implausible theory).
- ravi-delia 6y agoTo my knowledge the idea that depression is a result of low serotonin has not been accepted by the scientific community at any time; immediately after SSRIs were shown to have an effect lots of people assumed that serotonin was important, but reuptake inhibition wouldn't even treat low levels overall, let alone matching the super weird timing effects.
- justinboogaard 6y agoTLDR; conditions like depression may stem from a poor distribution of cholesterol in the neurotransmitter signaling process in the brain.
- hinkley 6y agoWhat I'm hearing you say is 'eat more bacon'. Sorry what was that? You're breaking up. I'm off to the store, ttyl.
- astrange 6y agoEating cholesterol doesn't affect your levels of internal cholesterol. (Do people who like bacon know they can just eat chashu?)
- ggm 6y agoYet, eating bacon and cha siu makes me happy...
- readflaggedcomm 6y agoSaturated fat does.
- loceng 6y agoI will read this in full later - though anyone care to reply with a TL;DR for everyone here?
- andrewflnr 6y agoIt's a short article. Just read it.
- loceng 6y agoI think there's more value in the comment you're replying to than your own comment - I imagine you took the time to downvote too? At least thank you for spending the effort of writing something.
- andrewflnr 6y agoI did not, because I thought enough others had done so already. Asking other people to do your thinking for you is noise, and belongs at the bottom of the thread. It's fine if you can't be bothered to read it right away: HN has a save feature just for that. But don't inflict your laziness on the commons, especially for an article that is so very short.
- Nbox9 6y agoI think this article was written for a more medically/biologically literate audience than the typical HR member. It assumes a level of jargon and background knowledge. I think it’s reasonable to ask for a summary targeted towards the HR audience.
- andrewflnr 6y agoThat would be more reasonable, but it's not what they asked for.
- loceng 6y ago
- omegaworks 6y agoSo cholesterol plays a huge role! The brain is the fattiest organ, so it makes a lot of sense. That we haven't found a correlation between statins and depression is certainly a quandary though. I wonder if our national obsession with anti-fat dietary advice has had an impact on depression's prevalence in our population. It would seem to make sense that if we depress people with low-fat frankenfoods they naturally react with lower physical activity levels. I wonder if omega-3 / omega-6 dietary balance changes the structure of the cell membranes to make them less permeable. Greater omega-3 cell membrane composition certainly seems to have a real impact on retina cells and the overall function of the retina[1]. 1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2174995/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2174995/
- mckirk 6y agoYou might be on to something. I think what the US has done to yogurt should be banned under the Geneva convention.
- potatoyogurt 6y agoWhat did the US do to yogurt?
- mckirk 6y agoBasically, you have to go to specialty food stores (the arabian ones are really awesome from my experience) to actually find yogurt that's deserving of the name. For some reason the yogurt sold in regular supermarkets in the US is 'low fat' and 'strange consistency'.
- bagacrap 6y agoI can buy full fat goat milk yogurt at 5 different grocery stores within 2 miles of my house here in the good ol' US of A.
- 6y ago
- heavyset_go 6y agoAntidepressants aren't just used for depression, they're also used to treat a spectrum of anxiety disorders like OCD and panic disorder, although the doses used to treat anxiety disorders are much higher than those used for depression. I don't think the BDNF-related hypothesis explains the efficacy of antidepressants in treating anxiety disorders, but I could be wrong.
- deleted 6y ago[deleted]
- doggodaddo78 6y agoAnd vice-versa. I'm taking vilazodone and lamotrigine (anti-epileptic), and they're just barely working.
- ineedasername 6y agoWithout going into too much detail on my own situation, in addition to other meds I'm also on Modafinil. This is mainly to combat fatigue side effects, but modafinil is also a very good (for me at least) anti-depressant. I'm depressed less often on it, and when depressed it keeps me much more functional. There's a decent body of research in its use for this purpose as a second-line anti-depressant, such as: https://pubmed.ncbi.nlm.nih.gov/16035049/ https://pubmed.ncbi.nlm.nih.gov/16035049/ Not all doctors are familiar with its use in this way. When I had to switch doctors after mine retired, I had to educate them in its use so that they would continue prescribing it. It is also not an automatic approval by insurance companies. However, if denied by your insurance, you can get it at a fairly reasonable price using GoodRX. If you're still struggling after what you're already one, and have gone through a few other options (and maybe even if you haven't) then I would highly recommend talking to your doctor about this. Something to keep in mind though is that this will, mostly in the first week, impact your sleeping patterns. Taking it first thing in the morning would be the best time, and perhaps ask your doctor about using an over-the-counter sleep aid such as diphenhydramine during initial usage.
- __blockcipher__ 6y ago
- sjg007 6y agoThis is fascinating. Cholesterol has long be associated with depression. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606915/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606915/
- momszack 6y agoThat associates statin use with depression, not cholesterol. That’s a huge difference. Those results (which are not an RCT) could easily be explained by those that are less depressed are more likely to seek any non-psychiatric outside medical treatment.
- m00x 6y agoFirst: cholesterols are a family of molecules, like alcohols, not just one thing. Second: statins inhibit cholesterols so while it is associated, it's good to mention that cholesterols are anti-depressive, which is something anyone with any university bio education will know.
- doggodaddo78 6y agoSo will this lead to a cure since I've tried 15 and only mirtazapine worked for a few years?
- royaltjames 6y agoGod I hope so. Just found a blend that's helping me feel human for the first time in these 35 years of living. I'm in the same boat with Mirtaz, altho I'm finding success with pairing it with Viibryd. A big help is genesight testing for upfront compatibility/sensitivity for a consultancy approach, rather than spray and pray.
- pyentropy 6y agoThere is very little evidence GeneSight results mean anything for efficacy. Tolerability and dose metabolism in the best case.
- yarg 6y agoPsilocybin genuinely works for me - when I can get it (difficult because it's class A and seasonal). The last time I had it was a bad night - I took about 7g. However, the suicidal thoughts that had been getting progressively more serious stopped overnight. I'll never touch another fucking SSRI. I'd rather not exist at all than become the unperson those things turn me into.
- winocm 6y agoI want to die too...
- yarg 6y agoMore than I want to die, I want not to be a part of the omnicidal stupidity that seems to define humanity. I really do want not to die, and I see a viable path forward with that as a result. An illegal and seasonal path. I last took a dose in July, and those malignant fucking thoughts are returning. And nurses keep telling me that psilocybin clearly has not worked (all the while advocating a pill a day, pill a day, pill a day). If you see a drowning man take a gasp of air, and the keep right on drowning that does not mean that the air did not work. The system is fucked - but try not to let it eat you.
- ineedasername 6y agoThis doesn't really seem to address how they work, in two fundamental ways: 1) We've had a good idea of the pharmacokinetics for a little while. All this research does is enhance that knowledge and take it one level deeper. Essentially, we've just gone one turtle lower in the pile of turtles standing on backs. 2) No theory of how antidepressants work will complete until we also understand why they so often do not work for many people.
- maybelsyrup 6y agoAgreed. This article doesn't address "how they work" - whether they "work" in the first place isn't at all clear, given how often they appear to either harm their users or simply do nothing - it's just elucidating "what they do" a little further. Two very different questions. No small task, of course, and the paper's pretty interesting, but it's not clear this has anything to do with what we call depression.
- dwaltrip 6y agoPrior to this article, I’ve never heard of the theory that SSRIs works by improving BDNF. Was this actually a widely accepted possibility?
- dj_mc_merlin 6y agoI have a feeling SSRIs work for a reason we would never expect. In fact, I have a feeling nearly all mental disorders work according to rules we do not even imagine now. It seems to me medical psychology has some great analogies to 1320s science, and the only answers that will come will be after my death.
- spurgu 6y agoYeah it's pretty much witchcraft at this point still.
- loveistheanswer 6y agoFunny you should put it that way, because Psychiatry as a field historically evolved directly out of the witch hunts of the Inquisition.[1] As the Church fell out of favor during the Enlightenment the very first Psychiatrists literally asserted that all the people who were labeled witches by the Inquisition were actually just "mentally ill", even though their understanding of the mind and their methods used to "treat" it (torture, mostly) had hardly changed at all. [1]https://www.amazon.com/Manufacture-Madness-Comparative-Inquisition-Movement/dp/0815604610 https://www.amazon.com/Manufacture-Madness-Comparative-Inqui...
- maxerickson 6y agoNuplazid seems to have a pretty clear theory of what it is doing. It's an anti-psychotic that is currently targeted at Parkinson's disease related psychosis; hallucinations and delusions are fairly common in people with Parkinson's disease.
- carapace 6y agoThere is an effective, rigorous school of psychology called Neurolinguistic Programming but it's got a bad rep in scientific/academic circles (the Wikipedia entry calls it out as pseudoscience.) FWIW I was cured of a chronic, crushing depression in a single session that lasted no more than ten minutes or so. (I don't know exactly how long it was because I was in a deep trance. Subjectively it was only a few moments.)
- mcherm 6y agoDepression is an incredibly complex system of effects. The best model for its workings that I have read was this: https://astralcodexten.substack.com/p/the-precision-of-sensory-evidence It's a long read, but my short version would be this: "Depression is a mode where the brain underweighs evidence from new experiences in favor of pre-existing negative prior assumptions."
- thinkingkong 6y agoI mean thats an excellent description of the experience of depression. But is that a mode induced by chemistry, biology, learned behaviour, etc?
- whalesalad 6y agoYes
- mahathu 6y agoSome people suffer from a state of what we call depression due to their life circumstances, not because their brain is malfunctioning.
- prionassembly 6y agoSome people have existential anxiety and call it depression. Hell, some people have narrow Generalized Anxiety Disorder and still call it depression.
- fshbbdssbbgdd 6y agoI think I have both, and it’s often hard to tell them apart.
- treeman79 6y agoSituationAl depression. A lot of people with an unknown medical issue are dismissed as depressed.
- 6y ago
- hexxiiiz 6y agoAlthough this seems compelling, there is also the role of 5HT2A receptors in weighting priors as Carhart-Harris and Friston discuss in https://www.researchgate.net/publication/333911957_REBUS_and_the_Anarchic_Brain_Toward_a_Unified_Model_of_the_Brain_Action_of_Psychedelics https://www.researchgate.net/publication/333911957_REBUS_and... While this primarily has to do with psychedelics, they address depression as well in the above.
- tsoukase 6y agoTrying to find how ADs work is like injecting a small piece of machine code to a running computer system and trying to find out what changes are produced. Its clinical effects are like the effects on the GUI. There are many abstraction levels in the process and mostly we have to make large jumps over them. Discl: I am a doctor specialized, among others, in adult psychiatry
- Xenograph 6y agoWhile I appreciate the intention, I think it's a bad analogy. Can you think of a small piece of machine code that you could inject into arbitrary computers that would produce useful effects in some significant proportion of the computer population? (Don't think so...) Computers and biological systems are so wildly different. Although perhaps you'd find better analogies comparing brains to machine learning systems. Eg. "Trying to find out how ADs work is like applying some simple numerical transformation on some particular part of a deep neural network and trying to find out what changes are produced". Oddly enough.. I think ML researchers often do find little "tricks" that improve the performance of neural nets without being able to fully grasp how or why. It's somewhat similar to how we use and understand ADs.
- tsoukase 6y agoSimilarly, if you prescribe an AD to an 'arbitrary' person, most probably you do more harm than good, but I am sure you can find an appropriate code to try to 'cure' an 'ill' system. The difference between biomedical and electronic systems vanishes when you approach them from the same abstraction levels, where the complexity of the brain forces us to stand: either extremely high (clinical/GUI) or extremely low (drugs/'therapeutic' machine code). My understanding of brain is on par with that most of HW audience has about computers and vice-versa. So, as you correctly thought, the intent was to brigde this gap. Another analogy I like is, treating brain diseases with drugs is like repairing a car by spraying chemicals.
- fuzzfactor 6y agoTalk about arbitrary, on the pharmaceutical front some very revealing and somewhat forgotten info seems to be in the comments: >anon the II says: 19 February, 2021 at 1:03 pm >About 27 years ago, a little company that I worked for was going through another transmutation in order to survive. We became a high-throughput screening/combinatorial chemistry company. The CEO told a story about how, by the time anyone figured out that we didn’t know what we were doing, we might actually figure out what we were doing. I volunteered to be the technical lead on the combi-chem side. Anyhow, we managed to get bought by Lilly in 1994 and shortly afterwards, we got a visit from Bryan Malloy (https://en.wikipedia.org/wiki/Bryan_Molloy https://en.wikipedia.org/wiki/Bryan_Molloy), the inventor of Prozac, who came down to see what his company had purchased. I met with Bryan and we had a lovely chat. But, he let me know that he thought that what we were doing was no better than “pissing in the wind”. >I guess this means that he was doing much the same.
- antman 6y agoFor the cognitive aspect of depression a nice comprehensive and dense video I found is [0], key factors in slide at 24:10 and the reasons for this approach are at a slide at 23:00 including why a medication only approach is intractable in the long term. [0]: https://youtu.be/TVgQ_tgWMyU https://youtu.be/TVgQ_tgWMyU
- jokoon 6y agoSometimes I try to think in more philosophically terms about the word "disease". It's often said depression is natural, and it only becomes a problem because of sedentary lifestyle. Diseases are bad, but when you dig, nature doesn't work in term of good or bad. I think it's difficult to really know at what point depression becomes problematic, since doctors have a hard time making a good diagnostic. Brains are complicated.
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