[HN Gopher] The serotonin theory of depression: a systematic rev...
___________________________________________________________________
The serotonin theory of depression: a systematic review of the
evidence (2022)
Author : flaxxen
Score : 143 points
Date : 2025-02-27 18:27 UTC (2 days ago)
(HTM) web link (www.nature.com)
(TXT) w3m dump (www.nature.com)
| Aurornis wrote:
| Important to note that the serotonin theory of depression doesn't
| have to be strictly true for SSRIs to be effective. People who
| having passing familiarity with neuroscience often assume that
| psychiatric medications work by correcting deficiencies, but this
| isn't true. It's also not accurate to say that SSRIs "give you
| more serotonin" or any of the other variations on that theme.
|
| Neurotransmitters aren't simple levels in the brain that go up
| and down, despite how much podcasters and fitness influencers
| talk about them like that. Neurotransmitter dynamics are complex
| and the long-term adaptations after taking medications like an
| SSRI can't be simply described in terms of "levels" going up and
| down. There are changes in frequency, duration, and movement of
| Serotonin across synapses that are much more complex. There are
| also adaptations to the receptors, including auto-receptors which
| modulate release of neurotransmitters (side note: some newer
| antidepressants also directly target those autoreceptors with
| possibly slight improvements in side effect profile).
|
| So keep that in mind when reading anything about the serotonin
| theory of depression. This is often brought up as a strawman
| argument to attack SSRIs, but we've known for decades that the
| serotonin theory of depression never fully explained the
| situation. We've also known that some conditions like anxiety
| disorders are associated with increased serotonin activity in
| parts of the brain, which SSRIs can normalize.
| kittikitti wrote:
| You should keep in mind that it's a serotonin hypothesis of
| depression, as noted in the article. Calling it a theory is
| unsupported by the science.
| Aurornis wrote:
| The title of the paper is "The serotonin theory of
| depression" and it uses the phrase throughout the paper.
| kittikitti wrote:
| Can you tell me where it referenced it as a theory outside
| of the headline? It also concluded that there is a lack of
| evidence for the association so why would the authors call
| it a theory?
| Aurornis wrote:
| Use your browser's search function. At least 4 instances
| throughout the article
|
| > It also concluded that there is a lack of evidence for
| the association so why would the authors call it a
| theory?
|
| Read the article. It explains this in the introduction.
| Click some of the citations.
| kittikitti wrote:
| "The main areas of serotonin research provide no
| consistent evidence of there being an association between
| serotonin and depression, and no support for the
| hypothesis that depression is caused by lowered serotonin
| activity or concentrations."
|
| I wouldn't call it a theory especially if you're being
| semantic about serotonin reuptuke. Perhaps it's you who
| is using words you don't understand?
| wasabi991011 wrote:
| The comment you are responding to makes it pretty clear that
| they know there is not enough evidence for it.
|
| I'm not sure it's worth commenting on the semantic difference
| between theory and hypothesis, especially since these words
| often overlap in meaning in casual conversation.
| tsimionescu wrote:
| A (scientific) theory is simply a collection of many
| interlocked observations and logical deductions. A theory can
| be well established (such as Newton's theory of gravity, or
| the germ theory of disease), or it can still be at a
| hypothesis level (such as string theory) or it can be
| debunked (such as the humor imbalance theory of disease, or
| the geocentric theory of astronomy).
| aeturnum wrote:
| Exactly this - SSRI's efficacy was established based on
| improvements in reports from depressed people and we formed a
| theory about the mechanism based on the interactions we
| understood. As we try to prove that theory out it turns out our
| theories don't hold - but people who are depressed still
| improve when on SSRIs! So we're still working on the mechanism
| (which we always knew was incomplete at best) but this work
| isn't about the underlying efficacy of the drugs on the
| condition. It's about the nerdy explanation for why SSRIs work.
| thomassmith65 wrote:
| but people who are depressed still improve when on SSRIs
|
| Does that mean 'over 50%' of them improve, or is it, as is
| more common with pharmaceuticals, closer to a rounding error?
|
| There was a deluge of media a couple decades ago about Prozac
| and its dramatic effects.
|
| A few years later, I read some report that the studies
| testing its efficacy had ambiguous conclusions.
| Aurornis wrote:
| > Does that mean 'over 50%' of them improve, or is it, as
| is more common with pharmaceuticals, closer to a rounding
| error?
|
| This question is more complicated than it appears.
|
| One of the biggest challenges with depression studies is
| that the placebo group always improves dramatically, too.
| Using your terms, "over 50%" of the placebo group would
| likely show improvements in their depression inventories.
|
| This makes it very complicated to interpret the studies,
| because now you have to look for how much more the active
| treatment group improves relative to the placebo group.
|
| This is a huge detail that gets abused a lot by anti-pharma
| people, who write headlines about how SSRIs are "barely
| better than placebo" and then ignore the actual statistics.
| Another common tactic is to try to reframe the thresholds
| in different terms like "effect size" and then pool studies
| together to try to show that the "effect size" is below
| some arbitrary threshold.
|
| Another challenge is that placebo response has been getting
| stronger over the years and nobody really knows why. Some
| antidepressant studies have even been halted because,
| ironically, the placebo group improved so much that there
| numerically wasn't much room left for the active group to
| be statistically better given the sample size. This is less
| of a problem with very large scale studies where smaller
| margins can be shown to be more statistically significant,
| but those are expensive and rare.
|
| There isn't really a question about whether or not they are
| effective for many patients in the world of empirical
| treatment. However, if you go digging through the internet
| you can find plenty of commentary trying to convince you
| they don't work. Sadly, I've had some close friends and
| family members delay SSRI treatment for years because they
| read too many of these studies, but when they finally gave
| in and did a trial it turned their life around. The drugs
| aren't perfect and don't work for every situation, but they
| do work for a lot of people.
| nostrebored wrote:
| Can you explain why low percentage improvement over
| placebo is not important?
| Aurornis wrote:
| Imagine you have a depression inventory (test) with 21
| questions, rated from 0-3. The highest score is 3 * 21 =
| 63 indicating the most severe depression. The lowest
| score is 0, indicating no depressive symptoms at all.
|
| In practice, the average person will fall more in the
| range of maybe 5-15 due to vague symptoms like "I don't
| sleep as well as I used to" triggering some of the
| points. The average depressed person who seeks treatment
| might fall in the range of 25-35.
|
| Now imagine the placebo group goes in with an average
| score of 35 and improves to a score of 25 by the end of
| the test. The SSRI group improves to an average of 20 by
| the end of the test. Is this significant? Well, it
| depends on how many patients you have in the sample size.
|
| That's the problem. There's only so much room in these
| scales for improvement, so when both groups improve a lot
| you need to have a larger sample size to get statistical
| significance. Getting a lot of patients in a study
| (hundreds) is very expensive, so it's only a small number
| of studies that can pull this off.
| nostrebored wrote:
| Right, but study power is really the responsibility of a
| pharma company. It's not like this is some new and novel
| medication, it's been used for decades and has been
| questionable for _literally the entirety of the time_.
| ants_everywhere wrote:
| The problem with being barely measurably better than a
| placebo is that each study is a coin flip whether it
| supports your drug or not. And you can just file drawer
| any study that didn't go your way (as happens with the
| majority of null results).
|
| So the published results are over-sampling studies where
| the statistics happened to work and under-sampling
| studies where they didn't.
| bawolff wrote:
| > This is a huge detail that gets abused a lot by anti-
| pharma people, who write headlines about how SSRIs are
| "barely better than placebo" and then ignore the actual
| statistics.
|
| Is this really abusing anything? It seems like the
| correct conclusion to draw from this is we should be
| giving depressed people placebos instead of SSRIs
| tsimionescu wrote:
| A big problem with the framing is that, if you look at
| the actual studies, what typically happens is that some
| patients improve significantly on the SSRI being studied,
| while most others don't get any real effect, not above
| placebo at least.
|
| What this should tell you is that SSRIs are almost always
| worth trying, because you might be one of the lucky ones
| for whom they work great - even if chances are they
| won't. Psychiatric treatment always works on this basis
| anyway - try one drug for a few weeks, see how well it
| does, then decide to either adjust dose, or try something
| else. Most patients eventually find something that works
| for them, though a the minority that don't is also large,
| unfortunately.
| amluto wrote:
| > Some antidepressant studies have even been halted
| because, ironically, the placebo group improved so much
| that there numerically wasn't much room left for the
| active group to be statistically better given the sample
| size.
|
| > but when they finally gave in and did a trial it turned
| their life around
|
| One might wonder: could this be, in potentially large
| part, the placebo effect? I suppose that a good answer to
| that question would be a very big deal.
| arcticbull wrote:
| SSRIs aren't shown to be much better than placebo and are
| shown to be about as effective as therapy -- which is
| actually durable.
|
| There's also rates of sexual side effects in excess of 70%
| [1] and they cause weight gain which is separately associated
| with depression.
|
| In fact industry data shows a smaller gap between SSRIs and
| placebo than FDA data. See Figure 1. [2]
|
| The problem with SSRIs is that serotonin receptors are all
| over the body including in the gonads and they play a large
| role in appetite regulation.
|
| They do something but it's not nearly what people assume.
|
| [1] https://pmc.ncbi.nlm.nih.gov/articles/PMC6007725/
|
| [2] https://pmc.ncbi.nlm.nih.gov/articles/PMC4592645/
| Aurornis wrote:
| > SSRIs aren't shown to be much better than placebo
|
| "Not much better than placebo" is burying the lede.
|
| The real problem is that placebo performs very well in
| depression studies. It's a well studied phenomenon.
|
| Effective antidepressants are marginally better than
| placebo in the studies because the placebo group improves
| so much, not because the antidepressants don't do anything.
|
| > and are shown to be about as effective as therapy --
| which is actually durable.
|
| False dichotomy. The recommendation is for people on SSRIs
| to also do therapy.
|
| You don't have to choose one or the other.
|
| > There's also rates of sexual side effects in excess of
| 70% [1]
|
| If you read further in your [1] you'll see that the rate of
| side effects is not "in excess of 70%" but lower, and it
| depends on both the medication and the dose. Switching
| medications and changing doses is often sufficient to
| ameliorate some or all of these effects.
|
| That paper also mentions newer alternatives such as
| Vilazodone (SSRI plus 5-HT1A action) which are shown to
| have lower incidence of these side effects.
|
| > and they cause weight gain which is separately associated
| with depression.
|
| SSRIs aren't really associated with weight gain once you
| exclude the older ones like Paroxetine which have
| anticholinergic effects. A lot of studies find
| statistically insignificant weight loss or slight gain.
|
| Weight gain is really a negligible decision factor in
| modern SSRI treatment:
| https://www.ccjm.org/content/ccjom/70/7/314.full.pdf
|
| There's a lot of misinformed fear mongering in your
| comment.
| treis wrote:
| >Effective antidepressants are marginally better than
| placebo in the studies because the placebo group improves
| so much, not because the antidepressants don't do
| anything.
|
| Not outperforming a placebo means they don't actually do
| anything.
| Blackthorn wrote:
| Marginally better means they do, in fact, outperform.
| arcticbull wrote:
| By like, a couple of percent, yes. So the question is, do
| the side-effects outweigh the very marginal difference.
| That's a decision you have to make for yourself.
| mike_ivanov wrote:
| Now do the same outside of the clinical conditions, in
| the patients' natural environment -- and compare the
| results.
| specialist wrote:
| There's 3 choices. Both placebos and SSRI perform better
| than doing _nothing_.
| Johanx64 wrote:
| > Not outperforming a placebo means they don't actually
| do anything.
|
| SSRIs are potent pharmaceutical drugs that have multiple,
| very strong effects.
|
| For example, Setraline (SSRI) is one of the most
| effective drugs to treat premature ejaculation. It used
| to be prescribed for exactly this purpose (and maybe
| still is). If anything, this is one of the most
| pronounced and easily measurable effects of SSRIs.
|
| If I took 25mg of setraline per day (extremely small
| dose) for a week, it would become impossible to
| ejaculate.
|
| It also has a whole multitude of other effects that are
| more dependent on individual (age, gender, bodyweight,
| etc), some other effects for males are -> crushing
| testosterone levels, weakness.
|
| For me personally, it turns me extremely, extremely
| emotional, makes me able to sleep all the time, and
| mentally turns you into a zombie where your lifes dreams
| and aspirations just disappear.
|
| Does it help with depression? I would say no. That
| however doesn't mean it doesn't do anyting, because they
| do all sorts of things. It is a very potent and poorly
| understood pharmaceutical.
| energy123 wrote:
| Placebo could be reversion to the mean. If you're cherry
| picking people who are elevated in X it should not be
| surprising to see X mean revert during the study period.
|
| For example, cherry pick people who have the flu. Some
| people in the placebo group curing their flu in the study
| period shouldn't be surprising. That happens by default.
| bmacho wrote:
| > Placebo could be reversion to the mean.
|
| If they are comparing the effect of placebo with no
| treatment at all, then no, the measured effect of placebo
| actually can't be that. The reversion to the mean effect
| would appear for the no treatment at all people too.
| tsimionescu wrote:
| There are no studies like that, though. It's very very
| hard to study how a group of people suffering from a
| disease evolves without treatment, both from an ethical
| perspective (you can't ethically force people not to seek
| treatment) and from a practical perspective (it's hard to
| find a significant cohort of people who recognize they
| have a disease like depression, do not want to seek
| treatment for it, but are willing to participate in a
| clinical study). This is especially true for depression,
| which manifests most of all as a lack of motivation to do
| anything in those who suffer from it (often with anxiety
| at the thought of doing new things).
|
| So no one really knows, in a scientific, quantifiable
| sense, how people who suffer from depression evolve
| without treatment.
| alduin32 wrote:
| > False dichotomy. The recommendation is for people on
| SSRIs to also do therapy.
|
| One problem with that is that SSRIs are much more
| accessible than therapy. In my country, they are fully
| covered by social security and procuring them is
| relatively easy, while therapy is too expensive for lots
| of people.
|
| > If you read further in your [1] you'll see that the
| rate of side effects is not "in excess of 70%" but lower,
| and it depends on both the medication and the dose.
| Switching medications and changing doses is often
| sufficient to ameliorate some or all of these effects.
|
| In my case, and according to studies I'm not the only
| one, the side effects can be persistent. Neither the
| doctors nor the medication's notice warned me of this. If
| I knew that when I was young, I would have made different
| choices.
|
| SSRIs did help me, but it cost me a lot, and I still cry
| about it. Of course, there is no way to know if this is a
| better outcome for me than what would have happened if I
| managed to refuse to take them.
| bluescrn wrote:
| > There's also rates of sexual side effects in excess of
| 70% [1] and they cause weight gain which is separately
| associated with depression.
|
| As an obese depression-sufferer currently taking Mounjaro,
| these new weight loss drugs seem way more effective at
| treating the depression than SSRIs.
|
| Actually losing a bit of weight with previously-
| unimaginable ease actually offers some genuine hope. It's
| not quite a miracle drug, the side-effects can be
| unpleasant, but when you're severely overweight they seem a
| small price to pay.
| IX-103 wrote:
| Yeah, the new "weight-loss" drugs seem to have
| significant psycho-active effects on the dopamine reward
| pathway. That seems like it may provide a more direct
| treatment than SSRIs.
| arcticbull wrote:
| Yeah calling them weight-loss drugs seems to really be
| under-selling them. I suspect the anti-depressant action
| has more to do with BDNF-TrkB and IL-6 signaling though!
| arcticbull wrote:
| Yep they do, in part because of the depression-obesity
| axis but also likely via an independent mechanism. They
| do a couple of interesting things. For one, they seem to
| have a systemic anti-inflammatory effect. They lower the
| levels of TNF-alpha and interleukins like IL-6. High
| levels of TNF-alpha and IL-6 are implicated in
| depression.
|
| > Various meta-analyses have consistently reported
| increased IL-6 and TNF-a concentrations in depressed
| patients compared to healthy controls. IL-6 and TNF-a are
| associated with specific symptoms and behaviors that co-
| occur with depression. [1]
|
| They also increase the levels of brain-derived
| neurotrophic factor (BDNF) and BDNF-TrkB signalling is
| also implicated in depression, especially major
| depression. [2]
|
| Second, GLP-1 RAs yield similar changes in BDNF, TNF-
| alpha and interleukin levels you see in atypical
| antidepressants and anxiolytics like the old Soviet-era
| Semax [3] and Selank [4]. The former is a peptide analog
| of ACTH and the latter a peptide analog of tuftsin.
| Consequently it makes perfect sense to me that GLP-1 RAs
| would also have atypical antidepressant activity via the
| same pathway.
|
| There's a lot more to GLP-1 RAs and depression than just
| making you feel better about yourself as a result of your
| weight loss, and I suspect we're going to hear a lot more
| about this in the coming years.
|
| They _also_ get you to the point where you feel good
| enough to exercise, which increases the levels of
| serotonin, dopamine and noradrenaline, and is also as
| effective as antidepressants. Unfortunately, depressed
| people can 't bring themselves to exercise. Breaking that
| cycle so you can and do can only help more.
|
| I've done a lot of digging on all this stuff over the
| last few years, it's really fascinating.
|
| tl;dr: There's definitely something to your lived
| experience. Congratulations on getting started on your
| journey.
|
| [1] https://www.nature.com/articles/s41598-025-85514-0
|
| [2] https://pmc.ncbi.nlm.nih.gov/articles/PMC8783167/
|
| [3] https://www.cambridge.org/core/journals/cns-
| spectrums/articl...
|
| [4] https://pmc.ncbi.nlm.nih.gov/articles/PMC5322660/
| Blackthorn wrote:
| > SSRIs aren't shown to be much better than placebo
|
| Or in other words: it's better than placebo.
| cess11 wrote:
| How did you determine that the side and negative social
| effects aren't large enough to outweigh that difference?
| Mistletoe wrote:
| When you use an active placebo like atropine, something
| that makes you feel "different" like SSRIs do, it is even
| worse.
|
| https://pubmed.ncbi.nlm.nih.gov/7037102/
|
| https://sci-
| hub.se/https://www.thelancet.com/journals/lanpsy...
|
| >Many years ago, adequately blinded trials of tricyclic
| antidepressants were done, in which the placebo contained
| atropine, which causes dryness in the mouth like the
| active drugs do. These trials reported very small,
| clinically insignificant effects of tricyclic
| antidepressants compared with placebo (standardised mean
| difference 0*17, 95% CI 0*00-0*34).
| usednet wrote:
| https://www.astralcodexten.com/p/all-medications-are-
| insigni...
| NickM wrote:
| Exactly this.
|
| Many double blind studies are completely broken due to
| side effects triggering a stronger placebo response, and
| this is an especially huge problem for drugs like SSRIs
| where a placebo gets you about 80% of the benefit of the
| actual drug.
|
| Similar to the study you linked, there was a more recent
| study where they found that for the SSRI escitalopram
| (aka Lexapro), the benefits disappear when you lie and
| tell people that they're receiving an active placebo that
| mimics the side effects of an SSRI. That is, if people
| don't actually think they're taking an SSRI, they don't
| get any benefit.
|
| https://app.dimensions.ai/details/publication/pub.1142338
| 190
| crdrost wrote:
| > Finally, Jauhar et al. argue that serotonin must be
| involved in depression because drugs which target the
| serotonin system are effective and other authors also
| argue that antidepressants 'work'. However, whether
| antidepressants produce a genuine and useful
| pharmacological effect that is independent of the placebo
| effect, has not been established. Antidepressants show
| marginal differences from placebo, which do not fulfil
| criteria for clinical relevance, and may represent
| amplified placebo effects due to unblinding [31,32,33].
| It is hard to reconcile even the most generous appraisal
| of their efficacy with the vast numbers of people now
| taking them. Contrary to Bartova et al's claims, the idea
| that antidepressants reduce suicide has not been
| established, and evidence from randomised trials suggests
| they increase the risk of suicidality in some age groups
| [34, 35].
|
| -- Monicreff et al. (2023),
| https://www.nature.com/articles/s41380-023-02094-z
| alpaca128 wrote:
| > whether antidepressants produce a genuine and useful
| pharmacological effect that is independent of the placebo
| effect, has not been established
|
| As someone who has experience with antidepressants that
| goes beyond looking at numbers I can assure you that
| effect has been established very clearly. And it has
| nothing to do with placebo, only the second medication
| was the one that worked - it did more in three days than
| the first one after months on the highest dose.
|
| These studies sound to me like the attempts to find out
| whether life exists on a planet by analyzing some light
| spectrum through a telescope. I am sure they are useful
| but they seem a bit blind to what's actually going on in
| real life.
| NickM wrote:
| Keep in mind that studies find a strong effect for
| placebos: the numbers are not saying "these pills do
| nothing" they're saying "these pills seem to do a lot,
| but placebos do almost as much".
|
| Obviously the effect feels extremely real to you, but we
| wouldn't see a strong placebo effect in the numbers if
| people on placebos didn't _genuinely feel much better_.
|
| I get that it feels like the second drug worked much
| better, but expectancy effects and internal narratives
| are extremely strong, and they're impossible to untangle
| at the level of an individual.
| wasabi991011 wrote:
| Maybe I just don't understand placebo particularly well,
| but why would it work on the second drug and not the
| first?
|
| Separately, I think part of what is missing from this
| discussion is that we currently have no mechanism for
| prescribing placebos to a large portion of the
| population.
| NickM wrote:
| Placebo is an expectancy effect. I don't know all the
| details of OP's story, but there are all kinds of
| plausible reasons I can imagine that someone might have
| different expectations for one drug over another.
|
| It might not even have anything to do with the drug
| itself: mental health issues tend to wax and wane on
| their own over time, so if someone happens to feel better
| right after starting a new medication, it's easy to think
| "oh hey this one must be working" and then that can
| trigger the placebo effect and turn into a positive
| feedback cycle.
| im3w1l wrote:
| For depression specifically, I could see placebo having
| another important effect. Agency. Taking action to
| resolve your problems feels good. Compare to rain dances,
| which while ineffective in bring about rain, surely helps
| reduce anxiety of the performer.
| Johanx64 wrote:
| The whole conversation is a version of "does alcohol help
| with depression better than a placebo?"
|
| Because just like alcohol - so do SSRIs have a very
| clear, pronounced psychoactive pharmaceutical effects.
| It's just that both effects have little to do with
| "depression". For example, setraline is one of the most
| effective drugs for PE(Premature Ejaculation), with
| easily measurable effect (it can be timed!).
|
| Do depressed people feel better when they are drunk and
| inebriated? Maybe, probably some do? There certainly are
| quite a lot of people that self medicate depression with
| alcohol!
|
| Do depressed people feel better when they are zombified
| out of their brain with SSRIs? Probably some do?
|
| From a certain point of view, prescribing SSRIs for
| depression isn't all that different from prescribing
| alcohol for depression. Both are hepatotoxic - pretty bad
| for your liver.
|
| And is just a symptom of stone-age we live in when it
| comes to medicine and understanding of the human body.
| bawolff wrote:
| > As someone who has experience with antidepressants that
| goes beyond looking at numbers I can assure you that
| effect has been established very clearly. And it has
| nothing to do with placebo, only the second medication
| was the one that worked - it did more in three days than
| the first one after months on the highest dose.
|
| I think this would still be consistent with it being a
| placebo. (Not saying it neccesarily is, just saying we
| would still expect to hear these types ancedotes even if
| it was a placebo)
| crdrost wrote:
| So that was a quote from a piece from the same author as
| the original article.
|
| I'm trained in physics, not medicine, so I am somewhat
| reluctant to give my own take. I have not been on SSRIs
| myself but I have been the responsible one for making
| sure that folks take them. But I would note these points
| about what I see in the general discussion:
|
| * Nobody is saying the SSRIs aren't psychoactive
| compounds that could maybe be helpful for at least short-
| term intervention. Everyone agrees on at least those two
| things. So, nobody is telling you that you didn't feel
| something helpful with that second one.
|
| * The psychiatric practice is indeed to "shop around" not
| just different drugs, but different generics of the same
| drug. To my mind this basically proves the point: if you
| _had_ had a serotonin problem, the first SSRI would have
| fixed it and the only question would be "can you tolerate
| the side effects?". So actually what 's fixing the
| problem is a side effect of the SSRI, it is not the main
| effect of boosting serotonin, but it's the other ways in
| which these particular drugs happen to be psychoactive.
|
| * Your first person anecdotal experience obviously is not
| a disproof of a placebo effect and it cannot be--this is
| I think you applying a popular misconception that placebo
| effects "don't feel real" or "don't last" or "aren't real
| medicine" or whatever, but they do, and they can, and
| they are. In these tests there is never a control that
| didn't get either the medicine or the placebo, which I
| actually find kinda frustrating--so "placebo" also means
| "control group." It's just a measure of all the things
| that you didn't have control over. But it's called that
| because they give the control group a placebo. But like I
| don't have control over air quality, air quality can
| affect sleep quality, sleep quality can affect
| depression, if I start my experiment during a week of bad
| air quality and it gets better for the rest of the
| experiment, that generates both a "placebo" signal and a
| "test" signal, even though that's not the placebo effect.
| If you're peeking in as a physicist you've got to
| remember that the body heals the vast majority of our
| medical problems on its own, and that psychiatric
| problems are even moreso because "I made a new best
| friend at the XYZ study, now we go for walks every day
| together and complain about all the things that are
| making us more depressed _this_ week" can fix a
| psychiatric problem much more easily than, say, putting
| cancer in remission. So like the body heals itself, the
| brain heals itself, the brain also has influence over
| physical context ("I am going to eat some broccoli and go
| on a walk today"), the brain also has influence over
| psychosocial context ("I'm gonna go no-contact with my
| abusive parent," vs "I will get stuck curled in a ball in
| bed saying 'I'm useless, I'm useless' until my physics-
| major housemate has to remind me to get up and drink a
| sip of water and swallow my medicine.") There 's just so
| many ways the contexts are plastic, and they are all
| valid medicine in that context, going no-contact with an
| abusive parent can absolutely be therapeutic. So, placebo
| means control, it doesn't mean that the healing wasn't
| real, it just means that the healing was out of the
| control of the experiment, which was only looking at this
| particular drug.
|
| * Finally, because these tests are done one drug at a
| time, this fact that they don't beat the placebo group
| with the test group, comes out even more nuanced.
| Remember that you are not being healed by the main effect
| of an SSRI but one of its side-effects. The question is,
| is _that_ repeatable for others with depression or did it
| only work for _your_ depression because it happened to
| take the edge off of this or that subsystem in _your_
| brain's feedback loops, but that subsystem isn 't
| critical to _someone else 's_ depression? Hypothesis: the
| failure of SSRIs to beat placebos in these tests, means
| that biologically there are 20+ different "depressions"
| and when you are "depressed" we don't know which one you
| have (or maybe you have even more than one!), and each of
| these drugs is only able to make an impact on say five of
| those different depressions, and whether it is worth the
| side effects depends on even more concerns. Meanwhile
| everyone in the control group gets to cure 4 of the
| depressions at random, say. Does your second medicine
| beat the placebo? Well, not for everybody. Not even for
| the vast majority. But for people in your particular
| circumstance it does. But we don't have the ability to
| isolate that circumstance.
|
| In conclusion, if you are looking at medicine as a
| physicist, everything is f*C/#ed and it's so much nicer
| to play with my quantum dots and lasers and liquid
| nitrogen.
| jbreckmckye wrote:
| But are they better than e.g. tricyclics, MAOIs? Placebo
| comparisons aren't very informative for patients when
| there are other existing drugs.
| aeturnum wrote:
| > _The problem with SSRIs [...]_
|
| Yah, serotonin is involved in a lot! I don't think that's a
| problem? You aren't saying it directly, but I feel like you
| are pointing to SSRI side effects as if they invalidate
| that SSRIs help depression. That's not true! People can
| choose if they want therapy or SSRIs or both. If your
| doctor has been telling you serotonin dis-regulation
| directly causes depression that's probably wrong - but if
| they tell you that SSRIs help many depressed people that's
| right.
| arcticbull wrote:
| I'm pointing at it as a problem because that's what
| causes the e.g. sexual side effects. It's why you don't
| get them from, e.g. bupropion (an NDRI and nicotinic
| receptor antagonist) that act on the noradrenergic,
| dopaminergic and nicotinic systems - and not on
| seratonergic.
|
| Regarding helping people with depression, the numbers
| don't really support a strong effect especially against
| an active placebo that makes you feel different like
| atropine.
|
| [edit] Don't misunderstand, I'm not saying that there's
| not a role for pharmaceuticals. Just that the data for
| SSRIs specifically is not nearly as compelling as the
| quantity of prescriptions for it would have you believe,
| and they probably shouldn't be front-line treatment.
| aeturnum wrote:
| Oh! Well sure SSRIs are over-prescribed and shouldn't be
| a "front line" treatment. I agree with that. That, to me,
| is a very different question.
|
| What we call "depression" seems to be a complex bundle of
| brain mess. We group by symptom but unfortunately need to
| treat by cause and they are not 1:1. So SSRIs are a tool
| "we" have on a population level - but each individual
| depressed person is their own situation.
|
| Remember that "better than a placebo" is a population-
| level measure. Individual people will find a SSRI helpful
| or hindering as they go. I think you are mixing...policy
| ("we shouldn't assume this works for everyone") with drug
| efficacy ("SSRIs don't help more than a sugar pill"). How
| each persons' depression works is different and up-
| regulating serotonin is helpful to some subset of people.
| We don't know why and it's not the whole population, but
| talking about them in this way is not helpful in my mind.
| alpaca128 wrote:
| It sounds like you think therapy can replace medication
| just because some numbers on a spreadsheet fit together. If
| that's the case I have to tell you that you're misled and I
| suggest you talk to some real people who actually had to
| deal with depression.
|
| Antidepressants can be a life-changer in ways that placebo
| could never match, and can be necessary to even be able to
| go see a therapist.
| IX-103 wrote:
| If you ask any practicing psychiatrist, you'll see that
| they are aware of the problems with SSRIs. They tell their
| patients that they may need to try several drinks until
| they find one right for them.
|
| The way you presented those statistics is very misleading.
| The 70% number for sexual side effects you quoted was
| actually for patients that stopped taking at last once drug
| for that reason. Typically patients will have to try 2-3
| drugs to find something that works for them and may need to
| transition to a new drug when the old one is no longer
| effective. So it's not like those patients are facing those
| side effects on an ongoing basis. It's just during the
| initial period when they are adjusting things.
|
| I suspect that the reason why SSRIs perform so poorly in
| the studies is that the amount of variation in these
| receptor targets is high, so some drugs actually are
| effectively placebos to a large fraction of people. But for
| other individuals they are a miracle. And if you multiply
| that by the number of different drugs, you can almost
| always find one of them that helps each patient.
|
| This goes into your assertion about "serotonin receptors
| are all over the body". That's something doctors and
| medical researchers have known for a long time. That's why
| the SSRIs are tailored to the specific variants of the
| serotonin receptors present in the organs they want to
| influence. That doesn't mean they have no effect on the
| receptors in other organs, but that the effect is minimized
| to the extent possible. But I suspect that one limitation
| in how tightly we're able to target the right receptors has
| to do with individual variation - make it specific enough
| that it doesn't affect other organs then it doesn't work
| for anybody with the slightest variation in target receptor
| shape.
|
| But I agree that the role serotonin plays in depression is
| poorly understood. But I don't agree with the implication
| of your post that we should stop using them. They are often
| helpful even in cases where therapy is insufficient, and
| improve outcomes in conjunction with therapy. They are too
| useful a tool to discard, even with their issues.
| jdietrich wrote:
| I read this sort of critique often, but what are people
| living with debilitating depression supposed to do? SSRIs
| are barely better than placebo, but so is psychotherapy;
| SSRIs have side-effects, but at least they're cheap and
| readily available. Exercise is also barely better than
| placebo, if you're actually capable of maintaining that
| effort. Everything else in the armamentarium is some
| combination of less effective, more risky and/or
| prohibitively expensive.
|
| Do we need better treatments for depression? Yes,
| desperately. Are some people with mild, self-limiting
| illness taking SSRIs unnecessarily? Probably, in some
| places. Are many people with serious depressive illness not
| trying drugs that might help them? Definitely. Does
| denigrating the least-worst treatment for most people
| actually help anyone?
| kypro wrote:
| > I read this sort of critique often, but what are people
| living with debilitating depression supposed to do?
|
| I don't disagree strongly with anything you've said here,
| but I think as someone more on the other side of this
| argument - that in most cases people are probably better
| off not taking SSRIs - that part of the problem is that
| people don't learn to deal with their depression anymore
| and as a society we don't care to help those suffering
| with depression beyond just telling them to take
| psychoactive drugs.
|
| As a depressed person myself and someone who knows a fair
| few depressed people, I do believe you can learn to
| manage it in the vast majority of cases. I think as a
| society if we tried to help people understand and manage
| their emotions then perhaps we could help people without
| medicating them to be honest. It's just that medicating
| them is easier, as you suggest.
|
| I don't really care what others do though. If people want
| to medicate then more power to them... All I can say is
| that in my experience it's the wrong thing to do and that
| the only long-term way to deal with depression is to
| learn to experience it without being overwhelmed or
| burdened by it. In this sense pushing people straight to
| SSRIs denies them the chance at a more lasting solution.
| Ideally I think SSRIs should be the last option.
| cbsmith wrote:
| > that in most cases people are probably better off not
| taking SSRIs - that part of the problem is that people
| don't learn to deal with their depression anymore and as
| a society we don't care to help those suffering with
| depression beyond just telling them to take psychoactive
| drugs.
|
| There's some inconsistencies in your logic there. If
| SSRIs aren't effective, how is it that people "don't
| learn to deal with their depression" due to SSRIs?
|
| > As a depressed person myself and someone who knows a
| fair few depressed people, I do believe you can learn to
| manage it in the vast majority of cases.
|
| The evidence supports that. The evidence also supports
| that without help, a lot of people won't learn to manage
| it, and many will literally die because of it.
| carabiner wrote:
| > I read this sort of critique often, but what are people
| living with debilitating depression supposed to do?
|
| Not waste money on useless treatments? Seek out other
| treatments like TMS (SAINT protocol), ECT, ketamine?
|
| I don't know why you suggest that useless treatments are
| better than nothing. You could also throw in prayer,
| naturopathy, and seeking a psychic.
|
| Americans hate to hear this: Not all problems have
| solutions. Really.
| DANmode wrote:
| > what are people living with debilitating depression
| supposed to do?
|
| Way more depression than anyone is aware is _clinical_
| depression.
|
| Address the issues in your life, and your long-tail
| health.
|
| For me, it was multiple systemic infections - took the
| drugs and buried it down, didn't realize until it got
| really bad. Luckily I was young enough to survive the
| mistake.
|
| If your endocrine system is doing the wrong thing, ask
| why.
| tsimionescu wrote:
| > Way more depression than anyone is aware is _clinical_
| depression.
|
| I don't know what you wanted to say here. _Clinical_
| depression is typically used as an explicit emphasis to
| either emphasise that it is professionally diagnosed (as
| opposed to layman observations), or to emphasise that it
| is depression so bad it requires hospitalization (such as
| people who are so depressed they literally can 't get out
| of bed for days on end).
|
| But you seem to be using this term to mean "depression
| symptoms caused by other diseases"?
| s__s wrote:
| Clinical depression is neither of those things.
|
| It's also called Major depressive disorder. It's
| basically depression that isn't a temporary response to
| something. It's long lasting depression that doesn't go
| away.
|
| You can easily look up the diagnostic criteria online.
| Modified3019 wrote:
| For me, I found Bupropion slightly effective, and
| Dextroamphetamine very effective for my depression.
|
| I had severe depression during Covid, manifesting as
| involuntary and passive suicidal ideation. Basically a
| hours long whirlpool of daydreaming about dying in some
| way, because it was the only thing which brought comfort
| to what I would best describe as a sort of mental _agony_
| , but without pain. Just the constant need to escape
| existing. Passive meaning at no point was I actively
| intending to act on it, but obviously this was not
| something to be allowed to continue.
|
| The depression basically severely reduced my ability to
| mitigate my ADHD symptoms, causing them to become _very_
| apparent, essentially being co-morbid with each other.
| With that context, I first did some non-stimulant
| preliminary alternatives like:
|
| * Bupropion HCL. This provided partial mitigation of the
| depression. Basically it was manageable and not
| threatening to implode my ability to do basic life tasks.
| No effect on my ADHD.
|
| * And Atomoxetine (Strattera) which within the week had
| brought back my involuntary hours long daydreams of
| dying, and really fucked up my dick/physical and mental
| sexual response, which lingered for a few months after
| despite quickly ending treatment. As a male, I severely
| underestimated how much having a healthy sexual response
| contributes to overall wellbeing.
|
| After that I tried extended release Dextroamphetamine.
|
| The very first day, I wasn't what I would consider
| _euphoric_ , but I had a distinct calm sort of sense of
| wellbeing that was very much in contrast to the previous
| several months. Basically I could actually start to
| _feel_ that things could be better, rather than trying to
| brute force reason while suffering. I liken it to what
| you feel when the pain from when you stub your toe fades,
| and you have some minor lingering endorphins.
|
| After that first day, I didn't feel anything else
| directly connected to taking the pill after that. I'd
| typically forget if I already took the pills 2-3 times a
| week (meaning skip the dose). All I could notice after
| resuming after skipping a day, was being slightly more
| chatty, and feeling like I was slightly worse at driving.
| The few times I probably doubled up, I'd feel this sort
| of mild head pressure.
|
| But the overall effect of Dextroamphetamine within 3 days
| was the complete elimination of my passive ideation.
| Intrusive thoughts are like flies, they land on everyone,
| but _healthy_ people can brush them away. I still had to
| take care not to voluntarily sustain negative thoughts,
| but it was actually voluntary now.
|
| I later moved to Lisdexamfetamine ER because the supply
| of dex at the time was severely constrained, but it was
| basically identical. Supposedly less addictive/abusable
| too, though for me either felt as addictive as a collagen
| supplement.
|
| After a few months, I had the dose lowered, and several
| months later, I halted taking stimulants. They didn't
| really do much for my ADHD symptoms, and I felt that
| whatever had triggered my depression had cleared up so I
| could manually deal with the symptoms like I always have.
|
| So that left some mild side effects of slight head
| pressure, probably being a slightly worse driver,
| probably being a slight detriment to my sleep, and
| possibly increasing jaw clenching (I now have a fitted
| nightguard), so I had zero reason to continue.
|
| But it's _very_ reassuring that if I get another severe
| depression episode for some reason, I now have a first
| response tool I can use.
| partomniscient wrote:
| Thanks for your personal empircal revelations.
|
| I'm sure you know Bupropion doesn't affect seratonin, its
| a dopamine re-uptake inhibitor.
|
| As someone who also doesn't seem to respond much to
| seratonin related meds, Burproprion worked somewhat but I
| suffer from increased insomnia as a side effect. I
| actually respond better to things mostly affecting GABA
| and NMDA rather than the 'classic' anti-depressents.
|
| That said I was trialled on methylphenidate and all it
| did was make me procrastinate waaaay faster, so
| personally I'm avoiding any stimulants stronger than
| caffeine.
| caycep wrote:
| bupropion does...a lot of things (including mildly doing
| what dextroamphetamine does...). A lot of these drugs
| don't just hit one receptor type...(don't get a pharmd
| started on receptor affinity binding profiles...)
| partomniscient wrote:
| Fair call. So much of this stuff is simplified for us
| laypeople, but yeah - when you look up what so-and-so
| molecule does and find out how many different binding
| sites it interacts with as an agonist/antagonist/catlyst
| (and sometimes they've only measured interactions in
| rats) you realise there's a heck of a lot of stuff going
| on.
|
| I also got slightly weirded out when I found out
| something I was taking interacted with the mu-opiod
| receptors even though it wasn't an opiate.
| catlifeonmars wrote:
| > The depression basically severely reduced my ability to
| mitigate my ADHD symptoms, causing them to become very
| apparent, essentially being co-morbid with each other.
|
| I had this experience as well; in particular it really
| impacted my ability to work/keep a job. The added stress
| in turn worsened my depression, etc.
|
| Fortunately, I was able to take almost half a year off
| and focus on stabilizing/recovering without further
| damaging my career or economic status. Many people are
| not so fortunate.
| amanaplanacanal wrote:
| Don't hold your breath for the sudden availability of
| thousands to millions more therapists becoming available.
| I'd love to see a lot more spending for mental health care,
| but it ain't going to happen. SSRIs are cheap and easy, so
| that's what we get
| mulderc wrote:
| I will say that an LLM helped me work through some past
| trauma in a way therapists never could. I don't think
| anyone should use these models in place of therapy but I
| was pretty amazed at how quickly it helped me with an
| issue I had been having for a long time.
| thatoneguy wrote:
| My-not-much-better-than-placebo sertraline sure has been
| working its placebo-like magic for 30 years next year.
|
| How long are these double-blind studies? Surely they're not
| years long to show that the placebo effect is maintained
| over a decade or something.
| vjk800 wrote:
| > There's also rates of sexual side effects in excess of
| 70% [1] and they cause weight gain which is separately
| associated with depression.
|
| I can't find the source now - if someone can, please help
| me here - but there was a theory that SSRIs work exactly
| because of the sexual "side effects" (which means that it's
| not actually a side effect but the main effect). The idea
| would be that the depression is due to some kind of deeply
| rooted sexual frustration, which is alleviated when the sex
| drive vanishes.
| Johanx64 wrote:
| There's also a theory that the reason why SSRIs end up
| not helping or making things worse in the end is that for
| males they crush testosterone levels, and if they didn't,
| they might have been an effective treatment otherwise.
| partomniscient wrote:
| I agree. When SSRI's were new, they became the hammer and
| anything vaguely depression related became all the nails.
|
| There's a reason modern pharma are not spending any more
| money researching SSRI's further.
| dondraper36 wrote:
| A fairly surprising fact revealing how little we understand the
| efficiency of SSRIs is that the serotonin level rises pretty
| quickly once you have started taking an SSRI.
|
| Still, there is an unexplained cascade of reactions that takes
| weeks before patients notice any improvement.
|
| As much as I respect proof-based medicine, the very fact that
| scientists can't explain how all this works made me want to
| stop my treatment and just do more weightlifting and running.
| TZubiri wrote:
| >how little we understand the efficiency of SSRIs
|
| A drug that is taken by millions of people, if your take is
| that we understand it too little, either you are deep enough
| in the subject to make some interest questions, or you are
| missing the forest for the trees.
|
| I'm not sure how useful it is to keep investigating exactly
| how it works on a chemical level, yeah for sure some people
| should look into it, but in the same way that some one should
| do 1600m in the regional competition of Minnesotta, as a
| niche.
|
| You can observe the effects of the medication on people,
| done.
|
| I remember seeing a video on a cannabis researcher explaining
| that they didn't find any difference between the indica and
| sativa strains for example, and she talked about chemical
| properties. Just get 10 people to smoke one or the other and
| you are done.
|
| There is such a thing as overintellectualizing, and FUTON
| bias isn't a particularly impressive way to do it.
| swores wrote:
| > _" I'm not sure how useful it is to keep investigating
| exactly how it works on a chemical level"_
|
| It has the potential to be incredibly useful.
|
| Not because there's a benefit to being able to tell
| patients "this is the technical explanation of how the SSRI
| we're giving you will help", but because we currently don't
| have a perfect treatment for depression, and understanding
| how existing imperfect (but useful) treatments actually
| work might lead to either creating better SSRIs that are
| more effective, or to creating non-SSRI treatments that we
| haven't yet thought of.
| TZubiri wrote:
| >treatment for depression
|
| That reads like a treatment for death, or a solution to
| poverty.
|
| Will you find the answer by doing 100 metastudies and
| taking advanced chemistry. Or will you find the wisdom by
| meditating and talking with your dad and priest.
|
| So I'm either an anti-intellectual, or you are a super-
| lectual.
| Aurornis wrote:
| There's actually far more research into what happens after
| starting an SSRI than you're implying. We know, for example,
| that certain downstream adaptations takes weeks to fully
| appear. We also know that the initial increase in serotonin
| concentrations is limited by 5-HT1A negative feedback, but
| 5-HT1A downregulates over time and allows the synaptic
| concentrations to increase again.
|
| > the very fact that scientists can't explain how all this
| works made me want to stop my treatment and just do more
| weightlifting and running
|
| Weightlifting and running are complimentary, not
| substitutive. Most people can't simply replace a powerful
| medication with _more_ running and weightlifting.
|
| You might also be surprised at how many modern medications
| operate on partial theories. There's not actually anything
| wrong with that. There are a lot of medications that
| hypothetically should work based on scientific understanding
| of the brain but don't seem to show efficacy in studies.
|
| It's more important that we validate the safety profile and
| efficacy in real-world testing.
| dondraper36 wrote:
| I am not saying that quitting SSRIs is the ultimate answer,
| it just works (sort of) for me mostly because I am not that
| depressed.
|
| Also, having partial theories is not wrong, but in the case
| of SSRIs, I deliberately chose to avoid medications that I
| can do without (again, this is highly subjective).
|
| Another concern of mine is that there are now warnings for
| some popular SSRIs that ED symptoms in men might be
| permanent.
| scns wrote:
| > Another concern of mine is that there are now warnings
| for some popular SSRIs that ED symptoms in men might be
| permanent.
|
| They are for some of the unlucky 10%. Buspirone might
| help.
| tsimionescu wrote:
| You should know that there are plenty of common drugs where
| we have almost no idea how they work. Perhaps the most
| surprising is metamizole, sold under brand names like
| Novalgin, Analgin, Algocalmin. One of the most common over-
| the-counter low grade pain meds and fever meds in the world,
| and yet we don't know the precise mechanism of action.
| TZubiri wrote:
| It sounds like a very naive explanation of depression. I'm
| cynical enough to believe that's why it's popular:
|
| "You are sad because you are missing happy chemicals"
|
| Reality is more complex, hitchen's razor tells us we don't need
| to spend more time down that road.
|
| That said, I'm open to the idea that ssri's (while certainly
| tangential to the theory) are more complex. If only because
| they may be prescribed early on either due to a physician
| desire for a simple theory or due to the patient's desire for
| it. But once you have gone down that road you can't change
| course easily.
|
| I believe whatever issue existed prior to SSRI onset becomes
| secondary (whether for better or worse) to the symptomps caused
| by SSRIs themselves, the patient becomes fungible and the
| disease a categorizable syndrome with clear treatment and
| support systems (and low suicide rates, which is usually the
| concern of family).
|
| On that note, the medication is not only taken for the patient,
| but some properties are designed/selected for the physician
| (low suicide/malpractice rates) and family (less outwardly
| symptons). In this way it's a milder version of lobotomies to
| my judgement.
|
| End rant
| amanaplanacanal wrote:
| Seems like less suicide would be better for the patient too.
| 42772827 wrote:
| > People who having passing familiarity with neuroscience often
| assume that psychiatric medications work by correcting
| deficiencies, but this isn't true.
|
| They think this because that's literally what the commercial
| for Zoloft said. [0]
|
| [0] https://youtu.be/twhvtzd6gXA
| agumonkey wrote:
| What I'm trying to figure out is the interplay between the
| transmitters, and "semantic" (sorry, making this term up, not a
| neurologist, basically your representation of the world) layers
| in the brain. What interpretation mechanism are affected by
| brain state to distort your perception of so many things.
| Lerc wrote:
| I think if it like a snow globe, occasionally the snow falls
| into patterns you don't like, there is an abundant body of
| science that covers principles of physics that dictate how the
| snow moves. You might be able to come up with some broad
| patterns that show what lead to outcomes that you don't want.
|
| Nevertheless the best option for fixing the undesirable pattern
| of snow is to give the globe a quick shake. Solutions do not
| necessarily require a complete understanding of the problem, or
| even directly target the problem.
|
| Now if you only wanted to move a few problematic flakes without
| shifting any others, that's a different, much harder problem.
| TwoPhonesOneKid wrote:
| All of this fine, but surely in your context the efficacy of
| SSRIs should not imply the accuracy of a serotonin theory of
| depression. At best we know that the medication works, at worst
| we know that it's actively encouraging people to kill
| themselves, although the latter seems a little unlikely atp.
|
| Having been on an SSRI myself I gave up on the hope of SSRIs
| forming the basis of real treatment decades ago. Bupropion
| seems less harmful but also seems to have similarly small
| impact.
| H8crilA wrote:
| Psychiatric benefits of SSRIs show around 2 to 4 weeks after
| the therapy starts, but the serotonin levels increase on the
| first day. It is obvious that depression is not just some
| "nutritional" problem in the synapses. It does look like it can
| be cured by systematic "overeating", though, at least in
| some/many cases.
| spondylosaurus wrote:
| It's interesting (1) how many drugs have effects on serotonin,
| even if they're not SSRIs and (2) how different SSRIs and SSRI-
| adjacent drugs can have notably different effects, like how
| buspirone affects serotonin but is an anti-anxiety drug rather
| than an antidepressant. There's clearly a lot going on with
| just that one neurotransmitter!
|
| The former can have some unfortunate consequences though, and
| to make matters worse, it's not always obvious which drugs you
| need to watch out for. Those "may increase risk of serotonin
| syndrome" warnings are no joke!
| mtlmtlmtlmtl wrote:
| Yep, all very good points. Neuropsychopharmacology is extremely
| and recursively complicated. It's turtles all the way down.
| Just take one component in all this, the receptor. One might
| want to think of a receptor as just a switch triggered by a
| chemical. But autoreceptors are a thing, as you mention.
| Receptors do different things in different areas of the brain.
| Receptors form complexes with eachother(e.g 5-HT-2a and D2),
| and we have essentially no idea why? Receptors have all sorts
| of different modes of interaction both with ligands and cell
| internals. Agonism, partial agonism, antagonism, inverse
| agonist, positive/negative allosteric modulation. The GABA-A
| receptor is not really one receptor, it's more like a family of
| receptors made up of a varying constellation of subunit
| proteins. Different constellations appear in different parts of
| the brain, and have different allosteric binding sites, which
| is why benzos vary widely in qualitative effects despite all
| being "GABA-A PAMs". NMDA receptors don't just bind to
| glutamate, but also glycine, and magnesium needs to be around?
| And NMDA triggers an intracellular cascade that regulates
| membrane expression of AMPA receptors. This is thought to be
| involved in memory. Cannabinoid receptors are expressed
| presynaptically carry signals in reverse, so that's weird. And
| there are 5 identified cannabinoid receptors. We only sort of
| understand what 2 of them even do. The other 3 are still quite
| mysterious(last time I checked). Most of the well studied
| neurotransmitters have not one, but many different receptors
| they interact with. 5-6 dopamine receptors, I can't even
| remember all the serotonin receptors, etc. Many of them are
| still poorly understood.
|
| And of course, neurotransmitter systems talk to eachother.
| Serotonin so much so that it's also been called a
| neuromodulator. Because it very often regulates release of
| other neurotransmitters(including itself).
|
| It's a field that, the more I dig into it, the more confused I
| get, honestly.
|
| So when I see someone say herp derp, serotonin hypothesis is
| false, therefore SSRIs are ineffective, the only conclusion I
| can make is they haven't even _tried_ to dig into it.
| Centigonal wrote:
| The analogy I've used with friends is that neurotransmitters
| are to brain communication as letters are to language.
|
| If something gives you "more E" or "less L" in your writing,
| the change in letter frequencies is probably not the thing
| that's directly making your sentences better, but the change
| shows it's clearly making a difference. There is an effect that
| is occurring on a level of complexity that we just can't fully
| decipher yet.
| caycep wrote:
| At some point, neuroscience HAS to replace "serotonin" and
| other monoamine hypotheses by what they're really getting at:
| serotonin/dopamine/glutamine etc are all data packets for a
| neural network, and a better way of describing the network-
| level changes for depression etc is sorely needed.
| debacle wrote:
| For anyone interested in their own depression, some anecdotal,
| unscientific non-medical advice that I received from HN about a
| year ago:
|
| 5-HTP is a serotonin precursor that you can take in low doses to
| help do a lot of different things. For me, it lowered food
| cravings and impulsiveness, balanced out sleeping anxiety, vastly
| improved my gut health, and really helped with my depression. I
| have a positive mood about me that I haven't had since I was a
| teenager, and I am so vastly enjoying life today, despite the
| trials. Before starting a daily regimen of 5-HTP, I was worried
| that I might one day lose myself to suicide. Now I treasure every
| day. Truly changed my life. Maybe it will change yours.
|
| Again this is completely anecdotal, unscientific non-medical
| advice.
| felizuno wrote:
| I have also had huge results with 5-HTP (in combination with
| vitamin D). I had that breakthrough in 2017 and it has been a
| consistent improvement ever since so I feel comfortable
| suggesting it. I have more recently had a similar "OMFG" moment
| with supplementing creatine but I'm only a few months into that
| so not ready to make claims about durability. I was diagnosed
| with chronic depression as a child (in 1994) and have taken
| Wellbutrin, Prozac, Lexapro, and Celexa at different points in
| my life. Personally I never experienced benefits that
| outweighed the side effects with any of those drugs. Taking an
| approach that centers on whole-body (and really specifically
| intestinal) serotonin has made the biggest difference in my
| life. Avoiding processed carbohydrates like pasta and bread has
| also been a piece of the puzzle, but unequivocally 5-HTP + VitD
| has been the standout difference maker.
| Imanari wrote:
| How much do you take? Just standard stuff from amazon?
| debacle wrote:
| I take the lowest dose (200mg/mcg?) from Amazon.
| BiteCode_dev wrote:
| What does are you taking? Do you need to ramp it up or cycle
| it? What's your source? Anything else important to know?
| xlbuttplug2 wrote:
| Just a reminder not to impulse buy without first doing some
| research. IIRC serotonin syndrome is a risk, especially if
| already on antidepressants.
|
| Some things to note in case you decide to go ahead anyway:
| https://www.reddit.com/r/Nootropics/comments/28489u/comment/...
| johnisgood wrote:
| Serotonin syndrome is a low risk, I believe. If it is as
| common as they make it out to be, I should have had it a
| million times, unless I am somehow the exception.
| usednet wrote:
| This was a seminal review in psychiatry that I am fully in
| agreement with but there are a lot of easy to draw conclusions
| from this review that are false.
|
| SRRI efficacy for one - The nature of SSRIs is that they are
| highly effective for some patients and useless/detrimental to
| others. This does not lend itself well to traditional measures of
| effect size. For those in the comments pointing out SSRIs low
| effect size, note that the effect size of morphine for pain is
| only 0.4 (SSRIs score 0.3). For instance, drugs that
| significantly improve 60-100% of patients are clinically
| insignificant under various guidelines. I can expound upon the
| various methodological reasons this is the case if there is
| interest.
|
| This is not to say that SSRIs are good. There is no doubt they
| are overprescribed, have underdiscussed side effects, and are
| barely understood by their prescribers. I was severely depressed
| with suicidal ideation since I was 6 years old until I was young
| adult. I have pored over the psychiatric scientific literature
| for many years now, and I will say that understanding the
| sociological reasons for depression was much more effective at
| helping me than learning about the biological or pharmacological
| aspects. If you are in a similar position, I cannot recommend
| enough reading Crazy Like Us: The Globalization of the American
| Psyche by Ethan Watters as a starting point.
| 6stringmerc wrote:
| Thank you for ending with a further reading suggestion as a
| useful complement to your personal experience and research.
| Your write up is a strong positive in continuing toward
| advancing education, open mindedness, and patience with a
| delicate subject. I appreciate your notes in this context and,
| as small as one voice is in "anecdata" context, I'm glad to see
| the mention of sociological factors because it's also in my
| journey of discovering more.
| pfisherman wrote:
| Another problem with measuring effectiveness that you are
| relying on patient (or caregiver) reported outcomes. There are
| no "objective" measurable criteria for depression, such as a
| biomarker on some lab test or survival at 5 years. Depression
| is assessed by asking people questions about how they feel,
| which is prone to all kinds of noise and bias.
|
| A lot of the problem with studying psychiatric disorders is
| that you can't just go around biopsying people's brains; so we
| don't have much of any idea what is going on at a molecular or
| cellular level. We just kind of know the behavioral tics that
| doctors can observe and what patients can tell us.
| ieie3366 wrote:
| Having taken SSRI for anxiety, it feels more like a second order
| effect. The brain is anxious, the serotonin goes in, the
| serotonin is not exactly "anti-anxiety" signal but "feel-good"
| signal.
|
| Repeat constantly every day for months and the brain thinks, "ok
| we constantly have this euphoria going on, time to turn the
| anxiety off no need for it anymore"
|
| This would also be why the serotonin increase is instant when
| starting SSRIs, but anti-anxiety effects take months and are
| gradual
| petesergeant wrote:
| > but anti-anxiety effects take months and are gradual
|
| Everyone is different, but the anti-anxiety effects happened
| almost overnight once I fixed my dosage, and I don't remember
| anything approaching euphoria
| gentleman11 wrote:
| Slight call for help:
|
| I'm close with somebody who is experiencing extreme 10/10
| withdrawal or other side effects from their ssri (escitalopram).
| They tried to quit, then went back ionto it due to severe
| withdrawal, and its actually gdtting worse every day now even 1.5
| weeks later. What should I read or watch to understand what is
| going on?
| froh wrote:
| ssri have to be phased out very slowly.
|
| and it helps a great deal if the life circumstances and the
| personal perspectives that lead to the need to take them have
| changed. long nested sentence. let me rephrase.
|
| shit was flying high, leading to the need to take ssri.
|
| is there objectivly less shit? or do they honestly no longer
| care / see it as existential shit?
|
| ssri ar great to create space for psychotherapy and life
| changes. and then you phase them out. or they, they phase them
| out.
| catlifeonmars wrote:
| > ssri ar great to create space for psychotherapy and life
| changes. and then you phase them out. or they, they phase
| them out.
|
| Well spoken. Creating space is a necessary first step.
|
| One thing I disagree with personally is that being medication
| free is always a useful goal. I take medication and therapy
| and I see both as a way to _maintain_ a healthy mental state.
| Sometimes there is not going to be objectively less shit; you
| cannot always change external circumstances.
| tsoukase wrote:
| Antidepressant drugs are actually anti-anxiety ones. If the
| anxiety causes depression, then the latter may be improved too.
| But there is absolutely no effect for a flat non-anxious mood.
| Only Venlafaxine may help in some cases
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