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Yeah, but thats hardly news, we have known that for decades. Otherwise direct serotonin releasers would be the most useful ADs. But these mostly give people nausea and serotonin syndrome. ADs work mostly by being FIASMAs, reducing inflammation and oxidative stress, increasing neurogenesis and neuroplasticity, increasing the activity of other monoaminergic systems, and the serotonergic portion is mostly explained by downregulation of 5-HT1A autoreceptors due to chronicly high extrasynaptic 5-HT levels. This also explains the delayed action of ADs.

At least this is my knowledge from when I last researched this topic in depth.

But that would be a little bit too much for the general public, so it is simplified, to this annoying effect that everyone talks of "low serotonin levels" where in fact the underlying systems are way more complex.

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I have a friend that's convinced that her ADHD 'causes depression' because her brain does not produce 'enough dopamine'. I'm noticing more and more among my peers a mythology around brain chemicals that's about as accurate as the four humors but with a scientific-sounding veneer. All brain function (and thus all bodily function, because the brain is the whole person /s) can be traced back to the presence or absence of a nominal amount of certain chemicals.

I wonder how the popular understanding of these processes will evolve as more and more is discovered and understood.

> I have a friend that's convinced that her ADHD 'causes depression' because her brain does not produce 'enough dopamine'

Interesting, and she is somewhat right, but is wrong about the 'enough dopamine' part, if I understand correctly. I have heard that dopamine plays a role in ADHD (seems likely our neurotransmitters don't absorb enough, but even that is an overly simplistic explanation of the unknown and true reality).

But yea, I also have ADHD and yes, it can cause depression. Not due to dopamine, but because of the negative feedback-loop ADHD can create.

For example, let's pretend I have some big assignment I need to complete, and I am without access treatment (professional or self-medication). If can't muster the "powers" to work on/finish said assignment, I start to get extremely anxious and/or I get depressed that I failed to finish said assignment. Said anxiety/depression only makes my ADHD symptoms worse which makes the anxiety/depression worse. Thus I will struggle more to complete future work, which only fuels said anxiety/depression even more, and the loop keeps on iterating.

Though, sometimes the anxiety can be extremely helpful. I can muster some insane kind of hyperfocus due to the pressure of a looming deadline. I spent decades of my life relying on anxiety to complete tasks, that even with treatment, it's extremely hard to start and finish tasks without the anxiety.

It's an annoying and rough way to live, but oh well, I am just grateful I do not have something worse.

I go through this process regularly when I have to put away groceries. I get progressively anxious about just leaving them on the counter, and it devolves into me ignoring them until I have to use them, by which time some of them are no longer usable.

The Andrew Huberman podcast has a great episode on the dynamics of ADHD. The brain does not properly distribute dopamine to where it wants to send it, which challenges your planning/reward matrices.

As much as I love the Huberman podcast, I do feel he spoke outside of his domain a bit too much on that episode in certain sections.

Sure, he is far more credentialed than I am, but it's not like he conducted any of the research himself. He is merely spouting off what one could find on PubMed, APA, etc..

While I think mindfulness can be beneficial, the research he cited about just 17 minutes (or whatever arbitrary number) can have permeant changes in the brains of individuals both with and without ADHD to be ridiculous.

I also find any research relating to ADHD and fish oil supplementation to be extremely dubious. It appears research is starting to back-track on that one too.

That being said, I do really enjoy his podcast, but just because he repeats something does not mean it's true/untrue. I would have preferred him to have an interview with an expert in the field of neuropsychiatry or of equal qualification.

There are studies about magnesium supplementation helping with adhd

Star Slate Codex (Scott Alexander) wrote that the evidence for such is basically non-existent. Thus such claims remain dubious at best. Though this was many moons ago, and things change. Do you happen to know of any research that supports this?

SSC also wrote a long article mildly trashing "The Body Keeps The Score" (which is truly excellent and important), with some very poor logic. He's not infallible.

I think ADHD causes depression because you get constant negative feedback from (many) teachers & bosses.

It's true, and I alluded to this more in depth in a comment in this chain.

Growing up in the semi-rural South East, USA, where kids didn't get diagnosed with ADHD. (Fun fact -- I had 5 boys who were my childhood friends that grew up with. We all lived within 3 miles of each other, and all of us have ADHD -- something in the water maybe?)

I didn't know I had ADHD until I was in a dark dark place in my early 20s after 4 years of college (only took me 6 years lol).

I swear I have some kind of CPTSD from growing up with it. I developed all kinds of healthy and unhealthy coping mechanisms and a lot of anger and negative self-talk that I struggle with still to this day.

I mean, I was chewed up and spit out by the public education system, little league sports, other children's parents, my peers, and even my own parents from time to time. Constantly, day in and day out, being punished, ridiculed, and humiliated for something I could not control. I didn't want to be that way, and I still don't want to be that way, but I am what I am.

I would not consider myself to be anything but average intelligence, maybe even below average, but if it weren't for sheer luck and a determination to prove everyone wrong, then I do not think I would have survived.

There is a reason alcoholism (and drug addiction) and ADHD strongly correlate. Coping and self medication are a big deal when it feels there is no other tools available or the negative externalities just get to be too severe. Add in addictive personality traits common to ADHD folks and it is quite a thing to overcome for more significant ADHD sufferers.

Did the ADHD cause CPTSD or the CPTSD that you might already have from childhood neglect/trauma that you're not aware of/dismiss/paint as "not too bad" manifests itself as ADHD?

Distraction from pain is one of the most common ways we deal with pain when it's not possible to escape it (which is the case for children that suffer emotional abuse/neglect).

I should probably have said that I am self-diagnosed with (C)PTSD, and have never consulted a professional about it, then again I truly believe we will one day look at psychologist of today like they look at Freud and psychiatrist like blood-letters of the past.

This may sound wild and woo-woo snake-oil, but using cannabis products coupled with mindfulness/deep-thought, I am sometimes able to fire up my "mental debugger" and access parts of my subconsciousness that I cannot tap during normal sobriety. I can pull out memories that I had subconsciously blocked, but I am able to process them in a healthy, compassionate, and understandable manner.

> Distraction from pain is one of the most common ways we deal with pain when it's not possible to escape it

Probably explains my compulsive levels of video games and screen time as a youth, then again... I grew up on a small horse farm on the outskirts of society, so it's not like I had anything else to do lol.

I do sincerely believe that anyone that ever wronged me (especially my family) ever did anything intentionally. Parents aren't given a "Parenting an ADHD Child 101" course or anything. Hell, both my parents probably have it themselves, and my parents swear on their life that the school system never told them anything.

I do think my ADHD manifested first though, for a variety of reasons. A lot of signs and stories seemed to point that I was even symptomatic from infancy. If anything, I wouldn't be surprised if it were environmental. All my male childhood school friends that grew up in a <small distance> radius of me all received the same diagnosis at one time or another.

So, while I do think you are on to something, I do not think it applies to me directly.

RSD (Rejection Sensitive Dysphoria) is a factor in many cases. Overreaction to external stimuli makes rejection hit harder. So it doesn't need to be constant or even more negative feedback - the same will be worse even if you are coping and getting things done.

https://www.webmd.com/add-adhd/rejection-sensitive-dysphoria

IMO, this hypothesis doesn't pass the smell test. One of the defining qualities of clinical depression is that personal success in life does not obviate the symptoms; there are many widely know examples of beloved and successful people being unable to overcome the burden of crushing depression.

Being beloved and successful does not negate negative feedback. In fact, rhetoric such as this is invalidating the experience of those who must thereby insist that, contrary to the signs you're seeing, they're actually feeling down, else they must further internalize the negative feedback which nevertheless exists in plethora. The notion that anyone could claim precisely what reasonably should bring another stranger happiness or resolve their depression is pure hubris. The defining qualities of this situation are all internal, and the externalities used in your measurement are correllative and either irrellevant or after-the-fact. A "smell test" one might consider is of empathy: if your mind ran quickly through various things which caught its attention, yet couldn't follow through with focus until resolution, negative feedback surely just recurs and piles up - it is neither sufficiently affected nor undone by positive feedback. OP's hypothesis smells true to me, but I choose to sniff the roots rather than the flower when we're looking for a cause more than an effect.

Well, first of all, I didn't say it was the only cause for depression; it's a condition that comes in lots of different flavors and this is only one.

Second, to elaborate a bit more, having to constantly manage your brain in order to get it to do what you need can be exhausting. Any success you achieve feels like it's extremely tenuous, and I'd say most AD(H)D people have had an experience of doing well for a while and then everything falling apart. So nothing ever feels safe. The negative feedback you get will tend to reverberate much more loudly in that environment than the positives.

I co-sign everything written here as

I never invited you people into my head and I don't like it

I understand this, lol. But you can also take heart that you don't struggle alone. You might be surprised at how many places you can be open about this stuff and have positive things result.

Another complicating factor is that it is assumed that there are a few different subtypes of depression. For example with and without psychotic features. Another subtypes is the "atypical depression", which actually has, in contrast to classical major depression, "reactive mood" and a high degree of "rejection sensisitivity": https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2990566/

I think a lot of this is about English (and probably most languages) being vary lacking in ways to describe both short-time and long-time mood effects. Talking about a dopamine rush from completing a difficult task or an endorphin rush from sport isn't very accurate, but despite everyone knowing the feeling we never made better words for them.

Similarly "I've low dopamine" is just a modern version of "I have the blues" or "I'm depressed". That's all good, as long as everyone involved knows that it's a short hand, or maybe a double-meaning of the word, not an actual medical description. Just like somebody who is "a little OCD" has none of the symptoms of actual OCD.

It’s more like she has quantitatively or qualitatively different dopamine receptors.

This is like the right/left brain generalization that everyone seems to still believe in.

The low-dopamine hypothesis for ADHD is a legitimate idea still being actively studied.

> legitimate idea still being actively studied.

Yes, but it is not conclusive.

I for one believe there are multiple types of ADHD. Be it lifestyle induced, lead-exposure induced, TBI induced, genetic, etc.. Us humans like to slap labels on things, but life is rarely so cut and dry.

And you forgot maybe the most important, common and often overlooked one: ADHD that is emotional trauma-induced.

Hmmm, I know (C)PTSD can have issues that seem similar to ADHD, but then again, all these disorders are just a collection of symptoms slapped together. Is cyan a hue of blue or a hue of green -- does it even matter?

The only issue I have with emotional trauma-induced ADHD, is that it's very easy to be a chicken vs. egg issue. I have ADHD, and I experienced what I would consider emotional trauma to some degree (often because of ADHD), but which came first? It seems very cyclical to me.

And now the opposite happens with headlines that imply "your medication is suddenly revealed to be useless" when in fact we've been aware that we don't know how it works for a while, but we're still reasonably sure it helps, which perhaps explains the increase in prescription more than the "serotonin is the only thing that matters" theory which the experts ruled out a while ago.

They barely work better than placebo, from what I saw in my reading of the literature.

There is also evidence that they might only work better than a typical placebo because the side effects make them an "active placebo", triggering a stronger placebo response. i.e. if you take a pill that doesn't make you feel any different, you may wonder if it's working, but if you feel weird and have unpleasant side effects then you know it's doing something.

This is particularly underappreciated in the research done on these drugs, because a double-blind study isn't actually double-blind if many of the participants can easily tell whether they're in the placebo group due to very noticeable side effects.

It's been mentioned in other comments, but I really recommend the work of Irving Kirsch on this; he's a brilliant scientist and his book The Emperor's New Drugs is a real eye-opener.

They work fantastically, from what I have seen firsthand many many times.

There is a very good reason for it's use in up to 20% of the population in some groups in the US.

Just because we haven't pinpointed why doesn't matter a bit.

“They work fantastically” is a statement that requires many qualifiers.

They work fantastically for some subset of people. For other people, they do nothing. For other people, they have negative side effects that make them not worth whatever benefits they provide. For some people, they cause extreme negative effects when the medication is removed. For some other people, they increase the chance that they will commit suicide.

It does matter that we haven’t pinpointed why they work for some people, because if we did, we might be able to avoid those negative effects and wasted time for the people for which they don’t work.

If the effect is systematic, real, and measurable, it's just a matter of giving the medication to the people that benefit from it, and not giving it to the people that don't.

The real question is by what level is the effect is systematic, real, and measurable?

Who should I trust? Peer reviewed literature, or one swampy boi?

Well, placebos work fairly well for depression. And it's not like doctors can prescribe them...

So the solution is prescribing something that has a lot of unpleasant side-effects for a lot of people? Medication that if you don't take will have SEVERE withdrawal symptoms?

SSRIs have mild side effects after the first few weeks. Withdrawal varies but is generally manageable if you taper slowly.

I'm open to alternatives but I'm convinced that antidepressants help people.

I suddenly became allergic to SSRIs and had to go off of them cold turkey. I didn't have any withdrawal problems at all so it's not a universal issue.

Wow, just wow. Quitting them cold turkey 0 problems, incredible.

I'm not trying to minimize the problems other people have had with withdrawal at all, just saying that it's possible to have a variety of different outcomes being on and off of them.

I wonder why you say 'SEVERE' so severely. It doesn't sound like you have any direct experience of this. I had to come off them and it wasn't a problem. My biggest fear, and it was huge, was that the depression would return. It didn't.

I had horrible withdrawal effects coming off lexapro/escitalopram, it was literally the worst experience of my life. I spent a month with maxed-out anxiety, feeling like I was going to die any moment, waking up at night with electric shocks running through my body, etc. I wouldn’t wish it on my worst enemy.

OK, that's an SSRI which is what I had to come off (prozac), with no major issues.

I'm not at all claiming it's a fun ride for everyone, just giving my one data point that it's not inevitably awful for absolutely everyone. Sorry you had to deal with it!

Because it's pretty damned severe with SNRIs. You probably only tried some SSRIs. Turns out not all medications are identical.

Yep, never taken SNRIs - for me it was straight prozac. Side effects while on it weren't pretty though.

Anecdotal. n+1.

I'm not sure what you're saying?

> It doesn't sound like you have any direct experience of this

It doesn't matter if I have personal experience with this although I do. A very bad personal experience with the mental health service that was provided as well as the side effects I was talking about.

> I had to come off them and it wasn't a problem.

This just comes off as ignorant, there is established literature on the withdrawal effects. I was not speculating or spreading FUD. They are real, documented and more common than your anecdotal lucky experience

So your bad experience is data, my ok experience is anecdote and is worth less than yours. Gotcha.

'I had no problem' means that bad problems aren't inevitable, which opposed the totally unqualified 'SEVERE' claim - they aren't always 'SEVERE'. That doesn't discount anyone's experiences when things do go bad as I acknowledged here https://news.ycombinator.com/item?id=32169654 - I'm not dissing anyone's experiences.

You keep missing the point, there's a reason every doctor who prescribes these drugs will also make sure to taper you off because if you suddenly come off them there will be consequences. Now I'm not gonna troll the literature to figure out what the exact numbers are.

It's not about you dissing anyone's experience, it is about you ignoring the reality of this issue just because you were lucky.

Yes, they taper you off. This is to prevent the reactions being potentially SEVERE. In some cases they will still be SEVERE (yours), in other cases they won't (mine). I don't dispute that and I never did.

So what are we disagreeing on?

They can however prescribe basically harmless pills that do more or less nothing. Low dose vitamin pills are sometimes used for this purpose.

Whether or not it's ethical for a doctor to tell a depression patient that the depression is caused by a treatable vitamin deficiency is another matter. Then again, maybe it really is caused by a lack of micronutients. After all we really don't understand depression very well.

The AMA says they can if the patient is informed of and agrees to their use. But wouldn't that significantly impact their effectiveness?

Why wouldn't doctors be able to prescribe placebos?

I’ve tried a number of antidepressant drugs and so far not been able to notice much difference with any of them.

Yes, but people are still being told by their psychiatrists that depression is caused by low serotonin levels as if it were an objective fact. Seeing this happen made me lose a lot of trust in the medical profession. Is it like this for all illnesses or just mental ones?

I don't think it is an isolated incident. Once something has become "known" among the public and the medical profession, it seems quite difficult to update it. Another example is the dietary cholesterol issue.

The human body is incredibly complex and we have quite limited tools to study it, so we are bound to arrive at wrong conclusions. That by itself is to be expected, but what does really worry me is this missing knowledge updating mechanism. It can take decades for quite a substantial update on what we thought we knew to trickle down from academia to practicing medical professionals.

At this point, if you have any kind of scientific literacy, it might be a good idea to verify whatever your doctor claims.

> It can take decades for quite a substantial update on what we thought we knew to trickle down from academia to practicing medical professionals.

A recent ep of the Trickle Down podcast (premium offshoot of a show that studies conspiratorial thinking, Q Anon Anonymous), discussed how we learned to treat ulcers with antibiotics and then lost that information for something like fifty years. Changing the scientific understanding of their cause had a Greek doctor going to his country’s health ministry over and over and getting rejected despite results. I think you nailed it.

I was told by a psychiatrist that I respect that one day in the future we may look back on psychiatry of today like we look at blood-letting and lobotomies of the past.

many illnesses are reproducible. you can give people viruses and they do indeed get sick. so i don't think you need to discount the entirety of medicine.

afaik, there is no reproducible causality for depression; we can't induce it. we only measure it's correlations and have % confidence in hypotheses.

Anytime I learn about bodily functions I become more and more aware of how shit it's engineering is. Works amazing, sure, but try and fix or debug anything? Good luck.

Erm, are you aware of any other machine, that is able for self repairing and self replicating in a complex and changing environment?

I really would not call my body bad engineering, just because I do not understand how it works in detail.

Rather the opposite, the more I learn, the more amazed I am, how awesome it all is. The complex interactions of chemical, electrical and physical components. (And who knows, maybe even quantum field elements.)

I could not design anything remotely complex at all.

Also, I debug and fix my body all the time, or rather, my body does this mostly in auto mode.

Are you saying God likes to yeet buggy unmaintainable spaghetti code directly into production?

DNA is spaghetti code exemplified. We are carried around tons of dead viral DNA for example - what amounts to shipping code with older code commented out.

I'm using this argument in my next code review meeting.

As a reviewer I'd then insist that your code was thrown into a software-eats-software world and given a few million reproductive cycles to see how it fares. If it's still thriving you'll get your PR approval.

Hmm. We really ARE created in his image - at least I am.

That thing where you can't accelerate to the speed of light is obviously a hack around some glitch that happens when you do so.

Or maybe this reality is actually a dev environment.

I guess we should be grateful our brains are complex enough to understand anything. Maybe it's too much to ask to ask them to be able to understand themselves. They would need to get more complex to understand themselves, but then that complexity would make them more difficult to understand. It's the snake trying to swallow its own tail.

Tractors don't know how to repair each other, either.

To be fair, tractors don't go on about how smart they are

almost like life is an MVP that could pivot at any time

How common is seretonin syndrome amongst people who take SSRIs?

My understanding of seretonin syndrome is that it's a serious life-threatening condition that can occasionally occur when people take too much MDMA.

Can you point us to a source for the accepted real physiological effects of ADs that you shared above?

Sure - I should have given some sources in my original comment. The order of my list of purported mechanisms is also not really ordered by significance. I think generally, more and more mechanisms of AD efficacy are discovered, and it can seem that the more we know, the less we know. Additionally of course, there are like 15 different classes of ADs, with hundreds of different compounds in total. What we know for sure I think is that the serotonin and also the monoamine hypotheses of depression are highly oversimplified and even internally contradictory, and many more targets and way more general biochemical mechanisms in the brain must be involved in depression.

But anyways, here are some pointers:

- Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1277931/)

- Wikipedia: Biology of Depression (https://en.wikipedia.org/wiki/Biology_of_depression#Monoamin...) has some good sources

- One source covering the 5-HT1A autoreceptor downregulation part in particular there is "Serotonin autoreceptor function and antidepressant drug action" (https://pubmed.ncbi.nlm.nih.gov/10890313/)

- This is also covered in "Mechanisms underlying the speed of onset of antidepressant response": https://link.springer.com/chapter/10.1007/978-3-0348-8344-3_...

- I personally like the books "Antidepressants" by Leonard (that the previous paper is a chapter of) and "Anxiolytics" by Briley and Nutt. These discuss really a wealth of observed/purported mechanisms, also for example including the significance of late gene products.

- Wikipedia: Pharmacology of antidepressants (https://en.wikipedia.org/wiki/Pharmacology_of_antidepressant...) has great sources, especially on the anti-inflammatory and immunomodulative pathways, and introducing HPA axis modulation as another possible pathway.

- Here's something about the significance of common ADs being FIASMAs: https://www.semanticscholar.org/paper/High-activity-of-acid-... - also check out the related articles below for more interesting material.

- ADs and neuroplasticity: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3025168/

- ADs and neurogenesis (this is not clear-cut in its clinical significance, and many ordinary things like exercise can promote neurogenesis): https://www.sciencedirect.com/science/article/abs/pii/S01637... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155214/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230505/

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