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.
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.
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?
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.
> 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.
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.
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...)
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.
> 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.
> 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.
> 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.
> 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"?
>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).
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.
> 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].
> 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.
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.
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.
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.
> 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)
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*¢#ed and it's so much nicer to play with my quantum dots and lasers and liquid nitrogen.
> 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.
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.
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!
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-α concentrations in depressed patients compared to healthy controls. IL-6 and TNF-α 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.
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
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.
> 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.
> 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.
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.
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.
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.
>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.
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.
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.
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.
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.
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.
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.
> 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.
> 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
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.
> 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.
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.
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_.
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.
It sounds like a very naïve 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.
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.
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.
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.
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.
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.
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.
> "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.
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.
> 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]
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.
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.
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!
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.
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.
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.
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.
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).
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?
"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?
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.
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.
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.
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.
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.
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.
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.
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
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
> 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.
Here's a paper with highlighting that shows the same:
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?
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.
> 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.
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.
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.
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/
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?
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.
> 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.
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.
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...)
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.
> 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.
> 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.
> 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.
> 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.
> 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"?
> SSRIs aren’t shown to be much better than placebo
Or in other words: it's better than placebo.
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).
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.1142338190
https://www.astralcodexten.com/p/all-medications-are-insigni...
> 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
> 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.
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.
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.
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.
> 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)
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*¢#ed and it's so much nicer to play with my quantum dots and lasers and liquid nitrogen.
But are they better than e.g. tricyclics, MAOIs? Placebo comparisons aren't very informative for patients when there are other existing drugs.
How did you determine that the side and negative social effects aren't large enough to outweigh that difference?
> 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.
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.
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!
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-α concentrations in depressed patients compared to healthy controls. IL-6 and TNF-α 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/
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
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.
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.
> 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.
> 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.
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.
> 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.
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.
>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.
Marginally better means they do, in fact, outperform.
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.
Now do the same outside of the clinical conditions, in the patients' natural environment -- and compare the results.
There's 3 choices. Both placebos and SSRI perform better than doing nothing.
> 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.
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.
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.
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.
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.
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.
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.
> 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.
> 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
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.
> 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.
Can you explain why low percentage improvement over placebo is not important?
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.
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_.
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.
It sounds like a very naïve 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
Seems like less suicide would be better for the patient too.
[dead]
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.
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.
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.
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.
> 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.
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.
>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.
> "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.
>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.
> 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
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.
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.
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!
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.
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.
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.
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.
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.
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).
The title of the paper is "The serotonin theory of depression" and it uses the phrase throughout the paper.
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?
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.
"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?
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.
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.
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.
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.
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.
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.
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/...
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.
How much do you take? Just standard stuff from amazon?
I take the lowest dose (200mg/mcg?) from Amazon.
What does are you taking? Do you need to ramp it up or cycle it? What's your source? Anything else important to know?
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
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
> 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.
Here's a paper with highlighting that shows the same:
https://pubmed.ncbi.nlm.nih.gov/31543474/#:~:text=treatment%...
Anxiety improves much before mood does.
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?
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.
> 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.