D-Machine

Wait, I finally found a paper that properly presents the results in a way that lets you decide for yourself! See figure 2 here: https://pmc.ncbi.nlm.nih.gov/articles/PMC9344377/#f2, you want to focus on the second plot with the dotted and dashed lines.

Basically, both placebo and drugs can have huge responses, but basically, for severe depression, yes, it looks like the drug is more likely to have a large positive effect than the placebo is likely to have a large positive effect.

There are still a lot of limitations, main one being that study criteria generating the data for this would exclude most cases of really high severity actually seen in practice. Also "blinding" is mostly BS in these kinds of studies, and antidepressants have massive, noticeable effects, so the proper comparison is really an active placebo, and we really can't be sure the whole apparent antidepressant effect is basically just "woah, I can really feel this doing shit", basically, at some level, and this is still bad because the placebo vs. drug difference is still super tiny and below what we would consider typical minimal clinically important differences.

So still hard to say. But, yeah, there is a good chance the drugs are more effective in severe cases, and, technically, you should definitely treat in a severe case.

> You simply completely ignored my core statement.

Most of it was junk, or included stuff about TMS which has zero relevance to antidepressants. Here's the junk:

> The truth is we took someone from being passively suicidal to functioning normally, and we fail to look at the self-reported problems, we just report them. The self reported problems tend to change from "I don't care about anything" to "I'm unhappy at my job" or "I'm stressed at how much I have to do with work and my kids and home." These are actually major improvements, the patient has gone from being actually clinically depressed to significant improvement but continued unhappiness with life circumstances as opposed to unhappiness with life in general.

Sorry, but, no, going from passively suicidal to normal function (including not getting out bed) would move HAM-D and almost other other depression rating scales massively, so we would see this in studies, but we don't. This doesn't pass the sniff test.

Could antidepressants help with other symptoms that are milder than suicidality, but which are not measured? Plausibly, but why would I trust you, a faithful zealot (literally: you will "fight tooth and nail", and "antidepressants are amazing")? Where are the papers? You are too biased to take at word.

> We're engaged in a long term research study to help demonstrate the value of a tightly integrated therapy/psych team and more advanced treatments and when you get everyone in the room pulling in the same direction patient outcomes are amazing.

Great, when it is published, I look forward to reading it. Doctors have felt this way since the dawn of time though, and since you are a zealot, I don't care until I see the paper.

That being said, yes, there is broad evidence that combination treatments (e.g. antidepressants + psychotherapy) are generally better than either alone, and it is quite reasonable when there is proper, regular communication amongst those teams that it is a bit better still. There are studies looking at this, but again, you find average effect sizes that really fail to meet anything like a minimally important difference.

And again in these cases it remains unclear how much of the patients that do experience clinically meaningful change are changing because of the antidepressants (or how much of the meaningful difference can be attributed to the antidepressants). It's the same basic problem, the science here is really, really poor.

> a metastudy [which] is only useful for indicating future research avenues, not drawing clinical decisions

Nonsense, you'd better be thinking about and looking at these kinds of things when making clinical decisions.

> You linked 4 studies you don't even understand because you misrepresented the data they report. One of them actually PROVES my point

You've shown me nothing to indicate you have a better understanding, none of them prove anything you are saying. Best you can say is some interpretations of some studies looking at the distribution of the treatment effect might be consistent with more individuals receiving antidepressants having large positive effects, but, as I said, this is remains only weakly supported in general, i.e. it isn't a clear finding and just remains a "maybe".

The MID issue is huge, and that you work in this area on a research committee board and can't deal with this, and appeal to authority without seeming to understand the basic measurement issues at hand here, is deeply concerning. As a true believer, your beliefs about the efficacy of esketamine are also widely overstated, and, we can be sure, ignore the MID issue as usual.

Nice try though.

EDIT: Okay, since burnte is too lazy to do the work, I did some looking for proper MID-based responder analyses. There are a some, and one is with eskatimine [1], and finds:

> By Day 28, 86.5% of patients reached or exceeded the PHQ-9 [MID] in the esketamine/AD group compared to 70% in the placebo/AD group. The most appropriate [MID] for the MADRS was -10 points. By Day 28, 78.2% of patients reached or exceeded the MADRS [MID] in the esketamine/AD group compared to 65.0% in the placebo/AD group.

So this is real research! And maybe esketamine really is something new. But then, why is competent research nearly impossible to find and results always presented in a way that aren't clinically interpretable and/or prevent seeing the distributions in a way that could easily answer these questions? Hmmm, maybe because the placebo vs. treatment distributions look so similar, like this: https://www.nature.com/articles/s41398-022-01882-5/figures/1

[1] https://pubmed.ncbi.nlm.nih.gov/33261932/

> SSRIs have an NNT around 7, depending on the study you look at [...] Which sounds terrible if you know nothing about NNT. But when you learn that Tylenol has an NNT of almost 5 and even a powerful drug like Xanax has an NNT of 4, you realize that NNT is a difficult measure of drug efficacy

This kind of comparison is utterly meaningless (like saying a Cohen's d of 0.3 is large for phenomena X, so if we see 0.4 in phenomena Y, it is large in Y), and is just one part of why NNT as usually reported is basically deceptive for antidepressants.

What qualifies as an effective "treatment" has to be anchored to a minimal important difference, and this is what antidepressants really don't clearly have, on average. I.e. saying the NNT of SSRIs is around 7 is not really practically interpretable, because they tend not to base NNTs here on the amount of patients that actually experienced a clinically meaningful change, they just count the number that exceed some arbitrary (usually purely statistical) threshold.

If you reformulate NNT competently to count number of people needed to be treated to ensure one has (on expectation) a minimally important difference in the depression scales, then the NNT gets even larger than is typically reported.

I am telling you to ask a chatbot because you are saying things so hilariously philosophically incompetent and ignorant that even a retarded LLM will improve your thinking.

You obviously don't care about thinking coherently though, or can't even recognize what coherent thought looks like (mainly because you seem to think something along the lines of "my few minutes of armchair reflections prove all philosophy is vague and retarded"), so this is clearly a waste of time. I will not be engaging further.

This is why the denialism about differences in visual experience are so indefensible: they basically require an assumption that the whole world is out to lie and deceive.

Like, so, people just say things like "I see it in my mind's eye", and insist it is not a metaphor... why, exactly? If the typical mind fallacy assumption of denialists was correct, then no one would have any incentive to use such metaphors, because they would feel false. So clearly minds do in fact differ.

To state otherwise is a kind of narcissism / solipsism, or at least there is something monstrous about this kind of denial. "Everyone else is clearly wrong about their experience and their descriptions of it. I know better".

> there are obviously no testable hypotheses about subjective descriptions

Clearly false if you take just 30 seconds to scroll through this thread. Embarrassing.

Frankly, it is very hard to tell at times.

If you want to get really kooky, read up on Western Esotericism and Chaos Magic or tantric Buddhist practices and etc. They make basically this exact claim that this is how you "do magic" or similar such things, via sustained, "one-pointedness" and focus of attention and the Will ("gnosis"), and that, yes, often this one-pointedness of mind/attention is what lets you manifest things.

Untrue, of course, but very clearly something people have believed almost universally for centuries.

I can almost always tell the projection and reality are different, but in some very rare and extreme cases (psychedelics, sleep deprivation, extremely protracted and deliberate meditative focus / practice, or e.g. in situations where the projection is properly aligned with the actual stimuli, like seeing a face in the clouds, or in vivid / lucid dreams), the differences can be so small that what allows you to distinguish the two can simply be knowledge of the will / effort involved or e.g. knowledge from laws of physics that what is visualized cannot be present, or, in the case of dreams, an inconsistency with autobiographical memory.

Otherwise, yes, in almost all other cases, I suspect our experiences aren't that much different.

Very cool

There are plenty of examples multiple times in this thread that show that what is self-reported is demonstrated in non-self-reported phenomena, so those self-reports are clearly not nonsense, basically by definition.

The aphantasia theory is clear and parsimoniously makes sense of all this, but your "it's all just semantics" does not, and additionally requires rather other extreme acrobatics with regards to much of the entirety of human experience and discourse. Scholarly research also basically says this.

Your mind is clearly closed and you do not have any serious interest in understanding anything here.

Honestly, every time I look into if the "treatment by severity effect" is clearly established, I feel I come away only able to shrug. It is at least plausible, but hasn't been clearly established or refuted.

What does seem clear to me is that the whole cost-benefit considerations change in favor of anti-depressants when the depression is severe. I wouldn't say anti-depressants should be first-line treatments for ordinary depression, but for severe depression, I think they are a very reasonable first-line option.

Sure, they still might not help, but the costs / harms don't seem so bad compared to the potential costs / harms of leaving the severe major depression untreated, and the other options look all pretty terrible here too.

I suppose it can be moralizing, and probably is in the parent comment.

For me I still feel the surprise because I've followed the evidence carefully for well over a decade, and the methodological problems and lack of evidence for meaningful effectiveness have always been clear. I.e. it is clear standardized effect sizes are meaningless, and you need to determine important differences, as this is just basic science, but only a tiny handful of papers ever bothered.

So it feels very much like "how can we have normalized something so incredibly scientifically shaky", i.e. for me the moralizing is not "drugs are bad, how are we normalizing drugs" it is "how can an entire medical field and society so recklessly adopt something so obviously weakly supported". I.e. my dismay is more about the weak epistemic standards of society than it is about drugs.

> As you point out, placebo antidepressants are fairly effective.

This is a misunderstanding of concepts like regression to the mean, and also the active placebo elements involved.

> but the experienced reality is that they help people a lot

And the evidence is that the reality people think they are experiencing is wrong, i.e, they are improving and factually experiencing improvement, but misattributing the cause to the drug.

> "As effective as placebo" does not mean worthless

In one sense of worthless, perhaps, but since drugs have larger costs relative to placebo, well, we can argue they are worse than worseless in another.

Better instead to talk about cost-benefit tradeoffs, number-needed-to-treat vs number-needed-to-harm and etc though, and try to get better at prescribing more carefully to those they clearly benefit.

To be polite, it is called "typical-mind fallacy". To be less polite, it is called "cope".

Yup, sadly the absolute denialists saying "it is just semantic confusion" don't really have a tenable position, as a quick read through this whole thread would instantly reveal.

There are measurable practical differences, besides differences in fMRI responses and pupil dilations as mentioned in the thread, there are also the ones I mention here (https://news.ycombinator.com/item?id=49471908) that involve different skin conductance responses, less response to image priming, less ability to produce image visual details from memory, and etc.

They just aren't obvious practical differences, because cognition or neural plasticity seems so flexible that we can compensate pretty impressively for surprisingly different sensory experiences, overall.

There are plenty of competent meditation approaches that don't really require visualization of any kind. Most Western "mindfulness" meditations don't require visualizations, nor does e.g. shi-ne / opening awareness, nor most forms of concentration meditations (e.g. transcendental where you focus on a sound like "ohm", meditations that have you focus on your breath, etc).

Agreed. The problem is largely that the pluses of antidepressants have been quite significantly overstated, and the minuses have been understated, meaning the cost-benefit equation is unfortunately quite different than what the general public assumes.

We don't want to get rid of them, we just need to recalibrate prescribing, and also to properly assess cessation at intervals more frequently than we have been.

The idea that simple serotonin deficiency is the whole entirety of all depressions is 100% discredited and completely incoherent in the face of current evidence, but yes, for sure it remains clear and plausible that some forms or aspects of depression involve a serotonin deficiency.

However, tianeptine is serotonin reuptake enhancer and also can help with depression, so any simple deficiency hypothesis also doesn't look good either.

Broadly, the "chemical imbalance" theory, left vague and unspecified, is still basically sane (though not specific enough to be super useful).

Agreed. They have to be significantly helping at least some, but we can't say who these people are for certain yet, or how many there really are.

And yes, in some cases, no other options are possible, so even if the evidence is pretty dismal for their effectiveness, they are still broadly safe enough to definitely be worth a try. They probably just shouldn't be the first-line approach.

> The truth is antidepressants have a larger effect on mental health than actually gets reported because of how improvements are measured.

The truth is actually exactly the opposite, and I provided very high-quality evidence demonstrating this to be the case. You have nothing but bald assertions.

I am not sure, but recommendations to prescribe in mild cases have quietly been reigned in a bit by e.g. NICE https://www.nice.org.uk/guidance/ng222/chapter/Recommendatio....

For some people the emotional blunting is desirable, especially as you said, if the problem is chronic anxiety. But for many other people, their depression is defined by a lack of positive affect and anhedonia, meaning that emotional blunting is literally making things worse.

Depression is highly heterogenous, and I am glad the medication helped you.

Yup, I would agree. The meta-research / methodological research and awareness here is really quite impressive, even though its conclusions are a bit grim and not well-known.

Best way to manage the withdrawal would be to dramatically reduce them being prescribed in the first place.

The linked article says they have "small to moderate effectiveness", but this is being far too generous. The correct way to measure drug effectiveness is if the treatment meets the standard of a minimal important difference. I.e. you measure depression on various rating scales, like the 17-point HAM-D, and research suggests a minimal important difference (i.e. one patients and clinicians can actually notice) needs to be about 3-5 points. But the average effects of almost all antidepressants do not meet these thresholds, i.e. the effect actually appears practically invisible. [1]

Then you'll get waffling like "oh, but it really has a big effect for some people", but, well, no, we've looked at that too, and the placebo groups get just as miraculous "big effects", i.e. evidence supporting the idea "they really help some people" is also largely lacking [2-3]. All the other attempted saves ("oh, but eventually you find one that works for you") are also not really well supported either [4].

Like, maybe they really help some people, but it is far, far less clear than most assume, and should be balanced with concerns like withdrawal and serious side effects like emotional blunting and sexual dysfunction.

EDIT: And just to be clear to anyone doing a drive-by downvote thinking this is about recent asinine US politics, it emphatically isn't. There are serious methodological concerns here that desperately need to be communicated to the public.

[1] https://pubmed.ncbi.nlm.nih.gov/33593736/

[2] https://pmc.ncbi.nlm.nih.gov/articles/PMC7451660/

[3] https://pubmed.ncbi.nlm.nih.gov/33175895/

[4] https://pmc.ncbi.nlm.nih.gov/articles/PMC11844611/

Almost certainly there is also a "latent" representation that isn't just based on sensory imagery (i.e. some kinds of logical relations).

But it is also not likely that an absence of sensory imagery is without impact, i.e. that only the latent representations matter. You can see this in studies where aphantasics can't be subconsciously primed by images as easily [1], have skin conductance responses to visual stimuli less to imagery compared to normal people [2], and miss more visual details when attempting to redraw complex images from memory [3]. I.e. the visualizations are likely important in some cases, with the latent (non-visual) representations alone being deficient in some very particular cases, at least.

[1] https://pubmed.ncbi.nlm.nih.gov/29175093/

[2] https://pubmed.ncbi.nlm.nih.gov/33715433/

[3] https://pubmed.ncbi.nlm.nih.gov/33383478/

Radical or hard or global social constructionism [1] (or perhaps more accurately radical/hard/global relativism about truth [2]) are discredited because both are manifestly incoherent and prevent any serious thought from being possible, since they amount to a total denial of the existence of any kind of observer- or society-independent reality, i.e. they devolve to a solipsism of some form. Solipsism is not a coherent (or workable, at least) worldview, so can safely dismissed.

It is hard to provide a citation for these points because these points are so philosophically obvious that few waste time spelling them out, but searching for "hard/global constructionism" or "hard/global relativism" (on e.g. Google Scholar), or asking an AI about problems with these views I hope will make it clear why they are dumb, if it isn't already obvious to you.

Soft forms are of course totally fine. But to say "conscious is only and exactly whatever we say it to be" is hard constructionism / relativism, so completely unserious. Very obviously there are aspects of consciousness that do not merely depend on what we believe or say about it, even if some social constructionist aspects are also involved.

[1] https://plato.stanford.edu/entries/social-construction-natur...

[2] https://plato.stanford.edu/entries/relativism/#RelAboTruAleR...

Cool, I was really worried I might be sounding dismissive. This has been an obsession of mine since long before it got popular, and I've been enjoying your comments particularly in this thread.

Reducing it to a binary "it is / isn't a skill issue" is surely wrong and unhelpful, but given that practicing visualization can enhance the richness and durability of those images (or that e.g. psychedelics or meditative and spiritual practices also can), there is clearly some skill involved, and so obviously for some people, some aspects of aphantasia can plausibly involve a skill issue.