The serotonin theory of depression: a systematic review of the evidence (2022)

> SSRIs aren’t shown to be much better than placebo

Or in other words: it's better than placebo.

How did you determine that the side and negative social effects aren't large enough to outweigh that difference?

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).

> 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.

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

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.

> 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)

But are they better than e.g. tricyclics, MAOIs? Placebo comparisons aren't very informative for patients when there are other existing drugs.

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.

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.

For depression specifically, I could see placebo having another important effect. Agency. Taking action to resolve your problems feels good. Compare to rain dances, which while ineffective in bring about rain, surely helps reduce anxiety of the performer.

The whole conversation is a version of "does alcohol help with depression better than a placebo?"

Because just like alcohol - so do SSRIs have a very clear, pronounced psychoactive pharmaceutical effects. It's just that both effects have little to do with "depression". For example, setraline is one of the most effective drugs for PE(Premature Ejaculation), with easily measurable effect (it can be timed!).

Do depressed people feel better when they are drunk and inebriated? Maybe, probably some do? There certainly are quite a lot of people that self medicate depression with alcohol!

Do depressed people feel better when they are zombified out of their brain with SSRIs? Probably some do?

From a certain point of view, prescribing SSRIs for depression isn't all that different from prescribing alcohol for depression. Both are hepatotoxic - pretty bad for your liver.

And is just a symptom of stone-age we live in when it comes to medicine and understanding of the human body.