As far as I'm aware, it's been known for decades that we don't actually know what causes depression, and that whilst we know that antidepressants work, we don't know why they work.
Except that no one really understands why SSRIs have an antidepressant effect in some patients. We have some hypotheses but the underlying neurochemical mechanism is still somewhat mysterious and unproven.
Hopefully no professional ever thought depression was caused by "chemical imbalances". That's a pop science myth, although one people strongly believe for some reason.
The correct answer is we don't know why SSRIs work, which isn't unusual for medicine.
No, we don't know the antidepressive mechanism of antidepressants, therefore we don't know how they work.
Understanding some neurochemical reactions and biological adaptations they cause is not enough.
(We also don't have a complete understanding of depressive disorders, we don't really have very effective medication/therapy for many depressive people, etc.)
We know the why is “because the antidepressants were taken”. But antidepressants only work sometimes – different antidepressants work for different people! We don't know the true, fundamental reason, but at least we've pinned it down a bit.
I call something pseudoscience when the “why” is “pinned down” as something wholly unrelated, and the people involved haven't noticed; if they were doing science instead of just theorising, they would've noticed.
I sympathize with you, I really do. I've had some similar experiences. But you're overstating the case. Numerous meta-analyses have found that antidepressants do work for people with severe depression, much better than placebo. Unfortunately there's many people for whom they don't work, and even when they work you may have to try many different kinds to find the right one(s). The state of depression treatment is sadly not very good right now, everyone knows this. But it's just not true that there's not "a single shred of proof that these medicines work".
Depression treatment doesn't depend on "chemical imbalance" as an explanation either. Research on whether antidepressants work proceeds alongside research on why they work, if they do--usually studies on the efficacy of drugs are completely independent of mechanism. They study clinical outcomes, not neurochemical or larger structural brain issues.
So even if we had no idea why antidepressants (potentially) work, we could still know that they do work based on clinical outcomes. And it's not exactly true that we have no clue at all. The past 20 or so years the monoamine hypothesis hasn't been the main avenue of research into the neurobiology of depression. These days, it's at best considered one possible factor, not the defining and only factor. There's a lot of research into the structural changes that follow depression and recovery. For instance it's now known that serotonin helps regulate the expression of BDNF, which in turn regulates the growth and repair of brain cells and synapses. So it may well be that serotonin triggers large-scale "repairs" in the brain in areas related to emotional processing, such as the amygdala. Here you can see that the focus isn't so much on individual levels of "chemicals" in the brain as on the structure of the brain and how different natural and exogenous factors affect that.
My experience with depression, an isolated major depressive episode that lasted most of a year, suggests that antidepressants were highly effective. I didn't feel like any clues were to be found. It felt much more like a chemical switch in my brain was in the wrong position.
Anti-depressants didn't ever do anything for me, either. Although I suspect that the only anxiety attack I've ever had could very well have been caused by them.
In his awesome book Bad Pharma, Ben Goldacre also hints that the link between depression and serotonin levels is not very well established. For those of you that don't know, Ben Goldacre is not some quack that pretends that science is wrong or something like that; in fact, what he asks for is precisely more rigorous science (specifically, more rigorous medical trials, all made public).
On the other hand, apparently there are a lot of people who have had a measurable level of benefit. My non-educated hypothesis is that there are several causes of depression and serotonin levels may be only one of them.
We sort of do know some of the mechanisms why they work: they increase BDNF and stimulate certain serotonin receptors, allowing new and healthier neural connections and associations to be formed, helping people more easily snap out of old ways of thinking, similar to how psilocybin and other newer "drugs" help people snap out of depression.
That's why antidepressants are ideally combined with CBT or other therapies that help people change their mindset.
One of the biggest surprises to me when I was taking advanced psychopathology courses was how little certainty there was around antidepressants and much of the drugs used to treat psychological disorders. For some people they work absolutely amazingly. For others it can actually have precisely the opposite intended effect. And for some it can have literally no effect.
I had a long discussion with a psychiatrist about this and they more or less acknowledged that it really isn't a science and is more of an art. You try this SSRI or that SSDI with a low dosage and see what happens. Then you Amp it up gently. If it works great. If it doesn't, then you dial it back and try something else. Slowly working to drugs with more and more adverse side effects until something works.
They have an idea of why it works but they don't really know precisely for every person.
IANA doctor, but my understanding from years of trying every antidepressant on the market is that we don't currently understand why SSRIs help (some people) with depression. We know the mechanics of what they do, but not why that function has an antidepressant effect in some people. We don't really have a good idea what mechanically causes depression at all - in some cases, it's related to serotonin, in which case an SSRI might help. But there are a lot of other cases that aren't so obvious, and as far as my understanding goes, the "lot of other cases" is enough to make those who might be genuinely helped by SSRIs' mechanical function (as opposed to a placebo function, which is a whole 'nother issue in this research) be effectively invisible in the data.
A very rough metaphor (and again IANA doctor or scientist, just someone who's struggled with this personally for two decades) would be, "Stitches help people who are bleeding!" Yes, that is true in some cases and under certain circumstances, but what we've been doing with antidepressant drugs is roughly the equivalent of treating every possible bleeding wound with some variant of stitches or butterfly closures. Very effective for some, not helpful for others, actively harmful for a minority.
For what we've been reading this last years, it's not like antidepressants are worthless, it's like antidepressants aren't doing what we think are doing.
The "depression is lack of serotonin" theories seem to have less and less base every day, but SSRIs don't only act on serotonin (just review their side effects).
I've done, mostly, vortioxetine and sertraline. For some of us, some SSRIs or SNRIs work. Some don't. Probably it's not because of the serotonin. They have weirdly different effects depending on the person. But there's something going on that we still don't understand. Both because we don't understand the whole mechanism of depression, nor WTF the SSRIs and SNRIs are doing in our mind and body.
The core finding in the article is: for 15% of people antidepressants provided large benefits independent of the placebo effect.
What this suggests to me is the syndrome we call "depression" has multiple root causes, and current antidepressant medication treats at least one of them, but not all of them. Identifying those causes and finding ways to test for them could bring huge benefits, both in identifying people who would benefit from drugs, and avoiding unnecessary treatments for those who would not.
There was a theory behind why SSRIs work that existed when they were developed (the serotonin theory of depression), but this theory was later shown to be wrong - basically, SSRIs do modulate serotonin but that has no relation to whether you are depressed; if SSRIs do work, its through another mechanism. In addition the efficacy is greatly overstated; large follow-up studies have shown that they only have measurable effects on the most severely depressed individuals. The vast majority of people being prescribed SSRIs do not fall in this category and likely receive no benefit beyond placebo.
But antidepressants do work for some people, even if we don't understand the precise mechanism. I agree that the 'chemical imbalance' theory is probably wrong and certainly oversimplified but for some individuals life is significantly better with antidepressants than without.
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