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

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?

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

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

> 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.

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.

> 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.

> 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.

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.

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.

> "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.