9 ms·

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 in

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.

thomassmith65 2y ago
but people who are depressed still improve when on SSRIs Does that mean 'over 50%' of them improve, or is it, as is more common with pharmaceuticals, closer to a rounding error? 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.
- Aurornis 2y ago
  > 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.
  - nostrebored 2y ago
    Can you explain why low percentage improvement over placebo is not important?
    - Aurornis 2y ago
      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.
      - nostrebored 2y ago
        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_.
      - ants_everywhere 2y ago
        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.
  - deleted 2y ago
    [deleted]
arcticbull 2y ago
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/ https://pmc.ncbi.nlm.nih.gov/articles/PMC6007725/ [2] https://pmc.ncbi.nlm.nih.gov/articles/PMC4592645/ https://pmc.ncbi.nlm.nih.gov/articles/PMC4592645/
- Aurornis 2y ago
  > 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 https://www.ccjm.org/content/ccjom/70/7/314.full.pdf There's a lot of misinformed fear mongering in your comment.
  - 2y ago
partomniscient 2y ago
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.

thomassmith65 2y ago

but people who are depressed still improve when on SSRIs Does that mean 'over 50%' of them improve, or is it, as is more common with pharmaceuticals, closer to a rounding error? 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.

Aurornis 2y ago
> 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.
- nostrebored 2y ago
  Can you explain why low percentage improvement over placebo is not important?
  - Aurornis 2y ago
    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.
    - nostrebored 2y ago
      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_.
    - ants_everywhere 2y ago
      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.
- deleted 2y ago
  [deleted]

arcticbull 2y ago

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/ https://pmc.ncbi.nlm.nih.gov/articles/PMC6007725/ [2] https://pmc.ncbi.nlm.nih.gov/articles/PMC4592645/ https://pmc.ncbi.nlm.nih.gov/articles/PMC4592645/

Aurornis 2y ago
> 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 https://www.ccjm.org/content/ccjom/70/7/314.full.pdf There's a lot of misinformed fear mongering in your comment.
- 2y ago

partomniscient 2y ago

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.