9 ms·

Why don't we know how antidepressants work yet?

92 points by XzetaU8 2y ago

P_I_Staker 2y ago
They don't.
- mberger 2y ago
  The fact that I am not a smear at the bottom of a tall building is a direct contradiction to your statement and shows that they do for some people. No, I was going to 'get better' without help. Yes, I fed trolls.
  - razodactyl 2y ago
    Did you get the "how could I use this to off myself" loop? I think antidepressants are only part of the equation but many stay on them and don't fix the underlying causes.
    - mberger 2y ago
      I was already there before the antidepressants kicked in. I would look at something and evaluate how much it would hurt, if it would work and what state I would be left in if it only kind of worked. I was also objectively in a good spot. I had a full time job with good people, a loving partner, a stable place to live, no kids and very few other stressors. I realized that there was very little I could do that I could summon the motivation for so I sought help. I was referred to a psychiatrist who put me on Prozac. There is a phrase that stuck with me that he said. He said it would give me a 'thicker skin'. I think this was key since every comment that was directed my way was over analyzed to look for signs of insult. It was as if everything in the world had a negative pressure on it. I think of it as events that happen like objects floating in water. The surface of the water is the neutral point, neither good nor bad. A comment would be like a ping pong ball, almost completely positive. Through my distorted view, it would be like a 10g weight was attached to it. It would become 90% negative and I would wonder what had prompted it. The antidepressants removed a lot of that weight so I can evaluate things without that bias. I feel like this is what people mean when they say they're drowning in sorrow. There is a weight attached to everything that makes the events more negative, less uplifting. The things that normally are buoyant don't support them anymore. I think it's the same for depression except that in sorrow, the cause is usually obvious. In depression, the swimmer is on their last few kicks. At worst, they've turned to temporary relief in the form of hard drugs that makes them bob.
    - amanaplanacanal 2y ago
      I think if we know the underlying cause, we don’t call it depression, we call it sadness.
      - goatforce5 2y ago
        Or it might be a case of situational depression: https://www.webmd.com/depression/situational-depression https://www.webmd.com/depression/situational-depression
        Sohcahtoa82 2y ago
        I've said before that I think a lot of people that think they suffer from depression are actually suffering from despair. I guess the more clinical term would be situational depression. It's understandable to constantly feel anxiety over rising rents and living expenses in the face of flat wages, and their constant poor mood from the stress makes them think they're suffering from depression, and they'll seek help. But a Prozac or whatever won't make you feel any better about having a 2-digit bank account after paying the bills.
    - mrguyorama 2y ago
      >don't fix the underlying causes. The underlying cause is that my brain is broken and we have a century worth of genetic evidence that it is simply a heritable thing to have a brain broken in certain ways. I get "sad" if the day is short FFS. Sure that's understandable from a biological perspective, but pretty incompatible with living at a high latitude with long winters. It's a genetic defect.
- throw18376 2y ago
  at the very least, they can induce manic episodes for some susceptible people. that alone proves these are real psychoactive drugs that have powerful effects on the brain. there is still a question of whether they are really an overall good treatment for depression. i think the answer is "yes", but certainly people could disagree in good faith. my problem is the most common anti-SSRI argument is that they are just placebos that do nothing at all, which is ridiculous.
kelseyfrog 2y ago
There's a strong bias toward assuming that an effective treatment must necessarily address the disease etiologically.
- hirvi74 2y ago
  I concur. If I am not mistaken, it's quite difficult to separate signal vs. noise. I remember readying a study that observed that something like 50% of depressive episodes in people spontaneously resolve within a year without any treatment whatsoever. Obviously that makes things quite difficult. If one starts an antidepressant, and six months later, is free from depression, then what evidence is there that the antidepressant vs. time was the resolution? Perhaps stopping the antidepressant would be an indication? But then again, any rebound depression might just be from the disruption in homeostasis that the body has become accustomed to from the antidepressant.
  - kelseyfrog 2y ago
    Even with a high signal, you can have non-etiologically-based treatments. I'm sure with a high enough sample size, you could statistically conclude that giving depressed people $1000/week their levels of depression as measured by the Beck Depression Inventory. That doesn't necessarily mean that being poor is etiologically connected to depression. I'm certain people were depressed before the invention of money. There is, however, a strong bias toward unnecessarily searching for a causal connection between treatment and disease, but also dismissing effective treatments where cause and treatment aren't sufficient connected in people's minds. eg: you're only treating the symptoms as if that can't substantially improve peoples' lives.
  - deleted 2y ago
    [deleted]
- idrathernot 2y ago
  Without empirical evidence we basically have no evidence at all.
  - 2y ago
hirvi74 2y ago
It's not just anti-depressants, no? If I am mistaken, we do not know why plenty of medications work -- especially those within in the domain of mental disorders. For example, why does lithium work, amphetamines, etc.? Obviously, we know such medications work, but not the "how"/"why."
- deleted 2y ago
  [deleted]
- vrc 2y ago
  Tylenol is my favorite drug in this bucket
  - hirvi74 2y ago
    I'll be the first to admit I know very little about acetaminophen, but what I know is that it can be good for breaking fevers and allegedly it's useful for pain relief (not my experiences)? I try my hardest to avoid it due to the associated hepatotoxicity which, to my understanding, is less likely/not observed in other NSAIDs.
    - gorlilla 2y ago
      It's not an NSAID at all, which have their own pitfalls with damage to the GI tract over time.
      - hirvi74 2y ago
        Huh, you are absolutely right. It's not an NSAID. Thank you for the correction. Sure, I do agree that NSAID have their own pitfalls. I am sure most, if not all, medications have pitfalls at some intersection between dosage and time. My understand of acetaminophen is that the line between therapeutic help and harm is rather small for compared to many other OTC medications. Just based off of a few brief searches it is recommended that an adult take no more than 2 tablets every 4 to 6 hours. One tablet is typically 325mg. According to this Harvard Health link [1]: "For the average healthy adult, the absolute maximum daily dose is no more than 4,000 milligrams (mg) from all sources. But in some people, doses close to the 4,000 mg daily limit for adults could still be toxic to the liver. It's safest to take only what you need, and to not exceed 3,000 mg a day whenever possible, especially if you use acetaminophen often." So, even with infrequent usage, and by following proper instructions, liver toxicity could still technically occur within just 24 hours of usage. How likely is it? Well, that I have not looked into. Overall, my point is: why risk even go down that road? Now, I could be wrong (again), but most research I have seen on the topic pertains to pain relief where Tylenol doesn't seem as effective as alternatives. Perhaps for other aliments it's better, but again, that begs the question -- better compared to what else and what are those risks? [1] https://www.health.harvard.edu/pain/acetaminophen-safety-be-cautious-but-not-afraid https://www.health.harvard.edu/pain/acetaminophen-safety-be-...
cosmin800 2y ago
Because they don't, just make people addicted, soooo many.
- alphager 2y ago
  Both anecdotes and data disprove your statement. They don't work in all cases and we currently don't know if that is because depression is actually a symptom of multiple diseases and antidepressants just work on some of them or if there's something in people's brains that make them immune to antidepressants.
- radiojosh 2y ago
  I think one of the biggest problems is that psychiatrists have to step through a procession of different drugs in an order specified by insurance companies. Cheap to expensive, traditional to exotic. And the most traditional drugs at this point are SSRIs, which have very mixed evidence for their effectiveness. After being dragged along through an endless series of different SSRIs, I finally found a psychiatrist who runs a genetic test prior to treatment. And wouldn't you know it, I have a gene that makes SSRIs ineffective if you're a Caucasian, and yes, I'm Caucasian. The test also says that I'm an ideal candidate for methylphenidate, that I barely feel CBD, and I'll have a hard time with all but the most exotic antidepressants.
raincom 2y ago
Here is a wiki page on drugs whose mechanism of action is unknown: https://en.m.wikipedia.org/wiki/Category:Drugs_with_unknown_mechanisms_of_action https://en.m.wikipedia.org/wiki/Category:Drugs_with_unknown_... This tells us why many species have found herbal stuff to alleviate pain, cure ailments, etc.
LegitShady 2y ago
brain complicated. many chemicals, many structures, many unknowns.
idiocrat 2y ago
> Moncrieff argues that drug companies, doctors and psychiatrists benefit from this situation because it’s profitable. I recently discovered low dose lithium for myself. (self-medicated OTC lithium orotate, 5mg 2x daily) This has greatly improved my mood and attitude to life. Lithium has removed most of my procrastination by eliminating negative thoughts (i.e. "that is a difficult task, so I better defer this to tomorrow"). Starting and finishing something has become so easy now. All work and household related tasks are now lightweight (chores, washing dishes, making beds). All things I found annoying to do before. I am generally happy, positive-minded and open-minded toward other people. Lithium is not a sedative or a pain killer -- I am still normally tired after a day, but now I am prioritizing my time rationally, and not based on negative emotions. Somebody said that Lithium is too cheap, no profit to make, so pharma companies will not spend much on further R&D. P.S. Of course lithium is a psycho-active substance, and surely has some side-effects. All above is only my personal experience. Please consult your doctor and be extremely careful with self-medication.
- butlike 2y ago
  Interesting. What's your sentiment on abrupt cessation vs titrating down, provided you ever wanted to stop taking it?
- cvz 2y ago
  Lithium salts would be a wonder drug if they didn't cause permanent kidney damage.
- herbst 2y ago
  Lithium worked amazing for my partner, but: - Kidney damage is very likely - It should not be combined with ibuprofen - Possibly safe Withdrawal took forever
razodactyl 2y ago
Antidepressants are interesting but only part of the story. People with depression don't fully understand how "broken" they actually are and normalise depressive behaviours further drilling in the issue. I've dealt with bad depression before to the point of suicidal ideation and weird conspiratorial paranoia... on the other side of it you get a very realised perspective of what these words mean to sufferers instead of a surface level description. Antidepressants seem to be a way to disrupt the usual flow of information and allow a rewrite to occur; LSD seems to be a theme these days for the same effect but I get the feeling something that's instantly hallucinogenic isn't the best way to rewire a mind... Research continues though. Another example could be (for those who have been) addiction to nicotine or any other substance: You don't understand why someone just doesn't stop until you've experienced it firsthand. There are drugs that disrupt the addiction pathways and allow an addict to recover.
abosley 2y ago
Even more evidence we have no idea what is going on: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10509198/#:~:text=These%20studies%20suggest%20that%20vagus,depression%20and%20other%20psychiatric%20disorders https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10509198/#:~:te.... My silly anecdotal theory is that the vagal nerve and the gut are very involved in these various disfunctions for some populations....also see use of SSRIs as off-label solutions for GERD, IBS etc.
chatmasta 2y ago
If you can’t quantify “level of depression,” then you can’t measure improvement from any intervention, pharmaceutical or otherwise. We can’t know how antidepressants work until we better understand how depression works.
henriquez 2y ago
Because we don’t know how the brain works yet. Modern psychology and psychiatry is a joke.
- skyyler 2y ago
  It's incomplete but it's the best we have. I think the next 50 years of psychiatric research are going to be wild.
- nradov 2y ago
  What would you propose as an alternative?
hnpolicestate 2y ago
Without antidepressants I'd be fully housebound from agoraphobia. They work. Not perfect. And tolerance at different dosages build over time. But it's not a placebo effect.
- dimal 2y ago
  Correction: they work _for you_. This may sound pedantic but I see this blanket assertion all the time from people who take psych meds and have them work for them. There is a very large group of people for whom they do not work, and others in which they cause serious harm. I’m glad they work for you, but please don’t assume that they work for everyone. They don’t.
  - burnished 2y ago
    Thats clear from context, not every personal account needs the PSA, especially since your access is mediated by layers of professionals.
    - dimal 2y ago
      I disagree. It’s not clear from the context. People often generalize their experiences to think they apply to everyone. With psych meds, this is very common. I don’t expect a PSA, just a recognition that “they work” cannot be stated as an absolute. I don’t know what you mean by access being mediated by layers of professionals.
      - burnished 2y ago
        You have to first see a doctor who will prescribe the medication followed by a pharmacist. I don't see a claim by OP that their experience generalizes absolutely. I'm also having a hard time seriously believing you don't think people are aware that folk can have varied reactions, people become aware of allergies as a concept usually well before psychiatric medication. Just to be clear - I don't mind you adding in that additional context/reminder, I think additional perspective like that is frequently helpful, but I do resent you demanding others add it in your stead like they've missed an obligation or made a mistake.

92 points by XzetaU8 2y ago

P_I_Staker 2y ago

They don't.

mberger 2y ago
The fact that I am not a smear at the bottom of a tall building is a direct contradiction to your statement and shows that they do for some people. No, I was going to 'get better' without help. Yes, I fed trolls.
- razodactyl 2y ago
  Did you get the "how could I use this to off myself" loop? I think antidepressants are only part of the equation but many stay on them and don't fix the underlying causes.
  - mberger 2y ago
    I was already there before the antidepressants kicked in. I would look at something and evaluate how much it would hurt, if it would work and what state I would be left in if it only kind of worked. I was also objectively in a good spot. I had a full time job with good people, a loving partner, a stable place to live, no kids and very few other stressors. I realized that there was very little I could do that I could summon the motivation for so I sought help. I was referred to a psychiatrist who put me on Prozac. There is a phrase that stuck with me that he said. He said it would give me a 'thicker skin'. I think this was key since every comment that was directed my way was over analyzed to look for signs of insult. It was as if everything in the world had a negative pressure on it. I think of it as events that happen like objects floating in water. The surface of the water is the neutral point, neither good nor bad. A comment would be like a ping pong ball, almost completely positive. Through my distorted view, it would be like a 10g weight was attached to it. It would become 90% negative and I would wonder what had prompted it. The antidepressants removed a lot of that weight so I can evaluate things without that bias. I feel like this is what people mean when they say they're drowning in sorrow. There is a weight attached to everything that makes the events more negative, less uplifting. The things that normally are buoyant don't support them anymore. I think it's the same for depression except that in sorrow, the cause is usually obvious. In depression, the swimmer is on their last few kicks. At worst, they've turned to temporary relief in the form of hard drugs that makes them bob.
  - amanaplanacanal 2y ago
    I think if we know the underlying cause, we don’t call it depression, we call it sadness.
    - goatforce5 2y ago
      Or it might be a case of situational depression: https://www.webmd.com/depression/situational-depression https://www.webmd.com/depression/situational-depression
      - Sohcahtoa82 2y ago
        I've said before that I think a lot of people that think they suffer from depression are actually suffering from despair. I guess the more clinical term would be situational depression. It's understandable to constantly feel anxiety over rising rents and living expenses in the face of flat wages, and their constant poor mood from the stress makes them think they're suffering from depression, and they'll seek help. But a Prozac or whatever won't make you feel any better about having a 2-digit bank account after paying the bills.
  - mrguyorama 2y ago
    >don't fix the underlying causes. The underlying cause is that my brain is broken and we have a century worth of genetic evidence that it is simply a heritable thing to have a brain broken in certain ways. I get "sad" if the day is short FFS. Sure that's understandable from a biological perspective, but pretty incompatible with living at a high latitude with long winters. It's a genetic defect.
throw18376 2y ago
at the very least, they can induce manic episodes for some susceptible people. that alone proves these are real psychoactive drugs that have powerful effects on the brain. there is still a question of whether they are really an overall good treatment for depression. i think the answer is "yes", but certainly people could disagree in good faith. my problem is the most common anti-SSRI argument is that they are just placebos that do nothing at all, which is ridiculous.

kelseyfrog 2y ago

There's a strong bias toward assuming that an effective treatment must necessarily address the disease etiologically.

hirvi74 2y ago
I concur. If I am not mistaken, it's quite difficult to separate signal vs. noise. I remember readying a study that observed that something like 50% of depressive episodes in people spontaneously resolve within a year without any treatment whatsoever. Obviously that makes things quite difficult. If one starts an antidepressant, and six months later, is free from depression, then what evidence is there that the antidepressant vs. time was the resolution? Perhaps stopping the antidepressant would be an indication? But then again, any rebound depression might just be from the disruption in homeostasis that the body has become accustomed to from the antidepressant.
- kelseyfrog 2y ago
  Even with a high signal, you can have non-etiologically-based treatments. I'm sure with a high enough sample size, you could statistically conclude that giving depressed people $1000/week their levels of depression as measured by the Beck Depression Inventory. That doesn't necessarily mean that being poor is etiologically connected to depression. I'm certain people were depressed before the invention of money. There is, however, a strong bias toward unnecessarily searching for a causal connection between treatment and disease, but also dismissing effective treatments where cause and treatment aren't sufficient connected in people's minds. eg: you're only treating the symptoms as if that can't substantially improve peoples' lives.
- deleted 2y ago
  [deleted]
idrathernot 2y ago
Without empirical evidence we basically have no evidence at all.
- 2y ago

hirvi74 2y ago

It's not just anti-depressants, no? If I am mistaken, we do not know why plenty of medications work -- especially those within in the domain of mental disorders. For example, why does lithium work, amphetamines, etc.? Obviously, we know such medications work, but not the "how"/"why."

deleted 2y ago
[deleted]
vrc 2y ago
Tylenol is my favorite drug in this bucket
- hirvi74 2y ago
  I'll be the first to admit I know very little about acetaminophen, but what I know is that it can be good for breaking fevers and allegedly it's useful for pain relief (not my experiences)? I try my hardest to avoid it due to the associated hepatotoxicity which, to my understanding, is less likely/not observed in other NSAIDs.
  - gorlilla 2y ago
    It's not an NSAID at all, which have their own pitfalls with damage to the GI tract over time.
    - hirvi74 2y ago
      Huh, you are absolutely right. It's not an NSAID. Thank you for the correction. Sure, I do agree that NSAID have their own pitfalls. I am sure most, if not all, medications have pitfalls at some intersection between dosage and time. My understand of acetaminophen is that the line between therapeutic help and harm is rather small for compared to many other OTC medications. Just based off of a few brief searches it is recommended that an adult take no more than 2 tablets every 4 to 6 hours. One tablet is typically 325mg. According to this Harvard Health link [1]: "For the average healthy adult, the absolute maximum daily dose is no more than 4,000 milligrams (mg) from all sources. But in some people, doses close to the 4,000 mg daily limit for adults could still be toxic to the liver. It's safest to take only what you need, and to not exceed 3,000 mg a day whenever possible, especially if you use acetaminophen often." So, even with infrequent usage, and by following proper instructions, liver toxicity could still technically occur within just 24 hours of usage. How likely is it? Well, that I have not looked into. Overall, my point is: why risk even go down that road? Now, I could be wrong (again), but most research I have seen on the topic pertains to pain relief where Tylenol doesn't seem as effective as alternatives. Perhaps for other aliments it's better, but again, that begs the question -- better compared to what else and what are those risks? [1] https://www.health.harvard.edu/pain/acetaminophen-safety-be-cautious-but-not-afraid https://www.health.harvard.edu/pain/acetaminophen-safety-be-...

cosmin800 2y ago

Because they don't, just make people addicted, soooo many.

alphager 2y ago
Both anecdotes and data disprove your statement. They don't work in all cases and we currently don't know if that is because depression is actually a symptom of multiple diseases and antidepressants just work on some of them or if there's something in people's brains that make them immune to antidepressants.
radiojosh 2y ago
I think one of the biggest problems is that psychiatrists have to step through a procession of different drugs in an order specified by insurance companies. Cheap to expensive, traditional to exotic. And the most traditional drugs at this point are SSRIs, which have very mixed evidence for their effectiveness. After being dragged along through an endless series of different SSRIs, I finally found a psychiatrist who runs a genetic test prior to treatment. And wouldn't you know it, I have a gene that makes SSRIs ineffective if you're a Caucasian, and yes, I'm Caucasian. The test also says that I'm an ideal candidate for methylphenidate, that I barely feel CBD, and I'll have a hard time with all but the most exotic antidepressants.

raincom 2y ago

Here is a wiki page on drugs whose mechanism of action is unknown: https://en.m.wikipedia.org/wiki/Category:Drugs_with_unknown_mechanisms_of_action https://en.m.wikipedia.org/wiki/Category:Drugs_with_unknown_... This tells us why many species have found herbal stuff to alleviate pain, cure ailments, etc.

LegitShady 2y ago

brain complicated. many chemicals, many structures, many unknowns.

idiocrat 2y ago

> Moncrieff argues that drug companies, doctors and psychiatrists benefit from this situation because it’s profitable. I recently discovered low dose lithium for myself. (self-medicated OTC lithium orotate, 5mg 2x daily) This has greatly improved my mood and attitude to life. Lithium has removed most of my procrastination by eliminating negative thoughts (i.e. "that is a difficult task, so I better defer this to tomorrow"). Starting and finishing something has become so easy now. All work and household related tasks are now lightweight (chores, washing dishes, making beds). All things I found annoying to do before. I am generally happy, positive-minded and open-minded toward other people. Lithium is not a sedative or a pain killer -- I am still normally tired after a day, but now I am prioritizing my time rationally, and not based on negative emotions. Somebody said that Lithium is too cheap, no profit to make, so pharma companies will not spend much on further R&D. P.S. Of course lithium is a psycho-active substance, and surely has some side-effects. All above is only my personal experience. Please consult your doctor and be extremely careful with self-medication.

butlike 2y ago
Interesting. What's your sentiment on abrupt cessation vs titrating down, provided you ever wanted to stop taking it?
cvz 2y ago
Lithium salts would be a wonder drug if they didn't cause permanent kidney damage.
herbst 2y ago
Lithium worked amazing for my partner, but: - Kidney damage is very likely - It should not be combined with ibuprofen - Possibly safe Withdrawal took forever

razodactyl 2y ago

Antidepressants are interesting but only part of the story. People with depression don't fully understand how "broken" they actually are and normalise depressive behaviours further drilling in the issue. I've dealt with bad depression before to the point of suicidal ideation and weird conspiratorial paranoia... on the other side of it you get a very realised perspective of what these words mean to sufferers instead of a surface level description. Antidepressants seem to be a way to disrupt the usual flow of information and allow a rewrite to occur; LSD seems to be a theme these days for the same effect but I get the feeling something that's instantly hallucinogenic isn't the best way to rewire a mind... Research continues though. Another example could be (for those who have been) addiction to nicotine or any other substance: You don't understand why someone just doesn't stop until you've experienced it firsthand. There are drugs that disrupt the addiction pathways and allow an addict to recover.

abosley 2y ago

Even more evidence we have no idea what is going on: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10509198/#:~:text=These%20studies%20suggest%20that%20vagus,depression%20and%20other%20psychiatric%20disorders https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10509198/#:~:te.... My silly anecdotal theory is that the vagal nerve and the gut are very involved in these various disfunctions for some populations....also see use of SSRIs as off-label solutions for GERD, IBS etc.

chatmasta 2y ago

If you can’t quantify “level of depression,” then you can’t measure improvement from any intervention, pharmaceutical or otherwise. We can’t know how antidepressants work until we better understand how depression works.

henriquez 2y ago

Because we don’t know how the brain works yet. Modern psychology and psychiatry is a joke.

skyyler 2y ago
It's incomplete but it's the best we have. I think the next 50 years of psychiatric research are going to be wild.
nradov 2y ago
What would you propose as an alternative?

hnpolicestate 2y ago

Without antidepressants I'd be fully housebound from agoraphobia. They work. Not perfect. And tolerance at different dosages build over time. But it's not a placebo effect.

dimal 2y ago
Correction: they work _for you_. This may sound pedantic but I see this blanket assertion all the time from people who take psych meds and have them work for them. There is a very large group of people for whom they do not work, and others in which they cause serious harm. I’m glad they work for you, but please don’t assume that they work for everyone. They don’t.
- burnished 2y ago
  Thats clear from context, not every personal account needs the PSA, especially since your access is mediated by layers of professionals.
  - dimal 2y ago
    I disagree. It’s not clear from the context. People often generalize their experiences to think they apply to everyone. With psych meds, this is very common. I don’t expect a PSA, just a recognition that “they work” cannot be stated as an absolute. I don’t know what you mean by access being mediated by layers of professionals.
    - burnished 2y ago
      You have to first see a doctor who will prescribe the medication followed by a pharmacist. I don't see a claim by OP that their experience generalizes absolutely. I'm also having a hard time seriously believing you don't think people are aware that folk can have varied reactions, people become aware of allergies as a concept usually well before psychiatric medication. Just to be clear - I don't mind you adding in that additional context/reminder, I think additional perspective like that is frequently helpful, but I do resent you demanding others add it in your stead like they've missed an obligation or made a mistake.