Why don't we know how antidepressants work yet?

https://www.chemistryworld.com/features/why-dont-we-know-how-antidepressants-work-yet/4019673.article

by XzetaU8 • 2 years ago

92 112 2 years ago

chemistryworld.com

henriquez• 2 years ago

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

skyyler• 2 years 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• 2 years ago

What would you propose as an alternative?

hnpolicestate2• 2 years 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.

beaglesss• 2 years ago

I am curious how they link to suicide and homicide. Antidepressants seem to be most dangerous when they make people just motivated enough to execute maladaptive ideas but not functional enough to become happy productive people.

This is obviously a corner case that doesn't apply to the vast majority of people on antidepressants but it brings up some worthwhile discussions.

more_corn2• 2 years ago

If you stop taking your SSRI suddenly, your depression is even worse than when you started. This is why doctors strongly urge patients to ween instead of dropping off suddenly. That effect (massive increase in symptoms in cases where patients stop medication suddenly) probably contributes to a significant portion of the risk.

yareally• 2 years ago

It may sound odd, but suicides can happen when the medication is actually working. It gives the patient just enough motivation to finally do what they were unable to do because they were so paralyzed by anxiety and depression. It's really sad.

more_corn2• 2 years ago

Exactly. We know that they DO work, but we don’t know how.

Not a doctor and this is not brain health advice, but SSRIs take several weeks to start working.

If they work because “more serotonin in the brain treatments depression” they should start working instantly. The two week lag indicates that they work based on a secondary effect caused by long term elevation of serotonin. And it’s maddening that we don’t seem to know what that effect is.

marssaxman• 2 years ago

Sometimes an SSRI does start working instantly. That was my experience the first time I took Zoloft; I remember leaving work early that afternoon for a walk in the park, marveling at the way all the colors in the world had become more vivid.

When I tried Zoloft again years later, during another bout of depression, I felt nothing: not right away, not for weeks after, no change at all.

I suspect that there is not really any such ailment as depression, any more than there is any such disease as fever; that is, the pattern of symptoms we see represents a reaction to some underlying problem, and many different kinds of problems may cause similar symptoms, while requiring different solutions.

dimal3• 2 years 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.

burnished3• 2 years ago

Thats clear from context, not every personal account needs the PSA, especially since your access is mediated by layers of professionals.

hnpolicestate2• 2 years ago

"There is a very large group of people for whom they do not work"

- many people are unwilling to wait the proper amount of time "4-6 weeks" for efficacy to manifest *especially* when for the first 2-3 weeks you many times feel much worse than baseline.

First month on Effexor made me feel miserable. More anxious but much, much more irritable and depressed. Then one day a month in I'm sitting at my desk and I suddenly feel high as a kite lol. Melting bliss.

That feeling too fades and then you just feel better than baseline until you build tolerance to current dose. Raise, rinse and repeat.

Better than having to be near an exit whenever inside a structure!

olyjohn• 2 years ago

This is the same for every drug. None of them work the same for everybody all the time. Like they say everybody is different.

kelseyfrog3• 2 years ago

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

hirvi749• 2 years 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.

kelseyfrog3• 2 years 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.

idrathernot2• 2 years ago

Without empirical evidence we basically have no evidence at all.

kelseyfrog3• 2 years ago

Empiricism is certainly an epistemic paradigm, but am I right in understanding that you only derive knowledge through empiricism? I find that hard to believe. Can you explain?

hirvi749• 2 years 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."

vrc2• 2 years ago

Tylenol is my favorite drug in this bucket

hirvi749• 2 years 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.

devilbunny3• 2 years ago

Amphetamines push catecholamines out of presynaptic neurons; that’s pretty settled.

Here’s a fun one: we don’t know how general anesthetics work. From ether to desflurane to propofol, they all exhibit similar behavior, but we actually don’t know exactly what that mechanism is.

Nasrudith• 2 years ago

I thought we got a major hint of it being from disrupting nerve transmission mechanisms. Due to of all things anesthesizing plants with gases resulting in disruption of "conscious" behavior like facing towards sunlight or venus flytraps closing upon being touched.

Bluescreenbuddy• 2 years ago

Tiny 2x4's whack the brain cells

hirvi749• 2 years ago

Amphetamines push catecholamines out of presynaptic neurons; that’s pretty settled.

Sure, I am not doubting that we have some understanding of some of the mechanisms. We know SSRI's affect serotonin, but not how they work in terms of providing therapeutic relief. My point about amphetamines was the same. We might know that catecholamines are pushed out of the presynaptic neurons, but how/why does that treat conditions like ADHD, Narcolepsy, Binge-Eating Disorder, etc.?

gofreddygo• 2 years ago

Classic property of medical science. The science of trials and errors. We know what works, under which conditions and doses and what side effects it may have. Thats useful, important and urgent with real consequences.

The "why" costs money, resources and an itch for genuine curiosity and ingenuity with mostly negative returns. So it remains unknown, while we focus on the combining 2 or more things we already know and see where that can be sold.

Another observation here is there's a lot of money riding on "pseudo science". See any superfood or beauty products for example. You take a data point that is demonstrated under certain conditions in a controlled environment. Make that single data point a centerpiece of evidence, tack the usual goop on it, market it, label it and place it on the front aisles of Trader Joe's. Now there's a lot of incentive to keep the "why" away from consumers walking those aisles.

MetalGuru• 2 years ago

God, what a depressing take

jmcgough2• 2 years ago

Here's an even better one - we don't know how alcohol works. I always assumed it was gabaergic in nature but it turns out that it's a really unusual drug with extremely weak binding, which is why it requires large amounts to have a psychoactive effect, making it challenging to use for binding studies.

P_I_Staker• 2 years ago

They don't.

mberger2• 2 years 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.

razodactyl3• 2 years 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.

throw18376• 2 years 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.

cosmin800• 2 years ago

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

alphager• 2 years 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• 2 years 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• 2 years ago

Here is a wiki page on drugs whose mechanism of action is unknown: 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• 2 years ago

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

idiocrat• 2 years 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.

butlike2• 2 years ago

Interesting. What's your sentiment on abrupt cessation vs titrating down, provided you ever wanted to stop taking it?

cvz• 2 years ago

Lithium salts would be a wonder drug if they didn't cause permanent kidney damage.

herbst• 2 years 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

razodactyl3• 2 years 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• 2 years ago

Even more evidence we have no idea what is going on: 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• 2 years 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.

Why don't we know how antidepressants work yet?

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