Why don't we know how antidepressants work yet?(chemistryworld.com)
chemistryworld.com
Why don't we know how antidepressants work yet?
https://www.chemistryworld.com/features/why-dont-we-know-how-antidepressants-work-yet/4019673.article
117 comments
Lithium salts would be a wonder drug if they didn't cause permanent kidney damage.
Lithium worked amazing for my partner, but:
- Kidney damage is very likely
- It should not be combined with ibuprofen
- Possibly safe Withdrawal took forever
- Kidney damage is very likely
- It should not be combined with ibuprofen
- Possibly safe Withdrawal took forever
Interesting. What's your sentiment on abrupt cessation vs titrating down, provided you ever wanted to stop taking it?
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."
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."
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.
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.
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.
Oh yeah, there are several plausible theories with decent evidence to support them, but nothing remotely definitive.
Anesthesia is weird. I'm an anesthesiologist; believe me, there are tons of weird things about the human body that you learn from throwing various compounds at bodies and seeing what happens. Xenon is an effective (though expensive) anesthetic gas by itself. People of West African descent occasionally (~10-20%, usually on the lower end of that) have a hypersalivatory response to cholinergic stimulation. Drugs that should be fine and got approved but turn out to kill kids disproportionately (rapacuronium).
Much of our practice is derived from "we've been doing this without too many bad effects for a long time with these drugs, so we're going to continue using them rather than try something new unless the new one brings something to the table that's a slam-dunk". Diethyl ether is slow, it smells awful, and it's flammable (and will form explosive peroxides if stored too long), but it's still a good anesthetic. If I had to re-create civilization from scratch, that would be one of the first drugs I tried to make.
Anesthesia is weird. I'm an anesthesiologist; believe me, there are tons of weird things about the human body that you learn from throwing various compounds at bodies and seeing what happens. Xenon is an effective (though expensive) anesthetic gas by itself. People of West African descent occasionally (~10-20%, usually on the lower end of that) have a hypersalivatory response to cholinergic stimulation. Drugs that should be fine and got approved but turn out to kill kids disproportionately (rapacuronium).
Much of our practice is derived from "we've been doing this without too many bad effects for a long time with these drugs, so we're going to continue using them rather than try something new unless the new one brings something to the table that's a slam-dunk". Diethyl ether is slow, it smells awful, and it's flammable (and will form explosive peroxides if stored too long), but it's still a good anesthetic. If I had to re-create civilization from scratch, that would be one of the first drugs I tried to make.
would chloroform work as well? it is easyer to produce.
Chloroform is toxic to the liver and kidneys and can cause arrhythmias
And a significant cardiac depressant, even by the standards of general anesthetics (which pretty much all have at least some cardiac depressant effect, even ketamine - you don't typically see drops in blood pressure because it stimulates the sympathetic nervous system, but if someone's been on an amphetamine binge and is out of catecholamines, ketamine will drop their pressure too).
In the days before routine pulse oximetry (which, in addition to measuring oxygenation of the blood, is proof of a pulse - it does not work on heart-lung bypass), the fact that the heart was beating was confirmed by using an esophageal or precordial stethoscope. This was typically connected to an earpiece that was molded to the individual user by a simple piece of tubing. Precordial stethoscopes are a neat thing to see; they are just the "bell" part of a stethoscope made out of a decent-sized piece of metal so that the weight would keep it on the patient's chest and prevent it from moving around. I'm told that anesthesiologists who practiced in this era, which was also before each anesthesia monitor had continuous gas sampling of the patient's respirations to determine the concentration of anesthetic agents, could recognize when a patient under halothane (which was also a well-known cardiac depressant, but unlike many other agents had a non-irritating smell and so could be used for pediatric cases without an existing IV, where anesthesia is induced by simply breathing the gas) was getting too deep by the change of the heart sounds. We have a newer, less cardiac-affecting anesthetic now, sevoflurane, which has essentially replaced halothane in developed countries and I would assume most less-developed ones as well (because it's now off-patent and pretty cheap).
In the days before routine pulse oximetry (which, in addition to measuring oxygenation of the blood, is proof of a pulse - it does not work on heart-lung bypass), the fact that the heart was beating was confirmed by using an esophageal or precordial stethoscope. This was typically connected to an earpiece that was molded to the individual user by a simple piece of tubing. Precordial stethoscopes are a neat thing to see; they are just the "bell" part of a stethoscope made out of a decent-sized piece of metal so that the weight would keep it on the patient's chest and prevent it from moving around. I'm told that anesthesiologists who practiced in this era, which was also before each anesthesia monitor had continuous gas sampling of the patient's respirations to determine the concentration of anesthetic agents, could recognize when a patient under halothane (which was also a well-known cardiac depressant, but unlike many other agents had a non-irritating smell and so could be used for pediatric cases without an existing IV, where anesthesia is induced by simply breathing the gas) was getting too deep by the change of the heart sounds. We have a newer, less cardiac-affecting anesthetic now, sevoflurane, which has essentially replaced halothane in developed countries and I would assume most less-developed ones as well (because it's now off-patent and pretty cheap).
> 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.?
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.?
Well, one reason we don't know why SSRIs give therapeutic relief is because they don't, actually!
There has been no clinical evidence on SSRIs mitigating the effects if clinical depression, and a lot if anecdata I've seen is that they're very hit-or-miss.
There has been no clinical evidence on SSRIs mitigating the effects if clinical depression, and a lot if anecdata I've seen is that they're very hit-or-miss.
We do know that for the lucky ones on which SSRIs do work, it seems to reverse some of the brain structure changes associated with depression -- some abnormally small parts tend to grow thicker. The reversal can be seen at one week after the start of medication use, before one can even tell whether an antidepressant has started working (a commonly-cited duration would be 2 weeks).
[1]: https://www.nature.com/articles/s44220-023-00187-w
[1]: https://www.nature.com/articles/s44220-023-00187-w
I was under the assumption norepinephrine was the desired neurotransmitter for ADHD patients, but in order to cross the blood-brain barrier, it needed to be attached to dopamine.
This makes the effects of extra dopamine in the system a side-effect, not the feature. But I'm not a doctor, so I could be wrong on that.
Could it be that catecholamines have a higher affinity for the presynaptic neurons, so we need the dopamine to push it out, at which point there's a chance the norepinephrine can get into the receptor?
This makes the effects of extra dopamine in the system a side-effect, not the feature. But I'm not a doctor, so I could be wrong on that.
Could it be that catecholamines have a higher affinity for the presynaptic neurons, so we need the dopamine to push it out, at which point there's a chance the norepinephrine can get into the receptor?
Norepinephrine is released from neurons both in the brain and in the peripheral nervous system, it is the drug that crosses the blood brain barrier not norepinephrine.
NE may be desirable in some subtypes of ADHD because varying mechanisms can cause the same symptomology, its complicated and we don't know enough yet. Dopamine also plays an important role in attention
In no way does dopamine "attach" to NE, so I'm not sure what you're trying to say there
There are receptors for catecholamines both pre and postsynaptically, so it is a misstatement to say that they have an affinity for one or the other.
The way that synaptic release works is generally through vesicular release but in the case of amphetamines what they do is not only stop the reuptake of dopamine or NE from their synapses but they can also cause efflux out of the reuptake transporter.
Generally speaking NE and dopamine are in different neurons but there may be some crossover.
https://en.m.wikipedia.org/wiki/Neuron
https://en.m.wikipedia.org/wiki/Synapse
NE may be desirable in some subtypes of ADHD because varying mechanisms can cause the same symptomology, its complicated and we don't know enough yet. Dopamine also plays an important role in attention
In no way does dopamine "attach" to NE, so I'm not sure what you're trying to say there
There are receptors for catecholamines both pre and postsynaptically, so it is a misstatement to say that they have an affinity for one or the other.
The way that synaptic release works is generally through vesicular release but in the case of amphetamines what they do is not only stop the reuptake of dopamine or NE from their synapses but they can also cause efflux out of the reuptake transporter.
Generally speaking NE and dopamine are in different neurons but there may be some crossover.
https://en.m.wikipedia.org/wiki/Neuron
https://en.m.wikipedia.org/wiki/Synapse
>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.?
those disorders are often characterized by inappropriate dopamine/norepinepherine levels.
if you push more catecholamines into availability, while also reducing the ability for them to be re-uptaked by their associated transport chains, then the patient begins to edge towards a more normal saturation level of the deficit chemicals.
those disorders are often characterized by inappropriate dopamine/norepinepherine levels.
if you push more catecholamines into availability, while also reducing the ability for them to be re-uptaked by their associated transport chains, then the patient begins to edge towards a more normal saturation level of the deficit chemicals.
> those disorders are often characterized by inappropriate dopamine/norepinepherine levels.
Those are secondary effects of underlying issues in ADHD, Binge-Eating, etc. The core issue is something not working well, such as in ADHD, the brain may have smaller prefrontal cortex regions (or less connected, etc) and thus have problem with self-regulation. You can sort of work around this by boosting dopamine, but it is working around the issue.
It is akin to an engine that is under powered so we figure you show to press the gas pedal harder (dopamine increases focus/effort/alert, so it is like pressing on the gas.) But the core issue is that the engine is underpowered in comparison to others. And it may be underpowered for a large variety of very specific reasons, including genetics (controlling development, or resistance to stressors), physical trauma, sleep, etc.
Those are secondary effects of underlying issues in ADHD, Binge-Eating, etc. The core issue is something not working well, such as in ADHD, the brain may have smaller prefrontal cortex regions (or less connected, etc) and thus have problem with self-regulation. You can sort of work around this by boosting dopamine, but it is working around the issue.
It is akin to an engine that is under powered so we figure you show to press the gas pedal harder (dopamine increases focus/effort/alert, so it is like pressing on the gas.) But the core issue is that the engine is underpowered in comparison to others. And it may be underpowered for a large variety of very specific reasons, including genetics (controlling development, or resistance to stressors), physical trauma, sleep, etc.
> those disorders are often characterized by inappropriate dopamine/norepinepherine levels.
My understanding is that is still hypothetical at this point, albeit the leading hypothesis. Personally, I think that ADHD is just an abstraction for a set of behaviors. I am not trying to downplay its severity, it's caused me undue suffering, but my point being that I believe there are multiple etiologies that have fairly similar symptoms.
After all, stimulants have a wide variance in efficacy for people with ADHD, and there are plenty of medications that are even non-stimulants, so I think that should be a sign that there is much more to this disorder(s) than just dopamine and norepinephrine.
But hey, what do I know?
My understanding is that is still hypothetical at this point, albeit the leading hypothesis. Personally, I think that ADHD is just an abstraction for a set of behaviors. I am not trying to downplay its severity, it's caused me undue suffering, but my point being that I believe there are multiple etiologies that have fairly similar symptoms.
After all, stimulants have a wide variance in efficacy for people with ADHD, and there are plenty of medications that are even non-stimulants, so I think that should be a sign that there is much more to this disorder(s) than just dopamine and norepinephrine.
But hey, what do I know?
That doesn't explain why SSRIs take weeks to work, rather than hours/days.
My understanding is that with SSRIs it's not the drug itself that helps but rather the repercussions of developing a "tolerance" to the drug.
Trying to remember what a neuroscience friend of mine said; your brain, like your body, tries to reach some sort of homeostasis. Inhibiting the reuptake of serotonin results in there being more serotonin in the brain, resulting in your brain changing somehow to handle this serotonin.
These changes take time to develop, thus the delay on the impact of ssris.
Generally, consistent use of any drug will cause these longer term changes in the brain. Since your body is trying to find homeostasis, these changes reduce the impact of the acute effect of the drug, thus the experience of tolerance. The experience of withdrawal is a side effect of having these changes without the acute effect of the drug.
Trying to remember what a neuroscience friend of mine said; your brain, like your body, tries to reach some sort of homeostasis. Inhibiting the reuptake of serotonin results in there being more serotonin in the brain, resulting in your brain changing somehow to handle this serotonin.
These changes take time to develop, thus the delay on the impact of ssris.
Generally, consistent use of any drug will cause these longer term changes in the brain. Since your body is trying to find homeostasis, these changes reduce the impact of the acute effect of the drug, thus the experience of tolerance. The experience of withdrawal is a side effect of having these changes without the acute effect of the drug.
Is the overload of presynaptic serotonin receptors that ends up causes endocytosis of those very receptors. The purpose of these receptors is to help regulate vesicular release of serotonin into the synapse by shutting down release when too much is detected. Less of those receptors means more serotonin in the synapse after long periods of treatment. The current overall theory (iirc) is that this helps to drive BDNF upregulation which is a neuronal growth factor that helps to drive more dendrite and bouton formation leading to new and more robust network connections
They were talking about amphetamines.
Tiny 2x4's whack the brain cells
Mate. This is actually a great perspective. Especially when going off them. Haha
Your comment needs a link, such as https://www.castlecraig.co.uk/addiction-resources/what-are-b...
to brain zaps. The phenomenon is not widely known and your comment will not be understood without it.
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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.
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.
God, what a depressing take
How is it depressing? If we waited for scientist's to fully understand the outcomes of their experiments prior to experimenting we’d still be living in caves. As long as the experimentation happens at a small enough scale, the “worst case” scenario is limited. What’s depressing is when things are scaled up in spite of an established body of evidence that such things are harmful.
The depressing part is the billions wasted on supplements, "superfoods" and health drinks that have pretty much zero evidence of effect behind them.
Turmeric is sold for like a dollar a pill. It's pure horseshit.
Turmeric is sold for like a dollar a pill. It's pure horseshit.
Humans have functioned like this as far back as there are records. There's been weird unfounded health crazes for centuries. In the 1920s health spas were putting radon rocks in their pools because radiation was the new health craze.
Consumers are lucky to get just horseshit instead of lead based yellow colorant.
Tylenol is my favorite drug in this bucket
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.
I try my hardest to avoid it due to the associated hepatotoxicity which, to my understanding, is less likely/not observed in other NSAIDs.
People are quick to break fevers, but probably shouldn’t, most of the time.
Fevers are there to kill the virus.
You only need to break them if they get high enough to pose a danger to the brain or other organs.
Which is a lot higher than a low-grade fever.
Fevers are there to kill the virus.
You only need to break them if they get high enough to pose a danger to the brain or other organs.
Which is a lot higher than a low-grade fever.
It's not an NSAID at all, which have their own pitfalls with damage to the GI tract over time.
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-...
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-...
As I'm sure you know, the AI in NSAID is anti-flammatory; thus if you have some kind of non-inflammation pain, paracetamol (aka acetaminophen, Tylenol and other brands) is better. It's also better for lowering fever temperatures. Ibuprofen and other NSAIDs are also contraindicated by other medications, I'm sure there are some for paracetamol too, but I'm not aware of them vs. a few for ibuprofen.
I think you're overstating the risk to your liver, it's not even a prescription drug in any country I'm aware of, there are guidelines and dosages stated for a very good reason, sure, but if you're not taking it routinely (rather just to address an occasional issue) it's fine. And if you are you should see a GP, but the outcome might still be that they agree and prescribe a daily dose.
Ibuprofen should be taken with food to mitigate risk of stomach ulcers, but how many people follow that guidance? It's processed by and a toxin to kidneys instead of liver, can result in AKIs/renal failure, at least you have two of those I guess?
Personally I take ibuprofen for a migraine etc., but paracetamol for a fever. Neither is happening frequently, so I don't worry about occasional use within the guidelines/on doctor advice of either of them.
I think you're overstating the risk to your liver, it's not even a prescription drug in any country I'm aware of, there are guidelines and dosages stated for a very good reason, sure, but if you're not taking it routinely (rather just to address an occasional issue) it's fine. And if you are you should see a GP, but the outcome might still be that they agree and prescribe a daily dose.
Ibuprofen should be taken with food to mitigate risk of stomach ulcers, but how many people follow that guidance? It's processed by and a toxin to kidneys instead of liver, can result in AKIs/renal failure, at least you have two of those I guess?
Personally I take ibuprofen for a migraine etc., but paracetamol for a fever. Neither is happening frequently, so I don't worry about occasional use within the guidelines/on doctor advice of either of them.
Might I add, if anyone is concerned about liver damage, just supplement NAC (n-acetyl-cysteine which is given for acetaminophen / paracetamol overdose), and milk thistle.
Because NSAIDs can lead to erosion and bleeding in your gut.
I've been told to avoid NSAIDs "forever", or at least until a gastroscopy has shown my stomach is fully recovered after using ibuprofen strictly within the dose limits. It's a known risk, and lowering the dose just reduces the odds - it doesn't remove the risk.
Acetaminophen/paracetamol overdoses do happen, but they're rare and usually involve significant overdoses rather than minor accidental excess use.
Their ability to bring down fevers etc. also tend to differ depending on source.
Acetaminophen/paracetamol is usually the first recourse in hospitals etc. because as long as you dose it right, the odds it both works and doesn't incur harm are better.
I've been told to avoid NSAIDs "forever", or at least until a gastroscopy has shown my stomach is fully recovered after using ibuprofen strictly within the dose limits. It's a known risk, and lowering the dose just reduces the odds - it doesn't remove the risk.
Acetaminophen/paracetamol overdoses do happen, but they're rare and usually involve significant overdoses rather than minor accidental excess use.
Their ability to bring down fevers etc. also tend to differ depending on source.
Acetaminophen/paracetamol is usually the first recourse in hospitals etc. because as long as you dose it right, the odds it both works and doesn't incur harm are better.
>even with infrequent usage, and by following proper instructions, liver toxicity could still technically occur within just 24 hours of usage.
Sorry, I find it hard to understand how you came to this conclusion. Even if taken every 4 hrs for the whole 24h (which is extreme case, rarely one needs more than 2-3 tablets for a pretty nasty fever) it gives us 6 doses per 325 mg = 1950 mg which is well below even the most cautious limit
Sorry, I find it hard to understand how you came to this conclusion. Even if taken every 4 hrs for the whole 24h (which is extreme case, rarely one needs more than 2-3 tablets for a pretty nasty fever) it gives us 6 doses per 325 mg = 1950 mg which is well below even the most cautious limit
Extra strength Tylenol in the US is sold in 500mg tabs with instructions to take 2 pills as needed every 6 hours.
It is often taken for long term chronic pain as opposed to a occasional fever as well. Could easily take 6 500mg pills a day for a long time. Add some drinking on top.
I was recently told by my cardiologist to avoid chronically taking ibuprofen and other NSAIDs for pain and to favor Tylenol. Not as a specific recommendation based on my own health either, just her general recommendation that they are not safe for chronic use.
Acetaminophen and ibuprofen are said to both have pro-inflammatory properties. My understanding is aspirin is basically safe, and naproxen (Aleve) is not terrible.
In India [1] the standard dose for acetaminophen has recently become 650mg, because the 500mg variant is price-controlled and allegedly one manufacturer spent roughly $ 120 million to market the 650mg variant to Indian doctors.
[1] https://science.thewire.in/health/paracetamol-650-mg-drug-pr...
[1] https://science.thewire.in/health/paracetamol-650-mg-drug-pr...
Prescription NSAIDs are one of the top 2-3 causes of adverse drug event hospitalizations in the US. Patients on opioids and NSAIDs lead to the highest rate of 10 day admissions. There is insufficient data capture of OTC drugs to factor them into this stat, I believe.
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NSAIDs tend to be taxing on the kidneys.
Interestingly, this is not because of toxicity, but because of reduced bloodflow.
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.
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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.
They work. Not perfect. And tolerance at different dosages build over time. But it's not a placebo effect.
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.
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.
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.
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.
Depression makes it hard to get things done. I heard that the SSRI can eliminate that symptom before it eliminates the desire to die, and that is where a lot of the risk of suicide comes from -- which of course is during the first weeks or months after starting the SSRI.
More or less.
Your actual perceived "mood" is generally the "last" thing to change with basically all flavors of traditional antidepressant, since it's more or less your calibration of how much life sucks over time, and it takes a while of noticing it sucks less to recalibrate.
So every doctor I've ever had has given me a very similar lecture about being very cautious, because depression is more or less characterized as having reduced or no ability to actually drive yourself to do things, and then you feel like shit as that keeps happening and your frame of mind goes sour. But conversely, if the antidepressant affects the "underlying" problem, your inability to turn thought into deed, it will take time (and possibly therapy) for you to recalibrate again, and then you have a window of "I want to die, nothing will ever improve", coupled with a newfound ability to successfully turn thought into deed.
It's one reason things like ketamine and psilocybin are seen as wild - when they work, both generally improve at once, so you avoid that problem.
Your actual perceived "mood" is generally the "last" thing to change with basically all flavors of traditional antidepressant, since it's more or less your calibration of how much life sucks over time, and it takes a while of noticing it sucks less to recalibrate.
So every doctor I've ever had has given me a very similar lecture about being very cautious, because depression is more or less characterized as having reduced or no ability to actually drive yourself to do things, and then you feel like shit as that keeps happening and your frame of mind goes sour. But conversely, if the antidepressant affects the "underlying" problem, your inability to turn thought into deed, it will take time (and possibly therapy) for you to recalibrate again, and then you have a window of "I want to die, nothing will ever improve", coupled with a newfound ability to successfully turn thought into deed.
It's one reason things like ketamine and psilocybin are seen as wild - when they work, both generally improve at once, so you avoid that problem.
I like your explanation better than my explanation.
Thank you; for all its long-windedness, I've had to explain things about this a lot of times to people who have no frame of reference, similar to having to explain to people who have never experienced a disconnect between intent to do something and doing it that no, it's not simply a matter of actually not wanting to do it, it's that I sit here frustrated, having decided I will do this, and still not doing it, for no evident reason.
Since that's completely outside their experience, they often conclude you're lying, not "people work differently".
Since that's completely outside their experience, they often conclude you're lying, not "people work differently".
I've also heard that some people with unipolar depression might actually be misdiagnosed and have a form of bipolar disorder. SSRIs can potentially invoke manic/mixed states in some individuals with bipolar disorder, which might also account for some of the increased risk in suicide from SSRIs.
One of the reasons for why they are commonly prescribed with benzodiazepines, at least in the first couple of weeks.
Also "brain zaps". Highly recommend listening to your physician with a proper roll off period instead of cold turkey. Also be wary of taking certain recreational drugs (Molly, X) due to seretonin syndrome.
Does the average GP know the proper protocol for weening off an SSRI? Or does someone need to go to a specialist for that?
In my experience, you wanna talk to a psychiatrist or in general some who specializes in prescribing drugs for mental health. Your GP just isn't gonna be familiar with all of the ins and outs
Most GPs I have talked to know next to nothing about psychiatric medications. The incompetence runs deep, not limited to psychiatric medications. Just for an example: they know absolutely nothing about seizures caused by withdrawal symptoms of benzodiazpines. In fact, I had a psychiatrist who I had an appointment to after one month, and he knew I was on 2 x 2 mg of alprazolam, well, imagine what would have happened if I could not have gotten my hands on benzodiazpines: seizures. I had them before. No one really cared, my psychiatrist didn't, my GP didn't.
I mean, isn't that true of plenty of substances?
What goes up must come down, to use such analogy.
Take a look at many psychoactive substances. Sudden cessation after prolong usage typically presents as symptoms that are the opposite of whatever the substance provided.
What goes up must come down, to use such analogy.
Take a look at many psychoactive substances. Sudden cessation after prolong usage typically presents as symptoms that are the opposite of whatever the substance provided.
No, its pretty unusual for a substance to cause noteworthy harm after sudden cessation. This is distinct from developing a tolerance, which as you note is pretty normal for humans.
What is defined as noteworthy harm? Are we talking about noteworthy short-term effects or as far on the spectrum as death?
I can think of quite a few substance which result in harm with sudden cessation after prolonged usage -- Alcohol, benzodiazapines, antihypertensives, etc.. Perhaps medications like: antipsychotics, anticonvulsants, immunosupressants, etc. as well?
Obviously individual reactions vary and nothing is a guarantee in medicine, but I believe many substances can cause noteworthy issues with sudden cessation that are greater than just the reemergence of the underlying condition being treated. However I am probably more wrong than right on most topics, so (anyone) feel free to correct me if I am mistaken.
I can think of quite a few substance which result in harm with sudden cessation after prolonged usage -- Alcohol, benzodiazapines, antihypertensives, etc.. Perhaps medications like: antipsychotics, anticonvulsants, immunosupressants, etc. as well?
Obviously individual reactions vary and nothing is a guarantee in medicine, but I believe many substances can cause noteworthy issues with sudden cessation that are greater than just the reemergence of the underlying condition being treated. However I am probably more wrong than right on most topics, so (anyone) feel free to correct me if I am mistaken.
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.
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.
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.
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.
For me sertaline was way more gradual. And it was never that I suddenly felt right - it's just that after few weeks I noticed my floor on feeling very down for up a bit.
(I got prescribed it for anxiety)
(I got prescribed it for anxiety)
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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.
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.
"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!
- 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!
Depending on the population and methodology, anywhere from 10-30% of people diagnosed with major depressive disorder are considered to have "treatment-resistant" depression, which usually means they've failed to respond to at least two antidepressants despite adequate compliance (exact definitions vary as this is not a separate diagnosis) [1].
[1] https://www.hopkinsmedicine.org/health/conditions-and-diseas...
[1] https://www.hopkinsmedicine.org/health/conditions-and-diseas...
Doctors I've talked to have said it's 4 to 6 weeks to reach a baseline, where the medication reaches a steady level in the blood and receptor changes in the brain reach a new equilibrium, but even up to 2+ months for the real effect to kick in.
Those 4-6 weeks are when your brain is adapting to an ever increasing serum level of antidepressants, and it takes about ~2 weeks for serotonin receptors to downregulate in response. That time can be very uncomfortable, specifically because SSRIs indirectly activate 5HT2C, leading to dysphoria, anxiety, etc, before the receptor is sufficiently downregulated.
tl;dr: it can take longer than 4-6 weeks for efficacy to manifest
Those 4-6 weeks are when your brain is adapting to an ever increasing serum level of antidepressants, and it takes about ~2 weeks for serotonin receptors to downregulate in response. That time can be very uncomfortable, specifically because SSRIs indirectly activate 5HT2C, leading to dysphoria, anxiety, etc, before the receptor is sufficiently downregulated.
tl;dr: it can take longer than 4-6 weeks for efficacy to manifest
This is what I've heard from those I know that take anti depressants - the time that is suggested before you would be able to look back and say: "I'm doing much better than four weeks ago", is a bit daunting.
First and foremost because you take them at a point in your life where you're, well, depressed (used as a blanket term here). So patiently waiting for the effect to manifest is a burden in itself, in addition to hoping it works and not being sure if you're experiencing a placebo or actual effect.
But what scares me more, personally, is that it takes such a long time to get on and ween off. It seems to fundamentally change something in the human body or brain. As opposed to e.g. amphetamines, and benzos, which may have long lasting effects from prolonged use, but otherwise appear to be pretty straight forward.
Having never needed antidepressants, I'm curious if others who have taken them, worried about this before or afterwards?
First and foremost because you take them at a point in your life where you're, well, depressed (used as a blanket term here). So patiently waiting for the effect to manifest is a burden in itself, in addition to hoping it works and not being sure if you're experiencing a placebo or actual effect.
But what scares me more, personally, is that it takes such a long time to get on and ween off. It seems to fundamentally change something in the human body or brain. As opposed to e.g. amphetamines, and benzos, which may have long lasting effects from prolonged use, but otherwise appear to be pretty straight forward.
Having never needed antidepressants, I'm curious if others who have taken them, worried about this before or afterwards?
At least in my experience, going off traditional SSRIs wasn't fun, but after it's out of your blood and you wait your ~2 weeks for what is essentially serotonin withdrawal to subside, there weren't any lasting effects.
I've experienced worse withdrawals from other drugs, but I've read that some people do get PAWS-like symptoms from SSRI, and especially SNRI, withdrawal.
I've experienced worse withdrawals from other drugs, but I've read that some people do get PAWS-like symptoms from SSRI, and especially SNRI, withdrawal.
> benzos
A friend working in rehab said benzos are very difficult to end taking - because of the way one gets addicted to em.
A friend working in rehab said benzos are very difficult to end taking - because of the way one gets addicted to em.
Yep, benzos work great for treating stuff like occasional anxiety attacks or sleep issue, but taking them regularly is never a good idea.
Benzos (and alcohol) withdrawal can both be deadly if not tapered. They are not to be fucked around with.
Well I was talking about how fast they have a noticable effect on people. Not about wether or not someone should take them, nor if they are addictive and to what degree. So I don't see the point in your reply, to be honest.
In my body, a Benzodiazepine cessation causes a drop of the blood pressure to around 70/30 for a few days. Kept me in bed.
Interesting that you talk about Effexor. Effexor was the one drug that “worked” for me.
But over time, my thinking and behavior became more and more erratic. I became highly unstable, doing bizarre and unsafe things I never would have considered prior to Effexor. So I needed to come off. Ok, then I had to endure a month of brain shivers, where moving my head made the world stutter like there was a strobe light. After getting through that, I developed dystonia, which lasted for the next fifteen years.
This is why I said that the statement needed clarification. Everyone that had them work for them thinks “they work”. Bullshit. They worked _for you_.
But over time, my thinking and behavior became more and more erratic. I became highly unstable, doing bizarre and unsafe things I never would have considered prior to Effexor. So I needed to come off. Ok, then I had to endure a month of brain shivers, where moving my head made the world stutter like there was a strobe light. After getting through that, I developed dystonia, which lasted for the next fifteen years.
This is why I said that the statement needed clarification. Everyone that had them work for them thinks “they work”. Bullshit. They worked _for you_.
Thats clear from context, not every personal account needs the PSA, especially since your access is mediated by layers of professionals.
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.
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.
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.
> mediated by layers of professionals.
In the developed world, yes. In much of the world (perhaps even most of the world) you can simply walk into a small local pharmacy and buy pretty much anything. Antidepressants, valium, antibiotics, whatever. Only uppers tend to have stricter controls, but I've heard you could find them with a bit of legwork.
In the developed world, yes. In much of the world (perhaps even most of the world) you can simply walk into a small local pharmacy and buy pretty much anything. Antidepressants, valium, antibiotics, whatever. Only uppers tend to have stricter controls, but I've heard you could find them with a bit of legwork.
This is the same for every drug. None of them work the same for everybody all the time. Like they say everybody is different.
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.
There's a strong bias toward assuming that an effective treatment must necessarily address the disease etiologically.
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.
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.
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.
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.
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Without empirical evidence we basically have no evidence at all.
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?
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.
This tells us why many species have found herbal stuff to alleviate pain, cure ailments, etc.
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.
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.
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.
We can’t know how antidepressants work until we better understand how depression works.
brain complicated. many chemicals, many structures, many unknowns.
They don't.
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.
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.
I think antidepressants are only part of the equation but many stay on them and don't fix the underlying causes.
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.
I think if we know the underlying cause, we don’t call it depression, we call it sadness.
Or it might be a case of situational depression:
https://www.webmd.com/depression/situational-depression
https://www.webmd.com/depression/situational-depression
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.
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.
>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.
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.
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.
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.
Because they don't, just make people addicted, soooo many.
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.
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.
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.
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.