Why don't we know how antidepressants work yet?
chemistryworld.com
chemistryworld.com
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.
- Kidney damage is very likely
- It should not be combined with ibuprofen
- Possibly safe Withdrawal took forever
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."
I try my hardest to avoid it due to the associated hepatotoxicity which, to my understanding, is less likely/not observed in other NSAIDs.
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-...
[1] https://science.thewire.in/health/paracetamol-650-mg-drug-pr...
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'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.
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
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.
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.
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.
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).
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.?
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.
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.
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.
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?
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?
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.
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.
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.
Turmeric is sold for like a dollar a pill. It's pure horseshit.
They work. Not perfect. And tolerance at different dosages build over time. But it's not a placebo effect.
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.
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.
Since that's completely outside their experience, they often conclude you're lying, not "people work differently".
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.
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.
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.
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.
(I got prescribed it for anxiety)
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.
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.
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.
- 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!
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
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?
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.
A friend working in rehab said benzos are very difficult to end taking - because of the way one gets addicted to em.
[1] https://www.hopkinsmedicine.org/health/conditions-and-diseas...
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_.
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.
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.
This tells us why many species have found herbal stuff to alleviate pain, cure ailments, etc.
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.
I think the next 50 years of psychiatric research are going to be wild.
We can’t know how antidepressants work until we better understand how depression works.
I think antidepressants are only part of the equation but many stay on them and don't fix the underlying causes.
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.
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.
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.
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.