"interaction of dopamine and acetylcholine systems in the rat ... to direct D-amphetamine administration ... The increases observed during amphetamine ... were both blocked by co-administration with the D1 antagonist ... but not with the D2 antagonist"
Amphetamine overusage isn't necessarily a great model of psychosis, or at least not of schizophrenia. It induces the "positive symptoms" of schizophrenia, but not so much the "negative symptoms" that can be more disabling and not as responsive to (or even worsened by) antipsychotics.
This article make very little sense to me, though I could be completely missing something here. Most psychotomimetic models of the dopamine receptor use D2 agonists (though this is not the only receptor that can be interacted with to generate these effects, IIRC. The glutamate system is implicated as well for direct effects, I believe. You'll have to check me on that one though).. Gen 3 antipsychotics for example partially agonise the receptor to block some psychotic effects without the full blockage that pure antagonists offer.
They use a non-psychotomimetic drug, amphetamines, which is warning sign number one. Warning sign number 2: IIRC, the D2 receptor is the _autoregulatory receptor_ for dopamine release, IIRC. That is, it's part of the brake system for that receptor. Of course blocking it will cause problems!
What is this article even reporting on? How did this get through? Am I missing something painfully obvious here? I am not a doctor or a medical researcher (yet?), just very interested in psychopharmacotherapeutics. :'////
People are downvoting you, but I'm going to upvote you and respond carefully because I think there's an important lesson about language and science here.
> That's not science, that's a cargo cult.
Science deals completely and exclusively with modeling "if this then that". And the breakdown for "if this then that" depends on the current observability of the scale you're trying to describe.
We don't know how gravity works, because we can't look inside gravity, we can only look at gravity's effects on other things, but we know that it does appear to work, and we believe that it works in the same way every time, and we can use observations and organized thinking to model gravity in a way that allows us to predict what will happen "if this".
So we can safely say we don't know how gravity itself works, but we can also safely say that we do know the relationship between gravity and mass, because that's something we can observe.
Likewise, we can safely say we don't know "how antipsychotics work inside the brain", but we can also safely say we do know "how antipsychotics work on populations", because populations are easily observed and inside the brain is not. Both use the word "how". The difference is what we're currently able to observe.
This is a language problem, not a science problem.
At an essential level, science can't answer how many things work, because the deeper into the unobserved you try to talk about (and the workings of the brain are still approximately 100% unobserved) "how", which is a question about things we can observe, becomes more and more a mis-use of the word "how" to talk about "why", which is a question about things we cannot observe, and science doesn't talk about things we cannot observe.
It would only be cargo culting if the "but...", which I assume went on to say "...it appears to be beneficial for many people", were instead "and we haven't bothered to observe whether it helps anyone". But again I assume that's not how the sentence ended.
> At an essential level, science can't answer how many things work...
Indeed, science provides scant information about how drugs work and that includes medications with effects (favorable or not) in the brain. The reality is that drugs have a great number of effects very few of which receive adequate study. IOW while there are useful target effects that are exploited, the fact that drugs are more or less tolerable is largely a matter of luck.
This reality is illustrated by instances of tragic drug outcomes despite long use in clinical practice. Of course observing for and identifying random events (adverse effects) depends on the sample size. Registration trials generally use hundreds to a few thousand people which is highly unlikely to reveal serious, rare outcomes occurring on the order of 1/100K recipients. Monitoring of after-market AEs is necessary to detect such anomalous outcomes.
The upshot is that clinical practice is at least as much art form as reliant on science. But as you say this is also the case with all science, albeit to a variable degree. It implies your statement should read "science can't answer how anything actually works" since there's no way to know what is not yet known.
That doesn't mean we have no useful knowledge, far from it, as the vast array of extant productive technologies clearly shows. But in truth we can't fully "explain" anything, we have to be content developing usable "working solutions" to real-world problems. To my mind process of science is satisfactory to the extent we accept the inherent constraints of human knowledge. With that acceptance we gain the flexibility to move forward, to find new and better working solutions, and add insightful observations to the knowledge base of science.
I found going to the doctor strange as a kid growing up. I had science class and had to know the details of things on the test. But going to the doctor, they didn't tell me what I had. They usually didn't know exactly. Mostly it was just treating the symptoms.
This bugged me, but I would get worn down by it and sort of give up the "search for truth". I feel bad, and then I rest, or take ibuprofen, or drink fluids, and my body just fixes it eventually and the mysteries continue.
Yeah, after all these years we still know very little about the body. Almost nothing, really, in the grand scheme of things. Most of the time the best thing we can do is literally rest and hope for the best.
And this is compounded by a major misalignment between expert goals and lay expectations.
The great misconception of medicine is that people think it's about healing when almost none of it is directed at healing, only at putting your body in a better position to heal itself. Medical intervention, nearly universally, aims to destroy or rearrange things considered to be anomalous by presence or arrangement. That's true from antibiotics to chemotherapy to appendectomies to skin grafts to casting broken bones. And if there's no bone to move or bacteria to kill or appendix to extract, there's nothing to do but destroy the pain. The healing is actually always done by your body.
Doctors don't make your body better. They only make your body less worse than normal. And those sound like they should be logically the same, but they aren't.
And then on top of all that, bodies are simultaneously both magical and complete, utter, absolute garbage. So you have people who live in constant pain, extreme pain, blinding, crippling, exhausting pain, and we either don't know why, or we don't know how to fix it, or the process for fixing it is too dangerous.
I would add that there's infinite gradations to how and why. Answers for how range from the extremely simplistic: you put the pill in your mouth and swallow it, down to questions about the fundamental forces of the universe, and the nature of consciousness, neither of which are understood
That's certainly an important point, though I would argue that it's just a consequence of there being many different levels and directions of observation.
"How does this pill work?" -> "You put it in your mouth" comes from observing at the level of your mouth, or alternately observing the intake process. It's not the most insightful detail to observe about the pill, but it's probably the most practically useful!
You could of course put the pill somewhere else, and maybe it would work there too or maybe not (it probably depends on where exactly you put it).
There's no generally accepted theory for the mechanism of action of inhalational anaesthetics like xenon, which induces a deep coma, somehow, despite being almost chemically inert.
My understanding for Xenon is that it's huge electron shell means that it has an induced dipole in the presence of other dipoles in the body. It then affects receptors with dipole-dipole bonds.
I was also confused by Xenon working as an anesthetic, and found it interesting that it can interact with the body without forming chemical bonds. Doesn't work for the lighter noble gasses.
That list seems pretty incomplete/sparse. It's pretty unsettling that paracetamol, as common as it is in modern medicine, would still lack a known mechanism of action. I wonder if it's just a hard question to answer, or something more boring like research cost vs benefit ratios etc.
It is an extremely hard question to answer. Think about how hard it is to debug software, even though software is designed by humans, is intended to be readable by humans, and has tools to help us in analyzing it. Then think about how much harder it would be to understand a system that instead came about by billions of years of chance mutations building up to develop self reproducing systems that are not at all meant to be easily understood, and that follow much more complex rules (quantum mechanics) than binary computers do.
Well given how complex the brain is, and how young neuroscience is, it’s no surprise that we haven’t unlocked deep knowledge about why psychopharmacological agents work. But granted the above, it isn’t prudent to wait decades for the brain to be understood before we try to help people struggling with mental health. If we can demonstrate that something is reasonably safe and makes a decent difference in helping someone’s life, shouldn’t we offer it to them (even if we don’t know on a deep level how it works)?
Yes, if. We can, and we have, but instead the field has been usurped by junk science, and those who would dump industrial waste on us and into the water supply.
But SSRIs do work. Experiment often proceeds theory. Uncertainty about the exact mechanism doesn't change the fact that SSRIs reduce symptoms of anxiety and major depression symptoms in many people. They have drastically improved my life and the lives of many family members and friends.
This is not at all settled, and for the people who believe it wholly, the effects that are claimed are marginal. It's fine to talk about the benefits of SSRIs, although they may be controversial, but to use them as a basis for believing in other things is like 12 steps too far.
> For the people who believe it wholly, the effects that are claimed are marginal
No, the effects are not marginal. Research, the experience of basically all clinicians who prescribe antidepressants, and my personal experience all show they treat depression.
For a given person, an SSRI may significantly relieve their symptoms, have a mild effect, or have no effect. Across the population, studies of SSRIs consistently show they work to treat major depression [1].
Every clinician I've met has observed SSRIs being effective. They see depression symptoms getting better when medication starts, and they observe relapses when medication stops.
When I started taking Escitalopram, I stopped being depressed. When I stopped taking Escitalopram, I became depressed again. When I re-started Escitalopram, I stopped being depressed again.
My grandfather had the same experience. When he went on Citalopram, he became calmer and less irritable than he'd ever been in his life. He stopped taking Citalopram for a few weeks, because of a physical illness that interrupted a prescription refill, and immediately slipped back into a depression. When he went back on Citalopram in the hospital, he was smiling and singing again two weeks later.
The trouble is that the placebo effect has been repeatedly demonstrated to be extremely, profoundly strong for depression and anxiety treatments.
Yes research has found improvements when you put people on SSRIs, but double blind placebo controlled studies generally find that about 80% of the benefits also occur in the placebo group, so the actual benefit over placebo is only about 2 points on the HAM-D scale. [1]
On top of that, SSRIs have well-known side effects that are pretty noticeable for most people, so it’s hard to know how much of their benefit vs placebo is due to loss of blinding and/or the “active placebo” effect.
It is, however, notable that one study found a loss of effect when subjects were deceived and told that the SSRI they were given was an active placebo with similar side effects to an SSRI, and the differences were visible on brain scans, not just in their subjective reports.[2]
> When I started taking Escitalopram, I stopped being depressed.
Ooh, anecdotes, and ignoring your own quoted text, I can do that too!
When I started taking it, I became numb, lost my sex drive, and basically exacerbated my underlying anxiety problem related to the depression. When I stopped taking it, I had extreme, severe withdrawal symptoms, orders of magnitude worse than any other withdrawal I've ever been through. When I stopped taking it, I had been practicing meditation and going to therapy. I also threw in real commitment to the gym for the first time in my life. Took a while for the sexual side effects to wear off too. Needless to say, I have extreme resentment for the doc that put me on that with zero guidance, warning, options, etc. I know have a beta blocker prescribed that I can take to prevent the physical symptoms of anxiety from exacerbating into a mini panic attack, but I basically don't need to take those anymore.
I can find a non-trivial number of studies that (happy to link them, don't want to spam or be over the top right now), either:
1. Show it's barely more effective than a placebo.
2. Show it's barely more effective than a placebo, except for about 15% of those taking it, who had a measurable improvement.
I'm not a doctor but I'm going to sublty imply that there are other treatments for depression, with more impressive statistics, that don't cause bi-minutely head-to-toe "body zaps" when trying to go off it.
> For a given person, an SSRI may significantly relieve their symptoms, have a mild effect, or have no effect.
In other words, SSRIs do not work for everyone who has depression. For some people, they do; for others, they don't. You and your grandfather apparently are in the first group; but there are also plenty of people in the second.
Now comes the obvious next question: is there a way to tell in advance (i.e., without trying the SSRI on the person and seeing whether it works or doesn't) which people are in each category? No, there isn't. That's the impact of not knowing the mechanism: treatments for illnesses like depression are trial and error. If you find a drug that works for you, great! But many people never do.
Problem with SSRIs is: Does depression cause reduced serotonin, or does reduced serotonin cause depression?
A recent paper [0], [1] claims there is no connection between reduced serotonin as a cause of depression.
Which in my book says depression is a software problem more than a hardware problem, even though the software problem can create reinforcing hardware problems.
This is a mischaracterization of the research. Recent research has indicated that Serotonin levels in depressed people are not lower than average. But SSRIs are effective for relieving depressive symptoms - either boosting serotonin levels above average works, or they work through some other pathway that hasn't been identified.
> Which in my book says depression is a software problem more than a hardware problem, even though the software problem can create reinforcing hardware problems.
A human isn't a computer. You can't separate psychology from the biology of the brain. This comment is really unhelpful in actually treating mental illness. Talk therapy helps depression, lifestyle changes help depression, and medication helps depression. Most people recover with some combination of all three.
I've never understood people who seem to take offense to the existence of antidepressants. If you don't want to take them, don't take them, but leave the people who benefit from them in peace.
> Recent research has indicated that Serotonin levels in depressed people are not lower than average. But SSRIs are effective for relieving depressive symptoms - either boosting serotonin levels above average works, or they work through some other pathway that hasn't been identified.
But that is exactly the point. If we don't know why something works, we can't even be sure that it does work.
Also SSRIs are only slightly more effective than placebo. [0]
Quote: "So, when we accessed the public domain data from the U.S. Food and Drug Administration (FDA) archives for the antidepressants approved between 1985 and 1997 (7), it quickly became apparent that many of the assumptions about the relative potency of antidepressants compared to placebo were not based on data from the contemporary trials but from an earlier era. Specifically, it became evident that the magnitude of symptom reduction was about 40% with antidepressants and about 30% with placebo."
Until/unless we can finally understand how the human endocrine system works, on both a broad statistical basis as well as on a predictable individual basis (i.e. in the same sense that statistically we know that X number of people die each year in automobile collisions but we don't know exactly WHICH people will die) we are making guesses.
The level of scientism our society exhibits - in which we cannot just accept that some things don't have answers that we can access at this time, and instead accept any answer "science" gives us - is unfortunate. Research we do is limited by what we look for, and the positivist approach we see in medicine ("Find diseases we can make money on") limits everything.
Not really, you don't have to understand something to take advantage of it. My grandmother doesn't really understand how computers work but she still loves using her computer.
Psychiatrists love SSRIs because they are efficacious (for a much smaller minority of those prescribed them than people realise), even when they're not more effective than placebo - placebos are actually pretty effective at treating issues.
They're relatively cheap, easy to get patients who might be going through various issues to comply with the treatment, SSRI's being efficacious for the first few months after starting treatment is not that controversial, and that can allow you to monkey branch to more sustainable forms of treatment.
The fact psychiatrists are prescribing drugs for a mental illness when they aren't aware of its mechanism of action is far from the worst sin of psychiatry. First off, the very notion that psychiatrists/doctors should gatekeep prescriptions in the first place being helpful isn't an evidence based practice, and how we define and diagnose mental illness in the first place is a Pandora's box of assumptions.
Last I heard we don't even know how anesthesia works fully. It's just kind of how medicine functions. I don't think it's bad. We're doing what we can to mitigate what we can while we figure out what the heck is actually happening.
I have some bad news for you about Tylenol/Paracetamol....
The science is "We did many double blind studies on a large population and observed these effects to a degree statistically significant compared to placebo"
We can reproduce the effects reliably, and the side effects are similarly predictable. We've also researched the pharmacokinetics to see what it's doing, but we don't necessarily understand how those changes cause it's effects.
Just because we don't know exactly how it works, doesn't mean we didn't observe what the effects are. When the good effects out way the bad effects then it's a possible treatment.
I'm not saying all studies are of quality, that there aren't unknown effects we haven't observed yet, that there aren't problems etc. What I'm saying is we have at least attempted to measure the effects and determine them to a statistically significant degree.
tl;dr - If we've measured effects to a statistically significant degree - that is not a cargo cult. How many people understand the electrical wiring in their house yet use a light switch daily?
How things work and if they work are very different problems that science can help us solve.
If you perform a double blind trial that throwing a brick at the back at someone's head will most likely cause a concussion or major injury you don't really have to understand the mechanism to get the result, just repeat the treatment.
Drugs can be classed into two categories. Those we know the mechanism of action and those we just know what effects it produces. A lot of mental health meds fall into the latter category.
There's a third class: drugs that were discovered because they caused an effect that was theorized to be related to the actual target by long-disproven ideas of how bodies worked, and that show little or no benefit to the target condition but are still prescribed as they have always been.
We decided that seizures made people sane, created drugs and treatments to spark controlled seizures, then tried to make drugs that seemed similar but didn't cause tardive dyskinesia. Tardive dyskinesia was the only reason these drugs were ever even investigated, but the field somehow still moves forward like a racehorse without a head, claiming effects 10% above placebo.
science is a mechanism for testing hypotheses. it may not be as medically rigorous as we want but modeling the complete receptor interactions and exactly what sorts and degrees of modulation happens as a result across the whole brain and body is really, really hard
btw this is why i think the phrase "the science" as it relates to a pseudointellectual synonym for "the answer" needs to die
"Last season crops grew better on that field after the cows were allowed to grazed on it, but the field where we kept out the cows was as bad as always. Let's try letting cows graze on both fields."
"What did we say about magical thinking?"
"Sorry dad. Let's keep the cows off the field like we always did."
If people were that good at noticing patterns, it wouldn't have taken Cortez arriving on the soil of the New World in order to bring the wheel to its inhabitants, who had been here 14,000 years and produced zero wheels.
Then with a little scientific method, you soon realize storms and dogs are uncorrelated. Or you find out a drug seems to work even if you can't fully explain why.
my guess is this is like saying the odd registers on a chip are involved, vs the even registers. But it is actually hard to infer what the actually program running does, not to mention what bug in the program is causing the problem. But some substance deactivates the odd registers somehow without taking down the whole chip.
