There's nothing wrong with bolstering the Psychiatrist's armamentarium with a novel drug that could help with clinical edge-cases of depression. This article was unfairly biased.
“the FDA set a worrisome new precedent by allowing Janssen to use a “withdrawal” study as its second “positive” study. These studies tend to be slanted in favour of the test drug because they only consist of patients who responded well to the drug in the short-term trials. For this reason, they have never previously been deemed adequate in satisfying FDA requirements.”
It is being tested and it's not a "dangerous, untested new derivative", it's a enantiomer of ketamine, it's literally 50% of the molecules in ketamine. And why don't we just use normal ketamine, why test any new drug, to see if it works better than what we had before.
> it's a enantiomer of ketamine, it's literally 50% of the molecules in ketamine
I’m not a biologist or a chemist. Why does this imply the chemical is as safe? What is the benefit? It seems like a blatant patent grab to bypass the low profit margins of ketamine. Is there evidence otherwise?
The short answer is it can be both (ie safe, beneficial and effectively a patent grab). It is also unlikely that an enantiopure chemical is less safe then it’s racemic counterpart and not unlikely that it is beneficial (this is not without precedent... this is also chemistry 101 and I don’t feel this is the forum for it)...
The doubt is not so much the safety but is the benefit of the enantiopure version worth the cost.
That was an example on the other direction. A pure chirality was safe, but a racemic mixture was dangerous. Here we know the racemic mixture is safe, which strongly suggests that either chirality in isolation is also safe.
And to make in the previous worse it would apparently "autobalance" and flip to chirality which meant that even if they 100% isolated it at great expense is why we never saw "rebranded Thalimoide but isolated to be all morning sickness drug no birth defects". I don't know enough details to tell how long it took and if it could even be used safely under ludicrously impractical assumptions like "if you it freshly isolated in bulk and take it within five seconds it would be safe but expire in an hour".
I think it flipped when in the body, so however long the shelf life was, it still wouldn't matter.
Incidentally, and AIUI, the body has a tagging system for unwanted proteins. Once tagged, the proteins are removed. Thalidomide tagged the proteins the were specific to embryonic limb formation, and the body duly cleared them, leading to the infamous result. Again AIUI.
Not a biologist or chemist either, but I'll try to give my layperson understanding: basically, many molecules exist in two different versions which are mirror images of each other (enantiomers). Most drugs are actually an equal mixture of both enantiomers (called a racemic mixture), but often only one of the enantiomers has the desired drug effect, and the other doesn't actually do anything. It is possible to create a drug which has only the effective enantiomer; usually, a pure dose of the effective enantiomer will be effective at half the dose as the racemic mixture. Medically, there are some advantages – both forms need to be metabolised by the liver, so being able to use half the dose to get the same effect gives the liver less work to do, which can reduce the risk of drug-induced liver injury. If the racemic mixture is already being widely used, then the risk of the pure effective enantiomer is likely to be low, since it is basically just a more effective form of the already used drug, and the side effect profile should be similar to the existing drug. Chemically, the manufacturing process is more complex, which adds to manufacturing costs; however, the main driver of additional costs is that you can get a new patent for the active enantiomer even after the patent on the racemic mixture is expired. For example, the common SSRI anti-depressant citalopram is the racemic mixture, whereas escitalopram is the S-enantiomer. Similarly, esketamine would be the S-enantiomer of ketamine.
Do you know of any examples where a racemic mixture has an effect dramatically different from what you'd expect from a combination of the enantiomers' effects?
"Thalidomide is provided as a racemic mixture of two enantiomers; while there are reports that only one of the enantiomers may cause birth defects, the body converts each enantiomer into the other through mechanisms that are not well understood."
[0] because a racemic mixture (https://en.wikipedia.org/wiki/Racemates) is a 50/50 mix of enantiomers: "In chemistry, a racemic mixture, or racemate [...] has equal amounts of left- and right-handed enantiomers of a chiral molecule" so if you took a racemic mixture surely you'd be getting a combination of the enantiomers' effects?
Amphetamine, for one. Levoamphetamine or dextroamphetamine provide two different physiological experiences (think coffee vs meth). The effects profile of racemic amphetamine is markedly different and much easier to handle physiologically than just dextroamphetamine by itself (the most common isomer found in amphetamine prescription products).
From a perspective of safety, I don't have any reason to suspect esketamine to be any worse. However from a psychological perspective, we could be talking pretty big differences in some individuals where subtle changes in behavior or thought can have cascading effects on mood.
But... that's why we're testing its efficacy, right? It's stupid not to try, and these test subjects are willing. One of the two isomers will be better in some categories. Could be that both together are the way to go. Having only encountered racemic ketamine I can definitely understand its uses in treating depression.
Commenters so far haven't actually answered your question. They just gave examples where the 2 enantiomers have different effects. There are countless examples of these since our bodies' molecules naturally have "handedness".
What you were essentially asking was would 100% of the "bad" enantiomer be significantly worse than a 50/50 mixture. This is the real question here. For there to be a significant difference in this case one of the ketamine enantiomers would need to counteract the other's ill effects.
Disclaimer: although I am a medical doctor, and my first University degree was in organic chemistry and biochemistry, some of this academic stuff is but a hazy memory for me.
> What you were essentially asking was would 100% of the "bad" enantiomer be significantly worse than a 50/50 mixture.
I literally said:
> The effects profile of racemic amphetamine is markedly different and much easier to handle physiologically than just dextroamphetamine by itself
I did answer the question... exactly as OP asked.
> For there to be a significant difference in this case one of the ketamine enantiomers would need to counteract the other's ill effects.
This is precisely the case with amphetamine, where levoamphetamine is more relaxing and subtle and dextroamphetamine is much more physiologically demanding. A racemic mixture provides the perfect combination of effects whereas just dextroamphetamine by itself can be pretty rough on you.
The difference in effect can be quite profound and drastically change your mood and behavior. I would know because I was force fed large amounts of amphetamines for my entire childhood. Name it and I've been prescribed to it.
> So a double strength dose of the racemic mixture has a much milder effect than a single strength dose of the strong enantiomer?
Is that the angle here? I thought we were comparing the total mass of each substance. OP asked about noticeable differences, not paradoxical effects. 25mg of dextro is obviously going to have a weaker overall effect than 50mg of racemic amp.
But that's not what OP asked and it's not the context. The context is whether esketamine and racemic ketamine could provide a noticeably different experience. And the answer is yes. Just like amphetamine, the ketamine isomers have similar pharmacokinetic properties but not necessarily similarly pharmacodynamic properties.
You do realise we can prescribe whatever dose we like, right? Some drugs I prescribe in grams, some in milligrams and some in micrograms. The strength of a drug is somewhat irrelevant. I'm not going to prescribe a new and expensive drug just because the dose is 150mg when it's well-established, cheap cousin is available that happens to need a dose of 300mg.
It certainly is the context, and I believe it's what OP asked. If it wasn't, it should be, because it's the only question that really matters to me as the prescriber.
If what you're saying about the different pharmacodynamics is true (and this is actually what I'm talking about. I only mentioned milder effect because that seemed to be the difference in pharmacodynamics you were getting at), then this is an important difference. It would still have to somehow be quite different to the effect of the racemic version at any arbitrary dose to be preferentially prescribed.
> You do realise we can prescribe whatever dose we like, right? Some drugs I prescribe in grams, some in milligrams and some in micrograms. The strength of a drug is somewhat irrelevant. I'm not going to prescribe a new and expensive drug just because the dose is 150mg when it's well-established, cheap cousin is available that happens to need a dose of 300mg.
I've no wish to argue here, but I am confused about how this has anything to do with it. No one brought up the idea that the doses would be different. We're talking equivalent doses of either an enantiopure or racemic substance.
> It would still have to somehow be quite different to the effect of the racemic version at any arbitrary dose to be preferentially prescribed.
Like I said, we don't know this about ketamine, thus the trials. But we do know this about amphetamine. You would simply have to experience each enantiomer and the racemic mixture in order to understand what I am saying here. The effects are markedly different. My analogy was coffee vs meth.
It amazes me how the problems with our drug and medical regulation system never come up even when it's staring us in the face. This article is typical, framing it as a problem with pharm companies rather than with the regulatory system. Between stuff like this, the opioid crisis, and cannabis deregulation, it should be obvious how broken and monopolistic the system is (referring to the FDA, DEA, and medical licensure system).
The article has a pretty balanced view and several of the people asked say that esketamine could have some benefit for some patients.
But other than that your statement doesn't make a lot of sense. Of course there can be everything wrong with a novel drug that "could" help with edge-cases. Because if you don't know if it helps and if it may harm people - it could very well do more harm than good. That's why we want robust science for new drugs: To decide whether they'll help more than harm.
I think people with severe treatment-resistant depression deserve treatment that is safe and effective.
The problem is that we have a drug that has a similar mechanism of action, and that we know is more effective than eskatamine. That's ketamine infusions.
We don't use that because it doesn't have a licence for this use, and because infusions are expensive and time consuming. But also, it's off-patent and so it's hard to make money from it.
Eskatamine only exists to bring a patentable medication to market, and so far the testing we have show it doesn't work particularly well.
So now patients will be offered to receive ketamine to treat their depressions, the drug they read so much about on the internet. But this time they'll get the RC Special K. Do you think the doctor will tell them all about the difference or just call it K?
> there are concerns about the drug’s withdrawal effects after three of the study’s participants committed suicide within 20 days of its end
It doesn't say how many people committed suicide from the control group, but regardless, 3 suicides sounds pretty bad for an anti-depressant. Who would approve a drug like this?
The cynic in me says an addictive drug with severe withdrawal effects is exactly what pharma companies want...
The drug is licensed for people with treatment resistant depression. This group has significantly higher risk of death by suicide. I dislike speculating on causes of suicides, but if they've been told "here's this thing that appears to give relief from depression for people like you", and they try it, and it doesn't, I can see how that would further increase their risk.
I cannot imagine being severely depressed, entering a study for it since I'm resistant to most of the drugs, finding one that works....
and then having to stop the thing that works and return to a crappy mind state. Only it is worse because I now have withdrawal symptoms on top of my severe depression, which already put me at risk for suicide.
In my opinion, the issue isn't that there is dependency nor that there is withdrawal effects. After all, these are things that happen and despite the risks, might still be the best available choice for relief. The bigger issue is that we didn't do enough to help folks during this time. We should have provided adequate medical care to keep folks safe. Perhaps we should wean folks off in a better manner and/or provided better psychiatric care to this vulnerable group of folks after trials ended.
I understand that. I was on prozac for years. I chose to come off it because it was messing me up, otherwise I'd have been happy to take it for the rest of my life (why not?)
I was aware that if the blackness returned and going back onto prozac failed to work (which can happen) then my lifespan would be a few months at the most.
People without really bad depression can't understand how bad it can be. Death really is better.
There's definitely a readjustment period where your brain tries to reach homeostasis again, which can lead to depressive episodes. But it's important to remember these people were likely morbidly depressed to begin with, and taking ketamine trials was an act of desperation.
Suicidal ideation is one symptom of depression, but so is demotivation and lack of energy. It's well understood that this depression-induced demotivation is a key factor in keeping depressive people from acting on their suicidal thoughts.
It naturally follows that there is a risk factor with starting on antidepressants — because antidepressants might work for you in a way that helps you with your motivation issues before they do anything about your suicidal thoughts, you are at a heightened suicide risk immediately after starting on antidepressants.
It could very well be the case that this is the exact opposite effect — on discontinuation, you could have the suicidal ideation symptoms come back before demotivation does.
> It's well understood that this depression-induced demotivation is a key factor in keeping depressive people from acting on their suicidal thoughts.
First of all, NOTHING is well understood in psychiatry. We are talking about drugs that get approved on a sliver of evidence (if any) on trails being run by some of the most corrupt organizations on the planet. No one understands how or why any anti-depressant works. And saying any of these drugs creates less "demotivation" isn't documented at all.
That being said, we can clearly say anti-depressants (specifically SSRIs) can and do cause suicidal ideation. Yes, suicidal ideation is symptom of depression, but when you give these drugs for non-depression cause such as OCD it still causes suicidal thinking. There is a reason for black box warning on many anti-depressants (and its not because of changes in demotivation).
I don't really get it. Why not just go with ketamine? Is it that the approval takes too much money which other companies could then reuse (the investement does not lead to benefits)?
There are hundreds of Ketamine clinics using it off-label already, the problem is that the insurance won't cover the off-label use and a course of about 10 infusions might cost around $5k at the current rates.
>the problem is that the insurance won't cover the off-label use and a course of about 10 infusions might cost around $5k at the current rates.
But I thought the goal of the pharmaceutical companies, according to your earlier comment, is to synthesize K to charge exorbitant prices. Aren't prices already exorbitant?
The ketamine their are using costs a few bucks. Most of the money goes to the clinics for facilitating the treatments. Depending on the kind of session it can take about 2 hours and there are a few medical professionals involved. This cost stays, the cost of esketamine will be added on top.
Vector of action is another reason - a nasal spray is far friendlier than injection. Although I don't know why that can't or shouldn't be done for ketamine.
So the half S, half R compound (I assume "esketamine" is S ketamine and "arketamine" R ketamine) is a commonly used drug in every emergency unit, probably in much higher doses than the ones used for depression.
Using the S half only seems a way to get it patented.
The concern seems to be that a nasal spray could lead to addiction beacuse fast assimilation. People that have used it illegally tell me that tolerance builds up very quickly, but they're talking about high (K-hole) doses. They don't use it often, just once in a month and mostly the racemate.
They say esketamine only is weird and a little scary. The R half is what gives the happines feeling and mild hallucinogen effect, while the S half is the cause for depersonalization.
A curious detail: the gq article says it's administered IV, while in vice article it's said that IV is dangerous because laryngospasm.
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[ 2.8 ms ] story [ 93.9 ms ] threadSounds pretty damning
I’m not a biologist or a chemist. Why does this imply the chemical is as safe? What is the benefit? It seems like a blatant patent grab to bypass the low profit margins of ketamine. Is there evidence otherwise?
The doubt is not so much the safety but is the benefit of the enantiopure version worth the cost.
Incidentally, and AIUI, the body has a tagging system for unwanted proteins. Once tagged, the proteins are removed. Thalidomide tagged the proteins the were specific to embryonic limb formation, and the body duly cleared them, leading to the infamous result. Again AIUI.
Water is H₂0. Hydrogen peroxide is H₂0₂. I wouldn't substitute one for the other.
"Thalidomide is provided as a racemic mixture of two enantiomers; while there are reports that only one of the enantiomers may cause birth defects, the body converts each enantiomer into the other through mechanisms that are not well understood."
[0] because a racemic mixture (https://en.wikipedia.org/wiki/Racemates) is a 50/50 mix of enantiomers: "In chemistry, a racemic mixture, or racemate [...] has equal amounts of left- and right-handed enantiomers of a chiral molecule" so if you took a racemic mixture surely you'd be getting a combination of the enantiomers' effects?
From a perspective of safety, I don't have any reason to suspect esketamine to be any worse. However from a psychological perspective, we could be talking pretty big differences in some individuals where subtle changes in behavior or thought can have cascading effects on mood.
But... that's why we're testing its efficacy, right? It's stupid not to try, and these test subjects are willing. One of the two isomers will be better in some categories. Could be that both together are the way to go. Having only encountered racemic ketamine I can definitely understand its uses in treating depression.
What you were essentially asking was would 100% of the "bad" enantiomer be significantly worse than a 50/50 mixture. This is the real question here. For there to be a significant difference in this case one of the ketamine enantiomers would need to counteract the other's ill effects.
Disclaimer: although I am a medical doctor, and my first University degree was in organic chemistry and biochemistry, some of this academic stuff is but a hazy memory for me.
I literally said:
> The effects profile of racemic amphetamine is markedly different and much easier to handle physiologically than just dextroamphetamine by itself
I did answer the question... exactly as OP asked.
> For there to be a significant difference in this case one of the ketamine enantiomers would need to counteract the other's ill effects.
This is precisely the case with amphetamine, where levoamphetamine is more relaxing and subtle and dextroamphetamine is much more physiologically demanding. A racemic mixture provides the perfect combination of effects whereas just dextroamphetamine by itself can be pretty rough on you.
The difference in effect can be quite profound and drastically change your mood and behavior. I would know because I was force fed large amounts of amphetamines for my entire childhood. Name it and I've been prescribed to it.
Is that the angle here? I thought we were comparing the total mass of each substance. OP asked about noticeable differences, not paradoxical effects. 25mg of dextro is obviously going to have a weaker overall effect than 50mg of racemic amp.
But that's not what OP asked and it's not the context. The context is whether esketamine and racemic ketamine could provide a noticeably different experience. And the answer is yes. Just like amphetamine, the ketamine isomers have similar pharmacokinetic properties but not necessarily similarly pharmacodynamic properties.
It certainly is the context, and I believe it's what OP asked. If it wasn't, it should be, because it's the only question that really matters to me as the prescriber.
If what you're saying about the different pharmacodynamics is true (and this is actually what I'm talking about. I only mentioned milder effect because that seemed to be the difference in pharmacodynamics you were getting at), then this is an important difference. It would still have to somehow be quite different to the effect of the racemic version at any arbitrary dose to be preferentially prescribed.
I've no wish to argue here, but I am confused about how this has anything to do with it. No one brought up the idea that the doses would be different. We're talking equivalent doses of either an enantiopure or racemic substance.
> It would still have to somehow be quite different to the effect of the racemic version at any arbitrary dose to be preferentially prescribed.
Like I said, we don't know this about ketamine, thus the trials. But we do know this about amphetamine. You would simply have to experience each enantiomer and the racemic mixture in order to understand what I am saying here. The effects are markedly different. My analogy was coffee vs meth.
The side effects of prozac and gamanil for me weren't at all nice but they were far better than the blackness.
In those circumstances, 'could' could be quite good enough for me.
But other than that your statement doesn't make a lot of sense. Of course there can be everything wrong with a novel drug that "could" help with edge-cases. Because if you don't know if it helps and if it may harm people - it could very well do more harm than good. That's why we want robust science for new drugs: To decide whether they'll help more than harm.
The problem is that we have a drug that has a similar mechanism of action, and that we know is more effective than eskatamine. That's ketamine infusions.
We don't use that because it doesn't have a licence for this use, and because infusions are expensive and time consuming. But also, it's off-patent and so it's hard to make money from it.
Eskatamine only exists to bring a patentable medication to market, and so far the testing we have show it doesn't work particularly well.
> there are concerns about the drug’s withdrawal effects after three of the study’s participants committed suicide within 20 days of its end
It doesn't say how many people committed suicide from the control group, but regardless, 3 suicides sounds pretty bad for an anti-depressant. Who would approve a drug like this?
The cynic in me says an addictive drug with severe withdrawal effects is exactly what pharma companies want...
and then having to stop the thing that works and return to a crappy mind state. Only it is worse because I now have withdrawal symptoms on top of my severe depression, which already put me at risk for suicide.
In my opinion, the issue isn't that there is dependency nor that there is withdrawal effects. After all, these are things that happen and despite the risks, might still be the best available choice for relief. The bigger issue is that we didn't do enough to help folks during this time. We should have provided adequate medical care to keep folks safe. Perhaps we should wean folks off in a better manner and/or provided better psychiatric care to this vulnerable group of folks after trials ended.
I was aware that if the blackness returned and going back onto prozac failed to work (which can happen) then my lifespan would be a few months at the most.
People without really bad depression can't understand how bad it can be. Death really is better.
It naturally follows that there is a risk factor with starting on antidepressants — because antidepressants might work for you in a way that helps you with your motivation issues before they do anything about your suicidal thoughts, you are at a heightened suicide risk immediately after starting on antidepressants.
It could very well be the case that this is the exact opposite effect — on discontinuation, you could have the suicidal ideation symptoms come back before demotivation does.
First of all, NOTHING is well understood in psychiatry. We are talking about drugs that get approved on a sliver of evidence (if any) on trails being run by some of the most corrupt organizations on the planet. No one understands how or why any anti-depressant works. And saying any of these drugs creates less "demotivation" isn't documented at all.
That being said, we can clearly say anti-depressants (specifically SSRIs) can and do cause suicidal ideation. Yes, suicidal ideation is symptom of depression, but when you give these drugs for non-depression cause such as OCD it still causes suicidal thinking. There is a reason for black box warning on many anti-depressants (and its not because of changes in demotivation).
But I thought the goal of the pharmaceutical companies, according to your earlier comment, is to synthesize K to charge exorbitant prices. Aren't prices already exorbitant?
https://www.vice.com/en_us/article/nzdnak/why-ketamine-is-th...
So the half S, half R compound (I assume "esketamine" is S ketamine and "arketamine" R ketamine) is a commonly used drug in every emergency unit, probably in much higher doses than the ones used for depression.
Using the S half only seems a way to get it patented.
The concern seems to be that a nasal spray could lead to addiction beacuse fast assimilation. People that have used it illegally tell me that tolerance builds up very quickly, but they're talking about high (K-hole) doses. They don't use it often, just once in a month and mostly the racemate.
They say esketamine only is weird and a little scary. The R half is what gives the happines feeling and mild hallucinogen effect, while the S half is the cause for depersonalization.
A curious detail: the gq article says it's administered IV, while in vice article it's said that IV is dangerous because laryngospasm.