Has esketamine been overhyped?
gq-magazine.co.uk
gq-magazine.co.uk
> 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).
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.
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?
Sounds 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.