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Esketamine Drug For Depression Treatment Nears FDA Approval (bloomberg.com)
72 points by pseudolus 38 days ago | hide | past | web | favorite | 72 comments

So, it's just enantiomerically pure S-ketamine - not really a new drug discovery. The drug is already around as an anesthetic but it is almost finished with the FDA's approval process for treatment-resistant depression. When used as an anesthetic it is administered intravenously, but the anti-depressant formulation is a nasal spray. Cool! That definitely makes it more accessible.

I wonder if J&J got a patent on S-ketamine? The patent system is often abused this way. First you sell the racemic mixture, then when that patent is about to expire, you start selling a new product that is just the active enantiomer. And you can tell customers that it's new and improved: that you only need to take half as much! See Prilosec/Nexium, Celexa/Lexapro, etc.

Although, maybe it's difficult to manufacture just the one enantiomer, at scale?

Why couldn't someone else jump ahead and patent S-ketamine first while the racemic mixtures is being sold?

It's even more confusing: R-ketamine is the more effective enantiomer, with less dissociative effects.

Sweet, I like that J&J is using S-ketamine then. I think the dissociative effects of ketamine are fantastic and beneficial, even though they can be surprising. At a low dose it likely won't be an issue.

Personally, I have no issues with the dissociative effects per se. However, studies have determined that they aren't related to the antidepressant effect. Fwiw, a full clinical dose feels like ~1/4 of a 'rail'. There's no introspective trip here, just slight drunkenness.

(Incidentally, we have some evidence that the metabolite that causes the effect can be blocked via concurrent CBD administration - without reducing the dissociative effect)

The standing appointment to get slightly high for a couple of hours every three days does get inconvenient (though it's not as problematic as the resultant insomnia). I expect esketamine will be more so, for less antidepressant effect. And, being a controlled substance, I'm concerned I'll be unable to increase my dosage to make up the difference.

People seem to still be arguing about that - [1] and [2] argue that they're directly correlated in ketamine treatment, and I can't begin to guess what research on {ar,es}ketamine and metabolite efficacy is going to produce when one of these becomes readily available.

[1] - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065787/

[2] - https://www.ncbi.nlm.nih.gov/pubmed/29501990

"But Meisel said he was convinced by a patient survey Johnson & Johnson conducted. 'We don’t take the patient voice into account enough,' he said."

I suppose it didn't occur to him that the company trying to get their drug approved might not have taken the patient voice into account enough either? Or maybe under-reported certain patient voices? (The adverse ones. Hey, it's not like it has never happened. At least take a closer look!)


Evidence and studies like this should not be done by the company itself. The OxyContin claims about low addictiveness should be a timely reminder for independent clinical studies. Reading that set off alarm bells for me.

The two are not mutually exclusive.

Opiates, for example, do solve certain problems very effectively. That doesn't mean they're not extremely abusable and dangerous to use without proper caution.

Frankly, it's also going to be hard to distinguish between some types of addictive behaviors and people desperately seeking to avoid sinking back into the morass of their mental states prior to effective treatment.

They said the same thing about Prozac -- that it made you better than well and that current licencing which restricted use to people with illness was denying people access to this wonder drug.

SSRIs are useful meds, but they're not miracles.

It might be a realy big milestone if it comes to market. Especially if it could come out as soon as within this year.

Sometimes I hear people mention that ketamine’s special effectiveness (in those whom it is effective, which isn’t 100% of people afaik) wears off over the length of a treatment protocol. It’d be nice to hear more about that, especially in comparison to the long-term effectiveness of traditional antidepressants and SSRIs in particular.

This. I've read some horror stories about patients that received infusions which for a time, gave them their life back, and suddenly for all intents and purposes it became ineffective. Some people described going back to feeling depressed after seeing the alternative to be even less bearable.

I'm eager to see it come to market, and for it to work, but I'm scared to work with my doctor to try it based on those stories.

Can confirm that this happens.

To put it mildly, not the most pleasant experience of my life, but still looking forward to seeing where the next iterations on rapid-acting antidepressants go, and whether they turn out to be any more durable.

(Also quite curious to see what research crops up about why the effects are sometimes not durable, but that's gonna be a decent wait.)

As far as I've read, ketamine trials have mostly focused on patients for whom traditional treatments haven't worked or haven't had a sustained effect ("treatment-resistant depression" or "treatment-refractory depression"). So I doubt that this is being positioned as something that would attempt to replace traditional treatments.

So rather than approve the existing drug that's off patent, they approved a knock-off that will undoubtedly cost 100x as much. How typical.

Is there anything stopping doctors from prescribing or administering ordinary ketamine off-label? I don't think the controlled substance issues would differ between the two.

If the answer is "no, but the marginal differences between ordinary ketamine and the new drug are enough that you'd want to prescribe the new drug instead"--well, that's new value added, isn't it?

Ketamine HCl can and is dispensed off label, both for in office IM/IV treatment and at home nasal spray, or sublingual troche.

that requires the pharmacy to somehow obtain nasal spray. Unfortunately, no manufacturer actually sells a nasal spray variety (yet) as there was no FDA-approved use for intranasal ketamine. That being said, compounders have been able to make intranasal ketamine formulations for a while now, since this treatment for acute depression has been well recognized in the literature for at least a decade.

The main reason would be that it doesn't get distributed in nasal spray bottles, but rather vials for injection.

Though I believe the antidepressant use of ketamine consists of one or two directly administered doses, so injection wouldn’t necessarily be a show-stopper.

It depends what treatment protocol you're following.

The IV protocols for non-life-threatening cases usually involve a number of treatments over a short period (say 6 over 2 weeks), then increased spacing until a satisfactory equilibrium between avoiding symptom recurrence and not spending too often strapped to an IV is achieved.

I believe the nasal spray treatments are more frequent and less potent, but I've no firsthand experience with those, just the knowledge that one of the major limiters on getting a ketamine derivative into people's hands outside of an IV bag is the variability of dosage through e.g. nasal spray. (You can get a prescription for ketamine in a nasal spray from compounding pharmacies right now, but you will likely have decent variability of dosage each time.)

That's not how the drug approval process goes in this country, for better or worse. Also noted some misinformation in the comments.

FDA will approve drugs from companies or individuals that pay for the application. The cost is pretty high today, something on the order of $2-3M USD just for the application. That's not including the cost of supporting data you need to have (Phase 1-3) that will likely cost a large amount to support (multiple centers, paying participants, wholesale cost of drug, paying investigators, researchers, statisticians, etc). Side note, should companies be able to justify exorbitant prices for their drugs based on this cost? No, probably not, but smarter people than myself have debated this on HN.

Why do I mention this? Because ketamine for use in intranasal form for treatment of depression is not off patent. That's right, Mount Sinai Hospital (Icahn School of Medicine) was granted that patent in 2007. A non-profit institution, mind you. So, if I were a drug company, looking to make a profitable form of intranasal ketamine, wouldn't I try and sidestep the patent entirely, reducing overhead on my end?

Also, calling esketamine a knock off is disingenuous. It's an enantiomer, therefore literally half of what is in normal ketamine. It's also probably the more potent half.

Edit: originally wrote that ketamine patent was granted in 2017, meant 2007. Edit2: originally wrote that NYU held the patent to intranasal ketamine when it was actually Mount sinai hospital.

The hard part is getting someone to fund the studies to prove safety and effectiveness for the off-patent version. I don't have a solution for that problem but that's why the FDA didn't approve regular ketamine: no company would be able to recoup the costs to get it approved.

Public money? The government spends enormous amounts of money on medicine and medical research. Just the government’s own savings (Medicare and otherwise) from the availability of better inexpensive drugs could pay for the necessary studies.

Ketamine is an approved drug that we use in clinical practice.

Using Ketamine as a surgical anaesthetic and giving it to outpatients to self administer nasally are two completely different use cases with different risk profiles.

The risk of abuse and addiction from using ketamine in a surgical setting is incredibly low. That's not necessarily the case (in fact, it definitely isn't) for nasal spray given as a treatment for depression.

Same drug, but completely different use case. It's very well known that it's a physically safe drug, but there is a definite risk of abuse and addiction, as evidenced by the number of people I know with ketamine abuse problems. It's not a drug that should just be given out willy nilly to everyone with depression, in fact a lot of people I know who have problems with ketamine abuse are clinically depressed or have other mental health issues.

Complete agreement from me re: big differences between how we're going to manage this as a post-surgical anesthetic and as an antidepressant.

Not approved to treat depression.

We're not limited by approved FDA indications, although we are (generally) limited by the standard of care. Granted, the current formulation is liquid and intended for IV or IM use (although there is academic literature on mixing ketamine into liquids for oral administration). The liquid part is the fundamental problem with using this off-label, in my opinion.

This doesn't really matter--off-label prescriptions are extremely common and don't seem to be strictly regulated.

You can totally get treated for depression with ketamine already, but the problem is insurance doesn't cover it so it's expensive- several thousand dollars a go, which is not absurd but is beyond most peoples' means. Whereas the hope is an FDA-approved therapy will be covered.

Who we the 14 people who approved?

I'm curious as to who voted against this. I mean, sure, abuse of this could be bad. But suicide caused by depression is far, far worse.

People who want recreational drugs will find them anyway. Letting innocent people die from treatment-resistant depression is a perverse priority.

It's slightly worrying the language from pharma is very similar to the early opiod days.

"The voice of the pain patient is underrepresented! We should approve opioids"

Now is

"The voice of the depressed patient is underrepresented! We should approve nasal ketamine".

I'm all for new therapies but ketamine can be highly addictive and causes really nasty side effects in high quantities (bladder problems being horrific from what I've heard). I hope we don't see a huge spike in ketamine abuse in 10 years time like what happened after overprescription of opioids.

I also think this will be extremely popular. Current antidepressants are not very effective and take a long time to work. This seems to work very quickly. Who would want to wait 8 weeks Vs hours to get better? It would not surprise me if J&J have massively downplayed the potential addiction risk of this.

Ketamine is plentiful on the street and you can legally buy ketamine analogs online. I don’t see this new route of getting it from a psychiatrist as a huge abuse risk.

Subjectively, it’s not as good a “take the pill and forget your problems” drug as opioids, benzos, and alcohol are. It can be used in that way if you take a huge “k-hole” dose and dissociate completely, and some people do get addicted. But at common doses, certainly whatever they are going to prescribe, it’s more of a “think about your problems and figure out how to solve or accept them” drug like mushrooms and LSD.

> Ketamine is plentiful on the street and you can legally buy ketamine analogs online. I don’t see this new route of getting it from a psychiatrist as a huge abuse risk.

Exactly the same thing could be said about opiates.

I'm all for new and novel methods for treating depression, but everyone seems to be jumping on this like it's a magical depression cure with no negative externalities.

You could use the same argument for Oxycontin surely. Heroin was always out there on the street, but it's only when opioids were prescribed to the masses via doctors that it reached ecedemic proportions.

I'm not saying it is addictive as heroin etc but it's definitely addictive. And will people start increasing their doses as they become tolerant to the antidepressant effects, etc?

I think responding to this requires giving a summary of the effects of different drugs, to build a simple mental model of how they could cause addiction.

Group A: Drugs like benzos, alcohol, and opioids provide pleasant sensations upfront, killing your pains and anxieties, but those problems return in even worse form when the drug wears off. It’s as though your brain’s baseline for what counts as suffering had been lowered by the experience of being coddled. It’s very clear how this leads to compulsive redosing and addiction.

Group B: Psychedelic drugs like mushrooms and LSD induce unpleasant feelings as they take effect, followed by a more positive (perhaps euphoric) experience once the brain adjusts to the presence of the drug, and then less potent pleasant after-effects when the drug wears off. It seems like the brain has raised the bar for suffering - suddenly the fact that you can see things in the correct color, gravity is pointing in the right direction, and you have clarity of thought makes life feel easy. You might redose to extend the peak effects, but you aren’t going to take any more for a while once it wears off. It would be tough to get addicted to these. However, a depressed person might have trouble with the come-up, and could experience a panic attack. You’d want a very skilled therapist if you’re trying to treat depression this way.

IMO ketamine kind of straddles the line here. The onset of the dissociation can be stressful, but it’s not that hard. You don’t forget your problems, but they feel like the problems of somebody that you know closely and care a lot about, so you can try to solve them from a different perspective. You can feel that you are doing something great, which can lead to compulsive redosing, but you keep the lessons you learn when it wears off. It’s not as though your problems come back in even worse form like you get with group A. Although if you really blast yourself, the dissociation can get so strong that you don’t care about your problems at all, which gives you more of a group A experience while you are peaking. I’m not a scientist and I may be wrong about this, but I think the antidepressant effects are not caused directly by the drug or metabolites that one could become tolerant of. I think that they are a result of the brain’s recent experience of looking at life from a non-depressed perspective.

Simply letting people die is not a sane solution to black market drug use. Drug distribution can be restricted without completely denying drug approval. Look at Xyrem for example.

I think you're misunderstanding my point. It's not that people will go to doctors and use it recreationally instead of getting off the black market. I'm sure that will happen to a certain degree but as you say it's not a huge driver to restricting treatments.

It's that millions of people will be taking it when they never would have before from a doctor, and it is definitely addictive. Drug companies have an insane incentive to down play/hide studies that show it is addictive.

I don't think it's true that using this as directed would cause addiction. But even if it were true, addiction treatment is a better outcome than a funeral any day of the week.

"Letting innocent people die from treatment-resistant depression is a perverse priority" is exactly how we ended up with OxyContin. The priority ought to be getting the good result (stopping deaths from treatment-resistant depression) without an expected or unexpected bad result (a horrible problem like OxyContin.)

Emotional language like "letting innocent people die" is a huge red flag when it comes to having a good discussion about the issue.

Without emotional thinking there is no reason to have an opinion on the issue.

"... lower than the abuse rates for other hallucinogens like ecstasy and LSD."

Ecstasy is a stimulant, not a hallucinogen. I thought bloomberg was generally considered to be better at fact checking than that.

Empathogen-entactogen with both stimulant and hallucinogen properties. You expose a(n) (over)simplified understanding and aren't really contributing, since you aren't a subject matter expert. Any given class of drug may have any number of additional effects outside of it's class, depending on structure and interactions. This example especially is not a complicated one.

Or expand the name, and recognise it as MDMethamphetamine.

Ecstasy is a stimulant, not a hallucinogen.

It’s both.

Ecstasy/MDMA. MDMA (3-4 methylenedioxymethamphetamine) is a synthetic, psychoactive drug chemically similar to the stimulant methamphetamine and the hallucinogen mescaline.


I thought bloomberg was generally considered to be better at fact checking than that.

They are. You’re not.

The use and abuse of MDMA (3,4-methylenedioxymethamphetamine, or ecstasy) is a significant public health concern. In the United States, MDMA is classified as a hallucinogen, a category comprising LSD (lysergic acid diethylamide), PCP (phencyclidine, or angel dust), peyote, mescaline, and psilocybin (mushrooms).


Assuming they mean MDMA when they say Ecstasy, it does in fact have hallucinogenic effects (depending on the person and dosage) in addition to being a stimulant.

I take it you didn't follow the SuperMicro supply chain attack story? (and subsequent fallout due to complete lack of fact-checking)

That was a huge blow to my ability to trust Bloomberg's journalistic credibility, along with several others' trust I'm sure.

Granted that was clearly a different reporter and a different field altogether, but the name "Bloomberg" alone should no longer lend the same credence in this era of fake news.

Food for thought.

Agreed, also LSD doesn't have a measurable abuse rate. It is literally anti-abuse.

I think that in the article, abuse is used to mean illegal unintended use, rather than abuse in the conventional sense.

"hallucinogen" is a silly word to begin with.

The primary effect of LSD isn't hallucination, but something far more strange and more difficult to describe.

Psychedelic is the correct term.

Psychedelic is one term that is almost certainly more correct. "Entheogen" is perhaps another. But "hallucinogen" and "psychotomimetic" do not properly describe my experience nor anyone I know.

The whole idea of lumping different drugs into discrete categories is flawed.

MDMA is both a stimulant and a hallucinogen. In smaller doses the effect isn't noticeable, but it's definitely there in larger doses.

Hmm but Prozac was never that great anyway.

There is very little evidence that depression is caused by chemical imbalance in the brain, it's something that big pharma have sold you so they can sell their drugs.

Great book on the topic, check out lost connections.

The best thing about publishing books is they don't need that pesky peer review!

I'm generally skeptical about SSRI's, but I think this goes too far into conspiracy territory.

The problem with SSRI's, especially in my experience and from my understanding, is that they aim for "mildly beneficial with minimal side effects" and hit somewhere closer to, "mildly beneficial with understated side effects that many patients will be too embarrassed to report". This doesn't mean SSRI's are total junk, but it does mean that they're kind of mediocre.

Ketamine is more of a high-risk high-reward drug, similar to the use of CNS stimulants to treat ADD. There's no question that amphetamines help people focus. There's also, understandably, far more concern about giving people amphetamines in the first place.

Also, it's easier to convince patients to take a boring prescription drug than to sell them on, "I think the real solution to your problem is this really scary-sounding drug that people take at raves; trust me, I'm a psychiatrist."

There’s very little evidence for a broken leg being caused by the lack of plaster around it, yet nobody questions its efficacy...

How is that comparable? Seems like a non sequitur

The treatment of a condition need not be the “inverse” of its cause.

A broken bone can be fixed by immobilizing it via a plaster cast. Did the bone break due to the lack of plaster?

Eczema can be fixed by applying topical steroids. Did eczema develop due to the lack of topical steroids?

Depression can be fixed by inducing changes in neurochemistry. Did depression arise due to an imbalance in neurochemistry?

There is however evidence that they work: https://www.nhs.uk/news/medication/big-new-study-confirms-an...

IIRC there have only been two studies on antidepressants that have gone on longer than 2 years and have been properly placebo controlled (active placebo, no washout group), so if a metastudy claims to include 21 studies then that's pretty good evidence that the metastudy is flawed.

This is noted in the limitations :

> The results are reported after 8 weeks of treatment, so we don't know if they apply to long-term use of antidepressants.

I'm not sure why you would discount an improvement in symptoms over 8 weeks though. Many major depressive episodes will be resolved in that time ("The median duration of MDE was 3.0 months; 50% of participants recovered within 3 months"[1]), so even if they are not suitable, or less effective, for long term care, that can still be a improvement in quality of life.

[1] https://www.ncbi.nlm.nih.gov/pubmed/12204924

(FWIW, it was 21 antidepressants, not 21 studies: "The researchers found 522 studies covering 116,477 patients in total. This included 101 previously unpublished studies.")

> I'm not sure why you would discount an improvement in symptoms over 8 weeks though.

I'm not, but I don't think anyone is arguing that SSRIs can't be effective for some people with severe depression when used in the short term. The issue is that that only represents a small percentage of patients.

As depression has an average course of 4 months I wonder what effects we should expect to see after years.

What's the average course of antidepressants, though? I know in my case it's been quite a lot longer than 4 months...

Yes, while the "moar serotonin = moar happy" explanation of why antidepressants work is oversimplified and wrong in many cases, there is empirical evidence that some antidepressants are effective at treating the symptoms of depression and other illnesses.

I'm to depressed to look it up again, but there was a Psychologist Dr. Irving Kirsh whom used the Freedom of Information Act to study All the studies on antidepressants.

He found they didn't work better than Placebo.

I looked up the first thing I found on Google.


This is written about Kirsh's study, and it's confusing. Kirsh interpolation of the raw data showed that antidepressants don't work, and work less so for extremely depressed patients.

This doctor claims the opposite?

Pesonally, I find the research on the efficacy of antidepressants very confusing.

To those whom are depressed, I can offer this, it does get better with age.

You can also check out Peter Kramer's "Ordinarily Well: The Case for Antidepressants" for the exact opposite take. And "Against Depression", also by Peter Kramer, is a good take on recent findings about the biological roots of depression.

Does Mr. Kramer have anything peer-reviewed?

Dr. Kramer - he's a psychiatrist, who specializes in depression. I only point this out as the gentleman who wrote "Lost Connections" is a journalist, and thus holds no education to the discussion.

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