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New studies zero in on roots of depression and how ketamine affects it (arstechnica.com)
290 points by rbanffy 11 months ago | hide | past | web | favorite | 130 comments

Most doctors are performing infusions with a loading procedure where the patient has six infusions in the span of two weeks. Then the patient is offered what they refer to as maintenance. The space between maintenance doses is a decision made by the patient. Some doctors prescribe additional anti-depressants to help patients sustain the effect until their next infusion. One of the problems with this treatment is that there aren't any studies that show this is effective long term.

I have had ketamine treatments at two different clinics and the procedure and methods varied. There were differences in monitoring and safety protocols.

Initial doses could run anywhere from $2100-$6000. One maintenance dose could be $300-$1000. Hopefully Rapastinel will be approved by the FDA soon and wipes out small industry that is partial to unproven science. Don't be influenced by the hype. Please try everything else before you try Ketamine infusions.

Edit: I also want to mention that there isn't any proof that Ketamine is anything but short acting. See this review by Cochrane: http://www.cochrane.org/CD011611/DEPRESSN_ketamine-and-other...

I've done this as an amateur. Medical grade ketamine isn't the hardest thing to find and I do not have the money to do it professionally.

A few years ago I remember my first time taking ketamine at all I went from near suicidal to feeling completely fine pretty much over night.

I think that the "side effects" as the article put it are actually pretty helpful. The dissociation gives you a sort of third person view of your problems and life that is very helpful in my opinion.

I found that eventually it stops being as effective but I think there has been some permanent changes. My lows don't feel as low anymore. I still have down periods but they're no where as bad as they used to be.

More recently I've just stuck to antidepressants (I take an NDRI) and vitamin D3.

I've tried some analogs of ketamine (2fdck, dck) and hope they take a look at some of them to see if there can be similar effects.

> Medical grade ketamine isn't the hardest thing to find

How do you know the quality?

I wouldn't trust it for injection unless it came in medical vial. It's on the darknet, though more expensive than powdered Ketamine.

How do you trust anything you get on the darknet?

In any system where an actor can be either honest or dishonest but certain qualities of correctness can be probabilistically ascertained, consensus is often a great replacement for trust.

In the case of an anonymous decentralized marketplace, vendor attributes like product quality can be ascertained by achieving consensus in the form of ratings and reviews.

Ultimately, without running the product through a mass spectrometer yourself, you are going to have to defer trust, so consensus aims to reduce the likelihood of dishonesty over an average.

For people in some parts of the world, the level of trustworthiness gauged from online marketplaces can supersede the level of trust given to local vendors.

Take Amazon for example, which, while not anonymous, uses consensus to assure quality in the form of validated reviews. Many people already prefer shopping by reviews than by trial-and-error at brick and mortar stores.

You roll the dice, having learned the odds are in your favour.

"The primary sources of street Ketamine in China include diversion or theft of legal pharmaceuticals from medical or veterinary licit trade with some supplies also manufactured in clandestine laboratories (United Nations Office on Drugs and Crime, 2010). It is therefore believed that the purity and the quality of street ketamine is high (no research data available) contributing to its increasing popularity among drug users in China." (2014)


I think the easiest answer is by testing it. I don't think a purity and substance test isn't that expensive.

How do you trust anything funded by companies who desire slanted research? You trade one governing body for another. In the darknet's case, you lean on consensus and ratings.

I'd be interested to know what you've exhausted.

Obviously Lexapro and friends.

And the tricyclics. And novels.

Nardil or Parnate?

Zoloft, remron, stratera, and a few I can't remember. Also tried Ritalin for ADHD though not sure I have that vs being depressed making me unable to focus. Found modafinil and armodafinil better for that purpose. Currently take bupropion. Wouldn't take a maoi inhibitor due to the diet restrictions. Have also tried 5htp but stopped when I started getting brain fog.

Haven't tried a tricyclic that I can remember. Won't take an ssri again because brain zaps scare me and zoloft made me feel like a zombie.

In the dissociative corner I've tried, ketamine, dck, 2fdck, MXE, 2oxopce 3meopce, 3meopcp, 3hopce, 3hopcp, Ephenidine, dxm, PCP, MXP and N2O. Would love to try Xenon but good luck with that.

I've had friends suggest trying microdosing but that doesn't seem sustainable to me.

Is the NDRI you are taking bupropion?

Yup. XR version.

I've come to see depression partially as a semi-stable brain-state with reinforcing feedback. Some of that feedback may be chemical while some is psychological (thought or feeling). It may even persist once the major stimuli that got to that state have been removed. As such, any intervention that pops the patient out of that state could be permanent so long as the other things that led there don't happen again. Or if those things are still present, any intervention will be short lived.

I can definitely see this being true. Likely why things like psychedelics can help but only for a few months. Also would explain why CBT works as well as it does. I actually wrote something on the looping nature of my own depression that was in the form of a loop.

If you feel like sharing it, I would be grateful!

Looping and recursion go together nicely don't they? ;-)

Hi, what is your profession?

Engineer/Programmer. I had a bout of depression some time ago and had an amazing time watching my own thought processes and reading about psychology. I hope to write about my experience some day.

That's a ridiculous price to pay for ketamine. Though I'm hoping that cost includes a doctor's supervision and stuff?

$6000 would buy me enough Special K for several life times ...

> Though I'm hoping that cost includes a doctor's supervision and stuff?

Supervision by a nurse. It's usually contracted out.

> $6000 would buy me enough Special K for several life times ...

If it's not the same procedure (IV) with a compound that is pure you might not be getting any of the benefits.

Med grade K pops up for about 140 USD a gram. It's not hard to get insulin needles. There are guides on how to IV on the internet.

This would likely last much shorter then an infusion as there's a limited options for setting a running IV as opposed to just a single injection.

That's US street price. On the dark web you can get medical grade for $20 a gram.

And from a veterinarian in Central America for less than $5 a gram. Is there a difference between "medical grade" and what is used for animals?

I said medical to differentiate it from street k which comes as a powder and is usually cut which is bad for injection.

And there shouldn't be a difference between animal and human ketamine.

Animals rarely sue their doctors.

Your "medical grade" could be fake on the darkweb, who knows what you are getting?

"In the village of Boshe, underground laboratories are producing ketamine cheaply in large amounts." from:


I also wouldn't be trusting the packaging wasn't fake (or refilled).

The darkweb is generally safer than buying shit from random people in real life

Don't think it'd be worth the trouble.

They'd more likely produce the powder as that's easier to conceal for shipping or more likely just make DCK which is still legal.

Just use a test kit

No you can't. Powder is 60-70 USD, vial liquid is 120-140 USD. If you want to import from South Africa it can be that cheap but that stuff sucks.

> If it's not the same procedure (IV) with a compound that is pure you might not be getting any of the benefits.

At the same time since insurance doesn't cover this the only real option for people who don't have that kind of money (myself included) is black market self-administration or more traditional therapies which may not be as effective.

> or more traditional therapies which may not be as effective.

It's not proven. There are a few articles and a few success stories. It isn't a panacea. The cost is only an issue after someone has tried many traditional therapies.

Street ketamine is usually from vets..

According to my psychiatrist, you are paying for the malpractice insurance of a doctor performing unestablished medical treatments.

That might be misinformed, although $2-6k per infusion is very very high. That price is simply providing a high profit to the provider

There is a group of doctors who provide ketamine therapy and they've created some resources for interested patients. They say cost should be $400-800 per infusion and outline the drivers: http://www.ketamineadvocacynetwork.org/cost/

Fwiw, $800 is the price I was quoted.

You're paying for the risk that the doctor is taking. It's going directly into his pocket though. That's why regional prices are so far apart.

There are providers who charge $2k+ per dose, but providers can charge much less and still make a profit. For a list of cheaper providers see here: http://www.ketamineadvocacynetwork.org/provider-directory/

Cost info here: http://www.ketamineadvocacynetwork.org/cost/

Wow, rapastinel: I dont kniw how I haven't cone across that before but thank you for mentioning it. I'm astonished something so close to "done" is so atypically effective. I know too much about these things to throw around the term "miracle drug" but it looks very well inside the "game changer" territory.

Why is medical grade ketamine so expensive when the street stuff is dirt cheap? That sounds like an unbelievable ripoff.

Street stuff is cut, and you're not paying someone to inject it into you.

U got scammed for that price

One infusion for me in a clinic in Florida was 500$ and a one month supply for maintenance was 30$

Supply of what? Intranasal?

What about the “K-hole” effect? Have you ever delayed one of your maintenance treatments for significantly longer than what you would consider “normal” (for yourself of course)?

I enjoy K-holes though it's been a while since I've gotten to one.

One thing people don't realize is that ketamine tolerance is very long and hard to get rid of. It's easy to find reports from recreational users of it lasting years.

K-hole effect happens to people who abuse ketamine. The treatment can still be very unpleasant though. I sweat profusely and puke.

I haven't experienced any tolerance and the effect is not actually lasting a month as I had hoped.

That the lateral habenula overfiring leads to depression, and the l.h.‘s purpose is to warn us of negative outcomes - that’s an amazing insight to me. I think CBT should listen up here. What if you can learn to dial down l.h. activity by deprioritizing negative outcomes in your daily life? This could be the shortcut everybody has been looking for, replacing years of treatment with only weeks/months?

Sure I mean CBT teaches you to observe negative thought patterns and answer them rationally. Writing a journal or talking to a therapist helps you escape the mind. But clinical depression has physiological effects too so medication helps with that.

In my experience, this is a bad idea. The negative thoughts can use the rationalization engine in your brain just as well as the other parts, so engaging with them on rational terms has, for me, only given them more influence.

Part of the point of CBT is recognize when you're engaging in rationalization behaviors so you can prevent it. CBT is meant to increase your awareness of what you're doing in your life to cause you harm and misery and to help you build patterns and habits which relieve you of those things. Maybe I'm being presumptuous, but it doesn't sound like you've had actual, therapist-led CBT.

By rationally I actually meant realistically. The negative engine is over estimating the risk. So you may take a negative thought to its logical conclusion and be depressed but you've forgotten to weight the likelihood of that outcome. And also that the input premise is likely false e.g. you are not a horrible person for example. Or you always do things wrong.

Part of the goal of CBT is to see yourself and your thoughts from the perspective of a detached, but curious, observer. Recognizing that you're an animal and that you have patterns to your thinking can help you build self-compassion.

It's an ongoing process though. The key is not to engage so much with the thoughts themselves or their implications but in the processes that arrive at those thoughts which cause so much pain. Recognizing the pattern well enough that you're able to step back and say "Ahhhh, I'm in that mood again."

I wonder if the author wrote this after seeing it here yesterday...


Hmm... that aligns somewhat with my own thoughts on the actual cause of depression. I've spent a lot of time thinking about since I spent a significant portion of my life depressed, and I find the current approach to it in health care unsettling.

Allow me, if you will, to engage in some inexpert speculation. If you read the following, please keep in mind that I am just some idiot on the internet and not in any way qualified to give advice.

It seems to me that depression is not a disorder, disease, or abnormality, but a necessary and purposeful reaction of the mind and brain to certain stimuli. Of course this is not always the case, and the same symptoms can be triggered by other factors that affect our neurochemistry or mental function, but in a normally functioning mind and brain I think this is true. When examined in this context, what do we find?

Depression makes us apathetic, reluctant to act, and unconfident. A while back there was an article on HN spitballing that depression and mania were related to our mind's assessment of its own ability to predict outcomes. Overconfidence in its own predictive ability manifests as mania, and low confidence manifests as depression. This makes some sense. If you are confident in your predictions you are more likely to act on them, and if you are not you are less likely to. Given this, I submit that it's possible that what depression really is, much of the time, is a philosophical problem.

Philosophy is our model of reality, and we use that model to make predictions and decide how to act in the world to affect change. When that model is known to be broken, we lower our confidence in it and act less. Over time, as more and more of our model is revealed as flawed and our confidence in it continues to plummet, we enter a state of learned helplessness. Finding ourselves unable to predict the results of our actions, we are unable to determine how to effect the changes we desire in our lives, leading to interesting contradictions like being bored and at the same time unmotivated to do things we used to enjoy. We don't want to be in this state, but we lack the ability to see a path out of it, so we become frustrated, angry, and/or sad. It can eventually reach a point where the only path out of the suffering that we're confident in, is death.

In fact, this model-breaking occurs many times in our minds' development. As we grow up we form several different models of reality, all of which are inevitably revealed to be flawed. This is the reason you find children who believe they are hidden just because they can't see you (their model of reality doesn't include the concept of different perspectives), and why the terrible twos are so terrible (the young mind is dealing with its model of reality failing), for instance. With children, however, there are plenty of people around them operating with better models of reality to help them work out a new one. Societies can also be modeled this way, and if we look at the past we find that human cultures also go through a similar pattern of forming a stable model of reality, eventually finding it flawed, suffering through process of dealing with that, and ultimately resolving the crisis. I say resolving because, in actuality, there are two solutions to the problem of realizing your model is broken: forming a new, more accurate, one; or ignoring the information that contradicts it.

This is the important point, I think: When an individual's model of reality is broken, and society cannot guide them towards a more accurate one because society itself is still operating on the model that individual has determined to be flawed, then chronic depression is a likely result. Our current societal philosophy, the one our health care system is also based on, see's this individual's suffering not as a transition period in which they form a new model, but a severe disorder. To them, the rejection of the model is a form of insanity, and unclear thinking. This is why you sometimes see people tell a depressed person an obvious platitude in an attempt to cheer them up, only for it to further frustrate the depressed individual: they are aware that the platitude is part of a flawed model.

Further, the health care system is, like most of current western society, firmly implanted in empiricism. Science and measurement are the hammer, and everything else is a nail. Society as a whole forms its model of depression on measurements and manipulation of the neurochemical and behavioral aspects of depression, the social side effects, etc, but without regard for its greater reason for being. They are witchdoctors, sacrificing chickens to drive out the demons and bloodletting to balance the humors. Sometimes it works, because even a broken clock is right twice a day, but a lot of times it doesn't.

If one were to assume that this assessment is accurate, then reason we get depressed is so that our mind is motivated to take a step back and build a more accurate model of reality. The thing to do, then, is to help the sufferer realize why they are suffering. There's nothing wrong with them, they don't have a chemical imbalance of the humors, they aren't bad people for feeling the way they do or for not having faith in what society tells them is true. They have in fact taken a step toward growth, and nearly all growth comes at the cost of suffering. They need to look hard at where reality has shone the light on their flawed conception of it, reason through the problems, and build a more accurate replacement, and we may not be equipped to help them.

Excellent comment. I have been struggling with some form of pseudo-depression (never got diagnosed) due to some odd mixture of social anxiety, too much narcissism, lack of motivation, poor biochemistry (probably porn addiction and too much "releasing"), malfunctioning relationships with parents/friends/coworkers. Its hard to actually wake up on any particular day and feel that "things are fine", so all my mind's resources are spent justifying how I might or might not be fine, reading too much internets about alleviating problems for which I might not even have, etc.

There was also an excellent thread and discussion a while back suggesting depression is more of an evolutionary mechanism: https://news.ycombinator.com/item?id=16216647.

I also wonder how much of depression is attributed by improper biochemistry in the brain, low serotonin etc. even though your environment/situation is actually fine.

Thank you for articulating it in a way I've never been able to. Although I do agree with other commenters that this might not explain every single case of depression, but personally your comment rings true. I still struggle with it from time to time, most recently a few days ago after what I felt like months of peace. Reframing it to this reinforcement model makes sense to me, instead of thinking I'm totally out of control.

This is the only sane answer I read here so far. I'm surprised that so many people still believe that depression is at large some kind of pathological condition. I'm even more surprised when people accept the most addictive drugs in existence as a "treatment" for anything.

You make some really great observations in your post. I found them very enlightening, eye-openers. However, I have to disagree on the fact that depression is usually/mostly a change of your perceptual model.

As you mentioned, depression is the state during which your prediction of the future (correctly or incorrectly) is that any action you take will result in a highly unpredictable, and mostly dangerous/damaging/negative feedback. Bad enough feedback for the best action plan to be doing nothing at all.

There are two main, and very important types of depression branching off here.

One is the type where your prediction is wrong. The other is the type that your prediction is right.

There are many cases where your modeling of reality is now flowed or outdated. Maybe you grew up with negative or mentally ill people, and you know no better. Maybe your school teachers were assholes. Etc. In this case someone needs to show you, possibly through demonstrations, that your perception of reality is actually flawed. Off the top of my head, most psychotherapy, like cognitive behavioral therapy, offers just that. Your therapist will try to prove your model of reality to be wrong (even if it's not, but that's another discussion), and convince you that things are better, to look at things positively etc. Some times, for some people, that works. Other might refuse to update their model and choose to ignore reality. Others find dysfunctional ways to cope with life. Others will get a terrible therapist with a worse model than theirs. Many things are possible.

The other main category of depression is the type where your model of reality and your prediction is correct. Like a dog or lab rat that gets zapped with 50% probability no matter what it does. At first it will try really hard to figure out what's going on, and in the end it will figure that trying isn't worth it and it will stop. You can give that animal all the ketamine in the world, and it still won't be happy, because their environment is flawed, not their perception or learning abilities. In real life, examples include dealing with unstable people (bipolar, narcissistic etc), being stuck at an actual dead-end situation with near-zero chances of recovery (homelessness, bad chronic illnesses), etc

In this case, someone needs to fix your environment (if possible, ie homeless or dealing with unstable people) and not your perception.

There is also a crossover between both cases you mentioned here which I see in some people close to me (and possibly I have succumbed to it too in the past) in struggling with the inability to change the flawed macro environment we all exist in. The person doesn't necessarily fall into any of the instability categories you mention and have otherwise covered their physical needs well. Typically these are people who expected more from the world and society than was reasonable. When this mental model breaks down the only way out of it is for them to update their model by choosing to ignore, or more accurately not care so much about non-immediate reality.

I agree and have lived through both of those categories. I should add as well that there is immense value in people knowing how to talk someone through this so that they are able to update their model of reality (over time as it does take work). I have found that if I can describe a potential better future with someone they can move towards that and better understand and deal with their current situation.

I’ve suffered from depression since entering adulthood, and I agree with your framework overall. Excellent post. I like the way Trent Reznor summarized: “It didn’t turn out the way you wanted it to ... now you know, this is what it feels like.”

The obsession with wanting things to turn out a certain way is in itself unhealthy. Life is much more interesting and rewarding if you follow a non-deterministic model. It's a journey with no goal and it's really really short. I've been much happier and achieved a lot more when I stopped hoping for outcomes and started enjoying the moment, the here and now. Life is what is happening right here right now, or as John Lennon (actually quoting Allen Saunders) eloquently put it, "Life is what happens to you while you are busy making other plans".

Extending from your outline:

Another source of depression is the realization that your life cannot work unless the world at large radically changes. Maybe you know what needs to change, but not how to make it change. Maybe you know what and how, but you also see the high cost involved where becoming the revolutionary leading the charge just lands you in prison or other drama and fails to get you the happy life you desire. Even if it benefits people who come after you, it won't benefit you. There is nearly zero hope of achieving a fulfilling life.

Death becomes the only relief you can imagine. Depression is the only alternative to hurling oneself into the path of potentially violent revolution.

Your depression theory has some resemblance to reinforcement learning. An agent learns to estimate the value of any state and to predict future states. When the value function is corrupted, it might get stuck in a very bad local optima. The way to escape is to try more things (to do random actions that might take you out of the loop). In RL, there needs to be a balance between exploration and exploitation. Depression seems to be a problem of too little exploration.

> see's this individual's suffering not as a transition period in which they form a new model, but a severe disorder.

This sounds like the unhelpful "it's just a phase, it will pass"

Just like a wound or a bruise, depression lasting weeks is ok, if it last years is a severe disorder.

> the health care system is, like most of current western society, firmly implanted in empiricism. Science and measurement are the hammer

That would be nice: science has been doing very well in the last 200 years. If anything, psychology and psychiatry are often accused of not being rigorous enough.

> They are witchdoctors, sacrificing chickens

You just wrote that medicine is firmly implanted in empiricism.

> we get depressed is so that our mind is motivated to take a step back and build a more accurate model of reality. The thing to do, then, is to help the sufferer realize why they are suffering.

Psychology "talk" therapy has been focusing on introspection since Freud. It's often not effective enough.

You needed to spend a week in a mental health facility observing patients with clinical / severe depression. Your model would fall apart pretty quickly. The most charitable thing I can say about your theory of depression is that in part it describes a small subset of depressed patients. Your modelling of mania is far from reality.

I've spent a combined total of 20 weeks being an in-patient with severe depression, and interacting with others. What specifically do you believe the parent would observe, that would cause them to rethink their viewpoint?

It would surprise me to hear that the majority of depressed people are in mental health facilities, therefore it seems more likely that your perspective is based on exposure to a small subset of depressed people.

While that's certainly another possibility, the most common cause of depression is purely chemical, as a symptom of magnesium deficiency. (which is common, and hard to diagnose, since it doesn't show on blood tests until you're suffering from muscle spasms and hallucinating)

I recently was on ciproflaxion and it depeted my magnesium levels. I never understood low feeling or depression before that. Boosting these levels and weed have pushed me back to normal.

Very well put. I would only add that by medicating we are simply treating the symptoms.

In the same way that cough syrup will never cure a cold, antidepressants alone will never cure depression.

Mood disorders might have underlying causes, but the diagnosis and definition is entirely based on the symptoms. Comparing it to having a cold is a bit misleading. It's more like having a couch, or itchy throat, that may be caused by cold, but it's not the diagnosis you'd get.

Could you cure a cough with couch syrup? Could you cure a sore throat with pain killers?

Antidepressants makes the basis for a depression diagnosis go away for some of those who are treated. Having no measurable level of depression is probably the closest we will ever get to a cure of depression at large.

If the depression is caused by something specific, say a vitamin deficiency, that underlying issue would of course not be treated by SSRI. But we don't know enough to say that there always is something specific causing the symptoms. What if the issue is actually a serotonin deficiency? Just like some people naturally produce to little vitamin D and have to take supplements.

What if not all DNA sequences lead to a happy life? There's nothing in evolution that enforces that all offspring has to be happy for survival to happen.

I think it’s pretty clear that “depression” is a normal psychological state, and that it is functional. It would be surprising to find such a common, and profound, behavior in a long running, successful species if it wasn’t.

As the example of learned helplessness illustrates, depression can be induced in a predictable way. Even on an intuitive level, a stance of submissive apathy could increase chances of survival, if one is a captive.

My (lay person’s) view is that what we see as clinical depression is a symptom of a “bias” or miscalibration issue, where the feedback circuits in the brain responsible for maintaining homeostasis have been forced to work outside of their functional ranges. The brain has a lot of redundancy and compensating routines, but they have their limits.

One of the most obvious causes would be having a weakened part of the brain, whether through injury, genetic, or environmental causes. The brain becomes miscalibrated, and can’t maintain equilibrium because some essential component is operating “out of spec.”

If you look at other human attributes and biological systems, they are all prone to disorder. Or perhaps, to having characteristics that fall on the outer edges of the distribution of the characteristic. As a simple example, when an individual is under a certain height, we call that a “disorder” or “syndrome.”

So there is an element of arbitrariness and imprecision as to where these definitional borders are drawn. They are fuzzy. But, looking at a larger population, you can start to see patterns where you can definitely place an individual into a sub population of people who have a disorder.

Mania, for example, has enough common symptoms, that I am confident it is an actual, physiologically based, “disorder. Even though the symptoms of mania are all behaviors and states experienced by “healthy” people, all the time.

I also have a theory that by the time a mental health problem starts to become perceptible by others, it is actually a pretty severe condition. The individual’s internal state is probably far more disordered than it appears to be. Because our brain is so flexible, and powerful, it can compensate even extremely disorder functioning, for the purpose of hiding the illness from others.

My ideas are largely consonant with yours. You’ve outlined a “model”of depression, which uses the concept of depression being a response to having ones mental construct of reality broken. That would be the functional aspect of depression.

My view is that “depression” the disease occurs when the brain can no longer maintain homeostasis. So if someone is being tortured, for example, depression would be a an expected response. If the torture is severe enough to push past the ability of the brain to maintain order, which is the point of torture, that’s a situation where calling the state a “disease” or an “expected response” is simply a matter of semantics.

Because depression is a normal state, part of a stress response, it’s symptoms can look, and be, very similar, even though the causes can be myriad. I think this is why the blunt instruments of psych drugs are used to treat these symptoms across so many different scenarios. They don’t work great, but they do work.


Thank you for taking the time to share your thoughts and insights on this, and articulating them so well.

Did you just equate modern science based medicine with witch doctors? LOL!

That's an interesting post, though I do think the cause you've suggested is only a subset of possible causes of depression.

Depression is an illness that is defined by its symptoms. The causes are diverse and can be deeply personal. This is unlike most other illnesses, where there is a much smaller set of possible causes for a given set of symptoms. For some illnesses the causes are unavoidable, I can't do anything to prevent the catching a cold, I have to step outside and interact with the world where the virus lives. For others causes can be addressed, for example, I experience stomach pains after drinking milk so I stop drinking it.

The current state of mental health care is in terrible shape. Doctors do not have the time to provide psychiatric advice but they do have just about enough time to sign off SSRI prescriptions. Your pills may help you get through the day a bit easier but if you do not address the cause of your illness your symptoms will eventually surface again. There are cases where perhaps the cause is completely due to a chemical imbalance but from all I've read about depression, this seems rare. Most of the time the suffer needs help addressing the root cause of their depression. Sometimes it's learned helpnessness which needs a change in our mental model, sometimes its about quitting destructive habits/addictions or sometimes we understand reality completely and just need to change our behaviors to become satisfied with life.

Reminder that the FDA seems to fast track the wrong drug:

They gave "breakthrough designation" ( https://en.wikipedia.org/wiki/Breakthrough_therapy ) to Esketamine under pressure from Johnson & Johnson:


Although Arketamine seems like it has a lot more responsibility for the antidepressant effect of racemic ketamine:



https://www.ncbi.nlm.nih.gov/pubmed/24316345 (2013)

http://www.cpn.or.kr/journal/view.html?doi=10.9758/cpn.2014.... (2014)

https://www.ncbi.nlm.nih.gov/pubmed/26327690 (2015)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910398/ (2016)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487269/#__sec4... (2017)

That isn't to say Esketamine doesn't have an antidepressant effect. In light of the fact that Esketamine makes you Trip Balls(tm) while Arketamine doesn't, I like to think of it this way:

You can likely get an antidepressant effect out of Esketamine in the same way that you can get an antidepressant effect out of psychdelics like LSD-25 & Psilocin. However, like those, it could possibly also make depression worse, and unlike Arketamine doesn't seem to represent anything awfully novel. It however also makes me suspect that like with other racemic drugs like Amphetamine, a shifted ratio preparation might make for a better drug overall than isolating the stereoisomers. For example, Adderall contains 75% dexamphetamine, 25% levoamphetamine, in the form of various amphetamine salts (wheras racemic amphetamine contains 50% of each, typically as a single salt.).

[Semi-related: I still don't comprehend why pharmaceutical companies have yet to create a combination preparation of Lisdexamfetamine with something like Lislevoamfetamine, - which I haven't seen synthesized but I don't see anything speaking against it -, in a ratio akin to the one seen in Adderall. The rational behind that ratio seems sound, albeit I'd perhaps go for an 80/20 split instead of a 75/25 split...]

I think the answers to your questions are unfortunately not scientific but business related

Fast track designation must be requested by the company developing the drug. J&j is developing esketamine; I don't know of any companies developing arketamine

I think a big reason j&j decided to develop esketamine vs ketamine is because ketamine is an old approved generic drug (i.e. Cheap). they chose it over arketamine probably for all the pharmacologic and therapeutic reasons cited in the second to last paper you link to. Last December they released phase 2 data that looked pretty good though there were dissociate side effects

The new data on arketamine are interesting but I view them with a grain of salt. There's only so much you can conclude about depression biology and structure activity relationship from animal models. Plus the mechanism of action of ketamine is so complex and poorly understood that by trying to be too precise with our receptor targeting we risk losing desired traits. We don't really know that AMPA is a better target than NMDAR; and we don't know the right ratio, and we don't know whether there are other important receptors beyond these

> You can likely get an antidepressant effect out of Esketamine in the same way that you can get an antidepressant effect out of psychdelics like LSD-25 & Psilocin.

LSD and magic mushrooms modulate serotonin, so the antidepressant effects that those drugs might have is easily explained. What isn't/wasn't so easily explained is why Ketamine specifically has long-lasting antidepressant qualities when it isn't serotogenic. The article mentions effects Ketamine has on the lateral habenula, which if targeted in the same was that Selective Serotonin Reuptake Inhibitors (SSRIs) do could lead to a class of antidepressants which are completely orthogonal to our current approach. This would be extremely valuable because depression is a fatal disease and frequently poorly treated.

I also wonder if the method of administration of esketamine is a good one. Oral is one of the worst ways to take traditional ketamine.

I look forward to the day where the suggested ROA of an FDA approved drug is insufflation

> You can likely get an antidepressant effect out of Esketamine in the same way that you can get an antidepressant effect out of psychdelics like LSD-25 & Psilocin.

LSD-25 and Psilocin simply amplify your emotional state at a given time, because they act on 5HT receptors. That’s not what an anti-depressant does. In fact, anti-depressants help one regulate emotions correctly. In that sense, Esketamine is truly novel for being a rapid anti-depressant, because it acts as a NMDA antagonist.

Psychedelics are not simply dumb emotional amplifiers as you characterize them, they can radically alter your mood (for the better or the worse) pretty radically from your initial mood. They can generate or amplify one small insight into a wonderful state of mind, or they can generate or amplify an absurd fear to the point that you lose all sense of hope and reality.

Correct, but that happens to you every day on a minor level. You just don’t notice it because there are filters in your brain. Psychedelics remove those filters.

It comes down to inhibitory control. People suffering from depression lack inhibitory control of negative thoughts and emotions, which leads to a feedback loop of thinking more negative thoughts and feeling more negative emotions.

They also tend to cause permanent personality changes (increasing "openness to experience")

Esketamine[0] works as a NMDA antagonist. Most nootropic drugs, and anti-AD drugs have some interaction with AMPA, NMDA, and glutamate.

I have a hunch that most mental illnesses have to do with a dysfunctional glutaminergic system, with some misbehaving AMPA/NMDA signaling thrown in there for good measure.

[0] https://en.m.wikipedia.org/wiki/Esketamine

DXM is a terrible antidepressant. So is Atomoxetine (strattera).

I do look forward to trying esketamine if I can. Probably going to be out of my price range even with insurance.

I wonder if it can be used to treat tinnitus.

Columbia University is doing a study on it: https://clinicaltrials.gov/ct2/show/NCT03336398

It is interesting to see an exploration of astrocyte involvement and the use of optogenetic techniques to establish causality is promising. Hopefully there's more work like this going forward

That said, animal models are poor predictors of human biological activity. Animal models of psychiatric disease are some of the worst offenders. There's plenty of data showing stuff works in rats / mice but not in humans, but just take a step back and think about it: the human brain is unique among all animals, and its uniqueness imbues humans with all sorts of important mental and emotional features (and bugs). a rat brain is a very poor approximation but it's often the best we can do.

Is the human brain a difference in kind or a difference in degree, or both?

Both; humans brains are obviously bigger, more complex, and a have larger and more complex cerebral cortex (among other differences)

This is a good overview of comparative anatomy in lay terms: https://canvas.brown.edu/courses/851434/pages/comparative-ne...

Does Ketamine possibly influence an increase in depression when it wears off?

And how long does it take for it’s anti-depression effects wear off?

Why are we still testing on rats? Don’t we have a better method?

Ketamine is legal for doctors to use on humans in most parts of the world, but most humans object to brain biopsies while alive, or injections directly into the brain while the instruments are monitoring what happens in the skull.

That's one reason that the method of action for plenty of approved treatments for mental health can be "???" - human clinical trials mostly check that it's not going to {kill you, make it worse} and works better than placebo, not "what's going on inside this live human brain", until we get better live monitoring non-invasive tooling for this sort of thing in humans.

Unfortunately we don't. Definitely puts a damper on the conclusions. The optogenetic technique involves gene delivery to specific brain cells which is not yet something we're comfortable doing in humans for basic research, although there are a few drugs using this tech in clinical trials

IIRC their brain chemistry is more similar to ours than most other animals.

They do simulations and petri dish testing as well, what would a better method look like?

We know ketamine is relatively safe for humans from the recreational use.

Ketamine was used to sedate my then two-year-old daughter in the ER when she needed stitches near her lip. The doc didn't want to foul up her face if she thrashed. It was definitely odd. She was awake, but no reaction AT ALL.

Ketamine gets more use in kids than adults because they tend to react better to the dissociative effects. Adults can become combative.

To your point, when the first dissociative hit the market, phencyclidine (PCP), it was a bit of a miracle drug. No respiratory depression, actually makes the heart beat a little stronger. It wasn't until the dissociative effects became more known was it withdrawn from the market.

If you are depressed- buy a horse.

Isnt it wonderfull how we can fix depression now, but nobody has worked on a chemical fix against beeing overly conformist behaviour? No legal drug on the market that cures a lack of rebellion.


As if what is declared disease and what is declared cure, is dependant upon how usefull it is to society- but wait, rebellion could be usefull for a scientific society too- so its dependant on how adaptable the "cure" makes you for a hierarchic society.

All those pheromones the queen emits, they make the little bees work.

go sign a study protocol and tell us

Strange. Ketamine alone is so insanely dark and boooring. When in combo with LSD it's a lot more enlightening. The researchers should try just that

Careful - overuse of ketamine can destroy your bladder.

Quote : “In this work the team induced depression in rats either chemically or by inducing what's called "learned helplessness." (The latter involves training the rats to recognize that they have no control over negative consequences in their environment.)”

Oh shit... that’s quite disturbing

The genesis of the learned optimism movement was Dr. Seligman locking dogs in a cage and giving them electric shocks until they gave up trying to avoid them. This is somewhat glossed over in his books...

Yeah, they basically torture rats to test antidepressants. It's really upsetting.

Apparently it's funny to most hn'ers. I'm guessing they aren't clear on what it takes to teach helplessness.

Let's not assume that about most HNers.

Apparently they made the rats work on maintaining legacy software.

While getting paid?

No, they sent them to get their Ph.D.

They train the doctoral rats to induce depression in other rats for research purposes, thus completing the cycle.

With the addendum that it's Class 1 biomedical device software and no one has any real clue about how it works.

That sounds kind of fun, if perhaps lethally risky for whatever poor soul is relying on the device.

If there weren't the results of mistakes leading to death or illness, I'd think black-box re-engineering a device like that would be one of the more interesting projects to take on.

Many a true word spoken in jest. Damn.

Good thing this study wasn't around during Y2K - the rats would have killed themselves.

and then updating the documentation and test plans

Now that is funny!

More than a few dogs show this behaviour.

The original studies on learned helplessness used dogs.


They made them watch the news!

Unless the rats turn to stoicism. Then the joke’s on the researchers.

This is exactly what I thought. Could it be that their results are confounded by a mix of rats for which the induced state of helplessness results in depression and some other rats for which this resulted in enlightenment of sorts.

is their enlightenment related to cheese ?

I'm sure the researchers control for this. Most likely they block the rats' access to HN at the firewall, thus preventing them from ever hearing about stoicism in the first place.

Learned helplessness would manifest differently than stoicism. In LH you don't take clearly good (for external observer) opportunities because you believe it will all end badly anyway.

How can the stoic be so much more knowledgeable about whether the opportunity will work out or not?

The stoic may have imperfect assesment of the opportunity's true value, but in LH the assesment is way more off - it's basically always zero for all opportunities.

> Research has found that a human's reaction to feeling a lack of control differs both between individuals and between situations. i.e. learned helplessness sometimes remains specific to one situation but at other times generalizes across situations.[6][8][9]

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