New studies zero in on roots of depression and how ketamine affects it

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There are many cases where your modeling of reality is now flowed or outdated.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.

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.

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

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.

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

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.

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.

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.

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

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

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.

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.

Mysterious.

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.

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

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

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.

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

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

I was first introduced to the concept by this video: https://www.youtube.com/watch?v=YMPzDiraNnA