
New studies zero in on roots of depression and how ketamine affects it - rbanffy
https://arstechnica.com/science/2018/02/new-studies-zero-in-on-roots-of-depression-and-why-ketamine-reverses-it/
======
manmal
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?

~~~
sjg007
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.

~~~
AnIdiotOnTheNet
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.

~~~
c3534l
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.

------
AnIdiotOnTheNet
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.

~~~
John_KZ
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.

~~~
rorykoehler
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.

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

[https://news.ycombinator.com/item?id=16393861](https://news.ycombinator.com/item?id=16393861)

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

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

[https://en.wikipedia.org/wiki/Esketamine#Depression](https://en.wikipedia.org/wiki/Esketamine#Depression)

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

[https://en.wikipedia.org/wiki/Arketamine#Novel_antidepressan...](https://en.wikipedia.org/wiki/Arketamine#Novel_antidepressant)

[https://en.wikipedia.org/wiki/Hydroxynorketamine](https://en.wikipedia.org/wiki/Hydroxynorketamine)

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

[http://www.cpn.or.kr/journal/view.html?doi=10.9758/cpn.2014....](http://www.cpn.or.kr/journal/view.html?doi=10.9758/cpn.2014.12.1.72)
(2014)

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

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

[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487269/#__sec4...](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487269/#__sec4title)
(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...]

~~~
LaikaF
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.

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

------
ShabbosGoy
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](https://en.m.wikipedia.org/wiki/Esketamine)

~~~
LaikaF
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.

------
tyhui
I wonder if it can be used to treat tinnitus.

~~~
notanai
Columbia University is doing a study on it:
[https://clinicaltrials.gov/ct2/show/NCT03336398](https://clinicaltrials.gov/ct2/show/NCT03336398)

------
aaavl2821
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.

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

~~~
aaavl2821
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...](https://canvas.brown.edu/courses/851434/pages/comparative-
neuroanatomy?module_item_id=6517341)

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

~~~
YCode
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?

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

~~~
shanecleveland
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.

~~~
refurb
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.

------
homakov
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

------
hoodoof
Careful - overuse of ketamine can destroy your bladder.

------
atomical
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...](http://www.cochrane.org/CD011611/DEPRESSN_ketamine-and-other-
glutamate-receptor-modulators-bipolar-depression)

~~~
LaikaF
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.

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

How do you know the quality?

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

~~~
rubicon33
How do you trust anything you get on the darknet?

~~~
kakarot
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.

------
eecc
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

~~~
hugi
Apparently they made the rats work on maintaining legacy software.

~~~
turbinerneiter
While getting paid?

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

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

------
gt_
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?

