Ketamine lifts depression via a byproduct of its metabolism
sciencedaily.com
sciencedaily.com
Chronic tinnitus is currently a condition which if one were to go to the doctor and ask for a cure one would be told to get used to it as there is not much that can be done.
The pace of medical and biotech advancement is increasing as the FDA has relaxed a bit and better understanding of human biology is creating cures for what once were incurable diseases. Exciting times, but not fast enough for me.
The most interesting question for me these days: How can we 10x the number of dollars and scientists engaged in medical research, and then 10x that?
"The treatment, delivered directly into the inner ear via three injections over three days, must catch the disorder while the problem is still within the ear, before the brain has begun overcompensating for the loss of hearing. Once that happens, no amount of adjustment to the receptors on the auditory nerves will do any good.
Because it is not known when that transition from ear to brain occurs, one of the current trials, of 300 European patients, is specifically testing tinnitus sufferers who have developed the condition no more than three months prior to treatment. The other, a study of 330 North American patients, is investigating a therapy within one year post-trauma. Preliminary results suggest that S-ketamine is effective beyond three months, but declines in effectiveness within a year of the initial trauma, so later stages of the trial are being refocused on the four- to six-month time frame. The trials will be completed at the end of this year, and Auris hopes to submit to the US Food and Drug Administration (FDA) for approval in the summer of 2016."
I'm not advocating taking up smoking, although it is something worthwhile to consider if things like ECT don't help. There's probably ways nicotine can be therapeutically administered without the negative side-effects of burning tobacco.
Turns out it wasn't depression, but type 2 bipolar. If stimulants are providing relief, you need to see a psychiatrist if you haven't already.
Let me get this straight...you are actually claiming that regulation increases knowledge? The mind boggles.
That is a shocking and novel epistemological formula - although obviously it has been the implicit subtext of public education in the u.s. for over a century.
'Our results demonstrate that overall electronic cigarettes seem to be less harmful than regular cigarettes, but their elevated content of toxic metals such as nickel and chromium do raise concerns," said Constantinos Sioutas, professor at the USC Viterbi School of Engineering, and corresponding author of the study, which was published online on August 22 by the Journal of Environmental Science, Processes and Impacts.
The metal particles likely come from the cartridge of the e-cigarette devices themselves - which opens up the possibility that better manufacturing standards for the devices could reduce the quantity of metals in the smoke," said Arian Saffari, a PhD student at USC Viterbi and lead author of the paper. "Studies of this kind are necessary for implementing effective regulatory measures. E-cigarettes are so new, there just isn't much research available on them yet.'
http://www.eurekalert.org/pub_releases/2014-08/uosc-ses08281...
But now that you mention it, the vapor does emit alarming levels of formaldehyde when the devices are used at high voltage:
However, it also gives people the false impression that all they need to do is chew on some shrooms and listen to the Grateful Dead for a couple of hours and suddenly they will be free of all addiction and depression forever.
Every time a study like this comes out there is a predictable pattern in patients' depression scores: immediately after psychedelic treatment, depression signs plunge, wade around the low end for a while, then steadily creep back up.
With the exception of people whose brains simply do not work as they should (I have a friend who is chronically depressed because his body can't produce enough serotonin even with antidepressants), depression is often as influenced by external factors as internal ones. A spectacular drug trip won't change the reality of having a death in the family, not being able to find a job after being laid off at 45, or simply the stress of the modern, always-on world.
Discoveries like these are always helpful towards understanding the brain and how to formulate effective treatment, but in the end, mental health will always be vastly more complex and harder to cure than any physical ailment. There will never be anything close to an ibuprofen for the brain.
http://bigthink.com/devil-in-the-data/the-chemical-imbalance...
#2) The novel method of ketamine doesn't really appear to be related to the psychedelic trip itself -- indeed many people are using regular sub-threshold doses of ketamine in their self-designed regimens and seem to be getting good results. LSD and psilocybin treatment seems to be mostly about insights gained during the experience -- much like a supercharged therapy session. Ketamine on the other hand, appears to have some sort of mode of action that isn't about insight and is more about a "brain reset" of sorts.
#3) I do agree with you that mental health issues defy reductivity simply because they encompass biological, psychological, and sociological systems that all interact.
http://motherboard.vice.com/read/a-brief-history-of-microdos...
Exactly the people these treatments target. I'm on of those people and I have never thought I could "chew on some shrooms and listen to the Grateful Dead for a couple of hours." Quite the opposite. Depression makes you think nothing will work. When I'm in a depressed state it takes a tremendous amount of will to do anything, including taking medication of any sort or even getting out of bed for that matter.
Fortunately SSRIs work for me, as well as tight control of my diet and exercise. Exercise alone has never made a difference for me, though. One of the worst episodes I ever had came at a time when I was in the best shape of my life, working out everyday.
SSRI seems to have done the trick. Apparently we all produce "normal amounts" of serotonin, but with depressed folk like myself, the serotonin doesn't hang on the synapse long enough ...i.e. our specific biology depletes it faster.
Looking at my wider family, this condition is so pervasive ... and inherited, it's not even funny in all the ways it wreaked havoc on people's lives in many ways. Glad I caught a break.
> Looking at my wider family, this condition is so pervasive ... and inherited, it's not even funny in all the ways it wreaked havoc on people's lives in many ways. Glad I caught a break.
I agree, it is quite sad. Like right now I'm certain that my father is depressed although the reasons for this are somewhat interconnected with real life events like unemployment, loss of loved ones, etc ...
It's true that drugs won't change reality, but our interpretation and reaction to reality is what's important, and therapy/drugs can certainly change that.
...as well as lowering the incidence of PTSD among people who had been treated with ketamine as an anesthetic prior to a traumatic experience. [2] [3]
[1] - https://www.ncbi.nlm.nih.gov/pubmed/24740528
[2] - http://www.biologicalpsychiatryjournal.com/article/S0006-322...
Have you ever taken hallucinogens? You don't experience a "spectacular drug trip" and suddenly feel better, you actively work on your problems and have a seemingly raw, uncompromising perspective on the external/internal factors that affect your life.
It's a bit like expedited therapy. It's a trying, intentional experience that you have to put effort into in order to get any benefit.
Self-interested, perhaps. But assuming that physicians are representative of the broader population when it comes to incompetence is really poorly-grounded.
There was stress in the old world too. Also, we work less than historically. I'd argue today's world is less stressed.
http://groups.csail.mit.edu/mac/users/rauch/worktime/hours_w...
Placebo control groups are absolutely critical in depression studies because the placebo response rate for depression is incredibly high. Moreover, placebo response rates are actually rising in recent years for unknown reasons. It's not uncommon for the placebo control group in a depression study to have response rates upwards of 60%, at least in the short-term timeframes of clinical studies. When you read sensational news articles about how SSRIs are barely better than placebo, remember that placebo is pretty damn good (again, in the short-term) at producing a response in depression studies. The story changes in clinical practice over the long-term, of course, but the point is that separating placebo response from actual treatment effects is critical for assessing anti-depressant efficacy, and psychedelic (not ketamine) studies lately have omitted placebo control groups completely, which is unfortunate.
It gets more complicated, though. In the case of psychedelics, the placebo effect may actually play a central role in the anti-depressant effects. Psychedelics are known to induce suggestibility and create a false sense of enlightenment. If that suggestibility and sense of enlightenment is deliberately framed in the context of depression treatment and actively guided by clinicians, as in the studies, then perhaps it's possible that the psychedelics are at least partially acting as an instrument for amplifying the placebo effect. To the depressed patient, it doesn't matter if the result is placebo effect or not, as long as the end result is the same. At that point, the real question is whether or not the end result is the same.
> However, it also gives people the false impression that all they need to do is chew on some shrooms and listen to the Grateful Dead for a couple of hours and suddenly they will be free of all addiction and depression forever.
I completely agree that public and media perception of these experimental depression treatments is completely off base. There is a lot of interesting potential in here, but many people are walking away with an idea that they can self-medicate their problems away by themselves in their basements. There are many people in forums and subreddits chasing ill-conceived plans to treat themselves with psychedelics or NMDA antagonists in ways that don't match the study protocols at all, and it's all very concerning.
> Every time a study like this comes out there is a predictable pattern in patients' depression scores: immediately after psychedelic treatment, depression signs plunge, wade around the low end for a while, then steadily creep back up.
Unfortunately, the same pattern is observed in placebo control groups for depression studies. That's why it's so critical to have a placebo control group such in depression studies.
> With the exception of people whose brains simply do not work as they should (I have a friend who is chronically depressed because his body can't produce enough serotonin even with antidepressants), depression is often as influenced by external factors as internal ones.
Your comments on external factors are spot-on. Training the brain to have healthy responses and coping mechanisms, as in CBT, is critical to depression treatment.
However, the comments about your friend's brain not producing enough serotonin is more pseudo-science than real science. I don't doubt that doctors have told your friend that, but it's a metaphor at best. SSRIs don't cause the brain to produce more serotonin, they modify the dynamics of serotonin transmission. The anti-depressant effects come from downstream changes that result from that alteration in serotonin dynamics, which are complex and multi-faceted.
But depression isn't simply a function of serotonin levels or balances like the over-simplified explanations would suggest. It's entirely possible to increase extra-synaptic serotonin functions well beyond normal, healthy ranges with medications without making the patient "feel" good. Depression is massively complex, and we modulate serotonin because it's one of the easiest and safest paths to manipulate brain function, not necessarily because patients don't have "enough" of it.
> mental health will always be vastly more complex and harder to cure than any physical ailment.
You're absolutely right that effective mental health treatment requires more than just a pill. But having effective medications to augment healthy mental habits, coping mechanisms, and CBT-type treatments makes it a whole lot easier.
I can't really agree with this. I was given ketamine in a surgical setting. The result could really only be described as what the cool kids call "tripping balls". Totally out-of-body experience.
Have you considered multiplying by 100? Note that the preceding sentence also has the advantage of having a real actual verb in it.
Though I suppose it's pointless to rail against insufferable tech buzzword-speak, or typical valley-style nonsensical 10x statements at this point. Oh well.
We detached this subthread from https://news.ycombinator.com/item?id=11903404 and marked it off-topic.
2) It seems like he said "10x...and then 10x" instead of "100x" as either A) an allusion to a multi-staged process, or B) a rhetorical device to emphasize the magnitude of the changes needed. Either way, it isn't exactly the same as just saying "100x".
3) Your comment has no substance and is just an attack. That's against HN rules.
Here's some more interesting info about the trials for s-ketamine as a tinnitus treatment.
The vision for the company that is trying to bring intratympanic s-ketamine to market as a tinnitus treatment was very interesting to me.
The founder was looking for new uses for drugs that are currently approved and with long safety records, that could be tested on animals.
I thought it was interesting criteria for a low-hanging fruit search of the problem space in medicine, considering regulatory realities as well as financial ones.
Correct. In fact, it simply doesn't happen at all in a category like medical research spending.
Even if it did it's not likely the returns to that spending would grow exponentially.
But to humor you, by what mechanism do you think medical spending in the U.S. will grow from its current $95bn per year amount to $9.5 trillion?
Is your assumption that basic medical research will grow to consume 57% of the country's GDP, or do you anticipate growing the size of our nation's economy by approximately 50% to accomplish this feat?
Assuming you've got that sorted, who do you think should get the $9.4 trillion dollars in additional medical research spending you propose?
The U.S once spent 75% of global research dollars, it's share has now dropped to below 50% as Asia has come online in this sphere.
If current spending is just 95 billion in the US, that has been quite a drop from previous years, but for a thought experiment, if US level research spending was the same per capita for the rest of the 96% of the human population, we would be somewhere around 2.3 Trillion globally.
There are billions of people outside the U.S, some with minds as sharp as WSU's Joe Harding, who as of right now are left out. But where do we find the money to lift them out of poverty?
One answer, we discover cures for some really expensive ailments, like diabetes, heart and respiratory disease.
What is the cost of disease? It is terrible. With an aging population, it has the capacity to ruin developed nations.
While we tinker around the edges, and manage chronic disease like diabetes with insulin, or Parkinson's with carbidopa, we spend large fortunes and get poor outcomes.
SENS is moving in the right direction. We need the ability to repair ourselves at the cellular level, and we are making progress in this regard.
What is the prize of discovering how to repair the inner workings of the molecular machinery that make us up?
> First, Non communicable diseases already pose a substantial economic burden and this burden will evolve into a staggering one over the next two decades. For example, with respect to cardiovascular disease, chronic respiratory disease, cancer, diabetes and mental health, the macroeconomic simulations suggest a cumulative output loss of US$ 47 trillion over the next two decades. This loss represents 75% of global GDP in 2010 (US$ 63 trillion). It also represents enough money to eradicate two dollar-a-day poverty among the 2.5 billion people in that state for more than half a century. [1]
So yes, $9.4 trillion is a good global goal, but I believe there is opportunity for tremendous cost savings.
Open source drug discovery, open source cancer treatment, that is what I am interested in these day. I would like to see an army of pro-amateurs collaborating online and performing experiments on mice in their garage, a hacker movement for biotech.
We are on the cusp of fantastic gains in health and longevity. We have only just begun to understand the molecular processes that age us and make us sick. Lets pick up the pace.
[1] http://www3.weforum.org/docs/WEF_Harvard_HE_GlobalEconomicBu...
And PS:
I checked out your page, you did some work for my favorite band, The Hold Steady. Awesome :)
However, this result is promising. This study has claimed to have isolated the anti-depressant effect to a particular product of ketamine metabolism, and that this compound contains none of the anesthetic and addictive properties. Obviously, this is just a single study, performed on mice, but it is a promising first step towards the potential development of a new anti-depressant.
Heh, these concepts are unrelated to the point that this statement could make a decent joke. As a rough example, it's on the level of "not to mention that you're installing a clock application on a computer that's already overclocked".
Can you give a source for that, and some examples? I couldn't find anything (googling "antidepressant depressant" is about as helpful as you'd think).
I'd still argue that the effects of depressants (the inhibition of neurotransmission) are in and of themselves not helpful for people depression.
I agree my phrasing was a bit confusing, I tend to value poignancy over explicitness :)
I guess it depends on how strict you are with your definition of a depressant, but looking at this list:
http://www.webmd.com/drugs/condition-1022-depression.aspx
If you establish a depressant <-> stimulant axis, the major drugs here are very much on the depressant side. As for their effectiveness, depressants generally feature a euphoric, "feel good" component. From there it's easy to see how some members of this class might be helpful against depression. It seems paradoxical that you might be worsening the lethargic aspect, but basically the treatment concentrates on the negative mood, loss of pleasure aspect, which appears to be a more effective way of approaching the problem (if you take for granted that chemicals are a good approach at all).
SSRI withdrawl effects last up to a month whereas Ketamine once a month produces no such effects.
So the current therapy for depression is more addictive, by design, than Ketamine.
"depressant" has also never meant "induces long term state of depression".
On a more practical level, many people with clinical depression suffer from reduced affect, lethargy, and general lack of energy. Depressants will make those symptoms worse.
Studies say otherwise.[1][2]
> On a more practical level, many people with clinical depression suffer from reduced affect, lethargy, and general lack of energy. Depressants will make those symptoms worse.
Reduced affect is brought up all the time when talking about various things and people go "Oh noes! Reduced affect!" which only goes to show that they have no idea what the phrase means. It's not particularly negative in itself; it's only a diagnostic criteria of underlying disorders which have negative effects.
Lethargy and general lack of energy are the same thing.
So basically you have one negative symptom you claim ketamine will cause because it's a depressant. Given that it's a party drug taken in much-higher-than-clinical doses at raves where people dance for hours on it, you should maybe consider the idea that you don't know what you're talking about and stop talking.
To be clear, I'm not particularly in favor of ketamine in treatment. If you knew what you were talking about, you might have, for example, cited the most obvious side effect of ketamine which is bladder damage. Ketamine needs to be studied more, in my opinion, to find out whether the positives outweigh the negatives.
But your ignorant opinion based on the etymology of "depression" is actually detracting from this conversation and doesn't help us to study it. You're just spreading misinformation for no reason except your own ego.
[1] https://www.clinicaltrials.gov/ct2/show/NCT00088699
[2] https://www.nimh.nih.gov/about/director/2014/ketamine.shtml
Dicking around with the chemistry of ketamine to make it safe and therapeutic as well as pre-cursory enough for consumption to generate the desired effect could take years though, and there still might be issues even then that would prevent it from general use....
Bit off topic - if there's one place where I am for patents, it's for pharma - takes years to find something that works, and when they finally do, it's only natural that they would want to recoup the money.
Who knows how much scientific justification they have to do so, but they are taking patients and so on.
> Given that it's a party drug taken in much-higher-than-clinical doses at raves where people dance for hours on it ...
You can make the same point about alcohol: people routinely ingest large amounts of alcohol and can still engage in lots of physical activity, despite it being a depressant.
If you decide to share your opinions on things you don't know about as if you do know about them, then I'm not sure what you're expecting. Warmth and acceptance?
> You can make the same point about alcohol: people routinely ingest large amounts of alcohol and can still engage in lots of physical activity, despite it being a depressant.
Yes and I will, because that's the entire point of what I'm saying. Just because something falls in the broad category of "depressant" doesn't mean it's going to make you lethargic.
Ketamine is used in a very small dose. There's plenty of research showing some beneficial effect.
However, it is possible that illegal recreational compounds can shed some light on body chemistry, and I think that's what happened here. The "ketamine is an antidepressant" story has been around for a while. It was considered kind of a deal because everything about depression previously dealt with serotonin, and ketamine clearly has nothing to do with serotonin.
Consequently there's people working on compounds with similar actions, but without ketamine's ill effects. The closest one I know to production is this one:
https://en.wikipedia.org/wiki/Rapastinel
Which, as a Phase III "breakthrough candidate", still has a long way to go, of course.
This new study is significant, though, if it is not the NMDA receptor that is really creating ketamine's anti-depressant effects. It may allow for alternate compounds to be explored beyond even what is being worked on now.
Ketamine is a dopamine reuptake inhibitor, possibly leading to some of the euphoric and reinforcing effects of the drug. Cocaine, methylphenidate and methamphetamine are examples of addictive and abused dopamine reuptake inhibitors. Addictive drugs have direct or downstream effects on the dopamine system. It also stimulates the D2 subtype of dopamine receptors.
Ketamine primarily acts on glutamate, one of the reasons it's such an "effective" anesthetic, as the specific glutamate receptor (NMDA) it acts on is involved both in memory formation and the rather complex neurological process that leads to experiencing chronic pain. Its effect on dopamine reuptake (along with norepinephrine and serotonin), GABA potentiation, and opioid receptors means, roughly, it affects much more of the brain's chemistry than the "unwashed masses" using it are aware of.
They think it's relatively safe because it wears off faster than PCP (it does) or other depressants (it does) but in reality it dramatically affects multiple systems in their bodies, with some effects building up over time to ultimately cause physical damage (like bladder wall thickening, or damage to cardiac tissues). And in the meantime, they come to relish the escape of the K-hole. At least, until they have a bad trip, because the hallucinations they have are still controlled by their own brains, and if they're having a bad time in life, their hallucinations aren't going to be helpful. What's worse, because they think it's like any other depressant, they freely combine it with Adderall. Ketamine is a cardiovascular stimulant, and mixing with Adderall has a very real risk of proving fatal.
Psychological addiction causes users to disregard all these risks, even the ones the users know about, and pursue taking the drug regardless, and is no less dangerous than physical addiction. In fact, because of its effects on dopaminergic modulation and opioid receptors, there is an easy argument to be made for the addictive potential of ketamine. Further, it's important to understand: rats will self-dose with it, humans rate the high they get from low doses of it as being likable and causing them to want more, daily users often go through withdrawal symptoms and experience cravings after they stop using, and users rapidly develop a tolerance for it - all of these are metrics used to determine how addictive something is. Which is to say, in the case of Ketamine, quite.
So, no, it's not a stretch at all.
That doesn't limit its usefulness in clinical settings, but do not fool yourself or anyone else that it's not addictive.
That's about as terrible as giving _ham_ to a hamster.