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Schizophrenia drugs may have been off target for decades, study finds

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Re: Schizophrenia drugs may have been off target for decades, study finds

#21

Post by pixl97 »

BurningFrog wrote: post #12
pixl97 wrote: post #7

Earlier quoted context omitted.

If instead of saying brain you say "The most complicated structure found in the known universe so far" it starts to make a little more sense on the enormity of the problem at hand. Most organs are composed of one or only a few types of cells and their particular arrangement doesn't matter that much. For example swapping kidneys between people doesn't change who they are (mostly, smaller edge conditions apply here). B…

You can also think of "the brain" as a collection of 10-20 separate organs, rather than one super complex one.

While true, the complexity of each organelle in the brain is still much higher than that of the typical organ elsewhere in the body. That and there is a high degree of connectivity and feedback between components where the API is completely and totally undocumented. It's not that you don't know what the known API calls do, you don't have any clue on how many API calls there even are. Accidently emulating one of these calls when attempting to trigger a different behavior can lead to wildly unexpected outcomes.

Re: Schizophrenia drugs may have been off target for decades, study finds

#22

Post by freeone3000 »

fragmede wrote: post #16
Aurornis wrote: post #10

The study used a mouse model where amphetamine is used to simulate schizophrenia. Obviously, it's not guaranteed to map to real humans having real schizophrenia. That doesn't mean it's a useless result, but everyone should remember that research is an accumulation of decades of many little pieces of information. This is another clue, not a "nail in the coffin" of old theories. The ultimate evaluation of medication is…

While everyone should be keenly aware the limitations of taking experimental results in mice and extrapolating to humans (aka, they often don't ), doesn't that mean what we really have, is a bunch of well tested medication for meth addicts? Which; if there was a way to get meth addicts off meth, would be a boon?

This wasn’t tested and wasn’t purported to test countering either addiction or acute overdose. This is a study showing the method of action. In mice (and humans, D2 receptor agonists are not new drugs), we have a method of countering the psychosis effect of meth. This has some value in ER and rehab settings where it is currently for healthcare provider safety; there is no evidence that it does anything else.

Re: Schizophrenia drugs may have been off target for decades, study finds

#23

Post by Ezku »

A_D_E_P_T wrote: post #2

Situation normal. Consider the discovery of valproic acid: "Valproic acid is a carboxylic acid, a clear liquid at room temperature. For many decades, its only use was in laboratories as a "metabolically inert" solvent for organic compounds. In 1962, the French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid while using it as a vehicle for a number of other compounds…

Your point is a very important one. Do we check the interactions of a tentative drug molecule against every single molecular target in the body, and do we track what happens as a result of all those interactions? It’s quite common that a group of ”usual suspects” on the researchers’ radar get checked for — but by necessity, a lot of ground goes uninvestigated.

  > Consider valproic acid: For many decades, its only use was in laboratories as a "metabolically inert" solvent for organic compounds
Speaking of ”inert” solvents:

  > Dimethyl sulfoxide (DMSO) is the most common organic solvent used in biochemical and cellular assays during drug discovery programs.
  > Despite its wide use, the effect of DMSO on several enzyme classes, which are crucial targets of the new therapeutic agents, are still unexplored.
  > 1-4% (v/v) DMSO, the commonly used experimental concentrations, showed ∼37-80% inhibition of human acetylcholine-degrading enzyme, acetylcholinesterase (AChE)
(DMSO: A Mixed-Competitive Inhibitor of Human Acetylcholinesterase. ACS Chem Neurosci. 2017 https://pubmed.ncbi.nlm.nih.gov/29017007/)

Oops! How many investigations on specific drugs were in fact showing mostly the results of what happens when interfering with one of the most ubiquitous-yet-underappreciated signalling systems, the cholinergic system?

I’m hoping widespread & systematic application of modern methods like in-silico molecular docking studies will lead to much fewer such oversights.

Re: Schizophrenia drugs may have been off target for decades, study finds

#24

Post by mtlmtlmtlmtl »

hinkley wrote: post #19
whats_a_quasar wrote: post #5

The brain is really complicated, and all psychiatric medications affect multiple receptors and subsystems. Framing this study as "antipsychotics were off target" is an editorial choice. The title could just as easily have been "Improved understanding of antipsychotic action means we may be able to design better antipsychotics." Edit: It also ought to be noted that the study was on mice that had been given amphetamine…

The serotonin model of antidepressants just doesn’t pass a sniff test. Something else is going on there. How they say they should work would mean they work in the first dose and possibly that don’t require tapering off. But that’s not what happens in the real world. If we understood what’s really happening we could target pathways better.

The "serotonin model", actually called the monoamine hypothesis, hasn't really been taken seriously in the field for decades, except by naysayers like yourself who continue to use it as a strawman.

Re: Schizophrenia drugs may have been off target for decades, study finds

#25

Post by aatd86 »

whats_a_quasar wrote: post #5

The brain is really complicated, and all psychiatric medications affect multiple receptors and subsystems. Framing this study as "antipsychotics were off target" is an editorial choice. The title could just as easily have been "Improved understanding of antipsychotic action means we may be able to design better antipsychotics." Edit: It also ought to be noted that the study was on mice that had been given amphetamine…

I think you might miss the point slightly, moving too far the discussion on the other side.

It's perfectly normal to wonder how can one administrate something when one doesn't understand it. Especially when there can be such debilitating effects.

In clinical settings, things are way less clear than you make it seem. All psychosis are not equal and even all diagnostic of a same patient are not equal.

There is a lot more caution that should be advised. Including in the administration protocols instead of handwaving and just claiming that it should be taken life-long (which betrays that it's not a cure).

It does not even make sense in the first place that there is no attempt at finding the base neuro-transmitter levels in and out of psychotic phases for each patient before deciding on the posology of a treatment. Managing plasma concentration in a finer-grained way might avoid some (not all) of the issues with neuroleptics.

Some people even only have a few episodes every few years and are still put on life-long treatment with all the side-effects that can then be seen.

It needs to be way more fine-grained if not restudied.

Re: Schizophrenia drugs may have been off target for decades, study finds

#26

Post by cyberax »

maybelsyrup wrote: post #14
rybosworld wrote: post #6

It's amazing how far the medical world has come in treating ailments of the body, but we've made comparatively little headway in ailments of the brain.

You’re correct overall, and I know what you mean. But to offer a small and somewhat provocative nitpick: these (the psychoses or any other so-called mental illness) aren’t “ailments of the brain”, as they’ve never been shown to be. None has any demonstrated underlying pathology, much less a clinically useful one.

> None has any demonstrated underlying pathology

Mechanical damage to parts of the brain can cause personality changes. Multiple neurological syndromes are directly linked to macroscopic brain changes. This includes schizophrenia, traumatic brain injuries dramatically increase its risk.

We also know that schizophrenia almost never happens along with epilepsy. They are almost mutually exclusive.

It's fair to say there is no single macroscopic trigger for schizophrenia, but that's it.

Re: Schizophrenia drugs may have been off target for decades, study finds

#28

Post by [deleted] »

hinkley wrote: post #19
whats_a_quasar wrote: post #5

The brain is really complicated, and all psychiatric medications affect multiple receptors and subsystems. Framing this study as "antipsychotics were off target" is an editorial choice. The title could just as easily have been "Improved understanding of antipsychotic action means we may be able to design better antipsychotics." Edit: It also ought to be noted that the study was on mice that had been given amphetamine…

The serotonin model of antidepressants just doesn’t pass a sniff test. Something else is going on there. How they say they should work would mean they work in the first dose and possibly that don’t require tapering off. But that’s not what happens in the real world. If we understood what’s really happening we could target pathways better.

[deleted]

Re: Schizophrenia drugs may have been off target for decades, study finds

#29

Post by psychphysic »

The pharmacodynamics of antipsychotics is such a rich topic, yet this article is so crap!

Surprised no mention of pimavanserin (which doesn't act on dopamine useful in those with Parkinson's and psychosis) and that L-dopa can reliably induce psychosis (used on Parkinson's).

Re: Schizophrenia drugs may have been off target for decades, study finds

#30

Post by tcj_phx »

Strictly speaking, psychosis is more strongly related to excess serotonin, 'the molecule of stress and inflammation'. Doctors sometimes recognize 'Serotonin Syndrome' in their ER patients: "too much serotonin causes signs and symptoms that can range from mild (shivering and diarrhea) to severe (muscle rigidity, fever and seizures)." Usually the Serotonin Syndrome is caused by a combination of prescriptions, or street drugs.

https://www.mayoclinic.org/diseases-conditions/serotonin-syn...

All the effective anti-psychotics seem to have anti-serotonin properties, in addition to their anti-dopamine effects. For example: "there are also recent studies that 'stumbled upon' the 'shocking' evidence that anti-dopamine drugs commonly used for treating schizophrenia such as haloperidol are actually potent serotonin antagonists as well." - http://haidut.me/?p=1297

One of you quoted my essay Cargo Cult Psychiatry in a comment on Sunday, on a submission of Feynman's Cargo Cult Science. I responded, then thought to submit my link to the original at Mad In America again: https://news.ycombinator.com/item?id=37110874

This paragraph from that comment is essential for helping anyone diagnosed with the label of "schizophrenia":

"The good news from the mental health world is that Chris Palmer, M.D. published Brain Energy [0] last year. I haven't read more than excerpts from google books [1]. My understanding is Dr. Palmer was a conventional palliative psychiatrist, then he had a patient whose schizophrenia improved on a ketogenic diet. The patient was able to discontinue antipsychotics: Dr. Palmer's mind was blown. Then he discovered the 70+ years of research establishing that mental health conditions are metabolic problems that can be successfully treated with pro-metabolic therapies.

  Perhaps the most bold and disruptive 
  aspect of Brain Energy is understanding 
  precisely how and why medications that 
  harm metabolism might reduce mental 
  health symptoms.

  The long-term consequences are of great 
  concern and require the urgent attention 
  of the psychiatric community.
-Chris Palmer, MD - https://twitter.com/ChrisPalmerMD/status/1687850270602981376 [...]

[0] https://brainenergy.com/ / [1] https://books.google.com/books?id=FoxlEAAAQBAJ&pg=PT233&dq=B "

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