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The Dopamine Hypothesis - schizophrenia

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Many years ago, I lost a friend to schizophrenia so using my education, I discovered that the cerebrospinal fluid of schizophrenics had EITHER an excess of DOPAC (dopamine metabolite) or a lack of NMDA. Today, ALL neuroleptics are based on the dopamine hypothesis. Refractive patients eventually end up with clozapine (a drug which increases morbidity, knocking an average of 10 years of the patients life). One of the effects of clozapine is to release D-serine (and agonist at the NMDA receptor) AND prevents the impaired expression of NMDA receptors.
Sarcosine was trialled on people suffering schizophrenia. This was a random sample of sufferers. It proved to have a positive impact in both negative and overall symptoms. I know LY-404,039 was trialled in Russia and proved to be statistically ineffective BUT, once again, no screening was carried out to see WHICH of the patients would have benefitted.
I don't think anyone has connected the dots before. Could it be that the people on the most hazardous neuroleptic are being totally ignored by Big Pharma because they can only expect it to benefit 10% of sufferers? This still adds up to millions of people BUT it seems that The NMDA Hypothesis is being actively ignored?

If you, or someone you know is on clozapine, please make them aware of these facts. For too long psychiatric patients have been talked down to with nobody listening to their voice.

If we can find a sufficient number of people prepared to hassle Lilly, the WORST neuroleptic could be removed from the shelves with safe, side-effect free medications that give their family back the WHOLE person.

Thank you for reading.
 
I wouldn't say that the role of NMDA is being ignored, necessarily...in pharmacological discussions it's frequently mentioned, along with the possible role of different neurotransmitters (dopamine, serotonin, norepinephrine, GABA etc) In fact just as the amphetamine model of psychosis may lend credence to the dopamine theory, the PCP model of psychosis may lend credence to the role of NMDA, as phencyclidine binds to NMDA and prevents the normal binding of glutamate to the receptor. I know that a whole host of abnormalities have been proposed in regards to schizophrenia (deficiencies in glutamatergic neurons, some abnormalities in regards to 5-HT2 serotonin receptors, etc) but none have been definitely proven (to the best of my knowledge)...the dopamine hypothesis does seem to be the dominant one, though. Primarily due to the pharmacological observation of dopamine antagonists apparently reducing the symptoms of psychosis.
 
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Personally I think the dopamine hypothesis is flawed and led to an uncountable number of wrong treatments, most of them just causing discomfort but some lasting damage. I've talked with too many people suffering from (semi?) permanent cognitive and emotional damage (not even talking about the physical side effects) due to overeager docs administering strong dopamine antagonists (neuroleptics) for years just due to comparatively minor psychical disturbances or a single psychotic episode. But I shouldn't rant.

Granted, it's state of art and sadly we don't have better (and accepted) treatments for serious psychosis available. But not everyone becomes psychotic just because of 'too much' dopamine - I suspect norepinephrine, glutamate and/or choline (and maybe a bunch of other mechanisms) to be involved in stimulant psychosis. And for some (like me, but I've read a few reports from other people) NMDA antagonism is actually antipsychotic too. Can be anti convulsive or pro convulsive either (at least in the case of memantine, seemingly). The brain chemistry is so fragile, complicatedly inter-connected and so different between individuals that it just feels plainly wrong to apply general dogmas of treatment to the whole population...
 
First off, clozapine and all atypicals have a mixed action, blocking dopamine receptors and also 5-HT2A (and potentially acting as 5-HT1A partial agonists). So it isn't really correct to think that only dopamine blockers are available. If that was the case then haloperidol would still be the gold standard.

Of course most people who work in the field don't believe that dopamine causes schizophrenia. But the problem is that no other drug classes are more effective than dopamine anyagonists. Lilly spent millions developing the prodrug for the mGlu2/3 agonist, and the initial clinical trial was promising, but it didn't end up being as effective as the atypical drug it was compared to. There is some evidence that patients with a particular 5-HT2A polymorphism may show the best response, so it may be a matter of finding the right patient population, but that would be a hard sell with the FDA.

Drug companies would love to find a new, highly effective therapeutic target for schozophrenia. It would mean they could get many new drugs approved. But so far none of the phase II trials have worked out.

In terms of NMDA as a target for schozophrenia, that is a dead end. NMDA has too many different functions.
 
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I've done a fair amount of research on the topic. Firstly, there is a substance that isn't said to work primarily as a d antagonist but that may be very helpful in psychosis: CBD. It is a CB1 antagonist and (if I remember correctly) a 5-Ht1a partial (as is abilify and clozaril) and though the literature is fairly scant on any of these proposed mechanisms an allosteric modulator at mu/delta. Given that THC is apparently a big culprit in the descent to psychosis, the first mechanism theoretically means it may be of particular use.

But clozapine, though it is one of the most sedating chemicals known to man, is only part of picture. It's main metabolite, nordesmethylclozapine, is a delta (partial?) agonist (which may explain part of why clozapine can lower the seizure threshold), and though my memory is a bit foggy is a D2 partial and possible a D1 agonist. In fact, those with higher levels of NDMC are said to have more reduced negative symptoms.

No study has conclusively yielded that clozapine reduces life at all. On the other hand, poor diet, sedentary lifestyle, and smoking are known to do such.

Clozapine isn't a hindrance, it's a gift. It allows millions, as you have implied, to live normal or semi-normal lives. It is the only neuroleptic found to be effective against treatment-resistant psychosis. It is also known for being very effective against suicidal ideation. That's why it's on the international essential medicines list.

I have no idea where you go this 10% from.

I get the thing about wanting the "whole person". Antipsychotics can take away from individuality/personality. That's why it's important to work with a doctor so that one is medicated enough that their symptoms are manageable, but not so much that are a zombie.

But the short answer is that we don't know how these medications work. But we know that by and large, they do work.
 
Pimavanserin (a 5-HT2A inverse agonist) just made it on breakthrough drug status for Parkinson's disease psychosis and is on other trials that have to do with schizophrenia. The other high affinity 2A inverse agonists showed tremendous improvements in sleep/depression. And I'm pretty sure 95% of antipsychotics especially atypicals are 2A antagonists as well. I wonder how something that is just 5-HT2A specific would help schizophrenia. 5-HT2A seems so important and far reaching.. Here is a lovely study http://jpet.aspetjournals.org/content/299/1/268.full.pdf -"5HT2A receptor inverse agonists as antipsychotics". The whole mutations at 2A thing is confusing too....

But anyways OP I think what you might be getting at is this: Lets say there are 4 kinds of schizophrenia. A medication is made that helps one of the 4 kinds (25% of the trial population). Now if that's considered to be effective this can likely be sold to ALL schizophrenics without regard to what specific kind of schizophrenia it was effective in treating because it's just more drug money, and your average psychiatric nurse practioner just writes a script and so forth without figuring out the type of schizophrenia their patient has. So there's actually not much incentive to say that "this drug only works in 25% of schizophrenics and this is how you identify them with genetic testing etc." because that's narrowing down the population you can sell the drug to. Idk if that's what you're getting at it but it makes sense to me that not all schizophrenia is the same. Some of it might even have more to do with thalamacortical dissonance type things that a medication can't necessarily fix but if those people exist they are going to receive the wrong treatment when they see a doc because we just prescribe drugs. If we pretend for a moment there are 4 kinds of shizophrenia: too much dopamine, serotonin, glutamate, or norepinephrine. It makes sense that if you could find a drug that had enough blanket effect to antagonize all of those 4 kinds it would help regardless of the kind of schizophrenia even though we should be trying for accuracy here regarding treatment of a specific disease with a specific drug, a blanket drug would just have more side effects.

If theoritically someone was getting too much dopamine (for example) from an interaction with 5-HT2A then yes antagonizing dopamine might help but would produce many side effects, antagonizing the root of the problem 2A would likely be a better solution for that specific flavor of schizophrenia.
It does seem the 2A inverse agonists improve extra pyramidal symptoms as an adjunct treatment with atypical antipsychotics.
 
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Clozapine works on the NMDA receptors as well as dopamine/serotonin. One day, someone will first TEST someone to see if they have 2 much DOPAC or too little NMDA (or both). But to have 10% 'refractive' patients & 10% having too little NMDA is a VERY strong trend - a hypothesis I would argue. I've lots one friend (late onset) who has been in a secure unit for 35 years and another who is on clozapine. No doubt it works and he is truly the most intelligent person I have met (Doctorate of history). And now we are waiting for his book to be released (it was his first attempt and BANG - got a publishing deal). He has to have all of the blood tests, has put on stacks of weight & is type II diabetic. The problem is, nobody has tested the NMDA allosteric modulators on the subgroup 'low NMDA' - I read the Russian tests and it helped a few, AMAZINGLY, but not the others.... no shit.

For a decade I have said that purely from a chemical-alteration perspective, what we call schizophrenia is 2 illnesses/disorders and yet I cannot find a single example of the 2 groups being tested on the disorder they were designed to treat.

Losing one friend in my early teenage years is what made me study medicinal chemistry and I think 10 years has been wasted because a drug company isn't going to risk the $ on a drug that only works on 10% of sufferers.... The industry is evil.
 
The NMDA receptor hypofunction model of psychosis.
(...) manifestations of the same general disinhibition process in which NMDA antagonists abolish GABAergic inhibition, resulting in the simultaneous excessive release of acetylcholine and glutamate (...)

Something is wrong there. Shouldn't dissociatives then be anxiogenic? (Or are they, and it's just countered by secondary mechanisms of K/MXE / the uncomfortable stimulation of diphenidine etc. is how pure NMDA antagonism feels?)
 
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I would argue that the industry is fairly amoral.

That's a common misconception. Clozapine works very well for those who are treatment-resistant as well as for first-episode patients. The risk of low white blood cell count is extremely low. But it has the potential to create legal situations that of course can be very costly so that's a testament to how well it works. A rough analogy can be drawn between that and Steven-Johnson's syndrome.

I remember reading somewhere that clozapine may be a GABA-A antagonist (again greater chance for seizures concurs). But I thought that it was a GABA-B agonist.

So the neurotransmitter theory of psychiatric illness in general might be off, but with what we know about brains, it's something. I think the high positive association found in many studies means something. But it's also a bit more complex in that D1 activity (mostly in the prefrontal cortex) is worlds away from D2 activity in the lmibic system. So I don't think any learned psychiatrist, if they had to give as precise an answer as possible, would simply state that overactive dopaminergic activity overall is what leads to psychotic symptoms.

The brain has yet to be explained. Some people experience worsening symptoms on antipsychotics. But I get the impression that such mostly goes on with the "weaker" antipsychotics like abilify. Regardless, we've improved drastically since the days when it was common practice to simply lock up schizophrenics for life and mask some of their symptoms by keeping them drunk on barbiturates.
 
Do battle with a filthy, rotten, stinkin' rich pharmaceutical corporation?

Good luck with that.
 
dopamimetic said:
The NMDA receptor hypofunction model of psychosis.
(...) manifestations of the same general disinhibition process in which NMDA antagonists abolish GABAergic inhibition, resulting in the simultaneous excessive release of acetylcholine and glutamate (...)

Something is wrong there. Shouldn't dissociatives then be anxiogenic? (Or are they, and it's just countered by secondary mechanisms of K/MXE / the uncomfortable stimulation of diphenidine etc. is how pure NMDA antagonism feels?)
Click to expand...

The interaction they are referring to occurs mainly in the cortex. That isn't the same population of GABA-A receptors that mediates the anxiolytic effects of benzodiazepines, which are located in the limbic system.
 
dopamimetic said:
Personally I think the dopamine hypothesis is flawed and led to an uncountable number of wrong treatments, most of them just causing discomfort but some lasting damage. I've talked with too many people suffering from (semi?) permanent cognitive and emotional damage (not even talking about the physical side effects) due to overeager docs administering strong dopamine antagonists (neuroleptics) for years just due to comparatively minor psychical disturbances or a single psychotic episode. But I shouldn't rant.

Granted, it's state of art and sadly we don't have better (and accepted) treatments for serious psychosis available. But not everyone becomes psychotic just because of 'too much' dopamine - I suspect norepinephrine, glutamate and/or choline (and maybe a bunch of other mechanisms) to be involved in stimulant psychosis. And for some (like me, but I've read a few reports from other people) NMDA antagonism is actually antipsychotic too. Can be anti convulsive or pro convulsive either (at least in the case of memantine, seemingly). The brain chemistry is so fragile, complicatedly inter-connected and so different between individuals that it just feels plainly wrong to apply general dogmas of treatment to the whole population...
Click to expand...

That was a beautiful read (and I've never suffered psychosis, so it's not that you're reassuring me).
 
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