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Schizophrenia: Negative Symptomatic Reduction With DA Agonists

A

AlphaMethylPhenyl

Moderator: TDS
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I have a best friend who unfortunately was diagnosed with Schizophrenia (NOS) a few months ago. I've noticed that since his symptoms have progressed he hasn't been quite as cognitively adept. He used to be a really loquacious kid.

I've always been interested in mental illness, neuroscience, and psychopharmacology, so I thought I'd do some research. I found three studies which state that after the stabilization of positive symptoms (those things which are "added" to a person with schizophrenia, such as hallucinations and delusions), stimulants can be effective for the negative symptoms (things "taken away", such as poor cognition and anhedonia). This is only for selected people, however.

http://www.sciencedirect.com/scienc...al.com/article/S0920-9964(13)00165-5/abstract

I know that one of these above (probably the most comprehensive) is basically from shire, which has wanted to approve vyvanse for everything from eating disorders to a depression adjunct (fail, but I'm sure it's still used) and is currently trying it out for the subject at hand; it has a decent n, a very low p, and is peer-reviewed. But what do you think about the quality of the studies? I understand that these studies aren't conclusive, but how difficult must it be to get funding for this? And it would be really difficult to conduct even primate studies because we're talking about the prefrontal cortex (mostly) here.

This one found a modest reduction but it's from 1996 http://www.biomedsearch.com/nih/Amphetamine-negative-symptoms-schizophrenia/8741946.html

And this one shows that DA release is confined to the cortical area in co-administration with haloperidol http://ajp.psychiatryonline.org/article.aspx?articleID=167362

This is the only course I've been able to find about the mechanism of negative symptoms other than the basic knowledge that it involves a depression of dopaminergic activity in the cortical system -which controls higher functions and which amphetamine has been known to stimulate DA release in (confirmation?) Any info on glutaminergic activity in the corticostriatal sphere?

http://www.biomedsearch.com/nih/Neu...al-hypotheses-negative-symptoms/24670212.html

Thalamocortical, so I bet the striatum is involved, but I know more about psychopharmacology than neuroscience.
http://onlinelibrary.wiley.com/doi/...sCustomisedMessage=&userIsAuthenticated=false

OT, but what I don't understand is why some schizophrenics abuse stims and others find them dysphoric - guess that lends credence to the vague nature of this diagnosis.
 
Hi,
Sorry to hear about this. With the new medications, it can be controlled much more and his experience of life will be far better than with the old neuroleptics. I am given 300mg of quietpine a day for bipolar and I can honestly say that after 12 years, I've had no side-effects. He was probably bottling it up for a while so he's put himself in a bad headspace and friends like you are the difference between some people swimming; not drowning. One of my oldest friends was diagnosed at 16 and at 52 he's still Truckin! YES, it does slow your mind down somewhat BUT the humour can adapt. I have a deep hatred of the DSM series. They are not based on measurable units and have no 'level' of illness - you either tick the box, not ask if it's mild or bad. There have been a few TED talks, but I know Eleanor from the hearing voices society:

http://www.ted.com/talks/eleanor_longden_the_voices_in_my_head

Has anyone else noted that the amount of DOPAC (dopamine metabolite) was too high or the amount off GABA too low (or both) in people labelled with a schizoform disorder? 90:10% i.e. the % of refractive patients. Cloazapine influences dopamine receptors AND interacts with GABAB?

Can anyone recommend any good articles that manages to find ANYthing apart from 'partly genetic, more in cities' which up until recently was about the lot? Many genes were implicated and upbringing as well but I have a deepseated distrust. I fell like there is a big sign that's so close to our noses, we don't see it. If it's an article that has to be purchaced, no problem.
 
While it is true that schizophrenia is (to the best of our knowledge) predominantly a dopamine story, it is not as simple as this thread would suggest. Dopamine occurs in four major pathways in the brain: the nigrostriatal, mesocortical, mesolimbic, and tuberoinfundibular. The negative symptoms of schizophrenia are associated with reduced dopaminergic activity in the mesocortical pathway which typically thought to involve cognition, communication, social function, etc. Positive symptoms on the other hand, are associated with excess dopaminergic activity in the mesolimbic pathway which is typically associated with arousal, motivational behavior, etc.

This is why the positive symptoms of schizophrenia are typically well controlled by first and second gen antipsychotics (D2 antagonists). In fact, in this case clinical efficacy is almost perfectly correlated to the extent of D2 antagonism. On the other hand, negative symptoms are often worsened by the first gen antipsychotics which, as a general rule of thumb, have a more focused hit on the D2 receptors than the 2nd gen which will often have inverse HTA2 agonism as well

So while it is possible D2 agonists would be useful, they would exacerbate positive symptoms of schizophrenia. In fact the hallucinations and what not that we associated with schizophrenia are also sometimes seen parkinsons patients that have their dopamine agonist drugs escalated too quickly.

This is obviously a very basic generalization of the drugs, but I hope it helps you understand what role dopamine plays in the schizophrenia story.
 
Yeah I can tell you didn't read the whole of my post nor the studies. When positive symptoms are stabilized beforehand they're not exacerbated by stimulants used for negative symptoms, and I believe I did touch on the deficiency/excessive nature of dopamine in those areas in regards to schizo-type disorders (or at least the deficiency in the cortical region).
 
Unfortunately the links you posted are broken so I did not read the studies. Assuming this is the study you are referring to, I think the response is obvious. Yes, when the positive symptoms are stabilized beforehand with dopamine antagonists, then dopaminergic agents (like amphetamine) may exacerbate positive symptoms less in some patients. This is common sense. But look at the response rates: 30-60%. That's a huge variation. Combine that with the small patient sample sizes and really drawing any conclusions based on this data is a risky proposition.

To get back to your original question about why schizophrenics abuse psychostimulants, we really don't know. The self-medication hypothesis has fallen out of favor and many clinicians feel that these drugs are typically abused for their ability to relieve the depression and stress that accompany the disease.

So as far as glutamate is concerned, it turns that PCP is a pretty damn good model for schizophrenia. What little research we have suggests there may be diminished glutamate activity which leads to issues in prefrontal cortex and lack of inhibition in the limbic system.
 
Actually only one of them is. And five minutes of searching should have you find it. Not less: there simply isn't the presence of positive symptoms. Where did you find those rates?
 
^The safest bet when providing sources is to link a pubmed entry to the article, it saves everyone a bit of time if they don't have access through the same publisher/library you do.
 
In my experience stimulants are the only things that completely my anhedonia and social withdrawal caused by my negative symptions, i beleive it would be effective for most people but for some it must be combined with memantine (wich itself has some effectiveness for shizophrenia) so tolerance doesnt occur rapidly and anti anhedonic and anti AVPD (social anxiety wich is related to shizo where amphetamine in contrast to gabaergics is the cure for most).
 
Sodium Nitroprusside is a big new name in this game. Anyone know if nitroglycerin or tetrahydro​biopterin work as well as sodium nitroprusside for positive and negative symptoms.
 
I'd like to add not just that this is a thread entirely for DA agonists in use for some symptoms of schizophrenia, but that this is not a common procedure, can definitely be extremely dangerous, and should only be prescribed by a competent doctor. I would strongly urge one not to try this on their own. It could easily lead to worsening of symptoms. If you have any inclination towards abuse, don't do it, even if a doctor would let you. If you experience bad paranoia while taking this, STOP taking it, as it could lead to permanent damage. I think we should make a mega thread about schizo-type treatments though.
 
I've often wondered if schizophrenia treatments might be best off not as complete D2 antagonists (0% efficacy), but leaving some D2 activity around (maybe 40% efficacy). This would be somewhere around aripiprazole (Abilify) 43% and modafinil (Remeron) 48%, cf an older post here. Modafinil of course is also a DRI so there are other effects in play.

http://en.wikipedia.org/wiki/Aripiprazole

In fact, the apparent better tolerability of second-generation drugs in schizophrenia may be partially due to increased D2 efficacy. A more selective drug with D2 activity comparable to aripiprazole would be interesting.
 
Ho-Chi-Minh said:
I'd like to add not just that this is a thread entirely for DA agonists in use for some symptoms of schizophrenia, but that this is not a common procedure, can definitely be extremely dangerous, and should only be prescribed by a competent doctor. I would strongly urge one not to try this on their own. It could easily lead to worsening of symptoms. If you have any inclination towards abuse, don't do it, even if a doctor would let you. If you experience bad paranoia while taking this, STOP taking it, as it could lead to permanent damage. I think we should make a mega thread about schizo-type treatments though.
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I combine ropinirole with stimulants for negative symptions in schizophrenia, if there are increased positives try things like nefiracetam (actually replace aps with it which imo are complete unnescessery in the treatment of schizophrenia.
 
I seriously would not ever recommend nefiracetam, it has been proven to cause testicular atrophy, involving toxic insult to and damage/destruction of Leydig cells.
 
Limpet_Chicken said:
I seriously would not ever recommend nefiracetam, it has been proven to cause testicular atrophy, involving toxic insult to and damage/destruction of Leydig cells.
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Its been studied in human for apathy without issues, if you are concered just monitor your test levels if they stay the same that's the proof its not toxic in humans.
 
What is the point in testing a potentially dangerous compound that happens to be but a single member of a larger family of relatives which are not? that is, why nefiracetam, when aniracetam, pramiracetam, etc. could be used?

Personally I'd rather not be the one to conduct the trials to see if my nadgers shrink after use, just in case it is toxic to humans in the same way as to canines.
 
It impairs generation of test in the testicles this occurs immediatly if its toxic for humans the balls only get damaged a period after so a simple monitoring of test is a way to avoid this.

Who says all the other racetams are safe? i havent seen any others tested on dogs with afterwards their testicles cut open and screened for damage.
 
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