Dopamine Receptors And Their Behavioural Affects

[Serhat]

Neuroleptics are so DIRTY. At least I can see some rational design in the atypical ones,

When I first studied them in 1992 my advisor pointed out that schizophrenia is considered to be as disabling as quadriplegia and so it was acceptable because it's treating a life-threatening illness. But their remain 4 different pharmacological models for the disease, a disease which is difficult to model in animal studies and the criteria are very broad. In essence, beyond using drugs to estimate schizophrenia, it's really only human studies that provide the bulk of the information. But if a candidate ligand reaches human trials, vast amounts of money have already been spent and so the pressure to produce a medication that can receive MA is very high indeed,

I have seen start-ups that essentially HAD to succeed with their first medicine to survive and so I suspect the researchers are very conservative.

I used to know a psychiatric nurse and he was able to convince the management of the RSU to allow me a tour. I have to say it WAS scary to interact with people who shared so few frames of reference, Almost all posed a risk to themselves rather than to anyone else but the distress was very clear to see. The paranoia wasn't 'senseless' from the perspective of the patient as the way they experienced the world was in conflict with what they were told.

Also interesting to note that roughly ⅓ of the patients seemed unusual BUT shared many frames of reference. About ⅓rd vacillated between shared and unshared reality but the final ⅓rd were some of the most interesting. After medication they would seem to be fine but as the hours passed, they displayed many of the more classic things like echolalia and word salad (I forget the correct term for this ) do apologize.

But it DID appear that for the MOST disturbed, the medication wasn't correctly applied or quite possibly was inappropriate, To find people who had been on haloperidol for 30+ years and what it had done to them seemed criminal. But I suppose at some point it was prescribed... and in 30 years no reassessment had ever been undertaken.

Asenapine has a fascinating structure with a chiral 2-alkoxy-5-chloro PEA molecules buried in it. 5HT2a (slightly selective) but all over the place on affinity to dopamine receptor subtypes.

BTW Neuroprotection - excellent work in explaining WHY certain targets are selected. I'm sure you know that the cerebrospinal fluid of schizophrenics has either elevated levels of DOPAC (dopamine metabolite suggesting too much dopamine in the brain) and/or too little NMDA. Clozapine was hailed as an amazing treatment for refractive patents because it appears to increase NMDA levels as well as being a D2 antagonist. But of course, being so dirty meant unexpected toxicity. Also, trials of drugs that JUST increased NMDA levels were amazingly successful for the minority (circa 10%) of patients who had normal dopamine levels, just too little NMDA were total success BUT a drug that only benefits (vastly improves life quality) of just 10% of patients wasn't considered viable... so now they are orphen drugs.

Thank you for sharing such an insightful perspective on the complexities surrounding the pharmacological treatment of schizophrenia. Your observations highlight the intricate balance that researchers, clinicians, and pharmaceutical companies must strike when developing and administering medications for this condition.

I agree that the term "dirty" often used for typical neuroleptics like haloperidol reflects their broad receptor profile, which can lead to a range of side effects. Atypical antipsychotics, as you mentioned, do show a more rational design, targeting specific receptor subtypes to minimize adverse effects. However, even they are not without their challenges, especially when it comes to long-term use.

Your point about the pressure to produce a medication that can receive Marketing Authorization (MA) is well-taken. The high costs associated with drug development indeed create an environment where there's a rush to get a return on investment. This can sometimes lead to medications being pushed through trials and into the market, perhaps before their long-term effects are fully understood.

The experience you shared about your tour of the RSU (Rehabilitation Services Unit, I presume) is eye-opening. It underscores the human element that is often missing in clinical discussions about schizophrenia. The variability in patient experiences and responses to medication is a crucial aspect that needs more attention in research and treatment plans.

Your mention of Asenapine and its unique molecular structure brings up an interesting point about the ongoing efforts to create more targeted therapies. The same goes for your note on Clozapine and its effects on NMDA levels. It's a reminder that while we've come a long way in understanding the neurochemistry of schizophrenia, there's still much to learn, especially when it comes to personalized treatment.

Lastly, your comments on "orphan drugs" that could benefit a minority of patients but aren't considered commercially viable highlight a significant ethical dilemma in pharmaceutical research. Shouldn't the focus be on improving the quality of life for all patients, regardless of the percentage they represent?

Thank you again for your comprehensive overview. It's discussions like these that push the field forward, encouraging us to continually reassess and refine our approaches to treating complex conditions like schizophrenia.

 

[AlsoTapered]

Regional Secure Unit - but I'm glad you found it of some interest.

Things like asenapine contains not 1 but 2 PEA scaffolds within it's structure. The chiral -Cl and -O- bridge overlay the 2,5-disubstitution pattern.

Look at some other atypicals and see indole and even tryptamine boisosteres. Rolf Hahn (spell check) who came up with the NBOMes also found a moiety that confers antagonist activity... and later it's found in a new atypical.

It seems like RC compounds are being used as templates.

I'm sure you know that indole versions of the NBOMes.....

 

[Neuroprotection]

Neuroleptics are so DIRTY. At least I can see some rational design in the atypical ones,

When I first studied them in 1992 my advisor pointed out that schizophrenia is considered to be as disabling as quadriplegia and so it was acceptable because it's treating a life-threatening illness. But their remain 4 different pharmacological models for the disease, a disease which is difficult to model in animal studies and the criteria are very broad. In essence, beyond using drugs to estimate schizophrenia, it's really only human studies that provide the bulk of the information. But if a candidate ligand reaches human trials, vast amounts of money have already been spent and so the pressure to produce a medication that can receive MA is very high indeed,

I have seen start-ups that essentially HAD to succeed with their first medicine to survive and so I suspect the researchers are very conservative.

I used to know a psychiatric nurse and he was able to convince the management of the RSU to allow me a tour. I have to say it WAS scary to interact with people who shared so few frames of reference, Almost all posed a risk to themselves rather than to anyone else but the distress was very clear to see. The paranoia wasn't 'senseless' from the perspective of the patient as the way they experienced the world was in conflict with what they were told.

Also interesting to note that roughly ⅓ of the patients seemed unusual BUT shared many frames of reference. About ⅓rd vacillated between shared and unshared reality but the final ⅓rd were some of the most interesting. After medication they would seem to be fine but as the hours passed, they displayed many of the more classic things like echolalia and word salad (I forget the correct term for this ) do apologize.

But it DID appear that for the MOST disturbed, the medication wasn't correctly applied or quite possibly was inappropriate, To find people who had been on haloperidol for 30+ years and what it had done to them seemed criminal. But I suppose at some point it was prescribed... and in 30 years no reassessment had ever been undertaken.

Asenapine has a fascinating structure with a chiral 2-alkoxy-5-chloro PEA molecules buried in it. 5HT2a (slightly selective) but all over the place on affinity to dopamine receptor subtypes.

BTW Neuroprotection - excellent work in explaining WHY certain targets are selected. I'm sure you know that the cerebrospinal fluid of schizophrenics has either elevated levels of DOPAC (dopamine metabolite suggesting too much dopamine in the brain) and/or too little NMDA. Clozapine was hailed as an amazing treatment for refractive patents because it appears to increase NMDA levels as well as being a D2 antagonist. But of course, being so dirty meant unexpected toxicity. Also, trials of drugs that JUST increased NMDA levels were amazingly successful for the minority (circa 10%) of patients who had normal dopamine levels, just too little NMDA were total success BUT a drug that only benefits (vastly improves life quality) of just 10% of patients wasn't considered viable... so now they are orphen drugs.

Thank you. In regards to antipsychotics, i’m hoping research focuses more on the downstream effects of dopamine receptor stimulation and how that leads to psychosis. There is an interesting hypothesis about inhibitory GABAergic interneurons and their dysfunction in psychosis. what is special about this hypothesis Is that it bridges both The dopamine and glutamate hypotheses of schizophrenia. The overarching idea is, that a lack of inhibitory input to cortical regions of the brain and possibly the hippocampus results in psychotic episodes and cognitive dysfunction. looking at modulating these neurons directly, or directly modulating their projection targets would allowers to completely move away from anti-dopaminergic therapy for schizophrenia. yes, atypical antipsychotics are quite good compared to the typical ones, but we really need much better.
You mentioned NMDA enhancers and I imagine they work quite well to improve cognition in schizophrenics, or at least a small number of them. The main difficulty with this strategy is often insufficient potency which is as yet almost impossible to address due to the extreme danger that lies in stronger NMDA agonists.
One possible strategy is the inhibition of the enzyme kynurenine aminotransferase which reportedly improves cognition and memory in animal models of schizophrenia and cognitive impairment.
As I’ve mentioned previously, it’s almost certainly possible to isolate The exact mechanism by which dopamine might lead to psychosis whether directly or indirectly. This is shown by the fact that the drug apomorphine failed to precipitate or worsen psychotic symptoms in schizophrenics.

 

[Neuroprotection]

I recently discovered how bad animal models of psychosis research as well as mental health terminology in general really are. while some multi variant models are excellent, many only Study one effect like PPI or locomotor activity. however, many drugs can affect these parameters without inducing psychosis in humans. then you get mental health websites and even scientific journal articles indirectly lumping conditions like psychosis and mania/hypomania together creating the impression that they are the same thing. unfortunately, I can’t find the Study anymore, but it was a very nice review which explain the strongly divergent and non-overlapping mechanisms of mania and psychosis. regarding the role of dopamine in psychosis, it’s interesting to note that the antimanic agent lithium can block the euphoric/activating effects of dextroamphetamine but not its psychotomimetic affects in schizophrenic humans. this indicates that The rolls of dopamine in drive/Motivation, energy and euphoria are clearly separable from it’s roll in psychosis.

I’m no scientist, but I think a truly effective medication for schizophrenia should either target Epigenetics, like histone acetylation/methylation or modulate glutamate receptors, especially the AMPA receptor. I think possibilities are endless and though I’m no fan of conspiracy theories, I can’t help but believe that the pharmaceutical industry is wilfully ignoring these avenues. maybe this is because such drugs might not have to be taken as often and may even have a disease modifying effect which could result in less profit for the company.

Almost forgot to mention, one quite promising target for both the positive and negative symptoms of schizophrenia is kappa opioid antagonism. apparently, such an approach has reward sensitising and anti-anhedonic effects, whilst simultaneously decreasing or blocking hallucinations/delusions. The main obstacle for this currently is that we probably need a very strong kappa opioid antagonist, but such a drug hasn’t been approved in humans and most researchers are focusing on short-acting/weaker antagonists for depression treatment.

 

[AlsoTapered]

I think your faith in the drug development pipeline is unwarranted.

Too many putative ligands have been abandoned for anyone to risk development of products other than those intended to be incremental improvements on what is known. Since dopamine antagonism is the MOST reliable, nobody is ever going to be funded to produce a medicine that doesn't act as a dopamine antagonist.

Remember what I said - just about the only physical 'test' for schizophrenia shows elevated dopamine levels and/or reduced NMDA levels.... and those who ONLY have reduced NMDA are <10% of cases - usually the refractive cases, OK so now we do (sometimes) try NMDA agonism (famously clozapine did both) dopamine antagonism is going to remain the activity sought in this class of drugs.

Since it's considered such a serious disorder, side-effects are acceptable.

Face it - it's easier to raise money for research into an illness that WE might become a victim of.

And although late-onset schizophrenia exists and some people live with it and are unmedicated (a third of suffers, would you believe), medication alone isn't a good treatment and never will be. BUT intensive and continuous work by a psychologist is simply too costly. I know at least 2 unmedicated suffers BUT they do have a box of whatever they were prescribed but THEY decide when they need it. But show me a psychiatrist who will go on record to say that intermittent medication, use of which is the choice of the patient is safe.

While vastly overstated, their are schizophrenics who are a risk to others... but the media latches on to the story and it scares people. The majority of the public think that people with schizophrenia should be medicated against their will. UK law does not allow this.

I don't believe ALL suffers can be treated without medication, but many could be.

BTW my visit to an RSU (Prestwich) also gave me the impression that many of the patients had additional mental health issues. One guy would adhere to the rules until it was decided that he could make unescorted visits into the town. Every single time he would walk straight to the 24 hour Tesco, pick up 2 bottles of spirits and begin drinking from one as fast has he could. The second bottle he used to lamp the security guard. So the police would arrive, ring the RSU and he would end up back on a high dependency ward. Now, I do not see that as behavior due to schizophrenia. He WAS using it as an excuse.

His behavior reminds me of 'Typhoid Mary' who, knowing she was a carrier, INSISTED on getting job after job as a cook which resulted in dozens if not scores of deaths. Clearly she had some form of psychopathy.

I hasten to add that he was in a tiny minority. Mostly I think unipolar depression, bipolar, ADHD and OCD were evident.

Then they just closed the place and almost all of the patients became part of the 'care in the community' movement.

In the town I live in their was a shared house for people with serious mental health issues but who were no danger to anyone. I think there were about 23 of them. 12 years later, it appears that at least 17 of them are dead. Alcoholism and simply not taking prescribed medication (for things like hypertension). A mental health worker showing up once a week simply wasn't any kind of answer...

THAT is what society seems to believe. The lives of people who suffer mental illness are of little to no value. Even medicated, they will just be a drain on society... so why waste the money on better medicines?

 

[Neuroprotection]

that’s fine. But if we must work with dopamine then at least the focus should be on which specific receptor(Probably D2) is responsible for psychosis, and which downstream process is causally correlated to psychosis. we could analyse which part of the brain is this process operating and then we can design better compounds which specifically target the offending pathway.

The psychiatric establishment can be very arrogant and difficult to change, but getting the right researchers and the public on side could force them to begin testing four novel strategies. drugs that modulate Epigenetics are actually really promising for schizophrenia and they don’t involve dopamine. on top of that, they could improve all symptom types in schizophrenia while simultaneously lacking tolerance potential and also preventing/Reversing tolerance to other drugs. however, I guess messing with Epigenetics Will raise so many safety, ethical and financial concerns that it might not be practical in the near future.

 

[Neuroprotection]

aside from schizophrenia, i’ve been researching how dopamine affects both well-being and procrastination. unfortunately, there is no clear answer and apparently, even in those with ADHD psychostimulants don’t necessarily address procrastination. contrary to this, others have suggested psychostimulants might actually help healthy people to perform higher effort tasks as they can focus better on the outcome reward rather than on the cost in terms of effort. I do wonder if some individuals, wrongly diagnosed with ADD still benefit from psychostimulants for purely this reason. Though I’ve never tried traditional dopaminergic psychostimulants, I noticed that regularly smoking cigarettes or chewing tobacco/nicotine gum actually help me to ignore the pain of difficult tasks and focus more on the outcome reward. to be honest, for me, that Ultimate reward came in the form of getting the piece of work out of the way

 

[AlsoTapered]

As I said - incremental improvements. But know of no d2 selective antagonist with an ADME making it useful as a treatment. The development goes on,

Identification of Novel Dopamine D2 Receptor Ligands—A Combined In Silico/In Vitro Approach

Diseases of the central nervous system are an alarming global problem showing an increasing prevalence. Dopamine receptor D[2] (D[2] R) has been shown to be involved in central nervous system diseases. While different D[2] R-targeting drugs have been ...

www.ncbi.nlm.nih.gov

But of course those won't be very effective in patients who also have reduced NMDA and totally inactive in the minority who only have reduced NMDA,

Dopamine is a monoamine - it's at the bottom of the stream. I presume you intended to suggest upstream i.e. WHY is too much dopamine and/or too little NMDA expressed.

The 'glutamate hypothesis' is upstream of NMDA.

The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies

A number of studies have indicated that antagonists of the N-methyl-d-aspartate (NMDA) subtypes of glutamate receptors can cause schizophrenia-like symptoms in healthy individuals and exacerbate symptoms in individuals with schizophrenia. These findings ...

www.ncbi.nlm.nih.gov

And I posit that the increased dopamine is due to the body trying to correct the lack of NMDA.

We KNOW from (unethical) human experiments that PCP will produce all of the positive and negative symptoms of schizophrenia in medicated patients (yep- they injected patients suffering schizophrenia with PCP). BUT their experiment had a MAJOR flaw. PCP is also a dopamine reuptake inhibitor....but it was 100% successful.

I don't know the doses used in the experiments but one would hope it was doses that would fail to produce symptoms in non-sufferers....

BUT the didn't have a group of non-sufferers to confirm that nor did they double-blind the study so it's low qualityevidence.

IF dizocilpine had been around in 1961, it's more selective -it only acts as an NMDA antagonist. IF all of the subjects/victims given doses that had no effect on non-schizophrenics ten it would lend weight to the glutamate hypothesis. But I do not imagine such an experiment would fly today.

I think the above is a good example of the arrogance you mentioned.

 

[t_xeplionhell]

Neuroleptics are so DIRTY. At least I can see some rational design in the atypical ones,

When I first studied them in 1992 my advisor pointed out that schizophrenia is considered to be as disabling as quadriplegia and so it was acceptable because it's treating a life-threatening illness. But their remain 4 different pharmacological models for the disease, a disease which is difficult to model in animal studies and the criteria are very broad. In essence, beyond using drugs to estimate schizophrenia, it's really only human studies that provide the bulk of the information. But if a candidate ligand reaches human trials, vast amounts of money have already been spent and so the pressure to produce a medication that can receive MA is very high indeed,

I have seen start-ups that essentially HAD to succeed with their first medicine to survive and so I suspect the researchers are very conservative.

I used to know a psychiatric nurse and he was able to convince the management of the RSU to allow me a tour. I have to say it WAS scary to interact with people who shared so few frames of reference, Almost all posed a risk to themselves rather than to anyone else but the distress was very clear to see. The paranoia wasn't 'senseless' from the perspective of the patient as the way they experienced the world was in conflict with what they were told.

Also interesting to note that roughly ⅓ of the patients seemed unusual BUT shared many frames of reference. About ⅓rd vacillated between shared and unshared reality but the final ⅓rd were some of the most interesting. After medication they would seem to be fine but as the hours passed, they displayed many of the more classic things like echolalia and word salad (I forget the correct term for this ) do apologize.

But it DID appear that for the MOST disturbed, the medication wasn't correctly applied or quite possibly was inappropriate, To find people who had been on haloperidol for 30+ years and what it had done to them seemed criminal. But I suppose at some point it was prescribed... and in 30 years no reassessment had ever been undertaken.

Asenapine has a fascinating structure with a chiral 2-alkoxy-5-chloro PEA molecules buried in it. 5HT2a (slightly selective) but all over the place on affinity to dopamine receptor subtypes.

BTW Neuroprotection - excellent work in explaining WHY certain targets are selected. I'm sure you know that the cerebrospinal fluid of schizophrenics has either elevated levels of DOPAC (dopamine metabolite suggesting too much dopamine in the brain) and/or too little NMDA. Clozapine was hailed as an amazing treatment for refractive patents because it appears to increase NMDA levels as well as being a D2 antagonist. But of course, being so dirty meant unexpected toxicity. Also, trials of drugs that JUST increased NMDA levels were amazingly successful for the minority (circa 10%) of patients who had normal dopamine levels, just too little NMDA were total success BUT a drug that only benefits (vastly improves life quality) of just 10% of patients wasn't considered viable... so now they are orphen drugs.

If it only caused cognitive side effects such as echolalia it wouldn't be that bad.

The damage does stacks, the more you take it, the worse it will be, but Invega Sustenna has the power to destroy most people with only the initial dose.

Strong APs with such massive dose like Invega Sustenna(it's atypical antipsychotic), will put you in a state of unmeasurable and unspeakable suffering, such extreme that it's insane to be given even to animals (for tests) or war criminals.

 

[AlsoTapered]

They are all torture,

I've tried chlorpromazine & thioridazine to experience what my friend was going through.

Hell.

Of course, stimulant psychosis and schizophrenia present with identical symptoms. At the end of the day a high-affinity D2 partial or mixed agonist might work. To TRULY work you would need to be able to produce a series to find the right 'balance' for each patient since the levels and concentrations differ per person. I don't see that happening, sadly.

Dopamine AGONISTS make you vomit, so that might be an issue.

It's so nice to be part of a group brainstorming a serious illness,

1% of the population will suffer from schizophrenia at some point in their life. BUT if they do the treatment is more or less ' go sit in this box and take THESE pills.

Check out the 'Hearing Voices Network'.

I would LOVE to hear a voice that was positive and useful. Talking to myself fails on both counts.

 

[Neuroprotection]

As I said - incremental improvements. But know of no d2 selective antagonist with an ADME making it useful as a treatment. The development goes on,

Identification of Novel Dopamine D2 Receptor Ligands—A Combined In Silico/In Vitro Approach

Diseases of the central nervous system are an alarming global problem showing an increasing prevalence. Dopamine receptor D[2] (D[2] R) has been shown to be involved in central nervous system diseases. While different D[2] R-targeting drugs have been ...

www.ncbi.nlm.nih.gov

But of course those won't be very effective in patients who also have reduced NMDA and totally inactive in the minority who only have reduced NMDA,

Dopamine is a monoamine - it's at the bottom of the stream. I presume you intended to suggest upstream i.e. WHY is too much dopamine and/or too little NMDA expressed.

The 'glutamate hypothesis' is upstream of NMDA.

The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies

A number of studies have indicated that antagonists of the N-methyl-d-aspartate (NMDA) subtypes of glutamate receptors can cause schizophrenia-like symptoms in healthy individuals and exacerbate symptoms in individuals with schizophrenia. These findings ...

www.ncbi.nlm.nih.gov

And I posit that the increased dopamine is due to the body trying to correct the lack of NMDA.

We KNOW from (unethical) human experiments that PCP will produce all of the positive and negative symptoms of schizophrenia in medicated patients (yep- they injected patients suffering schizophrenia with PCP). BUT their experiment had a MAJOR flaw. PCP is also a dopamine reuptake inhibitor....but it was 100% successful.

I don't know the doses used in the experiments but one would hope it was doses that would fail to produce symptoms in non-sufferers....

BUT the didn't have a group of non-sufferers to confirm that nor did they double-blind the study so it's low qualityevidence.

IF dizocilpine had been around in 1961, it's more selective -it only acts as an NMDA antagonist. IF all of the subjects/victims given doses that had no effect on non-schizophrenics ten it would lend weight to the glutamate hypothesis. But I do not imagine such an experiment would fly today.

I think the above is a good example of the arrogance you mentioned.

Thanks for that informative reply. The relationship between dopamine and NMDA receptors is very complex. firstly, there is the fact that D1 receptors generally potentiate NMDA function and increase NMDA receptor expression, whilst on the other hand, D2 receptor stimulation temporarily decreases NMDA currents and can induce temporary endocytosis of NMDA receptors. then there’s the fact that dopamine blocking antipsychotics do not block the psychotomimetic effects of NMDA receptor antagonists like ketamine in humans.
Sorry if I caused any confusion. What I mean by downstream is, how exactly excessive dopamine D2 receptor stimulation or too much dopamine in general causes psychosis.
In my opinion, the best explanation so far is the E/I balance hypothesis of psychosis and is part of the inhibitory interneuron dysfunction hypothesis.
Basically, if you look at all hallucinogenic or psychotomimetic drug classes ranging from classical psychedelics to disassociatives and probably even salvia, you’ll find that they all cause an overflow of glutamate into certain areas of the brain. it is this search of glutamate and strong stimulation of postsynaptic AMPA receptors that is directly linked to hallucinations. i’ll post some links if you like. what I’ve mentioned so far indicates a modified glutamate hypothesis of psychosis. since dopamine directly modulates glutamate receptor expression and function, we can start to see how excessive dopamine could contribute to the emergence of psychotic symptoms somewhere down the line. of course, we should be aware that schizophrenia is a complex syndrome and psychosis is just one aspect, though we can focus on psychosis in this regard, since dopamine is the topic of this thread and all current antipsychotics act on dopamine.
The psychiatric establishment’s insistence on targeting dopamine and resistance to try new ideas is identical to their attitude towards serotonin in depression. there’s almost always a new SSRI on the market even though many people don’t benefit from these drugs. hypocriticaly, whilst dopamine is at the centre of schizophrenia and even ADHD research/Therapy, it’s been completely disregarded in depression treatment where it might actually have the most noticeable and profound effect. to indicate how serious this is, I read a Study claiming that levodopa was really helpful to depressed patients. Can’t remember if it brought them immediate relief, I need to re-read it but there must be a significant dopamine deficiency if a harsh drug like levodopa is perceived as Pleasant. it’s also been observed that patients with major depression have a significant upregulation of D2 receptors in certain brain regions, thought to be a compensatory response to chronically Low dopamine. such patients also had an exaggerated positive response to dextroamphetamine with stimulation and euphoria possibly being much more intense than that felt by healthy people at the same dose.
Not saying we should necessarily give all depressed people amphetamine, just that we need to investigate the dopamine pathway for major depression.

 

[AlsoTapered]

It's well worth investigating the statistics on schizophrenia.

Between monozygotic (identical) twins their is a 50% chance that if one develops schizophrenia, so will the other. This is true regardless of them growing up together or apart. What does this tell us?

We know that stress is a major trigger and know that brain development is important... but we notice that people who grow up in cities (compared to the countryside) are at a higher risk...

A good friend of mine was adopted (a fact I only learnt when I was in my 20s) developed schizophrenia after heavy cannabis usage over years plus in ONE WEEK:

-He crashed his car
-His GF left him
-He lost his job
-His dog died

So, sadly, he very likely had the full set,

But I read the works of both R.D. Laing and michel foucault who both recognised that schizophrenia seems to have existed for at least as long as human civilization but has only been classed as a medical disorder for under 200 years and before that it's image was everything from 'satanic possession' to 'in direct communication with god'.

 

[Neuroprotection]

anyone have any thoughts on dopamine in depression? I know a significant number of people have benefited from the dual dopamine/norepinephrine reuptake inhibitor bupropion which has the added benefit of not interacting with the serotonergic system. This means it generally lacks the side-effects of emotional blunting and sexual dysfunction. meanwhile, the dopaminergic component can actually benefit sexual function.

 

[Neuroprotection]

Here are some links on dopamine and depression. sorry if I’ve posted these before, my memory isn’t great.

Dopamine System Dysregulation in Major Depressive Disorders

Anhedonia is considered a core feature of major depressive disorder, and the dopamine system plays a pivotal role in the hedonic deficits described in this disorder. Dopaminergic activity is complex and under the regulation of multiple brain structures, ...

www.ncbi.nlm.nih.gov

A Drug That Increases Dopamine Can Reverse the Effects of Inflammation on the Brain in Depression - Neuroscience News

Levodopa, a drug commonly prescribed for the treatment of Parkinson's disease that increases dopamine in the brain was found to reverse the effects of neuroinflammation on the reward system and improve symptoms associated with depression.

neurosciencenews.com

Psychostimulants in the therapy of treatment-resistant depression Review of the literature and findings from a retrospective study in 65 depressed patients

The use of psychostimulants as an adjuvant therapy in treatment-resistant depression is not very common nowadays and has been the subject of much criticism. This article gives a brief review of the literature and reports on the findings from a retrospective ...

www.ncbi.nlm.nih.gov

 

[Conky]

Any suggestions as to how I can purposely downregulate dopamine receptors in order to mitagate withdrawal symptoms induced by chronic use of haloperidol

I get bad withdrawals even from a 5 percent dose reduction, so a long taper isn't feasible

 

[AlsoTapered]

Thanks for that informative reply. The relationship between dopamine and NMDA receptors is very complex. firstly, there is the fact that D1 receptors generally potentiate NMDA function and increase NMDA receptor expression, whilst on the other hand, D2 receptor stimulation temporarily decreases NMDA currents and can induce temporary endocytosis of NMDA receptors. then there’s the fact that dopamine blocking antipsychotics do not block the psychotomimetic effects of NMDA receptor antagonists like ketamine in humans.
Sorry if I caused any confusion. What I mean by downstream is, how exactly excessive dopamine D2 receptor stimulation or too much dopamine in general causes psychosis.
In my opinion, the best explanation so far is the E/I balance hypothesis of psychosis and is part of the inhibitory interneuron dysfunction hypothesis.
Basically, if you look at all hallucinogenic or psychotomimetic drug classes ranging from classical psychedelics to disassociatives and probably even salvia, you’ll find that they all cause an overflow of glutamate into certain areas of the brain. it is this search of glutamate and strong stimulation of postsynaptic AMPA receptors that is directly linked to hallucinations. i’ll post some links if you like. what I’ve mentioned so far indicates a modified glutamate hypothesis of psychosis. since dopamine directly modulates glutamate receptor expression and function, we can start to see how excessive dopamine could contribute to the emergence of psychotic symptoms somewhere down the line. of course, we should be aware that schizophrenia is a complex syndrome and psychosis is just one aspect, though we can focus on psychosis in this regard, since dopamine is the topic of this thread and all current antipsychotics act on dopamine.
The psychiatric establishment’s insistence on targeting dopamine and resistance to try new ideas is identical to their attitude towards serotonin in depression. there’s almost always a new SSRI on the market even though many people don’t benefit from these drugs. hypocriticaly, whilst dopamine is at the centre of schizophrenia and even ADHD research/Therapy, it’s been completely disregarded in depression treatment where it might actually have the most noticeable and profound effect. to indicate how serious this is, I read a Study claiming that levodopa was really helpful to depressed patients. Can’t remember if it brought them immediate relief, I need to re-read it but there must be a significant dopamine deficiency if a harsh drug like levodopa is perceived as Pleasant. it’s also been observed that patients with major depression have a significant upregulation of D2 receptors in certain brain regions, thought to be a compensatory response to chronically Low dopamine. such patients also had an exaggerated positive response to dextroamphetamine with stimulation and euphoria possibly being much more intense than that felt by healthy people at the same dose.
Not saying we should necessarily give all depressed people amphetamine, just that we need to investigate the dopamine pathway for major depression.

I don't know if this is a clue but in 'The Case of the Frozen Addicts' the very first victim had produced an opioid that had MPTP as a major impurity. He was given L-DOPA to treat his symptoms but apparently 'abused his medication' until doctors switched him to something else. Apparently he purposefully overdosed on cocaine which doesn't sound a great way to go... but when given to treat Parkinson's disease (or poisoning that resulted in the same damage), L-DOPA has some abuse potential. But that's 1 guy.

There have been drugs like bupropion that act as dopamine reuptake inhibitors. I'm pretty sure it acts somewhat like amphetamines but with increased serotonin reuptake inhibition (due to the meta chloro moiety).

 

[AlsoTapered]

Any suggestions as to how I can purposely downregulate dopamine receptors in order to mitagate withdrawal symptoms induced by chronic use of haloperidol

I get bad withdrawals even from a 5 percent dose reduction, so a long taper isn't feasible

Wow - I seem to recall that compounds related to haloperidol possess opioid activity and that haloperidol is supposed to make opioid withdrawal less ugly. Haloperidol is a sigma receptor antagonist and back in the day, sigma receptors were believed to be a class of opiate receptor.

While their are a number of other neuroleptics related to haloperidol, I really don't know enough to suggest substitution.

I just know that Janssen stumbled upon some meperidine (pethidine) analogues that produced 'a long-lasting calming effect' in animal models. He refined it and that refinement led to haloperidol.

I'm not sure if this information is of use to you, I'm just posting what I can remember.

 

[Conky]

Wow - I seem to recall that compounds related to haloperidol possess opioid activity and that haloperidol is supposed to make opioid withdrawal less ugly. Haloperidol is a sigma receptor antagonist and back in the day, sigma receptors were believed to be a class of opiate receptor.

While their are a number of other neuroleptics related to haloperidol, I really don't know enough to suggest substitution.

I just know that Janssen stumbled upon some meperidine (pethidine) analogues that produced 'a long-lasting calming effect' in animal models. He refined it and that refinement led to haloperidol.

I'm not sure if this information is of use to you, I'm just posting what I can remember.

Interesting, I didn't know about the opioid activity and I doubt it has any significance since haloperidol can still cause harsh extrapyramidal symptoms. Opioids for example would reduce akathisia.

Haloperidol is probably used in opioid withdrawal due to it's strong anti emetic effects at low doses.

 

[AlsoTapered]

Interesting, I didn't know about the opioid activity and I doubt it has any significance since haloperidol can still cause harsh extrapyramidal symptoms. Opioids for example would reduce akathisia.

Haloperidol is probably used in opioid withdrawal due to it's strong anti emetic effects at low doses.

I didn't know haloperidol was used to treat the symptoms of opiate withdrawal. Live and learn.

Phenoperidine is the most structurally related opioid to haloperidol. It was only ever used for analgesia during surgical anesthesia. The Wiki page actually details how Janssen developed a number of structurally related compounds with diverse activity. I read it in an obscure book on the subject of opiates but the Wiki page sums it up quite well.

The addition of a 4-chloro was likely introduced to diminish opioid activity (and slowing metabolism) although the the '4-fluoro might be important to affinity. It's seen in closely related compounds such as benperidol, bromperidol, moperidone, pimozide and so on.

It has to be said that haloperidol is kind of a relic. I'm quite surprised it's still in use. I mean, I can see it's place in treatment in psychiatric emergencies but I had mistakenly presumed it was no longer a first-line treatment in other situations.

BUT maybe substitution with one of the related compounds might make reduction more practical?

There are stacks of articles on Google Scholar and if you want to read any that are behind a paywall, I will do my best to get them for you. I'm not a doctor much less a psychiatrist and the use of neuroleptics and their associated problems is not within my domain.

 

[Neuroprotection]

Any suggestions as to how I can purposely downregulate dopamine receptors in order to mitagate withdrawal symptoms induced by chronic use of haloperidol

I get bad withdrawals even from a 5 percent dose reduction, so a long taper isn't feasible

I think the best approach would be a very slow taper, Maybe even less than 1% reduction each time. very slow tapers over a period of years using liquid drug solutions has been successfully used to get people off SSRI antidepressants which can have severe withdrawals. Also, do you mind describing what the main symptoms you suffer when withdrawing from haloperidol?