An update to the dopamine hypothesis...

[Stagg737]

So this article from Wired came across my newsfeed a couple of days ago and caught my attention. Seemed like kind of a "look at this research" pop-psych type of title and article at first, but reading through it there's more depth than I expected. It's basically arguing that dysregulation of D1 receptors and not D2 receptors is primarily responsible for psychotic symptoms and that our drugs that are effective for psychosis primarily work on D1, whether directly or indirectly. I haven't read the primary study that the article is citing (I'll link both below), but it came out in Nature Nueroscience last month and seems like it was pretty well-done. If it's behind a paywall, the Wired article actually seems like a pretty good summary.

I'm curious what other people's thoughts are on this. If it turns out to be accurate, it could be one of the biggest steps forward in psychopharmacology we've had in a long time as well as a huge step in terms of understanding the neurobiology of psychosis. Links to the Wired article and original paper:

Everyone Was Wrong About Antipsychotics

An unprecedented look at dopamine in the brain reveals that psychosis drugs get developed with the wrong neurons in mind.

www.wired.com

Antipsychotic drug efficacy correlates with the modulation of D1 rather than D2 receptor-expressing striatal projection neurons - Nature Neuroscience

To understand how antipsychotics modulate neural activity in the striatum, Yun et al. used in vivo imaging and found a correlation between clinical efficacy and the modulation of D1R-expressing, rather than D2R-expressing, striatal neurons in mice.

www.nature.com

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[vanfanal]

Don’t we already know this to be untrue?. Dopamine dysregulation seems involved, but not the sole pathology or primary. The dopamine hypothesis and animal models seem good at producing positive symptoms of psychosis, but not the negative and cognitive symptoms. And our best medication for psychosis, clozapine, has little affinity and action at dopamine receptors. Other theories, currently predominantly the glumate theory- which is based on the schizophrenia-like effects that chronic PCP produce, aim to suggest that glutamate dysregulation may a more unifying factor that produces downstream dopamine dysregulation- perhaps a sub cortical hyperdopaminergic and cortical hypodopaminergic state.

 

[erg923]

So this article from Wired came across my newsfeed a couple of days ago and caught my attention. Seemed like kind of a "look at this research" pop-psych type of title and article at first, but reading through it there's more depth than I expected. It's basically arguing that dysregulation of D1 receptors and not D2 receptors is primarily responsible for psychotic symptoms and that our drugs that are effective for psychosis primarily work on D1, whether directly or indirectly. I haven't read the primary study that the article is citing (I'll link both below), but it came out in Nature Nueroscience last month and seems like it was pretty well-done. If it's behind a paywall, the Wired article actually seems like a pretty good summary.

I'm curious what other people's thoughts are on this. If it turns out to be accurate, it could be one of the biggest steps forward in psychopharmacology we've had in a long time as well as a huge step in terms of understanding the neurobiology of psychosis. Links to the Wired article and original paper:

Everyone Was Wrong About Antipsychotics

An unprecedented look at dopamine in the brain reveals that psychosis drugs get developed with the wrong neurons in mind.

www.wired.com

Antipsychotic drug efficacy correlates with the modulation of D1 rather than D2 receptor-expressing striatal projection neurons - Nature Neuroscience

To understand how antipsychotics modulate neural activity in the striatum, Yun et al. used in vivo imaging and found a correlation between clinical efficacy and the modulation of D1R-expressing, rather than D2R-expressing, striatal neurons in mice.

www.nature.com

I was under the impression that this was early 2000s stuff and that neurobiology/genetics/neuroscience/psychiatry had moved on from the "Dopamine Hypothesis" many years ago in favor of a more nuanced and developmental view of what we currently label as Schizophrenia and/or psychosis???

 

[tr]

I saw that. It seems like a reasonably well done paper.

At the same time, I feel that 'hypotheses' of psychiatric disease that are named after neurotransmitters are poorly conceived in general.

A neurotransmitter is a substrate. 95% of all the neurons in your brain use either glutamate or gaba. The fact that a few tiny circuits that contribute to psychiatrically relevant functions like reward/threat assessment, arousal, and motor activity, also happen to work with unusual neurotransmitters like serotonin and dopamine, so that we can (somewhat, partially) target them with pharmaceuticals directed to those neurotransmitters or their receptors, doesn't mean that the neurotransmitter itself is the key to any observed dysfunction.

The brain is a system of intercommunicating circuits. Mechanistic descriptions of psychopathology should involve an understanding of how the relevant circuit dynamics differ from those in a healthy state.

Invoking the name of a neurotransmitter and imagining that you have thereby shed some light on the matter at hand just entirely misses the point.

 

[Stagg737]

Don’t we already know this to be untrue?. Dopamine dysregulation seems involved, but not the sole pathology or primary. The dopamine hypothesis and animal models seem good at producing positive symptoms of psychosis, but not the negative and cognitive symptoms. And our best medication for psychosis, clozapine, has little affinity and action at dopamine receptors. Other theories, currently predominantly the glumate theory- which is based on the schizophrenia-like effects that chronic PCP produce, aim to suggest that glutamate dysregulation may a more unifying factor that produces downstream dopamine dysregulation- perhaps a sub cortical hyperdopaminergic and cortical hypodopaminergic state.

Yes and no. I wouldn't say that we know the dopamine hypothesis is untrue, just that we know it's not the full picture. The bigger point of this is that we've still believed that D2 were the primary dopamine receptors involved in antipsychotic efficacy which this study seems to show isn't correct. We believe Clozapine does have minimal effects at the D2 receptor (though their study suggested there are no active effects), but in this study they show it has pretty significant effects at the D1 receptor sites and that it significantly changes the ratio of activity of D1 : D2 receptors. They found that all antipsychotics they've tested, including clozapine and "non-dopaminergic" medications, have significant impacts on D1 receptors and not D2.

You mention glutamate which is actually quite relevant to these findings as there is far more involvement of D1 activity with NDMA-related pathways than with D2. So if D1 is plays a more significant role in psychosis and treatment than D2, then glutamates involvements fits into the model far better. Link for some nerdy molecular pathway review:

Frontiers | Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

Dopamine receptors are widely distributed within the brain where they play critical modulator roles on motor functions, motivation and drive, as well as cogn...

www.frontiersin.org

I was under the impression that this was early 2000s stuff and that neurobiology/genetics/neuroscience/psychiatry had moved on from the "Dopamine Hypothesis" many years ago in favor of a more nuanced and developmental view of what we currently label as Schizophrenia and/or psychosis?

Again, yes and no. As you say, it's more nuanced than the previous dopamine hypothesis suggested. There are plenty of patients who have near miraculous effects when started on classic antipsychotics. There are also plenty that are on multiple and just continue to decline. Meanwhile, some have great responses to some meds (like clozapine) and other meds barely do anything. Why? I think it's partially because we probably label multiple distinct disorders as "schizophrenia", but it may also be much simpler that we've been on the wrong path for decades.

Much of the research involved in seeking new meds look at other neurotransmitters altogether as vanfanal said, but what if studies were just focused on the wrong dopamine receptor, or if it's not just about antagonism but balance? This seems to suggest that we've been closer to a major breakthrough in understanding psychosis and potentially new treatment options than we thought for decades. Like we've been driving in the correct direction, just on the wrong road a couple of blocks over the whole time.

To be clear, we've known about D1 abnormalities in schizophrenia for a long time, but it hasn't been heavily studied or examined in the research. The reason I find this paper fascinating is the direct visualization of effects in mouse models as well as the finding that even antipsychotics we believe to have "very low potency for dopamine" have significant effects at the D1 receptor. It's the implication that we've been misinterpreting why all of our meds for that work for psychosis are actually effective that makes me feel this is could be a big deal and is worth examining closer. I've only skimmed the full 35 page article, but even the basic takeaways seem to imply that we're closer to a much stronger understanding than I've seen.

 

[erg923]

Yes and no. I wouldn't say that we know the dopamine hypothesis is untrue, just that we know it's not the full picture. The bigger point of this is that we've still believed that D2 were the primary dopamine receptors involved in antipsychotic efficacy which this study seems to show isn't correct. We believe Clozapine does have minimal effects at the D2 receptor (though their study suggested there are no active effects), but in this study they show it has pretty significant effects at the D1 receptor sites and that it significantly changes the ratio of activity of D😀2 receptors. They found that all antipsychotics they've tested, including clozapine and "non-dopaminergic" medications, have significant impacts on D1 receptors and not D2.

You mention glutamate which is actually quite relevant to these findings as there is far more involvement of D1 activity with NDMA-related pathways than with D2. So if D1 is plays a more significant role in psychosis and treatment than D2, then glutamates involvements fits into the model far better. Link for some nerdy molecular pathway review:

Frontiers | Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

Dopamine receptors are widely distributed within the brain where they play critical modulator roles on motor functions, motivation and drive, as well as cogn...

www.frontiersin.org

Again, yes and no. As you say, it's more nuanced than the previous dopamine hypothesis suggested. There are plenty of patients who have near miraculous effects when started on classic antipsychotics. There are also plenty that are on multiple and just continue to decline. Meanwhile, some have great responses to some meds (like clozapine) and other meds barely do anything. Why? I think it's partially because we probably label multiple distinct disorders as "schizophrenia", but it may also be much simpler that we've been on the wrong path for decades.

Much of the research involved in seeking new meds look at other neurotransmitters altogether as vanfanal said, but what if studies were just focused on the wrong dopamine receptor, or if it's not just about antagonism but balance? This seems to suggest that we've been closer to a major breakthrough in understanding psychosis and potentially new treatment options than we thought for decades. Like we've been driving in the correct direction, just on the wrong road a couple of blocks over the whole time.

To be clear, we've known about D1 abnormalities in schizophrenia for a long time, but it hasn't been heavily studied or examined in the research. The reason I find this paper fascinating is the direct visualization of effects in mouse models as well as the finding that even antipsychotics we believe to have "very low potency for dopamine" have significant effects at the D1 receptor. It's the implication that we've been misinterpreting why all of our meds for that work for psychosis are actually effective that makes me feel this is could be a big deal and is worth examining closer. I've only skimmed the full 35 page article, but even the basic takeaways seem to imply that we're closer to a much stronger understanding than I've seen.

Fair assessment. We have known, or thought we have known, alot of things in psychiatry for many, many years now. But, it turns out...we don't.

It is notable to admit that we know little more about what we call "Schizophrenia" than we did 40 years ago other than maybe the genetics of the disorder. Early intervention? Nothing since 2009 or so. Better medicine with less side effects? Probably not since the 90s.

Psychiatry is in a real rut here. I think oncology had this for a good decade in the 90s, btw.

Are we on the precipice of something else? I don't see it.

 

[Stagg737]

I saw that. It seems like a reasonably well done paper.

At the same time, I feel that 'hypotheses' of psychiatric disease that are named after neurotransmitters are poorly conceived in general.

A neurotransmitter is a substrate. 95% of all the neurons in your brain use either glutamate or gaba. The fact that a few tiny circuits that contribute to psychiatrically relevant functions like reward/threat assessment, arousal, and motor activity, also happen to work with unusual neurotransmitters like serotonin and dopamine, so that we can (somewhat, partially) target them with pharmaceuticals directed to those neurotransmitters or their receptors, doesn't mean that the neurotransmitter itself is the key to any observed dysfunction.

The brain is a system of intercommunicating circuits. Mechanistic descriptions of psychopathology should involve an understanding of how the relevant circuit dynamics differ from those in a healthy state.

Invoking the name of a neurotransmitter and imagining that you have thereby shed some light on the matter at hand just entirely misses the point.

Of course not, saying that the D1 receptor is the piece we've been missing to have a comprehensive understanding is a gross oversimplification, and I'm not trying to imply that it's the key to unlocking a cure or anything like that. The human body, especially the brain, is far to complicated for that. However, the idea that we've been basing the concept of the dopamine hypothesis on the wrong receptor sub-type for decades is kind of a huge deal if their findings are valid. It could significantly change the way we view a major underlying neurochemical process of at least some psychotic symptoms and how to treat them.

I think the bolded is especially important both in terms of our general approach and why I'm excited to read this paper. They seem to be suggesting that balance between D1 and D2 receptor activity in specific pathways plays a role in diseased vs healthy states and that the balance can be modulated by medications through direct observation. From my initial skim, it seems like the paper is compelling enough to warrant significant further exploration into pathways modulated by D1 as well as further examination regarding MOA of current meds.

Fair assessment. We have known, or thought we have known, about alot of things in psychiatry for many, many years now. But, it turns out...we don't.

It is notable to admit that we know little more about what we call "Schizophrenia" than we did 40 years ago other than maybe some of the genetics of the disorder. Early intervention? Nothing since 2009 or so. Better medicine with less side effects? Probably not since the 90s.

Are we on the precipice of something else? I don't see it.

Are we looking at some groundbreaking medication revolution that will change all of psychiatry? No. But if we can understand how these meds are actually working then maybe we can get something as effective or more effective than Clozapine without the side effect profile that comes with it. What if we could develop a class effective antipsychotics that have little to no risk of EPS (as this is d/t D2 effects)? That by itself would actually be a pretty big deal.

 

[erg923]

Of course not, saying that the D1 receptor is the piece we've been missing to have a comprehensive understanding is a gross oversimplification, and I'm not trying to imply that it's the key to unlocking a cure or anything like that. The human body, especially the brain, is far to complicated for that. However, the idea that we've been basing the concept of the dopamine hypothesis on the wrong receptor sub-type for decades is kind of a huge deal if their findings are valid. It could significantly change the way we view a major underlying neurochemical process of at least some psychotic symptoms and how to treat them.

I think the bolded is especially important both in terms of our general approach and why I'm excited to read this paper. They seem to be suggesting that balance between D1 and D2 receptor activity in specific pathways plays a role in diseased vs healthy states and that the balance can be modulated by medications through direct observation. From my initial skim, it seems like the paper is compelling enough to warrant significant further exploration into pathways modulated by D1 as well as further examination regarding MOA of current meds.



Are we looking at some groundbreaking medication revolution that will change all of psychiatry? No. But if we can understand how these meds are actually working then maybe we can get something as effective or more effective than Clozapine without the side effect profile that comes with it. What if we could develop a class effective antipsychotics that have little to no risk of EPS (as this is d/t D2 effects)? That by itself would actually be a pretty big deal.

Yes, son. What if? That's all I see here

Show me the money....

 

[Stagg737]

Yes, son. What if? That's all I see here

Show me the money....

Gotta have paper to print money...

 

[Sikrouf]

So this article from Wired came across my newsfeed a couple of days ago and caught my attention. Seemed like kind of a "look at this research" pop-psych type of title and article at first, but reading through it there's more depth than I expected. It's basically arguing that dysregulation of D1 receptors and not D2 receptors is primarily responsible for psychotic symptoms and that our drugs that are effective for psychosis primarily work on D1, whether directly or indirectly. I haven't read the primary study that the article is citing (I'll link both below), but it came out in Nature Nueroscience last month and seems like it was pretty well-done. If it's behind a paywall, the Wired article actually seems like a pretty good summary.

I'm curious what other people's thoughts are on this. If it turns out to be accurate, it could be one of the biggest steps forward in psychopharmacology we've had in a long time as well as a huge step in terms of understanding the neurobiology of psychosis. Links to the Wired article and original paper:

Everyone Was Wrong About Antipsychotics

An unprecedented look at dopamine in the brain reveals that psychosis drugs get developed with the wrong neurons in mind.

www.wired.com

Antipsychotic drug efficacy correlates with the modulation of D1 rather than D2 receptor-expressing striatal projection neurons - Nature Neuroscience

To understand how antipsychotics modulate neural activity in the striatum, Yun et al. used in vivo imaging and found a correlation between clinical efficacy and the modulation of D1R-expressing, rather than D2R-expressing, striatal neurons in mice.

www.nature.com

Thanks you so much I found this very interesting, will have to see how it unfolds

 

[Celexa]

This seems like as good a place as any to ask, if I want to really dig into receptor profiles of different medications what is a good source to look at that? I want to get past my basic understanding, including digging into side effect profiles more.

 

[Cath Up]

This seems like as good a place as any to ask, if I want to really dig into receptor profiles of different medications what is a good source to look at that? I want to get past my basic understanding, including digging into side effect profiles more.

I’d love to hear suggestions for this too.
Currently I use
Wikipedia + its sources
Advanced tool for pubmed searches, sci hub for paper access,
Stahl texts
Psychiatry and psychotherapy podcast resource library
And when all else fails, I ask SMI Advisor.

 

[aim-agm]

This seems like as good a place as any to ask, if I want to really dig into receptor profiles of different medications what is a good source to look at that? I want to get past my basic understanding, including digging into side effect profiles more.

https://pdsp.unc.edu/databases/pdsp.php

 

[romanticscience]

This seems like as good a place as any to ask, if I want to really dig into receptor profiles of different medications what is a good source to look at that? I want to get past my basic understanding, including digging into side effect profiles more.

DrugBank Online | Database for Drug and Drug Target Info

Access the world’s pharmaceutical knowledge database. Information on drugs, drug targets, and more, used by researchers and health professionals globally.

go.drugbank.com

 

[Stagg737]

DrugBank Online | Database for Drug and Drug Target Info

Access the world’s pharmaceutical knowledge database. Information on drugs, drug targets, and more, used by researchers and health professionals globally.

go.drugbank.com

PDSP above is good. But extra plug for DrugBank. One of the best and most comprehensive resources out there imo. I used it all the time in residency and still reference it frequently.

 

[romanticscience]

PDSP above is good. But extra plug for DrugBank. One of the best and most comprehensive resources out there imo. I used it all the time in residency and still reference it frequently.

I’ve begun to nerd out with it by reviewing the linked clinical trails on clinicaltrials.gov

 

[whopper]

Every few years an article such as antidepressants don't work at all, serotonin has nothing to do with depression, or that discontinuation syndrome is something psychiatrists don't know about and aren't dealing with it despite that it's complete BS comes out, and even gets published in a credible source.

This article alone isn't enough.

 

[genop]

This seems like as good a place as any to ask, if I want to really dig into receptor profiles of different medications what is a good source to look at that? I want to get past my basic understanding, including digging into side effect profiles more.

Do you have access to a board-certified psych pharmacist? Im sure they’d love to help you out. A local Drug Information Center could also be a good option.

 

[clausewitz2]

I’ve begun to nerd out with it by reviewing the linked clinical trails on clinicaltrials.gov

It's kind of shocking how often you find out that pre-registered endpoint measures changed inexplicably and without comment a few months before completion of trials that take years to run.

 

[Stagg737]

Every few years an article such as antidepressants don't work at all, serotonin has nothing to do with depression, or that discontinuation syndrome is something psychiatrists don't know about and aren't dealing with it despite that it's complete BS comes out, and even gets published in a credible source.

This article alone isn't enough.

Of course not, one article shouldn't be enough. I find this article interesting because they used an actual experimental model where they could visualize and measure dopamine receptor activity and pretty convincing results for induced symptoms. It's a starting point for a new direction of research, and stuff like this is a big reason I got into psych in the first place as we don't really see this in most other areas of medicine anymore.

It also opens a door for new medications. I bet big pharma would love it if this pans out even a little, as they could justify developing drugs specifically targeting D1 receptors instead of just developing another D2 antagonist and crossing their fingers that it'll get approval. Especially since a lot of the more recent drugs haven't really panned out like they had hoped (Pimavanserin, MP10 referenced in the article, etc).

 

[romanticscience]

It's kind of shocking how often you find out that pre-registered endpoint measures changed inexplicably and without comment a few months before completion of trials that take years to run.

There's also a surprising number with no reported outcomes. Do you know why that is?

 

[clausewitz2]

There's also a surprising number with no reported outcomes. Do you know why that is?

I imagine they either fail to recruit enough participants or the results are disappointing, so they go into the circular file.

 

[ObsequiousAplomb]

Of course not, one article shouldn't be enough. I find this article interesting because they used an actual experimental model where they could visualize and measure dopamine receptor activity and pretty convincing results for induced symptoms. It's a starting point for a new direction of research, and stuff like this is a big reason I got into psych in the first place as we don't really see this in most other areas of medicine anymore.

It also opens a door for new medications. I bet big pharma would love it if this pans out even a little, as they could justify developing drugs specifically targeting D1 receptors instead of just developing another D2 antagonist and crossing their fingers that it'll get approval. Especially since a lot of the more recent drugs haven't really panned out like they had hoped (Pimavanserin, MP10 referenced in the article, etc).

I'm confused how Pimavanserin not working is related to anything about the hypothesis for either D2 or D1, considering it was specifically NOT a dopamine-targeting drug

 

[Stagg737]

I'm confused how Pimavanserin not working is related to anything about the hypothesis for either D2 or D1, considering it was specifically NOT a dopamine-targeting drug

I haven’t looked if there’s any D1 activity with Pimavanserin (I know it’s reported there’s not, but I haven’t looked in detail) but the article is arguing that modulation of D1 is what we should be looking into more. Drugs that modulated D1, including Clozapine, were effective even if they had minimal or no D2 effects. If Pimavanserin has neither then that supports their findings. Their article suggests you need to modulate D1, even if indirectly through other receptors (like glutamate activity), to be effective.

 

[docksan]

D1 is excitatory, no? Makes sense dysregulation would lead to psychosis given excessive glutamate leads to neurotoxicity. I don't know that it's that simple though.

 

[ObsequiousAplomb]

I haven’t looked if there’s any D1 activity with Pimavanserin (I know it’s reported there’s not, but I haven’t looked in detail) but the article is arguing that modulation of D1 is what we should be looking into more. Drugs that modulated D1, including Clozapine, were effective even if they had minimal or no D2 effects. If Pimavanserin has neither then that supports their findings. Their article suggests you need to modulate D1, even if indirectly through other receptors (like glutamate activity), to be effective.

Thank you. I know you explained it already upthread but the re-explanation stuck this time. I understood all you were saying about the D1 and D2, I just had confused myself with the nots in the idea.

This is an interesting thing to be reading a discussion about. I remember being a medical student and the class was having a similar discussion about the topic 10 years ago, only the answer that the instructor gave was "while it's an interesting idea, we know that D1 isn't as important because the drugs we use that are effective specifically target D2 and not D1 as much." D1 and D2 are always listed as the options on medical school tests. Honestly, I think there was a question with that premise on the ABPN this year, lol. Neat to think about arguments in favor of the "obviously incorrect" answers on tests.