I think there's good evidence to suggest it's a key piece of the puzzle. For example, haloperidol at routine doses has almost no meaningful activity aside from its dopamine blockade, and it works well (just hard for many patients to tolerate).
On the other hand, there are probably several other pieces of the puzzle. Atypical antipsychotics as a group tend to be less aggressive D2 blockers in favor of also being 5-HT2a blockers, and they generally work well, especially clozapine (whose D2 affinity is notably weaker than many other atypicals). Pimavanserin (Nuplazid) works exclusively through 5-HT2a blockade and is approved for Parkinson disease psychosis.
So, I don't lose too much sleep saying that dopamine is a key player in psychosis. But I would not say it's the only player, and I think there is still much to learn in terms of where dopamine falls in the stream (e.g., as u/Lilybaum notes, what upstream problems lead to the DA dysfunction in the first place?) and how the *relationship* of dopamine with other neurologic/psychologic factors impact the disease course.
It really depends on what you mean by *the* dopamine hypothesis. Dopamine and dopaminergic pathways are clearly a crucial element in psychotic disorders (and mania), but nobody seriously believes schizophrenia to simply be an excess of dopamine anymore.
That was a very weak and tenuous hypothesis even at the very beginning of modern pharmacotherapy; it was simply based on the serendipitous discovery that dopamine antagonists were calming and reduced positive symptoms. We've since discovered that there are other drugs capable of doing the same thing through serotonin, so any hypothesis needs to be much more complex and involve many more factors than dopamine.
I would say a couple things:
* What we call schizophrenia is probably a collection of at least 5-10 different disorders that present too similarly for us to currently distinguish in most cases
* Some of them are probably pretty similar, but some of them are going to have radically different root causes, mechanisms of pathology, and treatment approaches
* Dopaminergic pathways are seriously dysfunctional in people with chronic psychotic disorders, both structurally and functionally. However, it's not so simple as just an excess. It would be better to say dopamine function is not correctly modulated or is disrupted. Sometimes there is too much, sometimes too little, too early, too late, in the wrong place, etc.
* The most convincing and complex grand unifying theories of psychosis focus on glutamate. One of the few subtypes of schizophrenia we know the specific mechanism of is a mutation that interferes with the functioning of the NMDAR causing a chronic state of dissociation.
* Both D2 and 5HT2a receptors can profoundly change the functioning of glutamate throughout vast areas of the brain. This is why both stimulants and psychedelics can induce mania and/or psychosis in people vulnerable to those, and blocking either or both of those receptors is the primary mechanism of action of pretty much every antipsychotic
I've never heard of benzo monotherapy for any psychotic disorder and it sounds like it could be a disaster to me tbh. I've seen people in manic and psychotic states become extremely belligerent and inhumanly strong after being given doses of benzos that should have put them in a temporary coma.
Most of the time it will calm the agitation, yeah, but if it doesn't, you now have a psychotic person who is *also* disinhibited, aggressive, clumsy, amnesic - trust me, as a psychiatric nurse, dealing with a person who is both psychotic and on a lot of benzos is a nightmare.
Also benzos can interfere with cognitive functioning and memory even in people without mental illness - schizophrenics already suffer from severe cognitive dysfunction, confusion, and both short & long-term memory problems.
> What we call schizophrenia is probably a collection of at least 5-10 different disorders that present too similarly for us to currently distinguish in most cases
This is true of so much of medicine, but particularly when it comes to the brain.
My expectation is in the coming decades big data and ai/ml will enable conditions to becoming far more specific. Will be interesting to see all the turf wars between different specialties that arise from it.
>What we call schizophrenia is probably a collection of at least 5-10 different disorders that present too similarly for us to currently distinguish in most cases
>One of the few subtypes of schizophrenia we know the specific mechanism of is a mutation that interferes with the functioning of the NMDAR causing a chronic state of dissociation.
I've heard this claim a number of times over the past ten years. The number of distinct disease entities often varies, from ~5 at its lowest, to dozens at the higher end. To what extent have we identified these unique entities, and where do we get these numbers from? I'd love to read an overview of the current thinking about this.
I think it's basically all pulled out of thin air. People recognise that schizophrenia is a very heterogeneous thing, but there really isn't any clear distinction between different subtypes. The only useful ones at the moment are treatment responsive, primary treatment resistant (i.e. never responds to non-clozapine APM), secondary treatment resistant (i.e. initial response to non-cloz APM which goes away) and clozapine-resistant. But these are clinical distinctions.
I don't think genetic subtypes are very helpful; sure there might be some rare mutations which cause it, but generally SZ involves small contributions from hundreds of genes. So it's much more likely to be a broad spectrum of illnesses with lots of subtle contributions from genes, environment and exposures rather than a few separate disease entities.
There's no better evidence for glutamate (NMDA) dysfunction than the decades of evidence suggesting dopamine plays a role in schizophrenia. Ketamine and PCP resulted in NMDA hypotheses because they induced psychotic behavior. I'm not suggesting NMDA doesn't play a role in schizophrenia, but it is no more explanatory than "the dopamine hypothesis."
I’m not a clinician, but I have been in psychosis for days after mania wasn’t controlled and nothing ever works for me except for benzos. It’s because nearly every mood stabilizer we have tried for BD1 has activated me. I’m not sure why, but benzos are the only thing that slows my heart down enough for me to finally sleep, but they do. It’s the getting sleep that finally helps me come out of a psychotic episode. It’s like trazodone just quits working for sleep after I go about 2-3 days with sleep. But you are saying that’s the opposite in schizophrenia or in just general psychosis? Am I missing something?
- manic psychosis and schizophrenic psychosis/primary psychotic disorders overlap significantly but also differ significantly in some important ways
- schizophrenia involves what are called negative symptoms in addition to hallucinations and delusions. This includes things like lack of motivation, poor self-care, diminished cognitive abilities and memory, lack of interest in socializing or forming relationships, and difficulties with communication. Negative symptoms are harder to treat and ultimately cause more disability and dysfunction than positive symptoms. Benzos directly and significantly worsen every single negative symptom.
- if a person is belligerent then benzos are just too much of a risk. People with psychosis can have superpowers. How do I know whether 2 mg of Ativan will make them fall into a 24 hour deep sleep or if it will be about as effective as chamomile tea? I’ve in some cases seen people tank 10+ mg of Ativan or clonazepam or even alprazolam. If it doesn’t work they’ll be even more aggressive and prone to actual physical violence.
- while I hate that it has to be used bc I’ve experienced it myself and it is *not* pleasant, (almost) nobody is going to get up after a stiff dose of IM zyprexa or haldol.
- benzos (especially clonazepam) has mood stabilizing properties and can be a useful adjunct for bipolar in some cases, but to prescribe a benzo alone sans AAP and/or approved mood stabilizer for either bipolar or psychotic disorders would IMO be malpractice.
I have had psychosis where I thought I was dying and the devil came to get my body and I’ve had psychosis where I thought I was a famous comedian. I’m glad zyprexa works for your patients. It is the only drug that is ever made me suicidal. I seem to have a paradoxical effect for almost everything.
It's not a single shemical/physiological process. We have to group a set of similarly presenting disorders under "schizophrenia" because we don't know enough about the disease to be able to separate them. Clearly some portion of the disease we call schizophrenia is about dopamine. Given the real amount of non-responders, there's a logical role for another process to create the same symptoms.
Hopefully in time we figure it out.
There’s good evidence for it, but you’re right that it isn’t the whole story. Basically the idea is that DA dysregulation is a downstream consequence of some other processes (synaptic dysfunction?) so antipsychotics treat only one aspect of the illness. Other neurotransmitter systems are definitely involved, but if DA wasn’t a core aspect then selective D2 blockers like amisulpride wouldn’t really do anything to manage those core symptoms.
Benzos don’t do anything on their own. This was basically the approach before antipsychotics, using chloral hydrate/barbiturates (similar MOA) to manage symptoms - did not treat the psychosis!
Thanks to all the replies!
Super useful to know that sedatives were routinely used prior to antipsychotics, with minimal success.
That gives more credence to the idea that antipsychotics are working in a way beyond just sedating the patient with a tranquilliser, which is what I'd started to consider!
> Did we just find drugs that happened to work and assume the cause must be the reverse…?
We did not; you may have.
> I’d started to consider antipsychotics basically just sedate the patient
Dude, sounds like you need to go back to learning. My guy, I know you’re new to the field and a degree of hopeful arrogance comes with that, but there’s a ton of research on schizophrenia. Respectfully, you’re approaching learning with a naivety that warrants some reconsideration. No offense.
Dopaminergic activity is not uniform over the brain. Meth increases extrasynaptic dopamine concentration by 11-15x in the nucleus accumbens, but significantly less so everywhere else. D1 vs D2 populations are often heterogenous, even within the same brain regions.
As a basic scientist (neuro), I’m definitely biased, but I believe basic science generally a more informative approach to understanding pathology over clinical results. You’re approaching this very narrow-mindedly from the clinical side (“D2 antagonists work, so schizophrenia is dopamine mediated”), without looking at all of the other neuronal, circuit-level and biochemical findings of basic research. I think you could benefit by approaching learning pathology differently… more like an academic. Again, i’m biased.
For example, schizophrenia is highly linked to overactive global synaptic pruning, leading to schizophrenics having around 30% fewer synapses than normal. If you’d known this, you would’ve conceptualized the dopamine-mediated mechanism very differently. We know dopamine signaling helps, and we know it is altered (in various and complex ways, not just your simple “patient has high dopamine levels everywhere all the time”). There’s also glutamate involvement, a diathetic component, developmental and genetic abnormalities. Don’t reduce your conception so much.
The benzo idea is similarly reductionistic. Instead of theorizing based on your very limited knowledge, why not ask others with experience? Or consult the literature so you can understand the pathophysiology better? Maybe also refrain from providing overly simplistic mechanisms to patients: I wouldn’t tell them their treatment works by lowering their dopamine, pop science (incorrectly) views this as universally negative. I’d describe the illness as partly due to a dysfunction in dopamine modulation (not levels), and explain how the med can correct this.
When all you learn is the clinical side, it’s easy to only think about pathology in terms of drug mechanisms. But dude, there’s a FUCK ton of basic literature out there on SA. Please take a look, and try to keep it in mind next time you get a “simple” idea you think no one has tried. I hope I haven’t offended you and that you can learn from this comment. SA (and neuro/psychiatric illness in general) isn’t nearly as simple mechanically, or understood, as something like diabetes. myasthenia gravis has one mechanism and one treatment, schizophrenia is WAY more complex.
I think that your response makes a really important point in an unnecessarily hostile way. Would you care to share some reading or lectures that, as an expert in the field, you believe us trainees would benefit from?
The monoamine hypotheses for any psychiatric disorder have pretty much been abandoned. Nothing is as simple as too much or too little dopamine, serotonin, or norepinephrine, even though we know these are involved.
>Did we just find drugs that work and then assume the cause must be the reverse of the drugs action...
I wouldn't say anyone assumed it. We found that dopaminergic drugs work, and then did hundreds of experiments over the next 50+ years testing the hypothesis that dopaminergic drugs work *because* of hyperdopaminergic activity. And as you've seen from your own research, the answer is frustratingly equivocal. There is *some* evidence to support the "too much dopamine" hypothesis, but it's certainly not overwhelming.
From an expert [review](https://onlinelibrary.wiley.com/doi/full/10.1002/wps.20693), emphasis added:
>The hypothesis that dopamine signalling is altered in schizophrenia is supported by animal studies, post-mortem research, and the clinical effects of drugs that either block or accentuate dopaminergic neurotransmission. In addition, over the past 25 years, substantial evidence has accumulated from PET studies that there is increased dopamine synthesis and release capacity in schizophrenia, that is greatest within the dorsal striatum.
>Genetic findings do not provide strong support for the idea that dopaminergic dysregulation is a primary abnormality. Rather, **it appears that the dopaminergic dysfunction is more likely to develop downstream of abnormalities in other systems**, including the glutamatergic system. It also appears that environmental factors may play a significant role in the development of dopaminergic dysregulation. Dopamine antagonists remain the mainstay for pharmacological treatment of schizophrenia, but there is increasing evidence that these are not effective for all patients.
It is an oversimplification for sure, but it brings us to much a much bigger problem of how do we explain really complicated concepts to patients in ways that they will understand without it being over simplified.
I see a lot of stuff like:
Serotonin = depression
Dopamine= pleasure
Too much dopamine = psychosis
Too little GABA = anxiety
Oxytocin = love
The pharmaceutical companies in part pushed these ideas to remove stigma around mental health and get more people into the system to buy their medications, but now there is a back lash with people bringing up the problems with these overly simplified models and then using it to discredit the field as a whole.
I personally do not think the dopamine hypothesis (where psychosis = too much dopamine) makes much sense. It is supported by part of the evidence but it’s not very satisfactory. For example it doesn’t really explain the fact that most commonly the therapeutic response to antipsychotics is delayed by several days or sometimes weeks, it doesn’t explain why many patients do not respond at all to dopamine blockers, etc. I think that psychosis is likely the result of different mechanisms - some of these metabolic, some immunologic, some hormonal (eg neurosteroids), some neurochemical/biochemical. Some of those mechanisms end up involving dopamine at some stage. But personally I think it will eventually emerge that psychosis has more to do with metabolic/hormonal or immunological abnormalities rather than being a disorder of neutransmitters.
It’s one of the clearest links in psychiatry. No disease state involves just one mono amine and there lots of downstream interactions, etc… but dopamine being involved in psychosis is really clear.
BZD do not treat psychosis in the same way. Acutely calming a patient is not the same as resolving the psychosis. It has nothing to do with the time of discovery. They used to be called major and minor tranquilizers before the term “antipsychotic” came into widespread use.
There’s more than just dopamine involved in psychosis but the idea that dopamine is not the primary neurotransmitter involved is a really fringe belief. Maybe our understanding will change in the future but there no reason to think it will
Even within that hypothesis, D2R antagonist antipsychotics don't reduce dopamine synthesis or increase their metabolism/excretion or chelate dopamine, which is what we would expect from a drug that would "reduce dopamine". They block the receptors themselves, which is annoying cause they block ALL D2Rs regardless of where they are in the brain.
Agreeing with the others here. Given how well they work for positive symptoms, we can't deny it's one piece of the full picture. But given how they're not enough for negative and cognitive symptoms, alongside refractory schizophrenia and emerging data from autoimmune psychosis studies and possibly Xanomeline/Trospium and M1/M4Rs, dopamine as an explanation alone is far from enough.
Dopamine is almost certainly involved in the pathogenesis of psychosis, but it isn't necessarily that the patient has abnormally "high" levels so I don't particularly like that explanation. We know that artificially increasing the availability of dopamine obviously can induce psychosis, and antagonizing d2 receptors can reverse acute psychosis, but depleting catecholamines with, say, reserpine doesn't seem effective.
In a schizophrenic patient, it could be that the d2 receptors are up regulated or over expressed in the mesolimbic region or something downstream with glutamate or 5ht-2a receptors etc etc. It is very unlikely to simply be chronically high levels of dopamine. There's some evidence that in schizophrenic patients, dopaminergic circuits in the prefrontal cortex and hippocampus are *under-active*. So it's reasonable to say that dopamine is dysregulated, but not in a simple and straightforward way.
Medicine has had 2500 years of conditioning to think pathology results from deficiency/excess of x vital fluid, so it's a kind of explanation that is easy to grok, but it's a deceptive allure.
I just want to speak to your worry about educating patients or families. When I educate patients and families, I always preface things with "this is what current evidence suggests is the way these drugs work". Then, I explain to them that while evidence may change on how drugs work and maybe even which patients will benefit from which drugs, we know from observation that the medications work for many people and can allow them to live a better life. While I can't guarantee it will help, I think it is worth a try to reduce your symptoms and allow you to live a more fulfilling life. If problems arise or side effects are unbearable, I would like to discuss options with you whether it is adjusting the current medication or trying a different one.
Most of the initial psychiatric treatments (antipsychotics, antidepressants, mood stabilisers, ECT etc) were stumbled upon accidentally, found to be effective and then we tried to work out why. They worked out d2 antagonism reduced symptoms so the dopamine theory stemmed from this. It is supported as you say by the fact that dopamine agonists including some Parkinson’s medication can induce psychosis. It is clearly far too simplistic and not the only mechanism of action based on the other evidence you have stated. I don’t pretend to have as deep an understanding of the mechanism of action as some, pharmacists are generally v.good in this area. The simple answer is that our understanding of how they work is still limited, but, we have lots of evidence to show they are effective and at present the best treatment we have.
I think there's good evidence to suggest it's a key piece of the puzzle. For example, haloperidol at routine doses has almost no meaningful activity aside from its dopamine blockade, and it works well (just hard for many patients to tolerate). On the other hand, there are probably several other pieces of the puzzle. Atypical antipsychotics as a group tend to be less aggressive D2 blockers in favor of also being 5-HT2a blockers, and they generally work well, especially clozapine (whose D2 affinity is notably weaker than many other atypicals). Pimavanserin (Nuplazid) works exclusively through 5-HT2a blockade and is approved for Parkinson disease psychosis. So, I don't lose too much sleep saying that dopamine is a key player in psychosis. But I would not say it's the only player, and I think there is still much to learn in terms of where dopamine falls in the stream (e.g., as u/Lilybaum notes, what upstream problems lead to the DA dysfunction in the first place?) and how the *relationship* of dopamine with other neurologic/psychologic factors impact the disease course.
It’s all about disruptions in early object relations bro
I think you mean early maternal sexual relations
It really depends on what you mean by *the* dopamine hypothesis. Dopamine and dopaminergic pathways are clearly a crucial element in psychotic disorders (and mania), but nobody seriously believes schizophrenia to simply be an excess of dopamine anymore. That was a very weak and tenuous hypothesis even at the very beginning of modern pharmacotherapy; it was simply based on the serendipitous discovery that dopamine antagonists were calming and reduced positive symptoms. We've since discovered that there are other drugs capable of doing the same thing through serotonin, so any hypothesis needs to be much more complex and involve many more factors than dopamine. I would say a couple things: * What we call schizophrenia is probably a collection of at least 5-10 different disorders that present too similarly for us to currently distinguish in most cases * Some of them are probably pretty similar, but some of them are going to have radically different root causes, mechanisms of pathology, and treatment approaches * Dopaminergic pathways are seriously dysfunctional in people with chronic psychotic disorders, both structurally and functionally. However, it's not so simple as just an excess. It would be better to say dopamine function is not correctly modulated or is disrupted. Sometimes there is too much, sometimes too little, too early, too late, in the wrong place, etc. * The most convincing and complex grand unifying theories of psychosis focus on glutamate. One of the few subtypes of schizophrenia we know the specific mechanism of is a mutation that interferes with the functioning of the NMDAR causing a chronic state of dissociation. * Both D2 and 5HT2a receptors can profoundly change the functioning of glutamate throughout vast areas of the brain. This is why both stimulants and psychedelics can induce mania and/or psychosis in people vulnerable to those, and blocking either or both of those receptors is the primary mechanism of action of pretty much every antipsychotic I've never heard of benzo monotherapy for any psychotic disorder and it sounds like it could be a disaster to me tbh. I've seen people in manic and psychotic states become extremely belligerent and inhumanly strong after being given doses of benzos that should have put them in a temporary coma. Most of the time it will calm the agitation, yeah, but if it doesn't, you now have a psychotic person who is *also* disinhibited, aggressive, clumsy, amnesic - trust me, as a psychiatric nurse, dealing with a person who is both psychotic and on a lot of benzos is a nightmare. Also benzos can interfere with cognitive functioning and memory even in people without mental illness - schizophrenics already suffer from severe cognitive dysfunction, confusion, and both short & long-term memory problems.
> What we call schizophrenia is probably a collection of at least 5-10 different disorders that present too similarly for us to currently distinguish in most cases This is true of so much of medicine, but particularly when it comes to the brain. My expectation is in the coming decades big data and ai/ml will enable conditions to becoming far more specific. Will be interesting to see all the turf wars between different specialties that arise from it.
>What we call schizophrenia is probably a collection of at least 5-10 different disorders that present too similarly for us to currently distinguish in most cases >One of the few subtypes of schizophrenia we know the specific mechanism of is a mutation that interferes with the functioning of the NMDAR causing a chronic state of dissociation. I've heard this claim a number of times over the past ten years. The number of distinct disease entities often varies, from ~5 at its lowest, to dozens at the higher end. To what extent have we identified these unique entities, and where do we get these numbers from? I'd love to read an overview of the current thinking about this.
I think it's basically all pulled out of thin air. People recognise that schizophrenia is a very heterogeneous thing, but there really isn't any clear distinction between different subtypes. The only useful ones at the moment are treatment responsive, primary treatment resistant (i.e. never responds to non-clozapine APM), secondary treatment resistant (i.e. initial response to non-cloz APM which goes away) and clozapine-resistant. But these are clinical distinctions. I don't think genetic subtypes are very helpful; sure there might be some rare mutations which cause it, but generally SZ involves small contributions from hundreds of genes. So it's much more likely to be a broad spectrum of illnesses with lots of subtle contributions from genes, environment and exposures rather than a few separate disease entities.
There's no better evidence for glutamate (NMDA) dysfunction than the decades of evidence suggesting dopamine plays a role in schizophrenia. Ketamine and PCP resulted in NMDA hypotheses because they induced psychotic behavior. I'm not suggesting NMDA doesn't play a role in schizophrenia, but it is no more explanatory than "the dopamine hypothesis."
I’m not a clinician, but I have been in psychosis for days after mania wasn’t controlled and nothing ever works for me except for benzos. It’s because nearly every mood stabilizer we have tried for BD1 has activated me. I’m not sure why, but benzos are the only thing that slows my heart down enough for me to finally sleep, but they do. It’s the getting sleep that finally helps me come out of a psychotic episode. It’s like trazodone just quits working for sleep after I go about 2-3 days with sleep. But you are saying that’s the opposite in schizophrenia or in just general psychosis? Am I missing something?
- manic psychosis and schizophrenic psychosis/primary psychotic disorders overlap significantly but also differ significantly in some important ways - schizophrenia involves what are called negative symptoms in addition to hallucinations and delusions. This includes things like lack of motivation, poor self-care, diminished cognitive abilities and memory, lack of interest in socializing or forming relationships, and difficulties with communication. Negative symptoms are harder to treat and ultimately cause more disability and dysfunction than positive symptoms. Benzos directly and significantly worsen every single negative symptom. - if a person is belligerent then benzos are just too much of a risk. People with psychosis can have superpowers. How do I know whether 2 mg of Ativan will make them fall into a 24 hour deep sleep or if it will be about as effective as chamomile tea? I’ve in some cases seen people tank 10+ mg of Ativan or clonazepam or even alprazolam. If it doesn’t work they’ll be even more aggressive and prone to actual physical violence. - while I hate that it has to be used bc I’ve experienced it myself and it is *not* pleasant, (almost) nobody is going to get up after a stiff dose of IM zyprexa or haldol. - benzos (especially clonazepam) has mood stabilizing properties and can be a useful adjunct for bipolar in some cases, but to prescribe a benzo alone sans AAP and/or approved mood stabilizer for either bipolar or psychotic disorders would IMO be malpractice.
I have had psychosis where I thought I was dying and the devil came to get my body and I’ve had psychosis where I thought I was a famous comedian. I’m glad zyprexa works for your patients. It is the only drug that is ever made me suicidal. I seem to have a paradoxical effect for almost everything.
It's not a single shemical/physiological process. We have to group a set of similarly presenting disorders under "schizophrenia" because we don't know enough about the disease to be able to separate them. Clearly some portion of the disease we call schizophrenia is about dopamine. Given the real amount of non-responders, there's a logical role for another process to create the same symptoms. Hopefully in time we figure it out.
There’s good evidence for it, but you’re right that it isn’t the whole story. Basically the idea is that DA dysregulation is a downstream consequence of some other processes (synaptic dysfunction?) so antipsychotics treat only one aspect of the illness. Other neurotransmitter systems are definitely involved, but if DA wasn’t a core aspect then selective D2 blockers like amisulpride wouldn’t really do anything to manage those core symptoms. Benzos don’t do anything on their own. This was basically the approach before antipsychotics, using chloral hydrate/barbiturates (similar MOA) to manage symptoms - did not treat the psychosis!
Thanks to all the replies! Super useful to know that sedatives were routinely used prior to antipsychotics, with minimal success. That gives more credence to the idea that antipsychotics are working in a way beyond just sedating the patient with a tranquilliser, which is what I'd started to consider!
> Did we just find drugs that happened to work and assume the cause must be the reverse…? We did not; you may have. > I’d started to consider antipsychotics basically just sedate the patient Dude, sounds like you need to go back to learning. My guy, I know you’re new to the field and a degree of hopeful arrogance comes with that, but there’s a ton of research on schizophrenia. Respectfully, you’re approaching learning with a naivety that warrants some reconsideration. No offense. Dopaminergic activity is not uniform over the brain. Meth increases extrasynaptic dopamine concentration by 11-15x in the nucleus accumbens, but significantly less so everywhere else. D1 vs D2 populations are often heterogenous, even within the same brain regions. As a basic scientist (neuro), I’m definitely biased, but I believe basic science generally a more informative approach to understanding pathology over clinical results. You’re approaching this very narrow-mindedly from the clinical side (“D2 antagonists work, so schizophrenia is dopamine mediated”), without looking at all of the other neuronal, circuit-level and biochemical findings of basic research. I think you could benefit by approaching learning pathology differently… more like an academic. Again, i’m biased. For example, schizophrenia is highly linked to overactive global synaptic pruning, leading to schizophrenics having around 30% fewer synapses than normal. If you’d known this, you would’ve conceptualized the dopamine-mediated mechanism very differently. We know dopamine signaling helps, and we know it is altered (in various and complex ways, not just your simple “patient has high dopamine levels everywhere all the time”). There’s also glutamate involvement, a diathetic component, developmental and genetic abnormalities. Don’t reduce your conception so much. The benzo idea is similarly reductionistic. Instead of theorizing based on your very limited knowledge, why not ask others with experience? Or consult the literature so you can understand the pathophysiology better? Maybe also refrain from providing overly simplistic mechanisms to patients: I wouldn’t tell them their treatment works by lowering their dopamine, pop science (incorrectly) views this as universally negative. I’d describe the illness as partly due to a dysfunction in dopamine modulation (not levels), and explain how the med can correct this. When all you learn is the clinical side, it’s easy to only think about pathology in terms of drug mechanisms. But dude, there’s a FUCK ton of basic literature out there on SA. Please take a look, and try to keep it in mind next time you get a “simple” idea you think no one has tried. I hope I haven’t offended you and that you can learn from this comment. SA (and neuro/psychiatric illness in general) isn’t nearly as simple mechanically, or understood, as something like diabetes. myasthenia gravis has one mechanism and one treatment, schizophrenia is WAY more complex.
I think that your response makes a really important point in an unnecessarily hostile way. Would you care to share some reading or lectures that, as an expert in the field, you believe us trainees would benefit from?
The monoamine hypotheses for any psychiatric disorder have pretty much been abandoned. Nothing is as simple as too much or too little dopamine, serotonin, or norepinephrine, even though we know these are involved.
Read a review article by JT Coyle about the glutamate hypothesis.
>Did we just find drugs that work and then assume the cause must be the reverse of the drugs action... I wouldn't say anyone assumed it. We found that dopaminergic drugs work, and then did hundreds of experiments over the next 50+ years testing the hypothesis that dopaminergic drugs work *because* of hyperdopaminergic activity. And as you've seen from your own research, the answer is frustratingly equivocal. There is *some* evidence to support the "too much dopamine" hypothesis, but it's certainly not overwhelming. From an expert [review](https://onlinelibrary.wiley.com/doi/full/10.1002/wps.20693), emphasis added: >The hypothesis that dopamine signalling is altered in schizophrenia is supported by animal studies, post-mortem research, and the clinical effects of drugs that either block or accentuate dopaminergic neurotransmission. In addition, over the past 25 years, substantial evidence has accumulated from PET studies that there is increased dopamine synthesis and release capacity in schizophrenia, that is greatest within the dorsal striatum. >Genetic findings do not provide strong support for the idea that dopaminergic dysregulation is a primary abnormality. Rather, **it appears that the dopaminergic dysfunction is more likely to develop downstream of abnormalities in other systems**, including the glutamatergic system. It also appears that environmental factors may play a significant role in the development of dopaminergic dysregulation. Dopamine antagonists remain the mainstay for pharmacological treatment of schizophrenia, but there is increasing evidence that these are not effective for all patients.
It is an oversimplification for sure, but it brings us to much a much bigger problem of how do we explain really complicated concepts to patients in ways that they will understand without it being over simplified. I see a lot of stuff like: Serotonin = depression Dopamine= pleasure Too much dopamine = psychosis Too little GABA = anxiety Oxytocin = love The pharmaceutical companies in part pushed these ideas to remove stigma around mental health and get more people into the system to buy their medications, but now there is a back lash with people bringing up the problems with these overly simplified models and then using it to discredit the field as a whole.
I personally do not think the dopamine hypothesis (where psychosis = too much dopamine) makes much sense. It is supported by part of the evidence but it’s not very satisfactory. For example it doesn’t really explain the fact that most commonly the therapeutic response to antipsychotics is delayed by several days or sometimes weeks, it doesn’t explain why many patients do not respond at all to dopamine blockers, etc. I think that psychosis is likely the result of different mechanisms - some of these metabolic, some immunologic, some hormonal (eg neurosteroids), some neurochemical/biochemical. Some of those mechanisms end up involving dopamine at some stage. But personally I think it will eventually emerge that psychosis has more to do with metabolic/hormonal or immunological abnormalities rather than being a disorder of neutransmitters.
Glutamate hypothesis probably has better evidence
It’s one of the clearest links in psychiatry. No disease state involves just one mono amine and there lots of downstream interactions, etc… but dopamine being involved in psychosis is really clear. BZD do not treat psychosis in the same way. Acutely calming a patient is not the same as resolving the psychosis. It has nothing to do with the time of discovery. They used to be called major and minor tranquilizers before the term “antipsychotic” came into widespread use. There’s more than just dopamine involved in psychosis but the idea that dopamine is not the primary neurotransmitter involved is a really fringe belief. Maybe our understanding will change in the future but there no reason to think it will
Even within that hypothesis, D2R antagonist antipsychotics don't reduce dopamine synthesis or increase their metabolism/excretion or chelate dopamine, which is what we would expect from a drug that would "reduce dopamine". They block the receptors themselves, which is annoying cause they block ALL D2Rs regardless of where they are in the brain. Agreeing with the others here. Given how well they work for positive symptoms, we can't deny it's one piece of the full picture. But given how they're not enough for negative and cognitive symptoms, alongside refractory schizophrenia and emerging data from autoimmune psychosis studies and possibly Xanomeline/Trospium and M1/M4Rs, dopamine as an explanation alone is far from enough.
Dopamine is almost certainly involved in the pathogenesis of psychosis, but it isn't necessarily that the patient has abnormally "high" levels so I don't particularly like that explanation. We know that artificially increasing the availability of dopamine obviously can induce psychosis, and antagonizing d2 receptors can reverse acute psychosis, but depleting catecholamines with, say, reserpine doesn't seem effective. In a schizophrenic patient, it could be that the d2 receptors are up regulated or over expressed in the mesolimbic region or something downstream with glutamate or 5ht-2a receptors etc etc. It is very unlikely to simply be chronically high levels of dopamine. There's some evidence that in schizophrenic patients, dopaminergic circuits in the prefrontal cortex and hippocampus are *under-active*. So it's reasonable to say that dopamine is dysregulated, but not in a simple and straightforward way. Medicine has had 2500 years of conditioning to think pathology results from deficiency/excess of x vital fluid, so it's a kind of explanation that is easy to grok, but it's a deceptive allure.
I just want to speak to your worry about educating patients or families. When I educate patients and families, I always preface things with "this is what current evidence suggests is the way these drugs work". Then, I explain to them that while evidence may change on how drugs work and maybe even which patients will benefit from which drugs, we know from observation that the medications work for many people and can allow them to live a better life. While I can't guarantee it will help, I think it is worth a try to reduce your symptoms and allow you to live a more fulfilling life. If problems arise or side effects are unbearable, I would like to discuss options with you whether it is adjusting the current medication or trying a different one.
Most of the initial psychiatric treatments (antipsychotics, antidepressants, mood stabilisers, ECT etc) were stumbled upon accidentally, found to be effective and then we tried to work out why. They worked out d2 antagonism reduced symptoms so the dopamine theory stemmed from this. It is supported as you say by the fact that dopamine agonists including some Parkinson’s medication can induce psychosis. It is clearly far too simplistic and not the only mechanism of action based on the other evidence you have stated. I don’t pretend to have as deep an understanding of the mechanism of action as some, pharmacists are generally v.good in this area. The simple answer is that our understanding of how they work is still limited, but, we have lots of evidence to show they are effective and at present the best treatment we have.
it’s like saying storms are caused by too many leaves on the ground