Serotonin (5-HT) may drive both schizophrenia and Alzheimer Disease (AD)

haidut

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Unbeknownst to most people, psychiatry has started to make a quiet "paradigm shift" in regards to psychotic conditions such as schizophrenia. Namely, after claiming for decades that psychotic states are caused by excessive dopamine levels/activity, psychiatry has now quietly change the official story to a more "nuanced" approach, after several studies confirmed that the "standard of care" antipsychotic drug haloperidol is a strong 5-HT antagonist in addition to its known effects as a dopamine antagonist. Moreover, other studies also demonstrated that eliminating haloperidol's dopamine blocking effects did not change its effectiveness for schizophrenia. Furthermore, a whole new class of drugs known as atypical antipsychotics have been approved for treating psychotic states such as schizophrenia and most of these drugs have pronounced 5-HT antagonism effects, often with little to no effects on dopamine. All in all, it looks like schzophrenia is primarily a condition of serotonin excess, which is something doctors suspected as early as the 1950s when observing that people with carcinoid syndrome/tumor (thus producing a lot of 5-HT) have mental symptoms shockingly similar to schizophrenia. This is one of the reasons I am posting the study below - i.e. is directly acknowledged that a drug with strong 5-HT inverse agonism (i.e. even stronger than an antagonist) known as sulpiride (working mostly as 5-HT7 inverse agonist) is used to treat schizophrenia. The second reason, and the main finding of the study, is that 5-HT7 receptor (over)activation apparently drives the AD structural abnormalities. Conversely, the administration of sulpiride, managed to block the structural changes seen in brains of animal models of AD, and apparently also reversed the cognitive symptoms of AD in those same animal models. Stage II human trials are set to begin later this year.

https://dx.doi.org/10.1002/alz.13090
Investigating a schizophrenia drug as a new therapy against dementia

"...A common feature of many neurodegenerative diseases are pathological protein deposits in the brain. These protein aggregates cause nerve cells to die and, as a result, entire brain areas to shrink, which manifests in affected individuals as progressive dementia. The so-called tau protein in particular is involved in the development of neurodegenerative diseases such as Alzheimer's and frontotemporal dementia. A research team led by Professor Dr. Evgeni Ponimaskin, a scientist at the MHH Institute of Neurophysiology, has already discovered that signal transmission through a specific serotonin receptor called 5-HT7R plays a crucial role in this process. Now, in collaboration with international scientists, the MHH team has investigated the effect of the antipsychotic amisulpride on the receptor. The drug, which is approved for the treatment of schizophrenia, can block the 5-HT7R and thus prevent the pathological accumulation of the tau protein. The effect of amisulpride has been successfully tested in various cellular models as well as in animal models of dementia. The results have now been published in the journal Alzheimer's & Dementia."

"...Serotonin is a messenger substance that controls a number of vital processes, such as blood clotting, learning processes or the sleep-wake rhythm. Since it also influences our mood, it is known as the "happiness hormone." The messenger substance mediates its effects by activating certain receptors that are bound to the cell membrane. These serotonin receptors occur in different variants and are increasingly found in brain regions that are affected in dementia. For the receptor 5-HT7R, Professor Ponimaskin has already found a high basal activity in previous studies. "This means that the receptor is permanently active, even without serotonin binding to it," explains the neurophysiologist. Through its high activity, 5-HT7R stimulates a chemical change in tau proteins that promotes pathological accumulation in the cell. However, the pathological overactivity can be stopped by using counterparts, so-called inverse agonists, to block the receptor's signal transmission."

"..."The antipsychotic amisulpride was found to be a potent inverse 5-HT7R receptor agonist," notes Dr. Josephine Labus, who conducted this study with Professor Ponimaskin. It is true that dead nerve cells could not be repaired. However, in the early stages of the disease, the drug could stop dementia or even prevent it altogether. The therapeutic effect of amisulpride was also shown, among other things, in nerve cells differentiated from human stem cells with disease-relevant mutations. "Now, in cooperation with the Neurological Clinic of the LMU Munich and the German Center for Neurodegenerative Diseases in Magdeburg, we are preparing a Phase II clinical trial to test the effect of amisulpride in the treatment of patients with dementia," explains Professor Ponimaskin. The study is to start before the end of this year."
 

Mauritio

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Great !

"Now, in cooperation with the Neurological Clinic of the LMU Munich and the German Center for Neurodegenerative Diseases in Magdeburg, we are preparing a Phase II clinical trial to test the effect of amisulpride in the treatment of patients with dementia," explains Professor Ponimaskin. The study is to start before the end of this year."
 

Mauritio

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When you realize serotonin isn't the happy hormone and your whole lifes been a lie
Screenshot_20230526-170223~2.png


Screenshot_20230526-170057~2.png
 

mostlylurking

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The so-called tau protein in particular is involved in the development of neurodegenerative diseases such as Alzheimer's and frontotemporal dementia.
"Thiamine deficiency has many consequences including hypometabolism, mitochondrial depression, oxidative stress, lactic acidosis and cerebral acidosis, amyloid deposition, tau deposition, synaptic dysfunction and abnormal neuro-transmission, astrocyte function, and blood brain barrier integrity, all of which are features of AD."
"...Serotonin is a messenger substance that controls a number of vital processes, such as blood clotting, learning processes or the sleep-wake rhythm. Since it also influences our mood, it is known as the "happiness hormone." The messenger substance mediates its effects by activating certain receptors that are bound to the cell membrane. These serotonin receptors occur in different variants and are increasingly found in brain regions that are affected in dementia.
Thiamine is needed to clear serotonin from the brain.
"Serotonin turnover has been investigated in regional brain areas of rats made thiamine deficient by pyrithiamine (PT). Following intracisternal injection of [14C]5-hydroxytryptamine ([14C]5-HT), a marked increase in the accumulation of [14C]5-hydroxyindoleacetic acid ([14C]5-HIAA) was found in the medulla-pons, hypothalamus and cerebral cortex. [14C]5-HT levels were normal in all of the brain areas except the cerebral cortex which had an increase of 58%. The ratio of [14C]5-HIAA/[14C]5-HT was significantly increased in every brain region of PT-treated rats except the cerebral cortex. Part of this increase in [14C]5-HIAA was shown to be due to impairment of active transport of this 5-HT metabolite out of the brain. However, increased 5-HT synthesis in the cerebellum, hypothalamus, striatum, hippocampus and cerebral cortex was demonstrated by measurement of 5-HT accumulation after inhibition of brain monoamine oxidase. PT-induced increase in endogenous 5-HIAA in the medulla-pons occurred simultaneously with the onset of neurological signs and both parameters were reversible by thiamine administration. These results suggest that acute thiamine deficiency, induced by PT, both increases brain 5-HT synthesis and impairs 5-HIAA efflux from the brain. There is a close correlation between neurological manifestations and changes in brain 5-HT metabolism in acute thiamine deficiency."

also:

Both of my siblings were diagnosed with schizophrenia by the age of 20. I've had my own health journey but thankfully I was spared that diagnosis. My own theory regarding the cause of my siblings' mental incapacitation (and my own long term health issues): The house we lived in as children was built in 1950. It had copper plumbing pipes, connected with lead solder. We all got lead poisoning so some degree. Lead poisoning causes thiamine deficiency. Opinions vary on how this happens; here's one:

"Heavy metal poisoning is typically characterized by symptoms common with thiamine deficiency since metals, such as arsenic or lead, block a crucial metabolic step converting thiamine to its coenzyme form."

Thiamine is a natural occurring substance so it cannot be patented; therefore the medical industrial complex, including the pharmaceutical research component will never pursue thiamine as the cure for many health issues.
 

Normal Human

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Unbeknownst to most people, psychiatry has started to make a quiet "paradigm shift" in regards to psychotic conditions such as schizophrenia. Namely, after claiming for decades that psychotic states are caused by excessive dopamine levels/activity, psychiatry has now quietly change the official story to a more "nuanced" approach, after several studies confirmed that the "standard of care" antipsychotic drug haloperidol is a strong 5-HT antagonist in addition to its known effects as a dopamine antagonist. Moreover, other studies also demonstrated that eliminating haloperidol's dopamine blocking effects did not change its effectiveness for schizophrenia. Furthermore, a whole new class of drugs known as atypical antipsychotics have been approved for treating psychotic states such as schizophrenia and most of these drugs have pronounced 5-HT antagonism effects, often with little to no effects on dopamine. All in all, it looks like schzophrenia is primarily a condition of serotonin excess, which is something doctors suspected as early as the 1950s when observing that people with carcinoid syndrome/tumor (thus producing a lot of 5-HT) have mental symptoms shockingly similar to schizophrenia. This is one of the reasons I am posting the study below - i.e. is directly acknowledged that a drug with strong 5-HT inverse agonism (i.e. even stronger than an antagonist) known as sulpiride (working mostly as 5-HT7 inverse agonist) is used to treat schizophrenia. The second reason, and the main finding of the study, is that 5-HT7 receptor (over)activation apparently drives the AD structural abnormalities. Conversely, the administration of sulpiride, managed to block the structural changes seen in brains of animal models of AD, and apparently also reversed the cognitive symptoms of AD in those same animal models. Stage II human trials are set to begin later this year.

https://dx.doi.org/10.1002/alz.13090
Investigating a schizophrenia drug as a new therapy against dementia

"...A common feature of many neurodegenerative diseases are pathological protein deposits in the brain. These protein aggregates cause nerve cells to die and, as a result, entire brain areas to shrink, which manifests in affected individuals as progressive dementia. The so-called tau protein in particular is involved in the development of neurodegenerative diseases such as Alzheimer's and frontotemporal dementia. A research team led by Professor Dr. Evgeni Ponimaskin, a scientist at the MHH Institute of Neurophysiology, has already discovered that signal transmission through a specific serotonin receptor called 5-HT7R plays a crucial role in this process. Now, in collaboration with international scientists, the MHH team has investigated the effect of the antipsychotic amisulpride on the receptor. The drug, which is approved for the treatment of schizophrenia, can block the 5-HT7R and thus prevent the pathological accumulation of the tau protein. The effect of amisulpride has been successfully tested in various cellular models as well as in animal models of dementia. The results have now been published in the journal Alzheimer's & Dementia."

"...Serotonin is a messenger substance that controls a number of vital processes, such as blood clotting, learning processes or the sleep-wake rhythm. Since it also influences our mood, it is known as the "happiness hormone." The messenger substance mediates its effects by activating certain receptors that are bound to the cell membrane. These serotonin receptors occur in different variants and are increasingly found in brain regions that are affected in dementia. For the receptor 5-HT7R, Professor Ponimaskin has already found a high basal activity in previous studies. "This means that the receptor is permanently active, even without serotonin binding to it," explains the neurophysiologist. Through its high activity, 5-HT7R stimulates a chemical change in tau proteins that promotes pathological accumulation in the cell. However, the pathological overactivity can be stopped by using counterparts, so-called inverse agonists, to block the receptor's signal transmission."

"..."The antipsychotic amisulpride was found to be a potent inverse 5-HT7R receptor agonist," notes Dr. Josephine Labus, who conducted this study with Professor Ponimaskin. It is true that dead nerve cells could not be repaired. However, in the early stages of the disease, the drug could stop dementia or even prevent it altogether. The therapeutic effect of amisulpride was also shown, among other things, in nerve cells differentiated from human stem cells with disease-relevant mutations. "Now, in cooperation with the Neurological Clinic of the LMU Munich and the German Center for Neurodegenerative Diseases in Magdeburg, we are preparing a Phase II clinical trial to test the effect of amisulpride in the treatment of patients with dementia," explains Professor Ponimaskin. The study is to start before the end of this year."
Here's a bit of empirical evidence to back this up. I know two people who suffer with Bipolar I, with concurrent psychosis during episodes. Through intensive trial and error (mostly error) it was eventually found that they respond remarkably well to a very low dose of olanzapine (Zyprexa) - I'm talking doses far below what is generally even considered "effective" by conventional medical standards. The dose they respond to is 2.5MG-5MG once per day when in the "psychotic flare", and then 5MG every 4-5 days when out of the flare in order to keep them out. Standard dosages for olanzapine are to start at 10-15MG once per day, and move up to a maintenence dose of 20MG per day, or, to do IM injections of 150-300MG every 2 weeks, or 405MG every 4 weeks. When these larger doses were tried with these individuals, the side effects were too bad to continue.

Now, stimulated by this study, I looked into the MOA further. Now, according to "Olanzapine" from StatPearls:

"Olanzapine is an atypical (second-generation) antipsychotic that exerts its action primarily on dopamine and serotonin receptors. It works on dopamine D2 receptors in the mesolimbic pathway as an antagonist, blocking dopamine from potential action at the post-synaptic receptor. Olanzapine binds loosely to the receptor and dissociates easily, allowing for normal dopamine neurotransmission.

The effect on the D2 receptors leads to a decrease in positive symptoms in patients, including hallucinations, delusions, and disorganized speech, thought, and behavior. Olanzapine works similarly on serotonin 5HT2A receptors in the frontal cortex as an antagonist.

The effect of olanzapine on serotonin decreases negative symptoms, including anhedonia, flat affect, alogia, avolition, and poor attention."

Note here they mention DA reduction as being responsible for the reduction of the "positive symptoms" and Serotonin antagonism as being responsible for reduction of the "negative symptoms". These two people both suffer much more from the positive symptoms rather than the negative symptoms.

The above (published in 2022) makes it seem like the effects on dopamine and serotonin are equally important for the clinical efficacy. However, in a Cochrane Review published in 2019, they put it the following way: "Olanzapine is a potent serotoniergic antagonist that is particularly potent antagonist at 5‐HT2A, 5‐HT2B, 5‐HT2C receptors, alpha 1‐adrenergic and histamine H1 receptors. It has relatively weaker potency as an antagonist at muscarinic receptors and dopamine D1 receptors (Bymaster 1999)."

It's been said that the Cochrane Review is less biased (at least sometimes), and that quote certainly paints a more accurate picture than the StatPearls quote.

However, here comes the good part. Based on your posted study and my experience with the benefits of a very low dose of olanzapine in these individuals, I decided to investigate whether there was differential binding of dopamine and serotonin receptors based on the size of administered doses.

From the study "5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation", published in 1998:

"Olanzapine induced near saturation of the 5-HT2 receptors, even at 5 mg/day. Its D2 occupancy increased with dose: patients taking 5-20 mg/day showed 43%-80% D2 occupancy, while patients taking 30-40 mg/day showed 83%-88%."


In other words, at much lower dosages, the antagonism of the serotonin receptors is nearly complete, while there is minimal effect upon dopamine receptors. I suspect this is why these small doses had unique effects in these cases and may present a further horizon of investigation for other psychiatric medications.

Olanzapine
Cochrane Library
5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation
 

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