THEORY - PAS and Dopamine Theory - (Negative Symptoms of Schizophrenia) - Plausible/Difficult to Treat/Testable

flynn

Administrator
Staff member
Feb 28, 2018
78
73
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#1
Another theory of PAS relates directly to dopamine. As mentioned in the serotonin theory, PAS almost certainly involves some dysfunction of the dopaminergic system. Dopamine activity in regions of the brain such as the mesolimbic pathway play a crucial role in pleasure, drive and reward seeking behaviour. Changes in dopamine activity in regions such as the prefrontal cortex would also help to explain changes in cognition and brain fog reported by users. The major reason androgens have an affect on behaviour and sex drive is primarily derived from the ability of androgens to alter dopaminergic activity. Thus its possible that Accutane has directly altered the dopaminergic system of the brain, which would explain why changing the levels of hormones such as testosterone has had little effect on the symptoms of PAS, as the androgens are unable to affect dopaminergic activity. I've also seen several reports of people who claim drugs which affect the dopamine system such as adderall and ritalin has far less effect post accutane.

An interesting observation is the similarity of symptoms between PAS and the negative symptoms of schizophrenia. Symptoms include loss of sex drive, apathy, emotional blunting, cognitive deficits, anhedonia, loss of motivation, social avolition etc.

The following paper outlines some of the links between retinoids and schizophrenia - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC33865/

Is it possible that Accutane has activated several Schizophrenia candidate genes in a subset of patients who are genetically susceptible?

One action of retinoic acid and therefore Accutane is its ability to increase the expression of dopamine-2 (D2) receptors. Studies of mice have shown that retinoid receptors appear to play a crucial role in the expression of D2 in the striatum (1). Now interestingly, increased D2 receptor expression in the striatum has been associated with schizophrenia (2). A study of
Transgenic mouse models with over-expression of dopamine receptors in the striatum display show similar symptoms to negative symptoms of schizophrenia associated with cognition and motivation. This study found that increased activity of dopamine firing in striatum led to alterations in firing of midbrain dopamine neurons of the VTA. These alterations were rescued when firing in striatum was reduced artificially. Increased D2R activity in the striatum also reduces level of NMDA receptor subunit expression in the mesolimbic DA VTA but not the nigrostriatal DA SN neurons (3). The striatum is divided into two sections. Studies suggest that the ventral striatum is associated with the negative symptoms of schizophrenia where as the positive symptoms are associated with dorsal striatium activity (4).

Correct me if I'm wrong, but papers seem to suggest that hyperactivity of the ventral striatum could lead to hypoactivity of the prefrontal cortex and perhaps other regions such as the mesolimbic pathway, helping to explain the cognitive symptoms (5). The activity of the ventral striatum has been correlated with symptoms such as emotional withdrawal and blunted effect (6).

Now as you can imagine, I view this scenario as a worst case scenario. The problem is that most schizophrenia drugs have been successful only in targeting the positive symptoms (hallucinations) but not the negative symptoms. Of course, as a condition there is a global demand and interest in developing drugs for the negative symptoms. So if this is the issue, then drugs developed for negative symptoms would likely benefit people with PAS.

Important things to note about this theory:

Now just for the record, I view this theory as one of the worst case scenarios next to brain damage. This would be a nasty turn of events, but there are reasons to doubt that this theory is correct. Firstly, we don't know which genes and aspects of Schizophrenia have been linked to Accutane. Most studies seem to link it to psychosis and are likely referring to the positive symptoms of Schizophrenia (hallucinations etc.), these symptoms certainly don't seem to be present or a common problem in PAS.

Secondly, there is a strong reason to believe that PAS is related to Post Finasteride Syndrome (PFS) due to its effect on 5 alpha reductase (5AR) activity. If you look at the side effects of PFS these also very closely resemble the symptoms of PAS and many of the negative symptoms of Schizophrenia leading people to draw a false conclusion or diagnosis for themselves.

If you look on the PFS forums, many sufferers complain not only of sexual side effects, depression and anxiety but also of loss of interest in hobbies/relationships/friendships, being less fun/caring, less zest for life, emotional flatness, anhedonia, memory and cognitive issues such as slowed problem solving, decreased comprehension, slowed thought processes. As you can see, all of these issues can manifest through 5AR/Finasteride related problems which are completely independent of Schizophrenia.

I also honestly doubt that people with Schizophrenia experience this degree of drug resistant sexual dysfunction.


What can be done?

1. It would be interesting to see if there are any schizophrenia gene candidates which are common amongst people with PAS.

2. A future study could investigate the level of D2 receptor expression in the brains of people with PAS and see if there is a difference in response to dopamine agonists such as apomorphine.

3. Trial drugs which have been shown to help the negative symptoms of schizophrenia to see if they have any effect. The problem is that most drugs for schizophrenia are anti-psychotics and so act as strong D2 antagonists which have their own set of problems, and I doubt would benefit us. If striatium hyperactivity is the problem, then selectively reducing striatium activity may help. I have listed some below:

Drugs:

Easiest/Safest/Cheapest options to try:

High dose glycine - Around 0.8g/kg, at least 30g per day for 8 weeks +, 60g per day has been found to be safe -
http://www.schizophrenia.com/glycine.htm#

High dose D-serine - 60-120mg+ per day for 4-16 weeks. D-serine passes blood brain barrier more effectively than Glycine. Anything higher and poses a risk of Kidney problems- https://www.ncbi.nlm.nih.gov/pubmed/26360284

Sarcosine - 1 to 2g per day - A study showed it improved mood, libido and drive in a schizophrenia patient -
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3921092/ Interestingly, this guy who has PAS also thinks sarcosine helped his anhedonia -

As far as I can understand the reason the above substances help, is due to their effect glutamatergic signalling through the
N-methyl-d-aspartate (NMDA) receptor. Activation of the NMDA receptor seems to alter dopamine activity in a beneficial way.

Other options:

CB1 receptor agonists - Increase meso-prefrontal dopamine activity -
https://www.ncbi.nlm.nih.gov/pubmed/9758152

Memantine - Shown to aid negative symptoms.

Clozapine - atypical antipsychotic which has shown effectiveness in treating negative symptoms.

Histamine H3 agonists - Shown to decreases dopamine release in the ventral striatum by reducing the activity of striatal cholinergic interneurons -
https://www.sciencedirect.com/science/article/pii/S0306452218300435



(1) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC24972/
(2) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866953/
(3) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3141950/
(4) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3576165/
(5) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929859/
(6) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3576165/

- Flynn
 
Last edited:

flynn

Administrator
Staff member
Feb 28, 2018
78
73
18
#3
An interesting and easy experiment to conduct here, would be to ask people with schizophrenia (predominantly negative symptoms) if they have ever have testosterone replacement therapy (TRT)/Steroids and how it affected them. Did it improve sex function (libido/desire etc.)?

This would be significant, as if it was found that it did noticeably improve sex drive. It would give the schizophrenia theory far less credibility. I say this, because TRT/steroids seem to have little/no effect on sexual function in PAS people. Thus it would indicate the cause of sexual dysfunction and other symptoms in PAS may have a different underlying cause than in Schizophrenia.

Does anyone have anybody they could ask this question to? I am going to post some questions on forums dedicated to people with schizophrenia.
 

Dubbya_B

Member
Staff member
Jun 27, 2018
31
20
8
USA
#4
This may be a link between both the the "loss of AR signalling" and "loss of 5-ar I expression" theories of PFS/PAS discussed on this forum and symptoms of negative schizophrenia some of us experience:

T. Aubele and M. F. Kritzer, “Androgen Influence on Prefrontal Dopamine Systems in Adult Male Rats: Localization of Cognate Intracellular Receptors in Medial Prefrontal Projections to the Ventral Tegmental Area and Effects of Gonadectomy and Hormone Replacement on Glutamate-Stimulated Extracellular Dopamine Level,” Cereb Cortex, vol. 22, no. 8, pp. 1799–1812, Aug. 2012.

@flynn - Thought you would be very interested in reading this one.
 
Likes: flynn
Mar 20, 2019
20
9
3
#5
Another theory of PAS relates directly to dopamine. As mentioned in the serotonin theory, PAS almost certainly involves some dysfunction of the dopaminergic system. Dopamine activity in regions of the brain such as the mesolimbic pathway play a crucial role in pleasure, drive and reward seeking behaviour. Changes in dopamine activity in regions such as the prefrontal cortex would also help to explain changes in cognition and brain fog reported by users. The major reason androgens have an affect on behaviour and sex drive is primarily derived from the ability of androgens to alter dopaminergic activity. Thus its possible that Accutane has directly altered the dopaminergic system of the brain, which would explain why changing the levels of hormones such as testosterone has had little effect on the symptoms of PAS, as the androgens are unable to affect dopaminergic activity. I've also seen several reports of people who claim drugs which affect the dopamine system such as adderall and ritalin has far less effect post accutane.

An interesting observation is the similarity of symptoms between PAS and the negative symptoms of schizophrenia. Symptoms include loss of sex drive, apathy, emotional blunting, cognitive deficits, anhedonia, loss of motivation, social avolition etc.

The following paper outlines some of the links between retinoids and schizophrenia - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC33865/

Is it possible that Accutane has activated several Schizophrenia candidate genes in a subset of patients who are genetically susceptible?

One action of retinoic acid and therefore Accutane is its ability to increase the expression of dopamine-2 (D2) receptors. Studies of mice have shown that retinoid receptors appear to play a crucial role in the expression of D2 in the striatum (1). Now interestingly, increased D2 receptor expression in the striatum has been associated with schizophrenia (2). A study of
Transgenic mouse models with over-expression of dopamine receptors in the striatum display show similar symptoms to negative symptoms of schizophrenia associated with cognition and motivation. This study found that increased activity of dopamine firing in striatum led to alterations in firing of midbrain dopamine neurons of the VTA. These alterations were rescued when firing in striatum was reduced artificially. Increased D2R activity in the striatum also reduces level of NMDA receptor subunit expression in the mesolimbic DA VTA but not the nigrostriatal DA SN neurons (3). The striatum is divided into two sections. Studies suggest that the ventral striatum is associated with the negative symptoms of schizophrenia where as the positive symptoms are associated with dorsal striatium activity (4).

Correct me if I'm wrong, but papers seem to suggest that hyperactivity of the ventral striatum could lead to hypoactivity of the prefrontal cortex and perhaps other regions such as the mesolimbic pathway, helping to explain the cognitive symptoms (5). The activity of the ventral striatum has been correlated with symptoms such as emotional withdrawal and blunted effect (6).

Now as you can imagine, I view this scenario as a worst case scenario. The problem is that most schizophrenia drugs have been successful only in targeting the positive symptoms (hallucinations) but not the negative symptoms. Of course, as a condition there is a global demand and interest in developing drugs for the negative symptoms. So if this is the issue, then drugs developed for negative symptoms would likely benefit people with PAS.

Important things to note about this theory:

Now just for the record, I view this theory as one of the worst case scenarios next to brain damage. This would be a nasty turn of events, but there are reasons to doubt that this theory is correct. Firstly, we don't know which genes and aspects of Schizophrenia have been linked to Accutane. Most studies seem to link it to psychosis and are likely referring to the positive symptoms of Schizophrenia (hallucinations etc.), these symptoms certainly don't seem to be present or a common problem in PAS.

Secondly, there is a strong reason to believe that PAS is related to Post Finasteride Syndrome (PFS) due to its effect on 5 alpha reductase (5AR) activity. If you look at the side effects of PFS these also very closely resemble the symptoms of PAS and many of the negative symptoms of Schizophrenia leading people to draw a false conclusion or diagnosis for themselves.

If you look on the PFS forums, many sufferers complain not only of sexual side effects, depression and anxiety but also of loss of interest in hobbies/relationships/friendships, being less fun/caring, less zest for life, emotional flatness, anhedonia, memory and cognitive issues such as slowed problem solving, decreased comprehension, slowed thought processes. As you can see, all of these issues can manifest through 5AR/Finasteride related problems which are completely independent of Schizophrenia.

I also honestly doubt that people with Schizophrenia experience this degree of drug resistant sexual dysfunction.


What can be done?

1. It would be interesting to see if there are any schizophrenia gene candidates which are common amongst people with PAS.

2. A future study could investigate the level of D2 receptor expression in the brains of people with PAS and see if there is a difference in response to dopamine agonists such as apomorphine.

3. Trial drugs which have been shown to help the negative symptoms of schizophrenia to see if they have any effect. The problem is that most drugs for schizophrenia are anti-psychotics and so act as strong D2 antagonists which have their own set of problems, and I doubt would benefit us. If striatium hyperactivity is the problem, then selectively reducing striatium activity may help. I have listed some below:

Drugs:

Easiest/Safest/Cheapest options to try:

High dose glycine - Around 0.8g/kg, at least 30g per day for 8 weeks +, 60g per day has been found to be safe -
http://www.schizophrenia.com/glycine.htm#

High dose D-serine - 60-120mg+ per day for 4-16 weeks. D-serine passes blood brain barrier more effectively than Glycine. Anything higher and poses a risk of Kidney problems- https://www.ncbi.nlm.nih.gov/pubmed/26360284

Sarcosine - 1 to 2g per day - A study showed it improved mood, libido and drive in a schizophrenia patient -
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3921092/ Interestingly, this guy who has PAS also thinks sarcosine helped his anhedonia -

As far as I can understand the reason the above substances help, is due to their effect glutamatergic signalling through the
N-methyl-d-aspartate (NMDA) receptor. Activation of the NMDA receptor seems to alter dopamine activity in a beneficial way.

Other options:

CB1 receptor agonists - Increase meso-prefrontal dopamine activity -
https://www.ncbi.nlm.nih.gov/pubmed/9758152

Memantine - Shown to aid negative symptoms.

Clozapine - atypical antipsychotic which has shown effectiveness in treating negative symptoms.

Histamine H3 agonists - Shown to decreases dopamine release in the ventral striatum by reducing the activity of striatal cholinergic interneurons -
https://www.sciencedirect.com/science/article/pii/S0306452218300435



(1) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC24972/
(2) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866953/
(3) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3141950/
(4) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3576165/
(5) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929859/
(6) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3576165/

- Flynn
I’m going to give daily bone broth a shot. Great post!