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Reversing post SSRI Anhedonia / PSSD

anhedonia post ssri

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#1 jaiho

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Posted 01 June 2015 - 06:12 AM


Has anyone tried the following theory?

 

SSRIs permanently increase serotonin in those who become numb & anhedonic / PSSD well after the SSRI is discontinued.

The theory is that 5ht1a presynpatic auto receptor is the culprit, which causes downstream effects of lowered dopamine transmission, increase prolactin, cortisol, less testosterone.

 

This thread is to help research those of us who suffer from this.

 

The only drug i can think of that is a presynaptic antagonist of 5HT1A is pindolol.

 

 

Would this upregulate the 5ht1a autoreceptor, and reverse SSRI damage?

 

Cheers

 

 



#2 shaister

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Posted 01 June 2015 - 01:52 PM

Jaiho check your inbox.



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#3 Flex

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Posted 01 June 2015 - 03:06 PM

I believe to read that G proteins are deregulated(uncoupled and/or decrease in number).

If I dont forget it, I will post the reference.

 

Dont waste Your time into at least certain Forums like the PSSD.

If You try to discuss and find a way to alter something hypothetical like g proteins, You get the response that You arent a scientists.

They suggest You to try wildly anything instead, so that YOu might by "acident" alter something like in the case of Vitamin K.

 

Its basically sensless because its rather a circle jerking than an approach to takle it.

And according to them, theres of course no cure !

 

But...

Antidepressant Treatment Reduces Serotonin-1AAutoreceptor Binding in Major Depressive Disorder

Relatedly, we have shown that subjects who have never beenexposed to antidepressants, or not exposed for at least 4 years,have higher 5-HT1A binding

http://www.academia....essive_Disorder

http://www.longecity...es/#entry723814

 

There are of course cases where this time is exeeded like 10 years and still no betterment.

But not to everyone.

 

Guess what ?

This post was also deleted as all of my other ones because I didnt responded polite enough to a harsh post and said the truth.

 

The Ego of the two Mods is just greater than this.

 

Edit:

 

Differential regulation of 5-HT1A receptor-G protein interactions in brain following chronic antidepressant administration.

Treatment of rats with fluoxetine, but not amitriptyline, resulted in an attenuation of 5-HT(1A) receptor-stimulated [(35)S]GTPgammaS binding in the dorsal and median raphe nuclei. The binding of the antagonist radioligand [3H]MPPF to 5-HT(1A) receptor sites was not altered, suggesting that the observed changes in 5-HT(1A) receptor-stimulated [(35)S]GTPgammaS binding were not due to changes in receptor number.

http://www.ncbi.nlm....pubmed/11927181


Edited by Flex, 01 June 2015 - 03:28 PM.


#4 MichaelTheAnhedonic

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Posted 01 June 2015 - 03:29 PM

I suffer from this. Not-SSRI induced, naturally. Really don't know what to do, I can't even think properly... 



#5 jaiho

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Posted 01 June 2015 - 09:48 PM

What's that mean in layman's term, Flex? I was trying to get my head around it with another anhedonic friend last night. We're constantly theorising how to sort out our anhedonia, both induced by ssri.
So changes to auroreceptor from ssri are not due to change in receptor numbers.. Are there any answers?

#6 forexworld12

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Posted 03 June 2015 - 03:11 PM

Weren't you on NSI 189 ? which reversed the ssri induced anhedonia ?  

you also tried notripyine + zoloft which you said worked for reversing ssri induced .. 

 

I suffer from the same stuff And I came up with this 

 

http://www.ncbi.nlm....pubmed/12019662



#7 jaiho

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Posted 03 June 2015 - 08:47 PM

Yes, i try to cycle nsi-189,it eliminates anhedonia about 70 percent. I believe the last 30 is ssri induced at the receptors, so looking at up regulating them. Nortriptyline blocks 5ht2c which is beneficial, then st johns wort for up regulating ht1a,5ht2a

#8 Flex

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Posted 03 June 2015 - 11:31 PM

What's that mean in layman's term, Flex? I was trying to get my head around it with another anhedonic friend last night. We're constantly theorising how to sort out our anhedonia, both induced by ssri.
So changes to auroreceptor from ssri are not due to change in receptor numbers.. Are there any answers?

 

No it could be that the effects of SSRI´s and their effects on pre- and post-synaptic receptors might be due a downstream target of the receptors which increases the needed ammount to exert its effects.

= more serotonine needed for the autoinhibition but more activation of "normal" postsynaptic ones 

 

Activating a receptor is not the end of the story in terms of signal transductions: altering their effects on G protein coupled receptors ( via decoupling or decreasing) "could" lead to such changes.

 

or, by activation/deactivation of a certain subset of them could lead to epigenetic modifications like in the case of Cannabis

(that might not be reversible by just inhibiting this certain pathway but perhaps by an opposite/concurent)

 

The posted study was just a possibility what might be the cause.

 

That what You and I experience is afaik mostly just too much serotonine. This above could be the cause, so it dont not help You for now.

Btw: Afaik, Serotonine decreases Dopamine transmission, so (if I´m not mistaken) its hard to overcome those effects by increasing dopamine signalling,

altough it depends on the severity of the symptoms. I had some good effects, unfortunaetly not lasting ones

 

If Youre planning to use Dopamine agonists --> Keep in mind the possible DAWS !!! theres a chance (afaik20%) that You cant function without it

http://www.longecity...ts/#entry680638

No sacremongering, just saying; warning

 

Anyway: heres more regarding this topic, altough its in contrast to the decreased presynaptic receptor reports:

 

Chronic fluoxetine treatment selectively uncouples raphe 5-HT(1A) receptors as measured by [(35)S]-GTP gamma S autoradiography.

Decreased [(35)S]-GTP gamma S binding was not due to receptor down-regulation, since the density of raphe [(3)H]-8-OH-DPAT binding sites was unaffected by fluoxetine treatment. 6. These results suggest that the desensitization of presynaptic 5-HT(1A) receptor function occurs at the level of receptor-G protein interaction on dorsal raphe neurons, and may underlie the therapeutic efficacy of long-term SSRI treatment.

http://www.ncbi.nlm....les/PMC1573219/

-------------------------

 

I might be wrong solely because I´m an amateur. I´m currently looking anyway how to reverse cannabis induced longterm effects on the Dopamine transmission + the resulting anhedonia

so I cant look more into this PSSD

http://www.longecity...se/#entry729209

 

I´m reading ~4 hours a day and any sucess, i.e. achievements, isnt guaranteed at all. Moreover, I could even make everything worser .. dont know.

As said, I got bashed for this attitude in the mentioned Forum but I see no other options, so I´m taking the risk.


Edited by Flex, 03 June 2015 - 11:38 PM.

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#9 forexworld12

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Posted 04 June 2015 - 07:09 AM

Yes, i try to cycle nsi-189,it eliminates anhedonia about 70 percent. I believe the last 30 is ssri induced at the receptors, so looking at up regulating them. Nortriptyline blocks 5ht2c which is beneficial, then st johns wort for up regulating ht1a,5ht2a

I have tried perika SJW and it was SHIT !!!

 

that's  very absurd - the 30% receptor due to ssri fault. Didn't a cocktail of moclobemide + NSI cure your anhedonia by 100% - moclobemide increases serotonin by inhibiting t's breakdown so in theory it should have made it worse but it didn't !

 

what has your exp been with notrypline ?   It's a TCA with  NRI prominence  !!  I sounds a lot similar to Wellbutrin which didn't help me at all 


Edited by forexworld12, 04 June 2015 - 07:09 AM.


#10 forexworld12

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Posted 04 June 2015 - 07:21 AM

 

What's that mean in layman's term, Flex? I was trying to get my head around it with another anhedonic friend last night. We're constantly theorising how to sort out our anhedonia, both induced by ssri.
So changes to auroreceptor from ssri are not due to change in receptor numbers.. Are there any answers?

 

No it could be that the effects of SSRI´s and their effects on pre- and post-synaptic receptors might be due a downstream target of the receptors which increases the needed ammount to exert its effects.

= more serotonine needed for the autoinhibition but more activation of "normal" postsynaptic ones 

 

Activating a receptor is not the end of the story in terms of signal transductions: altering their effects on G protein coupled receptors ( via decoupling or decreasing) "could" lead to such changes.

 

or, by activation/deactivation of a certain subset of them could lead to epigenetic modifications like in the case of Cannabis

(that might not be reversible by just inhibiting this certain pathway but perhaps by an opposite/concurent)

 

The posted study was just a possibility what might be the cause.

 

That what You and I experience is afaik mostly just too much serotonine. This above could be the cause, so it dont not help You for now.

Btw: Afaik, Serotonine decreases Dopamine transmission, so (if I´m not mistaken) its hard to overcome those effects by increasing dopamine signalling,

altough it depends on the severity of the symptoms. I had some good effects, unfortunaetly not lasting ones

 

If Youre planning to use Dopamine agonists --> Keep in mind the possible DAWS !!! theres a chance (afaik20%) that You cant function without it

http://www.longecity...ts/#entry680638

No sacremongering, just saying; warning

 

Anyway: heres more regarding this topic, altough its in contrast to the decreased presynaptic receptor reports:

 

Chronic fluoxetine treatment selectively uncouples raphe 5-HT(1A) receptors as measured by [(35)S]-GTP gamma S autoradiography.

Decreased [(35)S]-GTP gamma S binding was not due to receptor down-regulation, since the density of raphe [(3)H]-8-OH-DPAT binding sites was unaffected by fluoxetine treatment. 6. These results suggest that the desensitization of presynaptic 5-HT(1A) receptor function occurs at the level of receptor-G protein interaction on dorsal raphe neurons, and may underlie the therapeutic efficacy of long-term SSRI treatment.

http://www.ncbi.nlm....les/PMC1573219/

-------------------------

 

I might be wrong solely because I´m an amateur. I´m currently looking anyway how to reverse cannabis induced longterm effects on the Dopamine transmission + the resulting anhedonia

so I cant look more into this PSSD

http://www.longecity...se/#entry729209

 

I´m reading ~4 hours a day and any sucess, i.e. achievements, isnt guaranteed at all. Moreover, I could even make everything worser .. dont know.

As said, I got bashed for this attitude in the mentioned Forum but I see no other options, so I´m taking the risk.

 

I think a lot better option would be methyphenidate  for anhedonia which primariliy acts as An NDRI  that using dopamine agonist that directly stimulates the dopamine receptor .

 

You were banned from the PSSD forum for being too "broad minded/open minded" and throwing in a lot of theory and hypothesis.  PSSD-FORUM is very orthodox unlike longecity which is quite the opposite 



#11 Flex

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Posted 04 June 2015 - 11:58 PM

@ forexworld12

Thanks



#12 jaiho

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Posted 05 June 2015 - 12:05 AM

Moclobemide + nsi didn't cure me 100 percent. I still had PSSD. So perhaps hypericin extract SJW would be preferable?

Nortriptyline it's still early days, i dropped the ssri due to emotional blunting, as you do. But so far it's nice for energy and dp. Starting my next round of NSI.

Edited by jaiho, 05 June 2015 - 12:06 AM.


#13 jaiho

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Posted 05 June 2015 - 06:51 AM

could SERT be a culprit? this can only be upregulated by alcohol/cocaine.. Perhaps upregulating the reuptake would remove serotonin better, solving the issues of post SSRI...

Downside, become a cokehead / alcoholic.



#14 forexworld12

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Posted 05 June 2015 - 12:46 PM

Moclobemide + nsi didn't cure me 100 percent. I still had PSSD. So perhaps hypericin extract SJW would be preferable?

Nortriptyline it's still early days, i dropped the ssri due to emotional blunting, as you do. But so far it's nice for energy and dp. Starting my next round of NSI.

but the pssd was much less on that combo right ? besides the gential numbness ..

 

I am just coming again from my psy . he prescribed PRISTIQ 50 mg , - SNRI for addional norhenphrine effect, armodafinil 100mg and zyprexa 2.5 mg .. Hoping the combo would resolve the anhedonia . I''ll let you know

 

Currently on mirtazapine 30 mg and armodafinil 50 mg ......mirtazapine is shit alone and  they don't mix well together at all. very bad effect  Aromodafinil is much better alone.



#15 Flex

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Posted 05 June 2015 - 05:49 PM

could SERT be a culprit? this can only be upregulated by alcohol/cocaine.. Perhaps upregulating the reuptake would remove serotonin better, solving the issues of post SSRI...

Downside, become a cokehead / alcoholic.

 

No, evodiamine (Evodia rutaecarpa) and berberine (coptidis rhizoma) do it as well.

Berberine and evodiamine influence serotonin transporter (5-HTT) expression via the 5-HTT-linked polymorphic region

http://www.nature.co...tpj201124a.html

 

Dont give up searching ;)

 

I´ve tried allready Evodia rutaecarpa but the effects are transient and not that profound ( at least to me)

 

Zinc, via its negative allosteric actions, had better effects to me:

Allosteric modulation of 5-HT(1A) receptors by zinc: Binding studies.

http://www.ncbi.nlm....pubmed/18951909

 

dont exceed 30 mg. Side effects are vasoconstriction(for me at 30mg) and some fluctuations(up & downs) in anxiety and libido.

 

Vitamine K had some good and enduring effects to me, altough not strong. Be careful with the dose of Vitamine K !! it could lead to stroke & etc. more infos are here:

http://www.longecity...on/#entry729861

 

There are several PSSD threads here, just click on the tag PSSD and Youl find some suggestions ( but not all) like albizzia jurublissin which is a 5-ht1a agonist:

 

http://www.longecity...itive-function/

http://www.longecity...gs/forums/pssd/

http://www.longecity...on/#entry729861

 


Edited by Flex, 05 June 2015 - 05:59 PM.


#16 jaiho

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Posted 06 June 2015 - 05:32 AM

Cheers for the info. Would berb be effective?

Seems we need a potent 5ht1a antagonist to upregulate. Not enough research is done in this area so its frustrating.

 

I've gone downhil since trying SSRI + TCA, it was suggested to me by some neg schizo people who also have anhedonia.

 

Back to Moclobemide + NSI for me, and might try SJW / Berb



#17 jaiho

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Posted 06 June 2015 - 06:10 AM

 

Moclobemide + nsi didn't cure me 100 percent. I still had PSSD. So perhaps hypericin extract SJW would be preferable?

Nortriptyline it's still early days, i dropped the ssri due to emotional blunting, as you do. But so far it's nice for energy and dp. Starting my next round of NSI.

but the pssd was much less on that combo right ? besides the gential numbness ..

 

I am just coming again from my psy . he prescribed PRISTIQ 50 mg , - SNRI for addional norhenphrine effect, armodafinil 100mg and zyprexa 2.5 mg .. Hoping the combo would resolve the anhedonia . I''ll let you know

 

Currently on mirtazapine 30 mg and armodafinil 50 mg ......mirtazapine is shit alone and  they don't mix well together at all. very bad effect  Aromodafinil is much better alone.

 

 

Hmm, the only thing that helped physical pleasure was when i was on 5ht2c antagonists..

Agomelatine, Fluoxetine.

Nortriptyline hasnt kicked in yet, it's an inverse agonist so it's downregulating it i suppose, i've taken a turn for the worse since trying other combos, i should stick to what works.

 

Also i found this:

https://teamtlr.com/...userone-oa.html

 

"First-in-Class 5HT1A Positive Allosteric Modulator/Co-Agonist, Neurogenic & Acetylcholine Releaser

Research Indications for antidepressant, anxiolytic, pro-social, memory and cognition, neurogenic, and neuroprotectant research"



#18 Flex

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Posted 06 June 2015 - 04:02 PM

5-ht1a agonists havent done anything posititve for me, in fact it was a bit worser.

The sexuall side effects are afaik mostly related to post 5ht-1a overactivation but also on 5-ht2a to some extend.

 

as said zinc is for me superior than albizzia or other agonists, if Youre out for the PSSD.

In regards of anxiety, they "could" be helpful by decreasing the other serotonine receptors like 5-ht4 and 5-ht2c.

Perhaps a mixture of zinc and albizzia could help because zinc goes afaik only on the post side

but this is just my ameteurish opinion so its experimental and therefore are side-effects unknown

+ its nothing perresitent...

 

Btw: memantine has been shown to be good against negative symptoms

 

Tackling Negative Symptoms of Schizophrenia with Memantine

http://www.hindawi.c...014/384783/abs/

 

but afaik, ampa increases serotonine transmission.


Edited by Flex, 06 June 2015 - 04:59 PM.


#19 forexworld12

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Posted 07 June 2015 - 08:09 AM

 

 

Moclobemide + nsi didn't cure me 100 percent. I still had PSSD. So perhaps hypericin extract SJW would be preferable?

Nortriptyline it's still early days, i dropped the ssri due to emotional blunting, as you do. But so far it's nice for energy and dp. Starting my next round of NSI.

but the pssd was much less on that combo right ? besides the gential numbness ..

 

I am just coming again from my psy . he prescribed PRISTIQ 50 mg , - SNRI for addional norhenphrine effect, armodafinil 100mg and zyprexa 2.5 mg .. Hoping the combo would resolve the anhedonia . I''ll let you know

 

Currently on mirtazapine 30 mg and armodafinil 50 mg ......mirtazapine is shit alone and  they don't mix well together at all. very bad effect  Aromodafinil is much better alone.

 

 

Hmm, the only thing that helped physical pleasure was when i was on 5ht2c antagonists..

Agomelatine, Fluoxetine.

Nortriptyline hasnt kicked in yet, it's an inverse agonist so it's downregulating it i suppose, i've taken a turn for the worse since trying other combos, i should stick to what works.

 

Also i found this:

https://teamtlr.com/...userone-oa.html

 

"First-in-Class 5HT1A Positive Allosteric Modulator/Co-Agonist, Neurogenic & Acetylcholine Releaser

Research Indications for antidepressant, anxiolytic, pro-social, memory and cognition, neurogenic, and neuroprotectant research"

 

.Currently trying 30 mg pristiq - an SNRI with over 60 times less potency  on SERT and addional norphinphrine effect - much safer than any SSRI and  might be beneficial for anhedonia 

I think the pssd - ssri induced low libido cannot be treated before treating the "anhedonia" 

 I believe both are interconnected . first goes the anhedonia then goes the PSSD.  contrary to the neurotransmitter receptor doctrine has anyone ever got their full hormone checked ?  I have read a lot of people suffer from hormonal imbalance with pssd .. those with normal hormonal balance were mostly women.... weird.. ! one guy on the pssd forum reported a cure for 3 months following T3 intervention then he said it wasn't effective . 2 had significant increase in libido following testosterone increase 

SSRI supposedly disrupts the hormonal cycle lowering testosterone/ increasing estrogen and other thyroid problem.. my testosterone is 4.5 pg/ml .. the normal range in my report is 5.50 - 30 pg/ml ... my estrogen is above normal and guess what my prolactin is also high.... so much for a 21 year old ..



#20 forexworld12

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Posted 07 June 2015 - 08:29 AM

5-ht1a agonists havent done anything posititve for me, in fact it was a bit worser.

The sexuall side effects are afaik mostly related to post 5ht-1a overactivation but also on 5-ht2a to some extend.

 

as said zinc is for me superior than albizzia or other agonists, if Youre out for the PSSD.

In regards of anxiety, they "could" be helpful by decreasing the other serotonine receptors like 5-ht4 and 5-ht2c.

Perhaps a mixture of zinc and albizzia could help because zinc goes afaik only on the post side

but this is just my ameteurish opinion so its experimental and therefore are side-effects unknown

+ its nothing perresitent...

 

Btw: memantine has been shown to be good against negative symptoms

 

Tackling Negative Symptoms of Schizophrenia with Memantine

http://www.hindawi.c...014/384783/abs/

 

but afaik, ampa increases serotonine transmission.

 

5HT1A  is an autoreceptor so this particular receptor while most effected by ssri needs sensitization  for the drug to attach. A good guess is 5HT1A receptor desensitization is causing all problem - anhedonia and sexual problems ... if the desensitization is low/moderate - just PSSD , if it's severe - PSSD + Anhedonia

 

Since it's the pre-synaptic side that is desensitized a 5ht1a agonist would not attach here and would only attach to the post synaptic side - Post snyaptic 1A agonizing is going to make all problem worse which I suspect what happened with you ..  other good theories are That other serotonin receptors are desensitized 

 

How do we sensitize these receptors ? there's only assertion's and theories .. only One scientific  study shows that Cannibis sensitize/increase density of 1A receptors.. other than that   I think a complete lifestyle change could do it . 



#21 jaiho

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Posted 07 June 2015 - 09:35 AM

ECT upregulates 5HT1A if it comes to that..

so does SJW.

 

 


Edited by jaiho, 07 June 2015 - 09:35 AM.


#22 forexworld12

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Posted 08 June 2015 - 08:32 AM

ECT upregulates 5HT1A if it comes to that..

so does SJW.

There is a difference between upregulation and sensitization . both are not the same !

SJW - upregulates post synaptic 5HT1A in the PFC not in the raphe nuclei - our main area of target

I have tried perika SJW rich in hyperforin - I felt very irritable and more numb .. don't know about hyepricin 

 

 

 

2nd day on pristiq 50 mg..heavy onset of side effects like sweating,nausea,constipation, Impulsive movements,goosebumps on head, sleepiness,dissiness and fatigue.  also the additional norphenphrine is making me irritable ... No improvement in apathy ..Damn escitaporam was way better in the sense it didn't make me irritable and restless like pristiq 

 

I'll try for a a week lets see... 

 

I am thinknig about trying low dosage prozac. what do you think would be the best combination with it ?



#23 jaiho

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Posted 08 June 2015 - 11:24 AM

Nortriptyline with prozac was amazing until i fucked it up trying lsd.. Then i got serotonin syndrome and hugely spaced out. Emotions block was at maximum too. Just trying nortriptyline on its own for now. Prozac is the best ssri I've tried

#24 forexworld12

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Posted 08 June 2015 - 01:54 PM

Nortriptyline with prozac was amazing until i fucked it up trying lsd.. Then i got serotonin syndrome and hugely spaced out. Emotions block was at maximum too. Just trying nortriptyline on its own for now. Prozac is the best ssri I've tried

notriptyline + prozac sounds like a very risky combo . serotonin syndrome etc  my Pdoc would never agree .. 

 

will lower pristiq 50mg to 25 mg tomorrow .. causing mild depersonlization .... 

 

Its funny how you mention prozac . both paxil and prozac causes Persistent apathy. could apathy caused by paxil go away on prozac ? I have heard of many reports saying that prozac actually increased their libido . so might be going to prozac + something might reverse the apathy + libido

 


Edited by forexworld12, 08 June 2015 - 02:01 PM.


#25 jaiho

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Posted 09 June 2015 - 12:26 AM

It's not risky, it's very effective. You just use lower dose of nort with prozac. I only screwed it up combining with lsd, i was feeling great before that. I get meds from GPs then combine them myself on advice from an online pdoc who knows his shit

#26 forexworld12

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Posted 09 June 2015 - 01:24 PM

It's not risky, it's very effective. You just use lower dose of nort with prozac. I only screwed it up combining with lsd, i was feeling great before that. I get meds from GPs then combine them myself on advice from an online pdoc who knows his shit

I mean did you try the combo before or after ssri induced apathy ? it sounds like you were on that combo before you had ssri induced apathy ..

 

I have been reading all over the internet prozac causes apathy in itself Just like what paxil did to me.. 



#27 a355584

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Posted 07 February 2016 - 04:48 PM

Looking for a cure: are why focusing on the right way?

Everyone knows the main theory about the pathogenesis of PSSD: the excessive release of serotonin (which has a mixed but essentially inhibitory role on sexual functions) by the serotonergic neurons (concentrated in the raphe nuclei of the midbrain) caused the "desensitization" of 5-HT1A autoreceptors (that act as sentinels that regulate the release of a substance according on how much there is already in circulation, this mechanism is also called negative feedback)[1].
The "down regulation" of the 5-HT1A autoreceptors is instead caused by chronic and excessive activation by its natural "agonist" (serotonin) that is made available in abnormal quantities by the use of SSRIs. It is therefore natural to think to the autoreceptors as something that is "damaged" by excessive competition and that can be cured using an antagonist that lead him to be again "sensitive."

At this point that we have to do a reflection: the autoreceptor is a sentinel, a switch that if "on" sends a chemical signal. What the cell (neuron) have to do when it receives this chemical signal is written in the genes, that is in the sequence of the DNA; how much it should do (that is, how much to increase or decrease the release of serotonin) it depends on the genes expression.
Essentially two mechanism regulate gene expression:

• Binding of chemical groups directly to DNA (covalently) that function as silencers or activators. The main inhibitor is the methyl group that, binding at particular points of the promoter sequences, silences gene expression. The protein that bind methyl groups to DNA is the DNMT.

• The other is the tangling of the DNA around proteins (called histones): if the DNA is wrapped on itself, the molecular machines that should read the instruction contained in the DNA, cannot bind the DNA because there isn’t sufficient space. The ability of a histone to compact a DNA molecules (and thus repress gene expression) depends on the presence of particular molecules bound to the histone. The main one is the acetate group: if it binds to histone, forces him to expand and so molecular machines can come in and gene expression is activated.

The acetyl groups are linked to histone by HAT and detached from it by HDAC. Also histones can be methylated in some particular positions, and this has mixed effects on gene expression.

SSRIs activate gene silencing

It’s well known that SSRIs activate the gene-silencing mechanisms. During the assumption has been seen[2][3][4][5][6][7][8][9][10]:

• Increase in the expression of certain proteins that carry methyl groups (called MeCP2 and MBD1)

• Increase the mRNA synthesis of HDAC2 gene (the HDAC of a particular subtype of histone)

• There’s a decreased acetylation in the histone "H3" in three areas of serotonin projection: the caudate-putamen (striatum), the frontal cortex and the dentate gyrus (5-HT neurons are extensively arborized, and their axons reach all brain areas).

All this suggests the induction of gene silencing.
Now we can rethink to the neuron such a stubborn person who does something of wrong: we told him to correct his behavior (the autoreceptor send his message to the cell) but he will not change his behavior (excessive release of serotonin) because he is a person who does not listen what we told to him (reduced gene expression).

So we cannot think to reactivate the negative feedback mechanism only binding them an antagonist because who is stuck in a situation of "off" is not the autoreceptor, but the DNA is to be.

The right strategy therefore have to be the reactivation of gene plasticity which can then be guided in the right direction by the use of an antagonist of the 5-HT1A autoreceptors.

A possible partial theoretical confirmation of this hypothesis is the results of a study in which rats whit an animal model of tardive dyskinesia (a disorder in some ways similar to the PSSD) had a partial remission of the disease using a HDAC inhibitor[11].

How to induce gene expression plasticity

Firstly, we recall the main objectives:

• To promote the demethylation of DNA by inhibiting DNMT: the new synthesized DNA is less methylated and then whit an increased gene expression.

• Inhibit the deacetylation of histones, in particular inhibiting HDAC

• Encourage the acetylation of histones, in particular by increasing the activity of HAT

It has also been seen that the increase of histone acetylation is accompanied by a demethylation of DNA, that is, the two events have a synergistic effect[12]. It 'important to note first of all that these effects are time and dose dependent, ie the effects are proportional to the dose taken and manifests itself after some time.

Several compounds can do this. Most of them are natural occuring compounds and found in green tea but this does not mean that they are little effective: some are very promising for the treatment of other diseases in which the gene expression change is crucial. Other are drugs are already used for other purposes[13][14][15][16][17][18][19][20][21][22].
Unlucky, often they have a low biodisponibility and a short half-life, than high and multiple doses should be necessary.
Most promising are listed for first.

EPIGALLOCATECHINE GALLATE (EPCG)

One of most studied, well caracterized and most effective natural compound that influence gene expression. Is one of major component of green tea extract. It can easily cross blood-brain barrier and is demonstrated that directly bind DNA19[23][24][25]. It is DNMT1, DNMT3, HDAC1 inhibitor and a MeCP2 inhibitor using Mg2+ as cofactor. Increase amount of glutathione and indirectly the acetilation of histone H3 and H4. Unlucky it is also a weak inhibitor of HAT, has a very low biodisponibility and may be hepatotoxic. Has been demonstrated that minimum effective dose in order to induce genetic effect is 800 mg 2 times a day. The ingestion of high grade, dried green extract, which contains a lot of different catechine, gallate and flavonoid, is more effective then the ingestion of pure EPGC: all the “gallate” and “chatechin” compounds are generally HDAC and DNMT inhibitor and they have a synergistic effect. They’re generally recognized as safe.

QUERCITINE

A flavonoid, is a strong enhancer of H3 and H4 histone acetylation, thus activates SIRT1 and SIRT6 mediated deacetylation; Inhibit DNMT and LSD1 (histone demethylating protein). It is also a weak MAOI. Was found to be active at a concentration of 75-100 um.

GENISTEINA (and less DAIDZEINE and BIOCIANINE A)

They are phytoestrogens and belongs to the category of isoflavones. They are strong inhibitor of HDAC (mostly HDAC1) and DNMT (mostly DNMT1 and DNMT3); less strong inhibitor of MeCP2. Was proved to demethylate ipermethylated genomes without lead to ipomethylation. It has a strong and synergic effect whit other DNMT and HDAC inhibitor.
It is an estrogen receptor agonist and then may produce non-hormonal effects.

SODIUM BUTIRRATE

It is a strong and natural occurring HDAC inhibitor and one of most studied. It has a lot of other positive effects and has been demonstred to be neuroprotective.

VALPROATE and SULPIRIDE

Valproate is an anticonvulsive and a mood stabilizer drug that act as a strong HDAC inhibitor and this may account of its anticonvulsive and mood stabilizing effects. Sulpiride is a very effective antidepressant (I want to recommend to everyone because is a fantastic drug whit a rapid onset and persisting effect specially on ruminative though, anxiety and bad feeling). It was found that a combination of the two drugs in clinically relevant doses activate brain demethylation. This effect was studied on GABA neurons but may occur also in other type of neurons[26][27][28].

CURCUMINE

Strong inhibitor of HDAC, HAT, DNMT, MeCP2. Has been shown to be able to induce demetilation of hypermethylated zone of DNA, in a stronger way than genisteine. Because its potent HAT inhibitor activity it may be a second line treatment or can be used to prevent ssri’s induced modification of genetic expression.

LUTEOLINE

Luteolin is a flavone, a type of flavonoid. Increase histone acetylation, particularly H3 e H4, inhibiting their HDAC and activating SIRT6-mediated deacetylation; Inhibit DNMT and LSD1 (histone demetylating protein). Thus, weak diminish phosporylation on H3 and H4 and is a weak indirect antagonist of DNMT.

APIGENINE

A flavone, is a HDAT inhibitor (soprattuto H1 and H3) and weak activator of SIRT6 mediated deacetylation. Apigenin may also stimulate adult neurogenesis. Concentration over 5-10 um are not recommended because gaba agonism and other central effects. It is a weak MAOI.

DIALLIL SULFIDE, ANACARDIC ACID and GARLIC

A lot of compounds in garlic and broccoli are HDAC and DNMT inhibitor, then high grade dried garlic extract and to eat broccoli may be strongly recommended.

SAM, vitamins B and ZINC

S-Adenosil-Methionine is the natural transporter of methyl groups and work in a synergic way whit DNMT, than induce methylation. Its natural counterpart is S-Adenosil-Omocisteine, a strong demethylating agent which expression increase during the use of HDAC inhibitor: this mean that there’s a synergistic effect between increase of acetylation and the activation of demethylation. For this reason, the supplement of SAMe is not recommended.

The vitamins of group B are used to carrier and bind methyl group, then supplementation of high amount of B vitamins is not recommended if the increase of demethylation is wanted.

The Zn2+ ion is he natural cofactor of HDAC, then the uses of Zn2+ supplements may increase their activities.

I hope that a combination of the induction of gene’s plasticity and the antagonism to serotonin receptors may help to recover from the disease.  


[1] Mechanisms of control of 5-HT neurons are:

  • self-inhibition through 5-HT1A autoreceptors (activation of these receptors by 5-HT diminish neuronal firing and produce a negative feedback regulation of transmitter release)
  • 5-HT1B/1D receptors, located on nerve terminals, respond to 5-HT released locally in the terminal fields inhibiting further transmitter release.

 These 2 mechanisms ensure tight feedback control of the activity of serotonergic neurons and of terminal 5-HT release.
Thus, a prolonged treatment whit ssri may lead to a reduction of binding site for serotonin on SERT, then its ability to reuptake serotonin is chronically diminished.
Chronic administration of selective serotonin reuptake inhibitors (
but not amitriptyline) results in the desensitization of 5-HT1A somatodendritic autoreceptor function in the dorsal raphe but not in hippocampus, and also results in the desensitization of physiological responses mediated by postsynaptic 5-HT1A receptors.
In general, changes in 5-HT
1A receptor number have not been observed following chronic administration of antidepressants.
A study (Julie G Hensler, 2002) ipotizes that the desensitization of somatodendritic 5-HT1A autoreceptors in the dorsal and median raphe following chronic SSRI treatment do not appear to be mediated by changes in 5-HT1A receptor binding but may be due to a reduced capacity of the 5-HT1A receptor to activate G protein. By contrast, no significant change in postsynaptic 5-HT1A binding following chronic antidepressant treatment.
 

[2] Newton SS, Duman RS (August 2006). “Chromatin remodeling: a novel mechanism of psychotropic drug action”. Mol. Pharmacol. 70 (2)
 

[4] The genetics of selective serotonin reuptake inhibitors, Kroeze
 

[5] Epigenetic side-effects of common pharmaceuticals: A potential new field in medicine and pharmacology, Csoka
 

[6] Faure C, Mnie-Filali O, Haddjeri N (February 2006). Long-term adaptive changes induced by serotonergic antidepressant drugs”. Expert Rev Neurother
 

[7] Palotás M, Palotás A, Puskás LG, et al. (December 2004). “Gene expression profile analysis of the rat cortex following treatment with imipramine and citalopram”. Int. J. Neuropsychopharmacol
 

[8] Kálmán J, Palotás A, Juhász A, et al. (November 2005). “Impact of venlafaxine on gene expression profile in lymphocytes of the elderly with major depression–evolution of antidepressants and the role of the “neuro-immune” system”.
 

[9] Yamada M, Yamada M, Higuchi T (July 2005). “Antidepressant-elicited changes in gene expression: remodeling of neuronal circuits as a new hypothesis for drug efficacy”. Prog. Neuropsychopharmacol. Biol. Psychiatry
 

[10] Boehm C, Newrzella D, Herberger S, Schramm N, Eisenhardt G, Schenk V, Sonntag-Buck V, Sorgenfrei O (2006). “Effects of antidepressant treatment on gene expression profile in mouse brain: cell type-specific transcription profiling using laser microdissection and microarray analysis”.

[11] RGFP109, a histone deacetylase inhibitor attenuates L-DOPA-induced dyskinesia in the MPTP-lesioned marmoset: a proof-of-concept study, Johnston TH
[12] Histone deacetylase inhibitors reverse CpG methylation by regulating DNMT1 through ERK signaling, Sarkar S
[13] Green tea polyphenols for prostate cancer chemoprevention: A translational perspective J.J. Johnson

[14] Flavonoids Influence Epigenetic-Modifying Enzyme Activity: Structure-Function Relationships and the Therapeutic Potential for Cancer Gilbert, E.R.; Liu, D.

[15] Epigenetic activities of flavonoids in the prevention and treatment of cancer, Christian Busch
[17] Epigenome, Cancer Prevention and Flavonoids and Curcumin, Višnja Stepanić

[18] Dietary Polyphenols May Affect DNA Methylation, Mingzhu Fang

[19] Bioactive Nutraceuticals and Dietary Supplements in Neurological and Brain disease, Ronald Ross Watson,Victor R. Preedy

[20] Mechanisms for the Inhibition of DNA Methyltransferases by Tea Catechins and Bioflavonoids, Won Jun Lee

[21] The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells, Zhu WG
[22] Epigenetic changes induced by curcumin and other natural compounds, Simone Reuter
[23] Green Tea Polyphenols in drug discovery - a success or failure?, Thomas J. Smith
[24] Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E, Chow HH
[25] Molecular targets of (-)-epigallocatechin-3-gallate (EGCG): specificity and interaction with membrane lipid rafts, Patra SK
[26] Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation, Dong E
[27] Selective DNA Methylation of BDNF Promoter in Bipolar Disorder: Differences Among Patients with BDI and BDII, D'Addario C.

 

[28] Valproate induces DNA demethylation in nuclear extracts from adult mouse brain, Erbo Don

 


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#28 magniloquentc0unt

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Posted 03 April 2018 - 12:15 PM

interesting post, ill save it for when im out of ideas for my psychopharm russian roulette






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