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Anyone have success with KYNA inhibitors?

kyna nmda

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#1 experimenting

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Posted 08 December 2018 - 09:30 AM


Is this perhaps the holy grail of cognition? Seeing as KYNA inhibits AMPA and NMDA. Has anyone reduced it with any great effect?
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#2 mono

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Posted 08 December 2018 - 01:56 PM

I would also like to hear about this. It would seem galantamine and memantine have been used with some success in schizophrenia.

 

"Galantamine is an acetylcholinesterase inhibitor and a positive allosteric modulator of the α7nicotinic receptors. Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist. There is evidence to suggest that the combination of galantamine and memantine may be effective in the treatment of cognitive impairments in schizophrenia. There is a growing body of evidence that excess kynurenic acid (KYNA) is associated with cognitive impairments in schizophrenia. The α-7 nicotinic and the NMDA receptors may counteract the effects of kynurenic acid (KYNA) resulting in cognitive enhancement. Galantamine and memantine through its α-7 nicotinic and NMDA receptors respectively may counteract the effects of KYNA thereby improving cognitive impairments."

https://www.ncbi.nlm...les/PMC4824953/


Edited by mono, 08 December 2018 - 01:58 PM.


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#3 experimenting

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Posted 08 December 2018 - 05:33 PM

Anyone tried it?

#4 mono

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Posted 09 December 2018 - 12:22 AM

"Data revealed demonstrate the ability of Cerebrolysin to lower KYNA formation in homogenates. We suggest that the anti-dementia effect of Cerebrolysin observed in Alzheimer patients could be due to Cerebrolysin induced reduction of KYNA levels, thus enhancing the cholinergic and glutamatergic neurotransmissions."

"Interestingly, we found that D-cycloserine blockes significantly KATs activities in rat liver and brain homogenates and in the frontal cortex homogenate of human post mortem tissue, as well. These results allowed us to propose that lowering of KYNA content likely due to D- cycloserine inhibition of KATs activities might be involved in the postulated mechanism for D- cycloserine to act as a partial agonist at the glycine site of the NMDA receptor."

"Interestingly, we found that Jerusalem balsam blocks significantly KATs activities, too. Lowering of KYNA synthesis by Jerusalem balsam represents notable biochemical effect since it might influence KYNA levels."

https://www.omicsonl...rugs-79326.html

 

 

"Brain KYNA levels were dose-dependently increased by tryptophan intake, and these increase were consistent with kynurenine (KYN), the precursor to KYNA, levels in the brain, plasma and liver. Administration of the 1.5% tryptophan added diet reduced the extracellular DA level to 60%, and increased the extracellular KYNA to 320% in the striatum. The DA reduction was atten- uated through inhibiting KYNA synthesis with 2-aminoadipic acid. These results indicate that a high tryptophan diet can induce KYNA production and suppress DA release."

https://onlinelibrar...59.2011.07369.x

 

"Ten out of 19 amino acids (specifically, leucine, isoleucine, phenylalanine, methionine, tyrosine, alanine, cysteine, glutamine, glutamate, and aspartate) significantly reduced KYNA formation at 1 mmol/L. These amino acids showed inhibitory effects in a dose-dependent manner, and partially inhibited KYNA production at physiological concentrations. Leucine, isoleucine, methionine, phenylalanine, and tyrosine, all LAT substrates, also reduced tissue KYN concentrations in a dose-dependent manner, with their inhibitory rates for KYN uptake significantly correlated with KYNA formation. These results suggest that five LAT substrates inhibit KYNA formation via blockade of KYN transport, while the other amino acids act via blockade of the KYNA synthesis reaction in brain. Amino acids can be a good tool to modulate brain function by manipulation of KYNA formation in the brain. This approach may be useful in the treatment and prevention of neurological and psychiatric diseases associated with increased KYNA levels."

https://www.ncbi.nlm...les/PMC4318830/

 

"The non-selective COX-inhibitor diclofenac (50 mg/kg, i.p.) or indomethacin (50 mg/kg, i.p.), a non-selective inhibitor with a preferential selectivity for COX-1, produced an elevation in brain KYNA. In contrast, the COX-2 selective inhibitors parecoxib (25 mg/kg, i.p.) or meloxicam (5 mg/kg, i.p.) decreased brain KYNA."

https://www.ncbi.nlm...pubmed/15517427


Edited by mono, 09 December 2018 - 12:45 AM.

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#5 Nate-2004

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Posted 12 December 2018 - 05:06 AM

1. For galantamine to maybe help schizophrenics they need to stop using the antipsychotic medication as these drugs are anti-cholergenic.

2. It would be better to address the inflammation first. See below:

 

If you can get the patient to exercise very consistently, 4 times per week and use the sauna 20 mins 4 times per week, and eat properly, you wouldn't need any drugs. Though I am sure turmeric, DHA/EPA in phospholipids (krill oil), and other known anti-inflammatory compounds might help in conjunction, not alone.

 

I cannot get my friend to do these things. Minocycline is one of two known drugs that can reduce neuroinflammation and it is an antibiotic, not exactly practical for regular use. Perhaps it could get them feeling better enough temporarily to engage in those protocols/lifestyle interventions.

 

Another problem is that the gen 2 antipsychotics actually make it even harder for the patient to follow those lifestyle interventions.  It entraps them in a worsening feedback loop.

 

I actually read more about it with relation to D-Serine today. Apparently inflammation actually induces more D-serine production. This is odd. I don't know quite how to wrap my head around that. I was expecting to read the exact opposite.

 

Rhonda Patrick actually has a video on this KYNA issue. (5:45 ish but watch the whole thing)

 


Edited by Nate-2004, 12 December 2018 - 05:15 AM.


#6 Mind_Paralysis

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Posted 12 December 2018 - 11:00 AM

There are new third-generation antipsychotics now - Cariprazine and Brexpiprazole - have your friend try them out as well. They have more potent effects on depression than previous AP-drugs, and Brexpiprazole is actually the first AP to ever be officially chosen by the FDA as an actual antidepressant.

This implies that it may well have anti-inflammatory effects.

 

A third-gener might help your friend get into the regimen you suggest.

 

Also, a COX-2-inhibitor as mentioned above, may well help quite a bit - such compounds have been shown to have an effect on depressive symptoms in non-schizophrenics, after all. (notably, bipolar depression)

 

 

EDIT:

Mega-dosing of vitamin B6 may also be something... there are references in the litterature on how people with B6-deficiency show a marked increase of KYNA-levels.

 

Kynurenine pathway metabolites: relevant to vitamin B-6 deficiency and beyond1,2,3

https://www.ncbi.nlm...les/PMC4498264/

 

They also mention how KAT2-inhibitors are the best target for impairing KYNA-production - however, most such drugs do not actually cross the BBB to any greater extent - SO... perhaps a small mixture of a KAT2-inhibitor with a solvent, then administered intra-nasally, could get around this problem, until new drugs are devised?

 

 

Study of the Activity and Possible Mechanism of Action of a Reversible Inhibitor of Recombinant Human KAT-2: A Promising Lead in Neurodegenerative and Cognitive Disorders

https://www.mdpi.com...49/21/7/856/htm


Edited by Mind_Paralysis, 12 December 2018 - 11:22 AM.

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#7 YoungSchizo

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Posted 12 December 2018 - 08:36 PM

If you can get the patient to exercise very consistently, 4 times per week and use the sauna 20 mins 4 times per week, and eat properly, you wouldn't need any drugs. Though I am sure turmeric, DHA/EPA in phospholipids (krill oil), and other known anti-inflammatory compounds might help in conjunction, not alone.

 

 

If this were the case I should have been med-free for years. Exercise (+ sauna) does indeed help for lessening symptoms, though for that day only. The next day you HAVE to work-out to experience the same effects. When I don't in 2 out of 7 days my negatives and depressive symptoms are there and I just can't intensively(!) exercise for 7 days a row. (the more intense the work-out, the lesser the symptoms) . 


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#8 Nate-2004

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Posted 12 December 2018 - 09:12 PM

If this were the case I should have been med-free for years. Exercise (+ sauna) does indeed help for lessening symptoms, though for that day only. The next day you HAVE to work-out to experience the same effects. When I don't in 2 out of 7 days my negatives and depressive symptoms are there and I just can't intensively(!) exercise for 7 days a row. (the more intense the work-out, the lesser the symptoms) . 

 

No, that's not how exercise or sauna works for depression. People think it's supposed to instantly cure your depression. No. Four days a week is the sweet spot, not 7, not 2, not 3, and it doesn't even begin working effectively in a lasting way till you've been going at it for months on end (at least 6) of *consistent*, regular exercise and sauna *IN CONJUNCTION* with other lifestyle interventions such as more plant based foods, more sunlight, regular sleep rhythm and more social activity especially in the face of anxiety, i.e. bravely, willfully and repeatedly not avoiding social situations over long periods.  Ex: Take classes, do improv, etc

 

Also take the course on sleep over at sleepio.com, it's priceless information. Or see my guide on this board I pretty much listed everything there and then some.

 

Lifestyle interventions always take a lot of time and if you've been exercising for years for four days a week then there may need to be more added to your regimen as I listed. Including the supplements I mentioned earlier, see the video. Also consider cold thermogenesis and other techniques, there's a whole thread on that. Also see HighDesertWizard's threads on NF-kB inhibition and heatshock activation, it's not just about aging.

 

I even have a guide to conquering depression. I haven't been depressed in 2 years 11 months, 15 days. I was depressed since the age of thirteen but since some breaking point almost 3 years ago things only seem to get better.

 

Also, I used to get sick and that would disrupt my exercise routine. I figured out that I need to use that hand sanitizing gel at the gym obsessively until I've been going for a year consistently, at that point your immune system may actually be able to handle it the rest of the way. Seems that way for me at least, I haven't had so much as a cold in the 4 years since I tried that.


Edited by Nate-2004, 12 December 2018 - 09:24 PM.


#9 YoungSchizo

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Posted 12 December 2018 - 09:32 PM

No, that's not how exercise or sauna works for depression. People think it's supposed to instantly cure your depression. No. Four days a week is the sweet spot, not 7, not 2, not 3, and it doesn't even begin working till you've been going at it for months on end (at least 6) of *consistent*, regular exercise and sauna *IN CONJUNCTION* with other lifestyle interventions such as more plant based foods, more sunlight, regular sleep rhythm and more social activity especially in the face of anxiety, i.e. bravely, willfully and repeatedly not avoiding social situations over long periods.  Ex: Take classes, do improv, etc

 

Lifestyle interventions always take a lot of time and if you've been exercising for years for four days a week then there may need to be more added to your regimen as I listed. Including the supplements I mentioned earlier, see the video. Also consider cold thermogenesis and other techniques, there's a whole thread on that. Also see HighDesertWizard's threads on NF-kB inhibition and heatshock activation, it's not just about aging.

 

I even have a guide to conquering depression. I haven't been depressed in 2 years 11 months, 15 days. I was depressed since the age of thirteen but since some breaking point almost 3 years ago things only seem to get better.

 

Also, I used to get sick and that would disrupt my exercise routine. I figured out that I need to use that hand sanitizing gel at the gym obsessively until I've been going for a year consistently, at that point your immune system may actually be able to handle it the rest of the way. Seems that way for me at least, I haven't had so much as a cold in the 4 years since I tried that.

 

If you bring it like this, yes I could agree, it indeed may work and I believe someone maybe can overcome depression and maybe can manage to drop medication eventually or drop to the lowest dosage possible.

I still don't agree about the (four days sweet spot) exercise part though, I think the sweet spot for one is not the sweet spot for another, it depends/varies per individual. 


Edited by YoungSchizo, 12 December 2018 - 09:39 PM.

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#10 Nate-2004

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Posted 12 December 2018 - 09:58 PM

If you bring it like this, yes I could agree, it indeed may work and I believe someone maybe can overcome depression and maybe can manage to drop medication eventually or drop to the lowest dosage possible.

I still don't agree about the (four days sweet spot) exercise part though, I think the sweet spot for one is not the sweet spot for another, it depends/varies per individual. 

 

It might vary slightly, but I think for the average it does not vary at all. I think there is something to the 4 day rule.

 

The reason why exercise works to begin with is because of your body's endogenous net response to acute inflammation and oxidation extends beyond the point of what is necessary, providing a benefit well into the next day. Chronic exercise negates this net benefit, to little exercise doesn't extend it well enough to cover all 7 days. 

 

This review states somewhere between 3 and 5 days seems to be ideal, confirming my conclusion: https://www.ncbi.nlm...cles/PMC474733/

 

Here is more on exercise and why it works: https://www.scienced...568163707000384

 

I consider it to be more important than medication, and it *is* my medication. I have to take it. There is no skipping the medication. I also have to go to work. I also have to do a lot of things if I want to have all the benefits. It's just a have to, not optional.


Edited by Nate-2004, 12 December 2018 - 10:01 PM.


#11 YoungSchizo

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Posted 12 December 2018 - 10:26 PM

It might vary slightly, but I think for the average it does not vary at all. I think there is something to the 4 day rule.

 

The reason why exercise works to begin with is because of your body's endogenous net response to acute inflammation and oxidation extends beyond the point of what is necessary, providing a benefit well into the next day. Chronic exercise negates this net benefit, to little exercise doesn't extend it well enough to cover all 7 days. 

 

This review states somewhere between 3 and 5 days seems to be ideal, confirming my conclusion: https://www.ncbi.nlm...cles/PMC474733/

 

Here is more on exercise and why it works: https://www.scienced...568163707000384

 

I consider it to be more important than medication, and it *is* my medication. I have to take it. There is no skipping the medication. I also have to go to work. I also have to do a lot of things if I want to have all the benefits. It's just a have to, not optional.

 

Don't want to be arrogant but I won't read the articles because it doesn't apply for my schizo-affective disorder. Maybe for a healthy person that's in a bad place/period or someone who suffers from (plain) depression.

 

The last time I read a study about exercise and depression, the rule was 20/30 min. intensive (preferably HiiT) exercise (don't remember how many days a week though). For someone with psychotic-spectrum disorders it's a whole different story and there's not much study's done on it because that group is barely capable of exercising because of their psychotic/negative/depressive symptoms, antipsychotic drugs, depression (antidepressants), sleeping pills etc. etc.

 

Though, what counts for you also counts for me, exercise is my medication that treats depression (and partially) negative symptoms better than any chemical I have to down my throat daily. 7 days would be my sweet spot and unfortunately that's physically impossible to manage in the long-term.


Edited by YoungSchizo, 12 December 2018 - 10:30 PM.

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#12 Nate-2004

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Posted 13 December 2018 - 12:24 AM

Neuroinflammation is behind schizophrenic and schizo-affective disorders as well as depression. It all applies. Solid evidence everywhere I look for this. It's *why* minocycline works against schizophrenia and related disorders. So not reading the article is your choice and you can avoid all the evidence, but it's still there.  ¯\_(ツ)_/¯

 

I would argue that inflammation may actually be the root cause of ALL mental health problems but that may be an oversimplified reach. Lot of recent evidence on staving off dementia and alzheimers via exercise though...

 

 

"Dangerous" idea (according to mainstream psychiatry), but maybe talk to your doctor about weaning off all meds, look into a prescription for minocycline and immediately start working on anti-inflammatory interventions.  Antipsychotics are a trap, the depletion of dopamine via D2 antagonism and their anti-cholergenic effects just leaves users trapped between a choice of psychosis or greater lethargy/cognitive impairment and they don't address the root cause. Also, the anticholergenic properties of antipsychotics make things even worse than they already are with the negative symptoms so adding galantamine minus antipsychotics may do wonders.

 

Also, exercise induces HSP70, so does sauna use:

 

https://www.ncbi.nlm...pubmed/10401462

https://www.ncbi.nlm...pubmed/18299791

https://www.scirp.or...x?PaperID=26204

https://www.ncbi.nlm...pubmed/23893339

https://www.ncbi.nlm...les/PMC3988108/


Edited by Nate-2004, 13 December 2018 - 12:38 AM.

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#13 mono

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Posted 13 December 2018 - 12:49 AM

I'm not sure you understand the kind of damage that psychosis can do to a person if you are suggesting that they come off their antipsychotic medication in replacement of exercise...

 


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#14 Nate-2004

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Posted 13 December 2018 - 02:30 AM

I'm not sure you understand the kind of damage that psychosis can do to a person if you are suggesting that they come off their antipsychotic medication in replacement of exercise...

 

I understand it well, I may not have experienced it directly but my roommate has shown me what that entails and I've been trying to help him for a year. 

 

Also your reply makes no sense, did you read what I said? 

 

"Dangerous" idea (according to mainstream psychiatry), but maybe talk to your doctor about weaning off all meds, look into a prescription for minocycline and immediately start working on anti-inflammatory interventions."




 


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#15 mono

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Posted 13 December 2018 - 03:33 AM

Yes I did read what you said. But minocycline does not always work in every individual, I have done some reading in the past about it, and I do believe it would be more well known as a working treatment otherwise. I am not ruling it out, but I am not stopping my medication...

So, I think you are still suggesting to people who are schizophrenic to come off medication per your recommendations of anti-inflammatory interventions, which so far involves exercise, sauna and minocycline. I just personally think that is bad advice, these treatments don't have the efficacy that antipsychotics do, and you are damning APs when they are the only thing proven to improve functionality and reduce symptoms. Doesn't that make sense to you?

I am all for exploring new theories and collating research etc. but I just know the damage it can do suggesting to someone who is unwell to stop medication and that there is an alternative cure to their disease, etc. Perhaps dosages can be reduced slowly one day when symptoms improve, but that is between the doctor and you.


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#16 YoungSchizo

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Posted 13 December 2018 - 09:17 AM

LOL @Nate-2004

 

Just because 2-3 people out of 21 million schizophrenics got "cured" by Minocycline doesn't mean it counts for anyone. I've tried Minocycline together with your suggested "regimen, exercise and interventions" and I'm sorry to say it didn't CURE me.

 

The available antipsychotics are shit and far from a solution to prevent psychossis from still happening, everyone knows that but what you're suggesting doesn't make sense at ALL and it's irresponsible, downright ignorant, offensive and very dangerous to advise people with the worst mental illness outcome to come off medication and try your so called 'ultimate cure'. 

 

And as far as your roommate goes, leave that poor guy alone and be supportive and understanding instead of reading him a lesson if you really care and want to help him.

 

I'm pretty much done with this conversation, my advise for you is to take your BS somewhere else, I would suggest on a Scientology thread.

 

To the others on this thread, can we get back to the OP's KYNA question?


Edited by YoungSchizo, 13 December 2018 - 09:18 AM.

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#17 Mind_Paralysis

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Posted 13 December 2018 - 03:37 PM

Indeed - KAT2-inhibitors - what more do we know of them? Are there new drugs under development?

 

There's of course also EXTREME elimination-diet - eliminate Tryptophan-intake to the absolute bare minimum for survival - this will then, in turn, eventually lead to a dramatic decrease in KYNA-production. I am sadly not knowledgable to tell you what the end-result of a diet extremely low in Tryptophan will be, but I'm guessing it could lead to quite a few issues - obviously, your Melatonin and Serotonin will drop like a stone as well - but both of those can be supplemented with artificial substitutes.

 

Not sure if there's ever been any human testing with a tryptophan-deprived diet, but here's some testing with increased Tryptophan, which certainly shows effects on behaviour:

 

Acute Dietary Tryptophan Manipulation Differentially Alters Social Behavior, Brain Serotonin and Plasma Corticosterone in Three Inbred Mouse Strains

https://www.ncbi.nlm...les/PMC4276517/

 

 

Please also note how Autism and Schizophrenia are inherently almost opposites - Autistic children have been found to have abnormalities in their tryptophan-metabolism, as well as INCREASED activity in the NMDA-network - NMDA-antagonists like NITRO-memantine have also been shown to actually decrease autistic symptoms. And autistic brains have shown increased, aberant growth of synapses - the complete opposite of Schizophrenia.

 

Hypothetically... elimination-diet might then be able to affect Schizo-spectrum disorders to some extent as well, yes?

 

Of course, I don't expect any incredible results, but there should be SOME effect on the symptoms - if the diet is strict enough, almost every system in the body should be altered, Tryptophan is used for a lot of things.

 

 

EDIT:

There appears to be quite a bit of FRESH data on the enzymatic pathway which produces Kynurenic Acid btw - KYAT is the class of enzymes as I understand it, but there appears to be MULTIPLE different variations of the enzyme - perhaps it's only necessary to inhibit but a few of them?

 

https://en.wikipedia...te_transaminase


Edited by Mind_Paralysis, 13 December 2018 - 03:39 PM.


#18 Nate-2004

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Posted 13 December 2018 - 07:38 PM

LOL @Nate-2004

 

Just because 2-3 people out of 21 million schizophrenics got "cured" by Minocycline doesn't mean it counts for anyone. I've tried Minocycline together with your suggested "regimen, exercise and interventions" and I'm sorry to say it didn't CURE me.

 

The available antipsychotics are shit and far from a solution to prevent psychossis from still happening, everyone knows that but what you're suggesting doesn't make sense at ALL and it's irresponsible, downright ignorant, offensive and very dangerous to advise people with the worst mental illness outcome to come off medication and try your so called 'ultimate cure'. 

 

And as far as your roommate goes, leave that poor guy alone and be supportive and understanding instead of reading him a lesson if you really care and want to help him.

 

I'm pretty much done with this conversation, my advise for you is to take your BS somewhere else, I would suggest on a Scientology thread.

 

To the others on this thread, can we get back to the OP's KYNA question?

 

 

 

The studies included 548 schizophrenia patients. The mean duration of the trials was 18.5 weeks, with the longest running 48 weeks. In five trials, minocycline or placebo was added to risperidone monotherapy.

The primary outcome was change in the PANSS (Positive and Negative Syndrome Scale) total psychopathology score, and the positive, negative, and general symptom subscale scores.

 

The biggest benefit was on PANSS negative symptoms. Minocycline brought significantly greater improvement in this domain than placebo, with a standard mean difference (SMD) of –0.69 and a P value of less than .00001 (Eur Psychopharmacol. 2017 Jan;27[1]:8-18).

Sorry, 548 with a p value of less than .00001 is WAY more than 2 to 3 people.

 

You "tried" the intervention? How long? How often did you exercise? What sort of exercise? How often were you taking minocycline during this period? Were you still on APs?

 

I get sick and tired of people being "offended" by the mere suggestion that lifestyle interventions just might help with mental health problems. Especially considering that not only did I conquer 30 years or more of MAJOR depression via a comprehensive set of lifestyle interventions, but EVERYONE I know who suffers from mental illness is TERRIBLY sedentary, has HORRIBLE sleep hygiene (aka bad habits around sleep), smokes a fuckload of weed, and eats like they've never heard of nutrition.  If they do exercise it's very inconsistent and they all said "I tried exercise it didn't work." Frankly I say, no, you didn't actually try it. What else were they doing besides exercise? All these people I know are also coincidentally "offended" by the mere suggestion that they address their condition with considerable, consistent, and persistent lifestyle changes that address all the above habits.

 

Being offended doesn't change anything about the actual facts of reality.

 

KYNA is dramatically affected by inflammation. Inflammaging is a well studied phenomenon that is discussed at length on this message board. It's clear you won't accept evidence or even read the science because you'll reject anything that isn't an easy to swallow pill.

 

And no, not leaving my roommate and friend of 10 years alone. That's the last thing he needs right now. His lifestyle LITERALLY follows the below meme to a T. Also it follows THIS VIDEO  as if he were using it as a real set of life instructions on how to be miserable.

 

I GET IT, it's a feedback loop, you have a condition that makes it hard to break. But once you break it, you can stay out.

 

Don't worry, I'm done here. I am too tired of this repetitive objection to reason.

 

uc7fsb3tl4iz.jpg?width=960&crop=smart&au


Edited by Nate-2004, 13 December 2018 - 07:50 PM.

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#19 Heisok

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Posted 13 December 2018 - 08:57 PM

"minocycline or placebo was added to risperidone monotherapy." Added to ,not in place of the anti-Psychotic, like you are suggesting in other comments. Perhaps instead of suggesting that they ask their Dr. to switch off the anti-psychotic, you could suggest they ask for concurrent use of them

 

My experience seeing individuals who get the idea into their head, either through their own impetus or guidance by others,  that it is ok to stop medicine, is that they end up in a very bad condition.


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