217 replies to this topic

[medievil]

Thats all from my bed show, i'm sure in 20 years well have better options to extend lifespan itself, so dont care for that atm.

Right now i want to focus on my survival

[dilenja]

Rol82, I've noticed reading your regimen you're fond as well of luteolin as a means of PDE4 inhibition. Are there any luteolin supplements in particular which have gained your trust that you'd feel comfortable recommending? I've been looking for a pure luteolin extract for sometime now but have been unable to locate the compound unfortunately outside of olive leaf extract. Is there a particular dosage do you know which would be considered generally effective for achieving PDE4 inhibition?

Fascinating thread I'd like to add as well. I've personally taken a lot from reading your well-considered, intelligent and intriguing perspectives and contributions. I realize it must take a lot of time to maintain this thread and am appreciative of your continued efforts to preserve your experiences and advice here on imminst. Thanks so much, Dilenja

The inhibition of phosphodiesterase 4 is great target for increasing CREB, and when combined with the widely studied properties of the flavonoid, there should be statically significant effect on long term induction. My current dosage is 800 mg/day, which has been working great, but I haven't arrived at the optimal dose as of yet. When it comes to luteolin, and resveratrol, I'm less well versed, so perhaps you should shoot a message to someone like Maxwatt.

And I appreciate your sentiments, as I try to do my best in spite of my limited academic exposure to the sciences. Moreover, although others are loath to speak candidly about their experiences, I endeavor to be open as possible about the taboo illnesses that are criminally undertreated. This forum has been a valuable tool for my research efforts over the last two years, and I imagine others feel the same way. But I've witnessed far too many participants visit with the dim hope of relief, and leave disillusioned, which is a common outcome that has left me immensely dismayed, and is a pattern that I hope I can make somewhat of a humble contribution in altering. So I'm more than happy to sacrifice potentially pleasurable portions of my personal life for the sake of altruism---which is still a higher form of pleasure that can be rationalized by utilitarianism. And I suppose is healthier than sadistically manipulating and disheartening vulnerable women on Match.com---where you'll never find a more depressing population of easily seducible romantic idealists. But fortunately, I think I've permanently suppressed this more wicked side---which I sincerely hope others won't succumb to due to self-loathing or shallowness.

Anyway, based on your posting in the thread of the exceedingly embittered StrangeAeons----whom I suspect is perilously, and perhaps irretrievably close to suicide----I was somewhat shocked by your endorsement of the orthomolecular approach to psychiatry, which might be understandable under the conditions of desperation, but should be deemed ultimately futile. And given this dalliance, I'm curious about your current status? Have the amphetamine salts ceased to work? Are you facing an intransigent psychiatrist? Has something else gone awry?

Rol82, I can appreciate his and your hesitancy in accepting the rationality of this approach. Although I don't personally advocate the orthomolecular approach as a cure-all – in this particular instance, given the dire and understandably frustrated outlook of StrangeAeons, and his lack of progress in spite of a myriad of consultations with various health professionals, I believe orthomolecular and specifically high dosages of Inositol Hexanicotinate may indeed constitute a readily available, and affordable adjunct which should not interfere with his current course of treatment, and which could quite possibly provide further insights into his condition along with the remote possibility of relief. Although science has not yet validated many of its claims, the support base orthomolecular has garnered in the past 40+ year's spans such a breadth of patients and practitioners that I don't feel its efficacy can yet be outright refuted leaving it as merely an improbable but not impossible solution.

I recognize that I of all people possessing a limited background certainly don't hold the answers to resolving his strange affliction where so many other accredited medical professionals and knowledgeable individuals have tried to do so without avail. But given that many of the more traditional techniques have been ruled out due to inefficacy or inaccessibility, I feel as though there is a place for more exhaustive techniques which could be employed as I'm also noticing an increased sense of urgency evident in each succeeding post. I am very much inclined to agree with your observation that many of the mental symptoms presented appear to be characteristic of schizoaffective, and I thought as well that a sigma-1 agonist would be well indicated as a desirable course of treatment. I mentioned this to him via PM in July, however he has not since conveyed whether this is yet something he would be willing to consider. It's for these reasons I felt the improbable could now be considered within the realm of possibility, and given that 50g Inositol Hexanicotinate can bepurchased from iHerb for $6.50, purchasing a sufficient quantity to trial this for a week would IMO be a small price to pay in order to dismiss a treatment which so many claim has changed their lives. That said however I do find your subsequent recommendations for him were thought provoking and well elucidated,and in no way would suggest this orthomolecular approach as a substitute for innovative traditional ideas but rather as something that could be trialed over a very brief period alongside what is already being attempted.

As for myself, I'm still working diligently toward a meansof restoring my cognitive facilities to baseline and although I feel some progress has been achieved since the beginning of summer, I don't feel as though it is yet remarkable in terms of where I eventually would like to be. My regimen consists of 18mg Straterra, 2.5mg Escitalopram, and 10-20mg biphentin,and although I have an ongoing prescription for Vyvanse I find for one reason or another I tend away from using this unless it's really necessary. Vyvanse has been excellent for mood and processing, however I've found it does feel somewhat unnatural, and seems in my case to further exacerbate hyperfocus and the state of certain executive functions such as working memory and lateral thinking; both of which I am in need of being able to rely upon readily.

I've noticed encouraging results with noradrenergics such as Straterra, Pyritinol and Idebenone in the past and for this reason suspect suppression of norepinephrine currents or receptor sensitivity may play a pivitol role in influencing my chemistry. Of particular importance to me is finding a means with which to enhance vigilance, as I very rarely am able to achieve vigilant clarity even in circumstances which would otherwise facilitate this (such as adrenaline rushes).With Straterra and Pyritinol, I've noticed relative immediacy of effect but with diminishing efficacy over time and suspect autoreceptor upregulation as a possible culprit. I'm aware of Straterra's Kappa-Opiod metabolite as well and for these reasons am interested in finding another, more sustainable means of stimulating noradrenergic activity. I'm still interested in pursuing the glutamate hypothesis of I-ADD, and had a brief fling with memantine utilizing a slow and steady titration over a two month period but unfortunately did not find it tobe overly helpful for cognition. I suspect that a sigma-1 agonist such as donepezil or fluvoxamine could be of value for me in regulating prefrontal glutamate levels and am interested in trying one of these in the near future. I'dh ave tried it already, however you're correct in that my psychiatrist despite being very good overall does not typically oblige my interest in unindicated treatments. To try this I would need to find another doctor or place an orderfrom overseas, which I think I may very well do in the future.

Likely my best lead to date however occurred yesterday when I received some bloodwork results with TSH = 4.75, up from 3.5 last summer. Although not extraordinarily high, I have an extensive immediate family history of hashimoto's disorder and hypo-thyroidism which might be indicative of the underlying etiology of my condition. As one might have guessed, my family physician refuses to acknowledge these results as suspect and has not ordered further testing or offered a referral to an endocrinologist stating instead I am still within the 'normal' range… Nonetheless, I intend to begin treatment with T3 andT4 as soon as possible, ideally with Erfa or Naturethroid provided I'm somehow able to procure it. Although I've been having my levels tested for 8 years now, it's only been during the past two that I've been informed enough to ask for the levels directly rather than accepting the physician's opinion they are normal –so it's entirely possible this could have been the issue all along.

In the interim I'm taking a barrage of supplements to complement my scrips for various reasons, many of which are therapeutic and some of which I believe may assist in the event of a yet unknown pathogenic etiology; Jatamansi & Bacopa (Organix South), Olive Leaf (Gaia),Resveratrol (ReserveAge Organics), Gotu Kola (Now), Monolaurin (ReserveAgeOrganics), B-Complex (AOR), Polyunsaturated Phospatylcholine (Life Extension),Milk Thistle (Now), Gano-Reishi (Mushroom Science), Shisandra (Nature's Way),l-methylfolate (Solgar), zinc (Now), GLA (Jarrow), and EPA/DHA (Jarrow). I've been taking this combination for nearly three weeks, and notice in addition to it being highly anxiolytic, my thought patterns and cognitive facilities are beginning to normalize somewhat relative to where they were prior. I still have a very long way to go, however I now feel as though if I need a place to 'park' while I continue to look for answers that this isn't really such a bad place to be.

So, now that I've detracted sufficiently from the original spirit of your thread, lol… I certainly hold your advice and counsel in high esteem, and if you or anyone else have suggestions or questions which come to mind I'd be pleased to entertain these via PM or within another thread so as not to digress any further than I already have. Regards, Dil

Edited by dilenja, 01 October 2010 - 04:56 AM.

[Rational Madman]

Rol, i have a few questions for you since you have a extensive knowledge on a variaty of things.

As you may know i'm ignoring supplements (and not intrested) in supplements that slow down my aging, but rather things that reduce my chances of getting cancer and stuff (like curcumin and resveratrol).

I'm also interested in supplements that promote my chances of recovery in a deadly accident (i know pretty vague) something that increases tissue regeneration, slows the dying proces?, improve survival of my organs, and for example like to avoid things that thin my blood that reduce the chances of bleeding to death that sort of stuff.

Dunno wheter its even possible, just asking as you know your stuff. I'm mostly interested in increases chances of survival in my current lifespan, rather then focussing on increasing it.

My regime is very experimental, i'l make a thread about it on here soon, but have differend goals then most people here.

If, as I've surmised, that life extension is your overarching goal, then certain variables need to be covered....

Mitochondrial: Ubiquinol, Acetyl Carnitine, Carnosine, and R-Lipoic Acid.
Inflammation: Master Gene P16, Luteolin, Resveratrol, Curcumin, and EGCG.
Glycation: Benfotiamine, Benagene, and Arginine.
mRNA expression: Ribose and Methylfolate.

I apologize for my tardy reply, but I was quite busy this week. Anyway, the constituents of my regimen should also serve as a useful guide.

[maxwatt]

...
If, as I've surmised, that life extension is your overarching goal, then certain variables need to be covered....

Mitochondrial: Ubiquinol, Acetyl Carnitine, Carnosine, and R-Lipoic Acid.
Inflammation: Master Gene P16, Luteolin, Resveratrol, Curcumin, and EGCG.
Glycation: Benfotiamine, Benagene, and Arginine.
mRNA expression: Ribose and Methylfolate.

...

WRT Mitochondrial, consider methylene blue, 60 microgram dose. There are extensive threads on it here.
Inflammation (nfKappa-B as well a P16) Myricetin has some very promising studies to consider. And the glycoside is effective, and water soluble.
Glycation: resveratrol does block age formation. An interesting not-yet-available or even named stilbene, 2,3,5,4'-tetrahydroxy-stilbene extracted from Fo Ti blocks, and may even break to some degree AGEs. PMID: 20104848 and others; it seems to be much more potent than reseratrol in this regard. I'm trying to get somone with the requisite equipment to extract some.

Edited by maxwatt, 06 October 2010 - 01:11 PM.

[medievil]

Rol, i have a few questions for you since you have a extensive knowledge on a variaty of things.

As you may know i'm ignoring supplements (and not intrested) in supplements that slow down my aging, but rather things that reduce my chances of getting cancer and stuff (like curcumin and resveratrol).

I'm also interested in supplements that promote my chances of recovery in a deadly accident (i know pretty vague) something that increases tissue regeneration, slows the dying proces?, improve survival of my organs, and for example like to avoid things that thin my blood that reduce the chances of bleeding to death that sort of stuff.

Dunno wheter its even possible, just asking as you know your stuff. I'm mostly interested in increases chances of survival in my current lifespan, rather then focussing on increasing it.

My regime is very experimental, i'l make a thread about it on here soon, but have differend goals then most people here.

If, as I've surmised, that life extension is your overarching goal, then certain variables need to be covered....

Mitochondrial: Ubiquinol, Acetyl Carnitine, Carnosine, and R-Lipoic Acid.
Inflammation: Master Gene P16, Luteolin, Resveratrol, Curcumin, and EGCG.
Glycation: Benfotiamine, Benagene, and Arginine.
mRNA expression: Ribose and Methylfolate.

I apologize for my tardy reply, but I was quite busy this week. Anyway, the constituents of my regimen should also serve as a useful guide.

Thx!

I was thinking about methylene blue for my mitochondria, resveratrol and curcumin are supplements i'm allready taking and convinced off. I liked EGCG but decided to leave it tough due to my paranoia of supplements interacting and in the end getting less benefits then when combining less supplements, so im trying to only pick the most promosing one's (for now untill more data is available.)

Glycation and mRNA expression, thx for your suggestions i'l look into the benefits and available stuff for that.

Ive also recently started taking telmisertan due to my intrest in AT1 blockers:
http://www.imminst.o...xtend-lifespan/ (the link provided to the thread on mind and muscle shows some more interesting abstracts.)

Edited by medievil, 06 October 2010 - 01:07 PM.

[NG_F]

Animal perhaps your also interested in my own experience with amisulpiride.

It was the only pharmaceutical wich really adressed my anhedonia and motivational issues, it kept working for the 2 weeks i took it, however i stopped taking it due to the massive rise in prolactin it causes wich could cause trouble in the long run, i retried it a few times later but it never worked again.

I am also putting together a pharmacological and supplement compendium lol for an existing left head of Caudate lesion(Striatum) which is probably a lacunar hemorrhage.This measures 8x3mm on SWI due to the blooming effect of hemosiderin and was most likely caused by too rapid of a discontinuation of alprazolam.
This was foolishly done at a detox facility recomended by my treating Pdoc..The doctor who usually does and invented the protocol had an emergency surgery to go through for damage of his spine and I was left with a skeleton crew of a back up doc and a bunch of nurses.
Clonodine was not informed to me a this time as being used as an antihypertensive even though it is 4th line or not used anymore for regualar use.Advised as a protracted withdrawal medication.A few days of not needing caused a reboud norepinephrine/vasoconstriction state that caused a few episodes of transient skyrocketing blood pressure.
Monitoring BP carefully with a home monitor 4-6 times/day was not suggested and could have saved me from having this depressive disability.
Please see my previous posts.

Medievil could amisulpride be used to increase doapminergic tone from the striatal efferent circuits that terminate to the DLPFC? I think a safe ergot can mitigate any hyperprolactinemia.

[NG_F]

Well dam, that's like finding out the world isn't flat after all these months, haha. Thanks a lot for clearing that up Medievil

Still 5HT2A antagonism can be a good thing in some types of depression, but for those suffering from anhedonia or lack of energy its definatly a no go, i beleive that 5HT2A agonism is a highly interesting target hence my intrest in lisuride.

You'll have to excuse my oscillatory mind, but I'm beginning to have doubts about the merits of 5ht2a antagonism as well, and the mechanism of the tetracyclics, which also have an affinity for adrenergic receptors. A blockade of either is linked to an impairment of working memory. So, I'm re-examining the SSRIs, which have the advantage of inducing oxytocin synthesis, and positively influencing opioid pathways and the circadian rhythym. After consulting the literature, I may toy around with doses---starting at a low base---and make some other calibrations. Presently, I think the Sigma 1 agonists are probably still the best within this class. But, if forced to choose, would you choose Lexapro, or Luvox? Monotherapeutic SSRI use is a daft idea, but combined with other agents, much more efficacious. However, I'll have to reconsider my use of Tianeptine, since they aren't exactly synergistic. So, now I have greater motivation to try Valdoxan, but has anyone found a good price? The best I've found is $90 for 28 pills, which is a cost that may exceed the benefits. I'll try alibaba.com tonight, and see if I can find anything interesting.

WHat are you taking SSRI's for? Depression?

Well, yes, that's the prescribed purpose, but I'm also interested in the aforementioned benefits. Pending further research, I may reintroduce an SSRI, but probably not at the previous dosage of 150 mg.

Why don't you use sertraline or citalopram? I know you didn't appreciate sertraline's mild antagonism for the sigma receptor(I believe to be negligable) If you feel strong about this then you can start with low dose Citalopram eg.10mgs/day
Both of these have been shown to increase BDNF expression globally in the brains of mice(Huntington's disease model) and not just the hippocampus.

[NG_F]

Are you planning to keep on taking mirtazepine?

What do you think of lisuride its a potent 5HT1A and 5HT1B agonist wich stimulate oxytocin release, its also a potent 5HT2A agonist, basicly has a very interesting pharmacological profile. Its also a D2 agonist wich could replace cabergoline, or do the benefits of cabergoline come independly from another mechanism?
http://www.imminst.o...st-in-lisuride/

Its also been shown to potentiate the antidepressant effect of other antidepressants in rodents.

I would say low dose SSRI+lisuride would be very interesting, downside of it is the price and the half life tough.

I'll be tapering off of Mirtazapine, and resuming my use of Luvox, beginning with a dose of 75 mg. As for Lisuride, it's certainly interesting, and worthy of further examination, and free of any obvious red flags that might deter users from trying. But, I thought you already tried it, and assumed that your enthusiasm had been dampened. Are you trying a different dose, or would this be your first time?

Why are you discontinuing Mirtazapine? You favoured it earlier as for it's enhancement of cognition at 30mgs and up.were some of the adverse effects that you expected to dissipate lingering and not worth staying with, also Agomelatine can restore sleep patterns after 3 mos and with dosages of 25-50 mgs but I read that the initial period causes some unpleasant deprivation and fragmentation.Does whiskey really do the trick for you? lol I wish i was so lucky.

[NG_F]

Anyway, you're quite right, 5ht2a receptors exert a tonic inhibitory role on dopamine efflux in the prefrontal cortex, and inhibition should result in an increase of dopamine in the medial prefrontal cortex,

That isnt correct, 5HT2A does not inhibit dopamine in the frontal cortext and antagonism does not increase dopamine in any brainregio either, will post my source later have to go sleep now.

Whatever its effects, the antagonism of 5ht2a provides symptomatic relief to dysexecutive disorders through its activation of the orbitofrontal cortex, which maybe hypoactive, and causally linked to the presentation of symptoms. Indeed, there is indisputable evidence that antagonizing this target improves functional outcomes for some dysexecutive disorders, but for reasons that I've outline before, it's not an ideal target, and for disorders with a hyperactive orbitofrontal cortex---like OCD---antagonism would be contraindicated. In my case, I have not completely ruled out 5ht2a involvement, and may return at some point to Mirtazapine, but given its serious drawbacks, I would like to try other strategies first.

Can you please specify the drawbacks of your personal experience with Mirtazapine and are you still currently using Memantine for glutamate antagonism induced by stim's and Modafanil? or are you just needing your SSRI of choice(Luvox) and Valproic acid? What about Amantadine, do you think it has any potential benefit for you both a s a weaker NDMA antagonist and a dopamine agonist?
Thanks Rol 82

[KimberCT]

FWIW, mangosteen contains γ-mangostin, a selective 5-HT2A antagonist.  From my subjective experience, it's quite potent too.

[Animal]

Rol82 could you elaborate on your experience with Hydergine please, especially with regards to it's acute vs chronic effects on mood. I'm intending to start taking it at a dose of 9mg/day in two divided doses in approximately two weeks time, so thanks for any insight.

[NeuroGuy]

Something to consider for Cabergoline besides increasing glutathione,

(Keep in mind this is in lymphathic cancer cells, in rats)
http://joe.endocrino...tract/190/2/307

Journal of Endocrinology (2006) 190, 307-312 DOI: 10.1677/joe.1.06368
© 2006 Society for Endocrinology

Prolactin activates mammalian target-of-rapamycin through phosphatidylinositol 3-kinase and stimulates phosphorylation of p70S6K and 4E-binding protein-1 in lymphoma cells Jessica D Bishop1, Wei Lun Nien1, Shauna M Dauphinee1 and Catherine K L Too1,2
1 Department of Biochemistry and Molecular Biology and
2 Department of Obstetrics and Gynecology, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, B3H 1X5 Canada


Mitogens activate the mammalian target-of-rapamycin (mTOR) pathway through phosphatidylinositol 3-kinase (PI3K). The activated mTOR kinase phosphorylates/ activates ribosomal protein S6 kinase (p70S6K) and phosphorylates/inactivates eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), resulting in the initiation of translation and cell-cycle progression. The prolactin receptor signaling cascade has been implicated in crosstalk with the mTOR pathway, but whether prolactin (PRL) directly activates mTOR is not known. This study showed that PRL stimulated the phosphorylation of mTOR, p70S6K, Akt, and Jak2 kinases in a dose- and time-dependent manner in PRL-dependent rat Nb2 lymphoma cells. PRL-stimulated phosphorylation of mTOR was detected as early as 10 min, closely following the phosphorylation of Akt (upstream of mTOR), but preceding that of the downstream p70S6K. PRL activation of mTOR was inhibited by rapamycin (mTOR inhibitor), LY249002, and wortmannin (P13K inhibitors), but not by AG490 (Jak2 inhibitor), indicating that it was mediated by the P13K/Akt, but not Jak2, pathway. PRL also stimulated phosphorylation of 4E-BP1 in Nb2 cells. PRL-induced phosphorylation of p70S6K and 4E-BP1 was inhibited by rapamycin, but not by okadaic acid (inhibitor of protein phosphatase, PP2A). PRL induced a transient interaction between p70S6K and the catalytic subunit of PP2A (PP2Ac) in 1 and 2 h, whereas a PP2Ac–4E-BP1 complex was constitutively present in quiescent and PRL-treated Nb2 cells. These results suggested that p70S6K and 4E-BP1 were substrates of PP2A and the inhibition of mTOR promoted their dephosphorylation by PP2A. In summary, PRL-stimulated phosphorylation of mTOR is mediated by PI3K. PRL-activated mTOR may phosphorylate p70S6K and 4E-BP1 by restraining PP2A.

http://www.ncbi.nlm....pubmed/19489650

BioDrugs. 2009;23(2):77-91. doi: 10.2165/00063030-200923020-00002.

Current status and challenges associated with targeting mTOR for cancer therapy.
Dowling RJ, Pollak M, Sonenberg N.

Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada.

Abstract
The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in the regulation of cellular growth, survival, and proliferation. Inappropriate activation of PI3K/Akt/mTOR signaling can promote a cellular environment that is favorable for transformation. In fact, dysregulation of this pathway, as a result of genetic mutations and amplifications, is implicated in a variety of human cancers. Therefore, mTOR has emerged as a key target for the treatment of cancer, particularly in the treatment of tumors that exhibit increased mTOR signaling as a result of genetic lesions. The immunosuppressant sirolimus (rapamycin) directly inhibits mTOR activity and suppresses the growth of cancer cells in vitro and in vivo. As a result, a number of sirolimus derivatives have been developed as anti-cancer therapies, and these compounds are currently under investigation in phase I-III clinical trials. In this review, we summarize the use of sirolimus derivatives in clinical trials and address some of the challenges associated with targeting mTOR for the treatment of human cancer.

PMID: 19489650 [PubMed - indexed for MEDLINE]

Edited by NeuroGuy, 11 October 2010 - 07:25 PM.

[Rational Madman]

Rol82 could you elaborate on your experience with Hydergine please, especially with regards to it's acute vs chronic effects on mood. I'm intending to start taking it at a dose of 9mg/day in two divided doses in approximately two weeks time, so thanks for any insight.

In my experience, Hydergine initially provided a modulatory effect on my mood, and based on its mechanism, this certainly makes sense. Over time, it may yield other cognitive benefits through a promotion of nerve growth factors, but I'm not sure how statistically significant these effects are in vivo. In the end, I yielded to the paucity of evidence, which explains its near cessation of clinical use. In truth, it's a very weak drug, and I would look elsewhere. Based on what I've gathered about your symptoms, I would say that you're in need of a multiple pronged approach that includes stimulants, antidepressants, and maybe a low dose of one of the more benign mood stabilizers. The more refractory, the bigger the cocktail. So be bold, adventurous, keep calibrating, and don't become daunted.

Edited by Rol82, 20 October 2010 - 10:04 AM.

[Rational Madman]

Something to consider for Cabergoline besides increasing glutathione,

(Keep in mind this is in lymphathic cancer cells, in rats)
http://joe.endocrino...tract/190/2/307

Journal of Endocrinology (2006) 190, 307-312 DOI: 10.1677/joe.1.06368
© 2006 Society for Endocrinology

Prolactin activates mammalian target-of-rapamycin through phosphatidylinositol 3-kinase and stimulates phosphorylation of p70S6K and 4E-binding protein-1 in lymphoma cells Jessica D Bishop1, Wei Lun Nien1, Shauna M Dauphinee1 and Catherine K L Too1,2
1 Department of Biochemistry and Molecular Biology and
2 Department of Obstetrics and Gynecology, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, B3H 1X5 Canada


Mitogens activate the mammalian target-of-rapamycin (mTOR) pathway through phosphatidylinositol 3-kinase (PI3K). The activated mTOR kinase phosphorylates/ activates ribosomal protein S6 kinase (p70S6K) and phosphorylates/inactivates eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), resulting in the initiation of translation and cell-cycle progression. The prolactin receptor signaling cascade has been implicated in crosstalk with the mTOR pathway, but whether prolactin (PRL) directly activates mTOR is not known. This study showed that PRL stimulated the phosphorylation of mTOR, p70S6K, Akt, and Jak2 kinases in a dose- and time-dependent manner in PRL-dependent rat Nb2 lymphoma cells. PRL-stimulated phosphorylation of mTOR was detected as early as 10 min, closely following the phosphorylation of Akt (upstream of mTOR), but preceding that of the downstream p70S6K. PRL activation of mTOR was inhibited by rapamycin (mTOR inhibitor), LY249002, and wortmannin (P13K inhibitors), but not by AG490 (Jak2 inhibitor), indicating that it was mediated by the P13K/Akt, but not Jak2, pathway. PRL also stimulated phosphorylation of 4E-BP1 in Nb2 cells. PRL-induced phosphorylation of p70S6K and 4E-BP1 was inhibited by rapamycin, but not by okadaic acid (inhibitor of protein phosphatase, PP2A). PRL induced a transient interaction between p70S6K and the catalytic subunit of PP2A (PP2Ac) in 1 and 2 h, whereas a PP2Ac–4E-BP1 complex was constitutively present in quiescent and PRL-treated Nb2 cells. These results suggested that p70S6K and 4E-BP1 were substrates of PP2A and the inhibition of mTOR promoted their dephosphorylation by PP2A. In summary, PRL-stimulated phosphorylation of mTOR is mediated by PI3K. PRL-activated mTOR may phosphorylate p70S6K and 4E-BP1 by restraining PP2A.

http://www.ncbi.nlm....pubmed/19489650

BioDrugs. 2009;23(2):77-91. doi: 10.2165/00063030-200923020-00002.

Current status and challenges associated with targeting mTOR for cancer therapy.
Dowling RJ, Pollak M, Sonenberg N.

Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec, Canada.

Abstract
The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in the regulation of cellular growth, survival, and proliferation. Inappropriate activation of PI3K/Akt/mTOR signaling can promote a cellular environment that is favorable for transformation. In fact, dysregulation of this pathway, as a result of genetic mutations and amplifications, is implicated in a variety of human cancers. Therefore, mTOR has emerged as a key target for the treatment of cancer, particularly in the treatment of tumors that exhibit increased mTOR signaling as a result of genetic lesions. The immunosuppressant sirolimus (rapamycin) directly inhibits mTOR activity and suppresses the growth of cancer cells in vitro and in vivo. As a result, a number of sirolimus derivatives have been developed as anti-cancer therapies, and these compounds are currently under investigation in phase I-III clinical trials. In this review, we summarize the use of sirolimus derivatives in clinical trials and address some of the challenges associated with targeting mTOR for the treatment of human cancer.

PMID: 19489650 [PubMed - indexed for MEDLINE]

Good find, and yet another reason to be wary of anti-psychotics.

Edited by Rol82, 20 October 2010 - 10:03 AM.

[Rational Madman]

Rol82, I've noticed reading your regimen you're fond as well of luteolin as a means of PDE4 inhibition. Are there any luteolin supplements in particular which have gained your trust that you'd feel comfortable recommending? I've been looking for a pure luteolin extract for sometime now but have been unable to locate the compound unfortunately outside of olive leaf extract. Is there a particular dosage do you know which would be considered generally effective for achieving PDE4 inhibition?

Fascinating thread I'd like to add as well. I've personally taken a lot from reading your well-considered, intelligent and intriguing perspectives and contributions. I realize it must take a lot of time to maintain this thread and am appreciative of your continued efforts to preserve your experiences and advice here on imminst. Thanks so much, Dilenja

The inhibition of phosphodiesterase 4 is great target for increasing CREB, and when combined with the widely studied properties of the flavonoid, there should be statically significant effect on long term induction. My current dosage is 800 mg/day, which has been working great, but I haven't arrived at the optimal dose as of yet. When it comes to luteolin, and resveratrol, I'm less well versed, so perhaps you should shoot a message to someone like Maxwatt.

And I appreciate your sentiments, as I try to do my best in spite of my limited academic exposure to the sciences. Moreover, although others are loath to speak candidly about their experiences, I endeavor to be open as possible about the taboo illnesses that are criminally undertreated. This forum has been a valuable tool for my research efforts over the last two years, and I imagine others feel the same way. But I've witnessed far too many participants visit with the dim hope of relief, and leave disillusioned, which is a common outcome that has left me immensely dismayed, and is a pattern that I hope I can make somewhat of a humble contribution in altering. So I'm more than happy to sacrifice potentially pleasurable portions of my personal life for the sake of altruism---which is still a higher form of pleasure that can be rationalized by utilitarianism. And I suppose is healthier than sadistically manipulating and disheartening vulnerable women on Match.com---where you'll never find a more depressing population of easily seducible romantic idealists. But fortunately, I think I've permanently suppressed this more wicked side---which I sincerely hope others won't succumb to due to self-loathing or shallowness.

Anyway, based on your posting in the thread of the exceedingly embittered StrangeAeons----whom I suspect is perilously, and perhaps irretrievably close to suicide----I was somewhat shocked by your endorsement of the orthomolecular approach to psychiatry, which might be understandable under the conditions of desperation, but should be deemed ultimately futile. And given this dalliance, I'm curious about your current status? Have the amphetamine salts ceased to work? Are you facing an intransigent psychiatrist? Has something else gone awry?

Rol82, I can appreciate his and your hesitancy in accepting the rationality of this approach. Although I don't personally advocate the orthomolecular approach as a cure-all – in this particular instance, given the dire and understandably frustrated outlook of StrangeAeons, and his lack of progress in spite of a myriad of consultations with various health professionals, I believe orthomolecular and specifically high dosages of Inositol Hexanicotinate may indeed constitute a readily available, and affordable adjunct which should not interfere with his current course of treatment, and which could quite possibly provide further insights into his condition along with the remote possibility of relief. Although science has not yet validated many of its claims, the support base orthomolecular has garnered in the past 40+ year's spans such a breadth of patients and practitioners that I don't feel its efficacy can yet be outright refuted leaving it as merely an improbable but not impossible solution.

I recognize that I of all people possessing a limited background certainly don't hold the answers to resolving his strange affliction where so many other accredited medical professionals and knowledgeable individuals have tried to do so without avail. But given that many of the more traditional techniques have been ruled out due to inefficacy or inaccessibility, I feel as though there is a place for more exhaustive techniques which could be employed as I'm also noticing an increased sense of urgency evident in each succeeding post. I am very much inclined to agree with your observation that many of the mental symptoms presented appear to be characteristic of schizoaffective, and I thought as well that a sigma-1 agonist would be well indicated as a desirable course of treatment. I mentioned this to him via PM in July, however he has not since conveyed whether this is yet something he would be willing to consider. It's for these reasons I felt the improbable could now be considered within the realm of possibility, and given that 50g Inositol Hexanicotinate can bepurchased from iHerb for $6.50, purchasing a sufficient quantity to trial this for a week would IMO be a small price to pay in order to dismiss a treatment which so many claim has changed their lives. That said however I do find your subsequent recommendations for him were thought provoking and well elucidated,and in no way would suggest this orthomolecular approach as a substitute for innovative traditional ideas but rather as something that could be trialed over a very brief period alongside what is already being attempted.

As for myself, I'm still working diligently toward a meansof restoring my cognitive facilities to baseline and although I feel some progress has been achieved since the beginning of summer, I don't feel as though it is yet remarkable in terms of where I eventually would like to be. My regimen consists of 18mg Straterra, 2.5mg Escitalopram, and 10-20mg biphentin,and although I have an ongoing prescription for Vyvanse I find for one reason or another I tend away from using this unless it's really necessary. Vyvanse has been excellent for mood and processing, however I've found it does feel somewhat unnatural, and seems in my case to further exacerbate hyperfocus and the state of certain executive functions such as working memory and lateral thinking; both of which I am in need of being able to rely upon readily.

I've noticed encouraging results with noradrenergics such as Straterra, Pyritinol and Idebenone in the past and for this reason suspect suppression of norepinephrine currents or receptor sensitivity may play a pivitol role in influencing my chemistry. Of particular importance to me is finding a means with which to enhance vigilance, as I very rarely am able to achieve vigilant clarity even in circumstances which would otherwise facilitate this (such as adrenaline rushes).With Straterra and Pyritinol, I've noticed relative immediacy of effect but with diminishing efficacy over time and suspect autoreceptor upregulation as a possible culprit. I'm aware of Straterra's Kappa-Opiod metabolite as well and for these reasons am interested in finding another, more sustainable means of stimulating noradrenergic activity. I'm still interested in pursuing the glutamate hypothesis of I-ADD, and had a brief fling with memantine utilizing a slow and steady titration over a two month period but unfortunately did not find it tobe overly helpful for cognition. I suspect that a sigma-1 agonist such as donepezil or fluvoxamine could be of value for me in regulating prefrontal glutamate levels and am interested in trying one of these in the near future. I'dh ave tried it already, however you're correct in that my psychiatrist despite being very good overall does not typically oblige my interest in unindicated treatments. To try this I would need to find another doctor or place an orderfrom overseas, which I think I may very well do in the future.

Likely my best lead to date however occurred yesterday when I received some bloodwork results with TSH = 4.75, up from 3.5 last summer. Although not extraordinarily high, I have an extensive immediate family history of hashimoto's disorder and hypo-thyroidism which might be indicative of the underlying etiology of my condition. As one might have guessed, my family physician refuses to acknowledge these results as suspect and has not ordered further testing or offered a referral to an endocrinologist stating instead I am still within the 'normal' range… Nonetheless, I intend to begin treatment with T3 andT4 as soon as possible, ideally with Erfa or Naturethroid provided I'm somehow able to procure it. Although I've been having my levels tested for 8 years now, it's only been during the past two that I've been informed enough to ask for the levels directly rather than accepting the physician's opinion they are normal –so it's entirely possible this could have been the issue all along.

In the interim I'm taking a barrage of supplements to complement my scrips for various reasons, many of which are therapeutic and some of which I believe may assist in the event of a yet unknown pathogenic etiology; Jatamansi & Bacopa (Organix South), Olive Leaf (Gaia),Resveratrol (ReserveAge Organics), Gotu Kola (Now), Monolaurin (ReserveAgeOrganics), B-Complex (AOR), Polyunsaturated Phospatylcholine (Life Extension),Milk Thistle (Now), Gano-Reishi (Mushroom Science), Shisandra (Nature's Way),l-methylfolate (Solgar), zinc (Now), GLA (Jarrow), and EPA/DHA (Jarrow). I've been taking this combination for nearly three weeks, and notice in addition to it being highly anxiolytic, my thought patterns and cognitive facilities are beginning to normalize somewhat relative to where they were prior. I still have a very long way to go, however I now feel as though if I need a place to 'park' while I continue to look for answers that this isn't really such a bad place to be.

So, now that I've detracted sufficiently from the original spirit of your thread, lol… I certainly hold your advice and counsel in high esteem, and if you or anyone else have suggestions or questions which come to mind I'd be pleased to entertain these via PM or within another thread so as not to digress any further than I already have. Regards, Dil

...

Niacin shows some efficacy for neuropsychiatric symptoms because of its affinity for glycine receptors, but it has a very short half life, and when administered at acute doses, the patient has to contend with an alteration of liver enzymes and glucose metabolism---not to mention other nutritional imbalances. So, I would prefer to place my faith where the weight of evidence resides. When othomolecular medicine was in vogue in the 70s, sincere efforts were made to test its effects repeatedly, but to no avail. Which means that some serious methodological errors were made by advocates, and that patients likely succumbed to the very powerful effect of the placebo---which shouldn't be underestimated. On the message boards you encounter countless heartening testimonials, but ask yourself, how reliable are these testimonials? Are they accounting for only the transient and placebo effects? Furthermore, can you cite a single (and unquestionable) qualitative example of orthomolecular medicine leading to a remission of pervasive neuropsychiatric symptoms? Margot Kidder...still insane. Mark Vonnegut....disavowed orthomolecular medicine once he became sane with the right cocktail of drugs. In my experience, the patients convince themselves that there has been a profound change, but upon closer examination, there are serious issues that remain unresolved. So for the most part, they're maintaining a facade, which is why I don't discount the limited therapeutic potential of meditation, hypnosis, and behavioral therapy.

As for Strange, I trust he'll prevail in the end, since shock therapy can be quite efficacious, and because upon further reflection, he doesn't strike me as the sort that will concede a battle. He's a helluva guy, and I'm rooting for him.

For your case, I would suggest you consider the following:
-Increase your Lexapro dosage, because you're taking too low of a dose.
-Consider ordering some Modafinil for increased mental vigilance.
-Consider Mirtazapine or Trazodone as adjuncts, and don't be timid with the doses (My thinking has once again changed on these agents).
-Toy around with the Vyvanse dosage, because you could either be suffering from symptoms of I-ADD, or one of the schizoid disorders. If you suspect the latter is the case, then a high dose of Modafinil, and a lower dosage of Vyvanse would be more suitable.
-If you're left still unsatisfied, consider either Donepezil, or Rasagiline (I know some very reasonable and reliable pharmacies).
-Go slow, so you can fully appreciate the effects of each agent.
-Unless you're suffering from Alzheimer's, Huntington's Disease, or ALS, stay away from Memantine. Wait instead for evidence from carefully structured studies, not messageboard testimonials.
-In all likelihood, your family physician is probably right, and you're not suffering from hypothyroidism---even subclinical. You're just depressed! However, thyroid replacement therapy does have antidepressant properties, of course, which explains the selected successes of the Mary Shomon cult. The signs of Hashimito's are very telling, and I'm highly dubious about thyroid disorders being underdiagnosed---there are, of course, always frightening, but ultimately meaningless anecdotes to frighten the mentally ill, though. If you're worried about your energy levels and metabolism, the aforementioned should more than amply address these issues. If I'm wrong and all else fails, then maybe something is wrong.
-Dump most of your supplements, and consider: a better fish oil brand, Revgenetic's Nitro-Mx, maybe a multivitamin like Ortho-Core, perhaps Ortho-Mind, and if deemed necessary, Astral Fruit-C and Master Gene P-16. Rather, save most of your money for good food, drugs, and pleasurable activities.
-I know this might be difficult, but try not to obsess about your problems, since there is convincing evidence that such behavior increases symptom severity.
-Instead, enjoy the finer things, like a Bergman film, the scent of a woman, a Davidoff cigar, a bottle of expensive alcohol, a trip to a pretentious French restaurant, or a visit to the Sistine Chapel (or even better, a grand tour of Europe). Because I get the feeling that you're spending an inordinate time sedentary, which can also exacerbate your symptoms. In general, though, diversify your life as much as possible.

Edited by Rol82, 20 October 2010 - 10:02 AM.

[Rational Madman]

Animal perhaps your also interested in my own experience with amisulpiride.

It was the only pharmaceutical wich really adressed my anhedonia and motivational issues, it kept working for the 2 weeks i took it, however i stopped taking it due to the massive rise in prolactin it causes wich could cause trouble in the long run, i retried it a few times later but it never worked again.

I am also putting together a pharmacological and supplement compendium lol for an existing left head of Caudate lesion(Striatum) which is probably a lacunar hemorrhage.This measures 8x3mm on SWI due to the blooming effect of hemosiderin and was most likely caused by too rapid of a discontinuation of alprazolam.
This was foolishly done at a detox facility recomended by my treating Pdoc..The doctor who usually does and invented the protocol had an emergency surgery to go through for damage of his spine and I was left with a skeleton crew of a back up doc and a bunch of nurses.
Clonodine was not informed to me a this time as being used as an antihypertensive even though it is 4th line or not used anymore for regualar use.Advised as a protracted withdrawal medication.A few days of not needing caused a reboud norepinephrine/vasoconstriction state that caused a few episodes of transient skyrocketing blood pressure.
Monitoring BP carefully with a home monitor 4-6 times/day was not suggested and could have saved me from having this depressive disability.
Please see my previous posts.

Medievil could amisulpride be used to increase doapminergic tone from the striatal efferent circuits that terminate to the DLPFC? I think a safe ergot can mitigate any hyperprolactinemia.

If you can get a prescription, then I would go for Guanfacine, or alternatively Clonidine, which can be procured online. In your case, I would suggest a large dose of antidepressants, and something else that's highly neurotrophic like a mood stabilizer and/or an acetylcholinesterase inhibitor. Maybe throw in something like Rasagiline or Selegiline if the appropriate calibrations are made.

[Rational Madman]

Well dam, that's like finding out the world isn't flat after all these months, haha. Thanks a lot for clearing that up Medievil

Still 5HT2A antagonism can be a good thing in some types of depression, but for those suffering from anhedonia or lack of energy its definatly a no go, i beleive that 5HT2A agonism is a highly interesting target hence my intrest in lisuride.

You'll have to excuse my oscillatory mind, but I'm beginning to have doubts about the merits of 5ht2a antagonism as well, and the mechanism of the tetracyclics, which also have an affinity for adrenergic receptors. A blockade of either is linked to an impairment of working memory. So, I'm re-examining the SSRIs, which have the advantage of inducing oxytocin synthesis, and positively influencing opioid pathways and the circadian rhythym. After consulting the literature, I may toy around with doses---starting at a low base---and make some other calibrations. Presently, I think the Sigma 1 agonists are probably still the best within this class. But, if forced to choose, would you choose Lexapro, or Luvox? Monotherapeutic SSRI use is a daft idea, but combined with other agents, much more efficacious. However, I'll have to reconsider my use of Tianeptine, since they aren't exactly synergistic. So, now I have greater motivation to try Valdoxan, but has anyone found a good price? The best I've found is $90 for 28 pills, which is a cost that may exceed the benefits. I'll try alibaba.com tonight, and see if I can find anything interesting.

WHat are you taking SSRI's for? Depression?

Well, yes, that's the prescribed purpose, but I'm also interested in the aforementioned benefits. Pending further research, I may reintroduce an SSRI, but probably not at the previous dosage of 150 mg.

Why don't you use sertraline or citalopram? I know you didn't appreciate sertraline's mild antagonism for the sigma receptor(I believe to be negligable) If you feel strong about this then you can start with low dose Citalopram eg.10mgs/day
Both of these have been shown to increase BDNF expression globally in the brains of mice(Huntington's disease model) and not just the hippocampus.

I'm using Fluvoxamine because of its affinity for the serotonin transporters. As for the relative neurotrophic properties of antidepressants, they all promote the global expression of neurotrophic factors--but these effects aren't noted in every study. And why would you suggest Celexa over Lexapro, since their structures are extremely similar, and since the latter is simply an updated form of the former?

[Rational Madman]

Are you planning to keep on taking mirtazepine?

What do you think of lisuride its a potent 5HT1A and 5HT1B agonist wich stimulate oxytocin release, its also a potent 5HT2A agonist, basicly has a very interesting pharmacological profile. Its also a D2 agonist wich could replace cabergoline, or do the benefits of cabergoline come independly from another mechanism?
http://www.imminst.o...st-in-lisuride/

Its also been shown to potentiate the antidepressant effect of other antidepressants in rodents.

I would say low dose SSRI+lisuride would be very interesting, downside of it is the price and the half life tough.

I'll be tapering off of Mirtazapine, and resuming my use of Luvox, beginning with a dose of 75 mg. As for Lisuride, it's certainly interesting, and worthy of further examination, and free of any obvious red flags that might deter users from trying. But, I thought you already tried it, and assumed that your enthusiasm had been dampened. Are you trying a different dose, or would this be your first time?

Why are you discontinuing Mirtazapine? You favoured it earlier as for it's enhancement of cognition at 30mgs and up.were some of the adverse effects that you expected to dissipate lingering and not worth staying with, also Agomelatine can restore sleep patterns after 3 mos and with dosages of 25-50 mgs but I read that the initial period causes some unpleasant deprivation and fragmentation.Does whiskey really do the trick for you? lol I wish i was so lucky.

I'm back on Mirtazapine, because I think I accentuated the ostensible costs too much. My firm conclusion, 5ht2a blockade and 5ht1a agonism=good. And although Agomelatine should plausibly restore circadian rhythms, so can other antidepressants---which increase nocturnal melatonin synthesis, and stabilize daytime cortisol levels. Additionally, the latter can be easily obtained, have longer half-lives, greater treatment potential, and more importantly, more supporting evidence. To be sure, I'm still excited about the potential of Agomelatine, but I won't jump until the drug gains FDA approval, and is appropriately modified. As for whiskey, it certainly does do the trick for me, but I find Jameson Gold Reserve to be the most socially lubricating. Lately, I've been drinking a shot of Jameson, a shot of Ardbeg, and a glass of Pol Roger daily (spread out, of course). On weekends, I enjoy Pinot Noir and Cabernet Sauvignon (only French) at restaurants, and on rare occasions, I might add or substitute Armenian cognac. I strongly encourage you pay little heed of the Carrie Nation's of today, and consume 1-3 beverages daily. Especially since many of the cautionary studies reek of author bias.

Edited by Rol82, 20 October 2010 - 09:58 AM.

[Rational Madman]

FWIW, mangosteen contains γ-mangostin, a selective 5-HT2A antagonist. From my subjective experience, it's quite potent too.

Really, I got the impression that mangosteen was just another overhyped exotic fruit. Interesting...

[NG_F]

Well dam, that's like finding out the world isn't flat after all these months, haha. Thanks a lot for clearing that up Medievil

Still 5HT2A antagonism can be a good thing in some types of depression, but for those suffering from anhedonia or lack of energy its definatly a no go, i beleive that 5HT2A agonism is a highly interesting target hence my intrest in lisuride.

You'll have to excuse my oscillatory mind, but I'm beginning to have doubts about the merits of 5ht2a antagonism as well, and the mechanism of the tetracyclics, which also have an affinity for adrenergic receptors. A blockade of either is linked to an impairment of working memory. So, I'm re-examining the SSRIs, which have the advantage of inducing oxytocin synthesis, and positively influencing opioid pathways and the circadian rhythym. After consulting the literature, I may toy around with doses---starting at a low base---and make some other calibrations. Presently, I think the Sigma 1 agonists are probably still the best within this class. But, if forced to choose, would you choose Lexapro, or Luvox? Monotherapeutic SSRI use is a daft idea, but combined with other agents, much more efficacious. However, I'll have to reconsider my use of Tianeptine, since they aren't exactly synergistic. So, now I have greater motivation to try Valdoxan, but has anyone found a good price? The best I've found is $90 for 28 pills, which is a cost that may exceed the benefits. I'll try alibaba.com tonight, and see if I can find anything interesting.

WHat are you taking SSRI's for? Depression?

Well, yes, that's the prescribed purpose, but I'm also interested in the aforementioned benefits. Pending further research, I may reintroduce an SSRI, but probably not at the previous dosage of 150 mg.

Why don't you use sertraline or citalopram? I know you didn't appreciate sertraline's mild antagonism for the sigma receptor(I believe to be negligable) If you feel strong about this then you can start with low dose Citalopram eg.10mgs/day
Both of these have been shown to increase BDNF expression globally in the brains of mice(Huntington's disease model) and not just the hippocampus.

I'm using Fluvoxamine because of its affinity for the serotonin transporters. As for the relative neurotrophic properties of antidepressants, they all promote the global expression of neurotrophic factors--but these effects aren't noted in every study. And why would you suggest Celexa over Lexapro, since their structures are extremely similar, and since the latter is simply an updated form of the former?

I guess they all do to a degree in theory Rol, however sertraline and citalopram has been specifically tested and marked levels of BDNF has been measured in mice of course.I'm aware of the business aspects and celexa and zoloft are old drugs so I doubt their agenda is trying to resurect declining sales of these ssri's as appposed to something that never really took off as the flavour of the year like Luvox.I dont doubt that Luvox is a great SSRI but the scientists chose these 2 for specific reasons.
Also many drug studies are done with Citalopram, even now.

I talked to a few Neuropsychiatrists and a movement disorder Neurologist and they all prefer the administration of citalopram over escitalopram.The notion that the cleaner Entaniomer of a chemical delivers the same efficacy with deminished adverse effects is just a plain business ploy IMO. You can see this with Methylphenidate compared to Dexmethylphenidate and Venlafaxine -Desvenlafaxine.
I heard on many ocassions that people were more compliant and experienced less adverse effects with venlafaxine as opposed to Dex.I cannot coment on Citalopram except that from my understanding it is supposedly less likely to cause as much weight gain compared to Escitaloprm.

The Neuropsychiatrists and Neurologist administer it all the time to stroke patients or elders that presented with pseudo dementia and they have found that once therapeutic blood levels have been stable for a few months that these elders were living a finer quality of life without any dementia symptoms.
They all hold the belief that these small doses of SSRI's will do nothing to relieve depression or dampen the overactive cingulate circuits.

I dont like SSRI's period but they expressed that I wont even start feeling any relief or improvement with anergia,attention problems,cognition, improved sleep and mitigation of OCD, depression and anxiety until I reach 40mgs of citalopram or 200mgs of sertraline.
I was shocked that one Neuropsychiatrist who had a great deal of experience with SSRI's actually told me he found more patients reported less brain fog on Citalopram as opposed to sertraline?

I was always under the impression that sertraline would have a better profile with cognition due to it's slight Dopamine RI properties at does of 100mgs or more which I know is still negligible compared to other DRI's like Methylphenidate or some of the other Stim's. I guess it varies with different individuals and their brain chemistry but in my experience citalopram had less activation and more fatigue/apathy then sertraline or fluoxetine.

What benefits have you found with fluvoxamine as far as cognition and adverse effects? I recall you stating that it wasn't as mind clouding.How was your sleep on it?Also I recall that you liked it's Sigma properties.

Do you still like the cognitive nurturing properties of a good dose of Mirtazapine and have you decided to revisit yet?

It seems as if I may have some good news.I sent all 7 of my MRI's and 2 CTA's to one of the best Neuroradiologists in the Nation and his finding was that of a cavernous angioma measuring 8mm x 3mm.There is no volume loss and no mass effect.Cav-malformations usually dont involve any parenchymal tissue and are very slow flow and are not connected directly to an artery or arteriole.They are a group of thin weak walled capillaries that can ooze out blood and cause seizures,headache and other neurological symptoms or can be asymptomatoic forever.

The Head of the Left Caudate is a very elequent area and you dont get seizures when a bleed occurs there but you can experience memory and attention problems,stuttering,OCD,slight right sided weakness.It's also a very risky area to operate in as it is in midbrain and even in the hands of a skilled surgeon you may have more problems than you started off with.
The Cavernoma is resected usually interhemispherically through the top of the skull and through the genu of the corpus callosum, which the surgicentres will tell you there are silent areas.This is very doubtful.

My scans reveal low signal intensity on all iron sensitive sequences especially Gradient Echo and SWI.No lesion demonstration on CT as it's too small.It is far to small to be a caudate hemorrhage as these present with a hyperattenuation at about 2cm or larger. they usually present together with the putamen and can also be seen as a straitocapsular hemorrhage that mostly always bleeds into the lateral ventricles.

As far as microhemorrhages thye are very rare in the head of the Caudate nucleus, they are rarely solitary, measure usually 4mm and less and occur from a long standing history of hypertensive disease and NOT from a few weeks of hypertensive surges.

DDx include cappilary telangectasia or a neoplasm which my lesion is not.

If I do decide to go through with surgery it will be only to avoid further rebleeding so that I can do a safe and propper benzo taper this time.I will be using an SSRI with the least amount of BP elevation and vasoconstrictive effects which will be Citalopram, Trileptal as opposed to Neurontin,clonodine and a cross over from alprazolam to clonazepam or Diazepam. I will be using Magnesium and L-Taurine and my other bag of tricks to control glutamate and Calcium Influx.I may entertain the usage of Memantine if I really do need it.

As I approach the last 1mg of clonazepam or diazepam I will be using compounded solutions as to be able to make tiny decrements each week.

I have a long journey as I've been plagued by these toxic drugs since first given after my 2nd concussion in 1995, but the knowledge I've attained will go a long way to help me succeed once and for all.

[someidiot]

Rol-
a couple of questions if I may ask:

are you using cabergoline just for glutathione or/and to hit D1 receptors? Have you ever considered pergolide for stronger D1 agonism, if so, what turned you off to it besides fibrosis? I procured cabergoline to use intermittently due to its anticholinergic properties and potential fibrosis, so I am currently on pramipexole--negligible D1 agonism, but a dopamine agonist nonetheless.

You haven't found a reputable choline source to be sufficient enough without recourse to AChE inhibitors? I am wary to take pharmaceutical AChEIs. However, I'm extremely interested in nAChR upregulation; I reckon I'm too young to fool around with AChEIs, but if you notice a difference, perhaps I'll give it a go since you are my age.

Moreover, since I'm an idiot, I bought memantine prematurely for it's purported upregulation, yet out of frugality, I scour the literature in vain to make some use of it--preferably with least insult to cognition.

[penisbreath]

Rol82 - I've enlisted your help once or twice before, and appreciated the depth of your knowledge. My treatment history is extremely arduous and longwinded, and I won't go into too much detail here, but after nearly 3 years of battling, I am finally on the verge of being correctly diagnosed as suffering from comorbid inattentive ADD and OCD. The hoops and misdiagnoses I've had to jump through to have my condition recognized here in the Southern hemisphere have been more than taxing, and pushed my patience/sanity/faith to heretofore unexpressed limits.

I am just awaiting the results of some neuropsychiatric testing to round things off. Anyway, I know you have written before that the best way to treat the condition would be the cautious addition of a psychostimulant to an SSRI. I was curious if you thought a particular SSRI might be best suited to augmenting a stimulant (I'm guessing Dexamphetamine would be the ideal choice)?

I have tried Luvox before but for some reason experienced severe Restless Leg Syndrome on it.

I was also curious about options for sleep. I have used Mirtazapine in the past, but found it exacerbated my OCD at 30mg (though not 15mg).

Do you think an SSRI + stimulant + Remeron for sleep might be a wise treatment plan?

[TheFountain]

With the inclusion of each, there is an increase in the chance of side effects, and because of this, I am careful to monitor markers of health through regular blood testing (either ordered by a physician or secured through an online acquired requisition form), examination, and through a diligent health diary.

Shouldn't it be necessary to report your experimental doses of pharmaceuticals to your health care physician if, as you say, 'regular blood testing' is to help you determine whether or not any would be side effects are the result of said combination? Are you doing this?

[Rational Madman]

Rol-
a couple of questions if I may ask:

are you using cabergoline just for glutathione or/and to hit D1 receptors? Have you ever considered pergolide for stronger D1 agonism, if so, what turned you off to it besides fibrosis? I procured cabergoline to use intermittently due to its anticholinergic properties and potential fibrosis, so I am currently on pramipexole--negligible D1 agonism, but a dopamine agonist nonetheless.

You haven't found a reputable choline source to be sufficient enough without recourse to AChE inhibitors? I am wary to take pharmaceutical AChEIs. However, I'm extremely interested in nAChR upregulation; I reckon I'm too young to fool around with AChEIs, but if you notice a difference, perhaps I'll give it a go since you are my age.

Moreover, since I'm an idiot, I bought memantine prematurely for it's purported upregulation, yet out of frugality, I scour the literature in vain to make some use of it--preferably with least insult to cognition.

Cabergoline has several utilities, and the synthesis of glutathione is one of many. However, I've decided to decrease the frequency of my use, because I'm no longer convinced that it's a very necessary, or worthwhile component. Like other Parkinson's drugs, its binding affinity at the D1 site is negligible, and would not be a suitable candidate if the D1 site was the primary pharmacological target for therapy. Presently, I maintain a daily dosage of 5-10 mg of Donepezil, which has yielded noticeable effects on certain categories of memory, but because of the absence of profound neurodegeneration, I don't expect (nor should anyone) the results to be comparable to the outcomes of administration to Alzheimer's subjects. There are some grounds for worrying about unwanted neurochemical alterations in healthy subjects, but I haven't encountered any data or a theoretical conflict that I consider to be worrisome enough to force a reevaluation. For the upregulation of nAChR, it would be premature to look to acethylcholinesterase inhibitors, because there isn't enough data on the dosage requirements for upregulating this site, and in subjects with a pathological alteration in receptor behavior, the results of administration have been mixed. Further, I would cease your dalliance with Memantine, since it's likely a dead end, and because my rationale for this position should already be painfully clear to those that follow my postings. Finally, you're clearly not an idiot, so dispense with the self-depreciation, because it's destructive, and not in anyway amusing.

Edited by Rol82, 27 October 2010 - 03:42 AM.

[Rational Madman]

With the inclusion of each, there is an increase in the chance of side effects, and because of this, I am careful to monitor markers of health through regular blood testing (either ordered by a physician or secured through an online acquired requisition form), examination, and through a diligent health diary.

Shouldn't it be necessary to report your experimental doses of pharmaceuticals to your health care physician if, as you say, 'regular blood testing' is to help you determine whether or not any would be side effects are the result of said combination? Are you doing this?

If I have reason for concern about potential interaction problems or health complications associated with use, I either consult the literature, or hypothetically propose the combination to my psychiatrist---since we often spend sessions discussing matters not ostensibly germane to my case. In any case, I appreciate your concern, but I'm cognizant of the potential risks involved, and have been careful to state that interested parties shouldn't carelessly imitate my drug regimen. In a perfect world, I would be completely candid about the full extent of my drug regimen, but because my polypharamaceutical approach is unorthodox, and would be frowned upon by a medical establishment that deems patient safety to be paramount, I'm not going to present my psychiatrist with a dilemma or problem that might place his career in disrepute. Instead, I've decided to assume complete ownership of my decision.

Edited by Rol82, 27 October 2010 - 11:07 PM.

[Rational Madman]

Rol82 - I've enlisted your help once or twice before, and appreciated the depth of your knowledge. My treatment history is extremely arduous and longwinded, and I won't go into too much detail here, but after nearly 3 years of battling, I am finally on the verge of being correctly diagnosed as suffering from comorbid inattentive ADD and OCD. The hoops and misdiagnoses I've had to jump through to have my condition recognized here in the Southern hemisphere have been more than taxing, and pushed my patience/sanity/faith to heretofore unexpressed limits.

I am just awaiting the results of some neuropsychiatric testing to round things off. Anyway, I know you have written before that the best way to treat the condition would be the cautious addition of a psychostimulant to an SSRI. I was curious if you thought a particular SSRI might be best suited to augmenting a stimulant (I'm guessing Dexamphetamine would be the ideal choice)?

I have tried Luvox before but for some reason experienced severe Restless Leg Syndrome on it.

I was also curious about options for sleep. I have used Mirtazapine in the past, but found it exacerbated my OCD at 30mg (though not 15mg).

Do you think an SSRI + stimulant + Remeron for sleep might be a wise treatment plan?

The proposed combination is sound, and I would proceed if there is an urgency for results.

[Rational Madman]

Well dam, that's like finding out the world isn't flat after all these months, haha. Thanks a lot for clearing that up Medievil

Still 5HT2A antagonism can be a good thing in some types of depression, but for those suffering from anhedonia or lack of energy its definatly a no go, i beleive that 5HT2A agonism is a highly interesting target hence my intrest in lisuride.

You'll have to excuse my oscillatory mind, but I'm beginning to have doubts about the merits of 5ht2a antagonism as well, and the mechanism of the tetracyclics, which also have an affinity for adrenergic receptors. A blockade of either is linked to an impairment of working memory. So, I'm re-examining the SSRIs, which have the advantage of inducing oxytocin synthesis, and positively influencing opioid pathways and the circadian rhythym. After consulting the literature, I may toy around with doses---starting at a low base---and make some other calibrations. Presently, I think the Sigma 1 agonists are probably still the best within this class. But, if forced to choose, would you choose Lexapro, or Luvox? Monotherapeutic SSRI use is a daft idea, but combined with other agents, much more efficacious. However, I'll have to reconsider my use of Tianeptine, since they aren't exactly synergistic. So, now I have greater motivation to try Valdoxan, but has anyone found a good price? The best I've found is $90 for 28 pills, which is a cost that may exceed the benefits. I'll try alibaba.com tonight, and see if I can find anything interesting.

WHat are you taking SSRI's for? Depression?

Well, yes, that's the prescribed purpose, but I'm also interested in the aforementioned benefits. Pending further research, I may reintroduce an SSRI, but probably not at the previous dosage of 150 mg.

Why don't you use sertraline or citalopram? I know you didn't appreciate sertraline's mild antagonism for the sigma receptor(I believe to be negligable) If you feel strong about this then you can start with low dose Citalopram eg.10mgs/day
Both of these have been shown to increase BDNF expression globally in the brains of mice(Huntington's disease model) and not just the hippocampus.

I'm using Fluvoxamine because of its affinity for the serotonin transporters. As for the relative neurotrophic properties of antidepressants, they all promote the global expression of neurotrophic factors--but these effects aren't noted in every study. And why would you suggest Celexa over Lexapro, since their structures are extremely similar, and since the latter is simply an updated form of the former?

I guess they all do to a degree in theory Rol, however sertraline and citalopram has been specifically tested and marked levels of BDNF has been measured in mice of course.I'm aware of the business aspects and celexa and zoloft are old drugs so I doubt their agenda is trying to resurect declining sales of these ssri's as appposed to something that never really took off as the flavour of the year like Luvox.I dont doubt that Luvox is a great SSRI but the scientists chose these 2 for specific reasons.
Also many drug studies are done with Citalopram, even now.

I talked to a few Neuropsychiatrists and a movement disorder Neurologist and they all prefer the administration of citalopram over escitalopram.The notion that the cleaner Entaniomer of a chemical delivers the same efficacy with deminished adverse effects is just a plain business ploy IMO. You can see this with Methylphenidate compared to Dexmethylphenidate and Venlafaxine -Desvenlafaxine.
I heard on many ocassions that people were more compliant and experienced less adverse effects with venlafaxine as opposed to Dex.I cannot coment on Citalopram except that from my understanding it is supposedly less likely to cause as much weight gain compared to Escitaloprm.

The Neuropsychiatrists and Neurologist administer it all the time to stroke patients or elders that presented with pseudo dementia and they have found that once therapeutic blood levels have been stable for a few months that these elders were living a finer quality of life without any dementia symptoms.
They all hold the belief that these small doses of SSRI's will do nothing to relieve depression or dampen the overactive cingulate circuits.

I dont like SSRI's period but they expressed that I wont even start feeling any relief or improvement with anergia,attention problems,cognition, improved sleep and mitigation of OCD, depression and anxiety until I reach 40mgs of citalopram or 200mgs of sertraline.
I was shocked that one Neuropsychiatrist who had a great deal of experience with SSRI's actually told me he found more patients reported less brain fog on Citalopram as opposed to sertraline?

I was always under the impression that sertraline would have a better profile with cognition due to it's slight Dopamine RI properties at does of 100mgs or more which I know is still negligible compared to other DRI's like Methylphenidate or some of the other Stim's. I guess it varies with different individuals and their brain chemistry but in my experience citalopram had less activation and more fatigue/apathy then sertraline or fluoxetine.

What benefits have you found with fluvoxamine as far as cognition and adverse effects? I recall you stating that it wasn't as mind clouding.How was your sleep on it?Also I recall that you liked it's Sigma properties.

Do you still like the cognitive nurturing properties of a good dose of Mirtazapine and have you decided to revisit yet?

It seems as if I may have some good news.I sent all 7 of my MRI's and 2 CTA's to one of the best Neuroradiologists in the Nation and his finding was that of a cavernous angioma measuring 8mm x 3mm.There is no volume loss and no mass effect.Cav-malformations usually dont involve any parenchymal tissue and are very slow flow and are not connected directly to an artery or arteriole.They are a group of thin weak walled capillaries that can ooze out blood and cause seizures,headache and other neurological symptoms or can be asymptomatoic forever.

The Head of the Left Caudate is a very elequent area and you dont get seizures when a bleed occurs there but you can experience memory and attention problems,stuttering,OCD,slight right sided weakness.It's also a very risky area to operate in as it is in midbrain and even in the hands of a skilled surgeon you may have more problems than you started off with.
The Cavernoma is resected usually interhemispherically through the top of the skull and through the genu of the corpus callosum, which the surgicentres will tell you there are silent areas.This is very doubtful.

My scans reveal low signal intensity on all iron sensitive sequences especially Gradient Echo and SWI.No lesion demonstration on CT as it's too small.It is far to small to be a caudate hemorrhage as these present with a hyperattenuation at about 2cm or larger. they usually present together with the putamen and can also be seen as a straitocapsular hemorrhage that mostly always bleeds into the lateral ventricles.

As far as microhemorrhages thye are very rare in the head of the Caudate nucleus, they are rarely solitary, measure usually 4mm and less and occur from a long standing history of hypertensive disease and NOT from a few weeks of hypertensive surges.

DDx include cappilary telangectasia or a neoplasm which my lesion is not.

If I do decide to go through with surgery it will be only to avoid further rebleeding so that I can do a safe and propper benzo taper this time.I will be using an SSRI with the least amount of BP elevation and vasoconstrictive effects which will be Citalopram, Trileptal as opposed to Neurontin,clonodine and a cross over from alprazolam to clonazepam or Diazepam. I will be using Magnesium and L-Taurine and my other bag of tricks to control glutamate and Calcium Influx.I may entertain the usage of Memantine if I really do need it.

As I approach the last 1mg of clonazepam or diazepam I will be using compounded solutions as to be able to make tiny decrements each week.

I have a long journey as I've been plagued by these toxic drugs since first given after my 2nd concussion in 1995, but the knowledge I've attained will go a long way to help me succeed once and for all.

If I was compelled to only use an SSRI, I might consider Sertaline, but since this is not the case, its effects on the volume of other amines is of little importance. When combined with the other drugs in my cocktail, there are no discernible adverse effects that might alter my cost/benefit assessment. Most antidepressants should have a positive impact on circadian patterns, but I'm not prepared to comment on their relative quantitative effects---since I've had little cause to delve into the subject. I can only tell you that empirical data supports the efficacy of Fluvoxamine for many indications, and that it has gained considerable currency for its efficacy as a treatment for obsessive-compulsive depressives. As much as I would like to render assistance in your case, I have the humility to admit that it might be outside of my grasp, since I'm not a trained professional, nor comfortable with lending advice in very delicate cases of brain injury. I can only suggest that you consult a well credentialed professional, and heed their advice if you consider it to be without question.

Edited by Rol82, 27 October 2010 - 04:40 AM.

[Rational Madman]

Okay, it has been quite some time since I've written about my regimen, and this should be interpreted as a rather positive development. Because it represents an indication of feeling qualitatively better, and in all honesty, I am feeling subjectively better. I for instance, no longer feel compelled to spend hours obsessing about my health, there has been an improvement in all symptom categories, and as a consequence, I'm living a happier and more productive life. Will my regimen work for everyone? Probably not. Am I doing something right? It's very likely. Do I care to spend hours determining the causative weight of each component. Not particularly. What have I learned from experience? Supplements and medication certainly help a great deal, but not enough of an emphasis is being placed on addressing environmental variables. Which means that most subjects should consider behavioral therapy, diverse environments, a rich social life, and a rewarding career of purpose to be especially worthy remedies. But since this is a thread on my regimen, I suppose I'll provide a detailed update of where I'm at presently.

Diet: I'm not as fanatical as I used to be, combining pleasurable foods with exceptionally healthy foods daily. I'm not a practitioner of calorie restriction (nor do I have the slightest interest in doing so), I don't exclude items from my diet because of unfounded suspicions about ostensible intolerances, and I don't force myself to eat copious amounts of fruits and vegetables. Rather, I eat fish and lamb for protein on most days, I satisfy my caloric needs, use very liberal amounts of spices, use olive oil as a condiment in most meals, drink a lot of tea and water (but a good amount of diet soda as well), eat a lot of chocolate (at least 85% cocoa), eat a jar of artichokes or a bag of freeze dried kale daily, enjoy a bag or two of frozen cranberries, will usually have some French pastries, drink about a carton of almond milk, smoke a pipe or cigar without fail, religiously drink wine and single malt scotch in the evening, eat a small amount of grains, and usually consume two or three sweet potatoes. So that's it, there's nothing really exceptional about my diet, I won't subject myself to the madness of measuring calories, I eat when I'm hungry, and usually most of my food is prepared by restaurants.

Exercise: Not very rigorous, just a brisk walk in the park with my dog and girlfriend, or maybe some friends on most days. On the weekends, I've been playing intense games of basketball with some buddies, I may sometimes lift weights, and when I feel up to it, I play racquet sports.

Supplements: Krill oil, Green/White Tea Extract, Ortho Mind, Glycocarn, Arginine, Magnesium Orotate, Ortho Core, Curecumin, RevGenetics' Nitro-Mx, Rev Genetics' Astral Fruit-C, Methylcobalamin, Vitamin K2, and Aleve.

Medication: Luvox, Donepezil, Strattera, Vyvanse, Rasagiline (occasionally), Modafinil, and sometimes Trazodone for sleep.

So take what you will from all of this....
But my very casual approach to my regimen should be telling.

Edited by Rol82, 20 November 2010 - 09:49 AM.

[rwac]

I take it you never had reason to try the valproate ?

[Rational Madman]

I take it you never had reason to try the valproate ?

Well, it just seemed kind of superfluous. I made a decision to limit the number of medications that I was taking, and Valproate just didn't make the cut. Everything that I'm taking is neurotrophic, which beyond Valproate's mood stabilizing properties, is why a number of people take similar agents---like Lithium. But I would still endorse it as a cheap neuroprotectant. However, be careful with the dosing.