![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 10 of 10. This is the beginning of the thread.
Posted by desolationrower on September 20, 2009, at 4:10:45
Maybe someones still having akathisia. i remember people with it before, maybe someone will remember/find this thread next time someone comes around asking about it, which probably won't be too long if abilify keeps getting rxed.
N-Acetyl Cysteine as a Glutathione Precursor for SchizophreniaA Double-Blind, Randomized, Placebo-Controlled Trial
Michael Berkabc, David Copolovad, Olivia Deanae, Kristy Lub, Sue Jeavonsfg, Ian Schapkaitzb, Murray Anderson-Huntb, Fiona Juddf, Fiona Katzg, Paul Katzg, Sean Ording-Jesperseng, John Littleh, Philippe Conusj, Michel Cuenodj, Kim Q. Doj, Ashley I. BushaikCorresponding Author Informationemail address
Received 16 November 2007; received in revised form 29 February 2008; accepted 3 March 2008. published online 24 April 2008.
BackgroundBrain glutathione levels are decreased in schizophrenia, a disorder that often is chronic and refractory to treatment. N-acetyl cysteine (NAC) increases brain glutathione in rodents. This study was conducted to evaluate the safety and effectiveness of oral NAC (1 g orally twice daily [b.i.d.]) as an add-on to maintenance medication for the treatment of chronic schizophrenia over a 24-week period.
MethodsA randomized, multicenter, double-blind, placebo-controlled study. The primary readout was change from baseline on the Positive and Negative Symptoms Scale (PANSS) and its components. Secondary readouts included the Clinical Global Impression (CGI) Severity and Improvement scales, as well as general functioning and extrapyramidal rating scales. Changes following a 4-week treatment discontinuation were evaluated. One hundred forty people with chronic schizophrenia on maintenance antipsychotic medication were randomized; 84 completed treatment.
ResultsIntent-to-treat analysis revealed that subjects treated with NAC improved more than placebo-treated subjects over the study period in PANSS total [−5.97 (−10.44, −1.51), p = .009], PANSS negative [mean difference −1.83 (95% confidence interval: −3.33, −.32), p = .018], and PANSS general [−2.79 (−5.38, −.20), p = .035], CGI-Severity (CGI-S) [−.26 (−.44, −.08), p = .004], and CGI-Improvement (CGI-I) [−.22 (−.41, −.03), p = .025] scores. No significant change on the PANSS positive subscale was seen. N-acetyl cysteine treatment also was associated with an improvement in akathisia (p = .022). Effect sizes at end point were consistent with moderate benefits.
ConclusionsThese data suggest that adjunctive NAC has potential as a safe and moderately effective augmentation strategy for chronic schizophrenia.
-d/r
Posted by SLS on September 20, 2009, at 7:28:59
In reply to NAC - for akathisia, posted by desolationrower on September 20, 2009, at 4:10:45
It is interesting that NAC improved negative but not positive symtoms (if I am reading the study properly).
I might start taking NAC once I see in what direction my lithium therapy is going. It is a potent antioxidant and neuroprotective. I was hoping that it might slow down the progression of tissue loss in the hippocampus.
What is glutathione important for?
- Scott
Posted by rjlockhart04-08 on September 20, 2009, at 11:45:30
In reply to NAC - for akathisia, posted by desolationrower on September 20, 2009, at 4:10:45
I twich on Geodon....that's starting make me worried.
Does Zyprexa have the same effect?
Posted by floatingbridge on September 20, 2009, at 12:38:50
In reply to Re: NAC - for akathisia » desolationrower, posted by SLS on September 20, 2009, at 7:28:59
I started NAC today. I'll follow this thread with interest. Thanks d/r.
fb
> It is interesting that NAC improved negative but not positive symtoms (if I am reading the study properly).
>
> I might start taking NAC once I see in what direction my lithium therapy is going. It is a potent antioxidant and neuroprotective. I was hoping that it might slow down the progression of tissue loss in the hippocampus.
>
> What is glutathione important for?
>
>
> - Scott
>
>
Posted by desolationrower on September 20, 2009, at 19:54:44
In reply to Re: NAC - for akathisia » desolationrower, posted by SLS on September 20, 2009, at 7:28:59
> It is interesting that NAC improved negative but not positive symtoms (if I am reading the study properly).
>
> I might start taking NAC once I see in what direction my lithium therapy is going. It is a potent antioxidant and neuroprotective. I was hoping that it might slow down the progression of tissue loss in the hippocampus.
>
> What is glutathione important for?
>
>
> - Scott
>
>it is the primary endogenous antioxidant int eh body. however, i don't think the glutathione is the only thing going on, though for bp/shiz it might important. sls did you see the stuff on NAC and Cystine-Glutamate antiporter. mostly re: cocaine (and nicotine/heroin) addiction? it reduces cue-induced responding aka reinstatement (relapse). probably by improving learning. however i see some connexion between this learning function, and reduced craving, and the ADHDi/"negative symptoms" problems. like restoring effects of stimulant to early doses, not stereotypy.
here is a paper suggesting that nmda hypofunction causes gaba interneuron deficiency, inflammation and increased oxidation (which would indicate a positive role for glutathione)[2]
hm, heres some data on connexion to adhd. which has some similar pfc dysfunctionality, and adhdi and neg sx are rather similar. [3]
i'm not totally sure its beneficial for ADHDi though. the AMP induced locomotor activation may be the goal. (and NAC has effect of stimulating Mglur2/3 receptors[1] which decreases the stim sensitization) but it does have a lot of similarities with neg sx. my mental model for AMP benefits here is basically the long time frame means you get sensitized for 'craving' normal acitivties, not the drug itself/drug ritual. so, you perform normal rewarding activities, like doing work or cleaning your room. but i'm not sure 'low reward' is the same as 'intermittent reward'. also, the role of 'stress' - tends to cause relapse/craving. but 'stress' like a deadline often helps adhdi people get their *ss in gear. but it might be a more generic sense of learning that whatever complex ritual results in a reward that is benefit of AMP treatment. and for myself, i can't imagine being addicted to something, just because intertia>>>>any desire for something. lack of risk of addiction is closely integrated with the problem.
at any rate, hypofrontality might be related to hyperactivity of glutamate. which, would be similar to the hyperactivity->hypoactivity course that people with ADHD have, especially if the glutamate is causing excitotoxic damage over time.
"Abnormal glutamate function in terminal areas of dopaminergic neurons have been hypothesized to contribute to the development of ADHD (13). Methylphenidate and amphetamine affect dopamine and norepinephrine pathways crucial to frontal lobe function (14) and have been shown to increase extracellular dopamine in the brain by blocking dopamine reuptake following glutamate-stimulated release of dopamine in the nucleus accumbens (13, 15, 16). Dopamine acting on D4 receptors inhibits glutamate release from prefrontal cortical afferents in the nucleus accumbens (13). One could speculate that reduced dopamine in the nucleus accumbens could lead to increased glutamate in the prefrontal cortex and that treatment with stimulants could, in turn, lead to reductions in glutamate in the prefrontal cortex." [4]
and NAC blocks cortex glutamate excess from pcp [5] (note: it also increases glut levles to normal in cocaine w/d)
anyway given its broad spectrum of benefits (bipolar depression, OCD, negative sx, AMP neurotoxicity, etc.) its def. one of my top chemicals. maybe for GAD too, mglur2/3 drugs have been tested there too, and the improved extinction learning would be good for combating anxieties.
papers:
[1]N-Acetylcysteine reverses cocaine-induced metaplasticity.Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in cortico-accumbens circuitry crucial for regulating motivated behavior. We found that rats withdrawn from cocaine self-administration had a marked in vivo deficit in the ability to develop long-term potentiation (LTP) and long-term depression (LTD) in the nucleus accumbens core subregion after stimulation of the prefrontal cortex. N-acetylcysteine (NAC) treatment prevents relapse in animal models and craving in humans by activating cystine-glutamate exchange and thereby stimulating extrasynaptic metabotropic glutamate receptors (mGluR). NAC treatment of rats restored the ability to induce LTP and LTD by indirectly stimulating mGluR2/3 and mGluR5, respectively. Our findings show that cocaine self-administration induces metaplasticity that inhibits further induction of synaptic plasticity, and this impairment can be reversed by NAC, a drug that also prevents relapse.
[2]
An imbalance in the redox-state of the brain may be part of the underlying pathophysiology in schizophrenia. Inflammatory mediators, such as IL-6, which can tip the redox balance into a pro-oxidant state, have been consistently found to be altered in schizophrenia patients. However, the relationship of altered redox-state to altered brain functions observed in the disease has been unclear. Recent data from a pharmacological model of schizophrenia suggest that redox and inflammatory imbalances may be directly linked to the pathophysiology of the disease by alterations in fast-spiking interneurons. Repetitive adult exposure to the NMDA-R antagonist ketamine increases the levels of the proinflammatory cytokine interleukin-6 in brain which, through activation of the superoxide-producing enzyme NADPH oxidase (Nox2), leads to the loss of the GABAergic phenotype of PV-interneurons and to decreased inhibitory activity in prefrontal cortex. This effect is not observed after a single exposure to ketamine, suggesting that the first exposure to the NMDA-R antagonist primes the brain such that deleterious effects on PV-interneurons appear upon repetitive exposures. The effects of activation of the
IL-6/Nox2 pathway on the PV-interneuronal system are reversible in the adult brain, but permanent in the developing cortex. The slow development of PV-interneurons, although essential for shaping of neuronal circuits during postnatal brain development, increases their vulnerability to deleterious insults that can permanently affect their maturational process. Thus, in individuals with genetic predisposition, the persistent activation of the IL-6/Nox2 pathway may be an environmental factor that tips the redox balance leading to schizophrenia symptoms in late adolescence and early adulthood.
http://papers.cnl.salk.edu/PDFs/Does%20Schizophrenia%20Arise%20from%20Oxidative%20Dysregulation%20of%20Parvalbumin-Interneurons%20in%20the%20Developing%20Cortex_%202009-4143.pdf[3]
Glutamatergic changes with treatment in attention deficit hyperactivity disorder: a preliminary case series.
J Child Adolesc Psychopharmacol 2002 Winter;12(4):331-6
"Magnetic resonance spectroscopy, a noninvasive neuroimaging method, is a technique with the potential to measure in vivo neurochemical changes to different medication treatments. Symptoms of attention deficit hyperactivity disorder (ADHD) improved in two children treated with methylphenidate and two children treated with atomoxetine, for whom pre- and posttreatment proton magnetic resonance spectroscopy examinations were obtained to assess the relation between the neurochemical profiles in the striatum and prefrontal cortex among symptom severity and response to treatment. In the striatum, a striking decrease in the glutamate/creatine ratio (mean change 56.1%) was observed between 14 and 18 weeks of therapy in all four children with ADHD. In the prefrontal cortex, however, changes in the glutamate/creatine ratio were noted only in subjects receiving atomoxetine, not in those receiving methylphenidate. These data suggest that in vivo magnetic resonance spectroscopy measurement has the potential to assess response to psychopharmacological treatment in children with ADHD." [Abstract]
http://scholar.google.com/scholar?hl=en&lr=&cluster=6993088770786227990&um=1&ie=UTF-8&ei=1be2Sou-HtLU8Abvi4zNDQ&sa=X&oi=science_links&resnum=1&ct=sl-allversions[4]
http://ajp.psychiatryonline.org/cgi/content/full/163/2/316[5]
Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystineglutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystineglutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by N-acetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystineglutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystineglutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystineglutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystineglutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP.
http://www.nature.com/npp/journal/v33/n7/abs/1301532a.html
-d/r
Posted by floatingbridge on September 20, 2009, at 22:11:23
In reply to Re: NAC - for akathisia - expansion (long), posted by desolationrower on September 20, 2009, at 19:54:44
Posted by SLS on September 20, 2009, at 22:32:12
In reply to Re: NAC - for akathisia - expansion (long), posted by desolationrower on September 20, 2009, at 19:54:44
Posted by g_g_g_unit on September 26, 2009, at 4:13:19
In reply to Re: NAC - for akathisia - expansion (long), posted by desolationrower on September 20, 2009, at 19:54:44
i *really* want to try this for OCD. is the pulmonary hypertension still a big concern?
Posted by desolationrower on September 30, 2009, at 0:35:22
In reply to Re: NAC - for akathisia - expansion (long), posted by g_g_g_unit on September 26, 2009, at 4:13:19
hm, i went and looked for anything new. i would say its unclear. i haven't seen much in the way of new research.
using mouse size[1] data, and the pulmonary heart thing study [2] i estimate 60mg NAC/mouse/day. a 75kg human is 2500x as big, so a daily dose of 150g. mouse metabolism adjustment factor (based on lore) of 6x is 25g/day. which is about 10x as much as a high dose.
but this study indicates some markers of hypoxia occuring at more reasonable doses [3] although they see it as normalizing things which are going out of line. maybe getting some free-radical generating excercise is important here or something. and normalizing might be also what is going on for someone using it who has symptoms like ocd/schizophrenia/whatever.
ace inhibitors (otc options include pomegranite juice and to a lesser extent tea) stop hypoxia-induced pul.h[4] egcg (green tea) also seems so direclty inhibit the HIFalpha that is downstream of the NO mediated NAC effect and on balance i think it would reduce the risk. [7][8] dhea also prevents remodeling, maybe.
NAC has mixed effects on overal cardiac function, see review:[5] maybe something to do with glutathione levels
but this 'replaces the effect of chronic intermittent hypoxia: "CIH decreased the reduced-to-oxidized glutathione ratio and increased the relative amount of PKC isoform- in the particulate fraction; NAC prevented these effects. The expression of PKC- was decreased by CIH and not affected by NAC"[6] i'm not sure whre it fits in.
mortality data shows no change in anything i could find either.
maybe taking an NSAID would mimick the enos negative rats that didn't have the PH response to NAC [9] However, NSAIds block pgi2 creation(from w-6), and pgi3(from w-3).
[1]mouse info: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1397713
[2] S-Nitrosothiols signal hypoxia-mimetic vascular pathology
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17786245[3]http://bloodjournal.hematologylibrary.org/cgi/content/full/99/5/1552
[4] http://ajrccm.atsjournals.org/cgi/content/abstract/157/5/1423
[5] http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1884975
[7] http://mct.aacrjournals.org/content/5/5/1227.abstract
[8] http://linkinghub.elsevier.com/retrieve/pii/S0891584907007290
[9]http://jpet.aspetjournals.org/cgi/content/full/326/3/745#FIG2
also of interest: http://0-ajpheart.physiology.org.library.pcc.edu/cgi/content/full/294/2/H570
original articles for reference:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1952645
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1952618-d/r
Posted by SLS on September 30, 2009, at 5:54:12
In reply to Re: NAC - for akathisia - expansion (long), posted by desolationrower on September 30, 2009, at 0:35:22
Increased levels of glutathione and neuroprotection is seen with:
- Lithium
- Depakote
- Lamictal
- Tegretol
- Scott
This is the end of the thread.
Psycho-Babble Medication | Extras | FAQ
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.org
Script revised: February 4, 2008
URL: http://www.dr-bob.org/cgi-bin/pb/mget.pl
Copyright 2006-17 Robert Hsiung.
Owned and operated by Dr. Bob LLC and not the University of Chicago.