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#31 fishinghat

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Posted 16 November 2021 - 10:03 AM

That is a good point. If my memory serves me correctly I believe I have read studies to that effect. I will see what I can find (hopefully) later today.


#32 fishinghat

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Posted 17 November 2021 - 10:30 AM

Per your request...

 

J Biol Chem. 2014 Sep 5; 289(36): 25177–25185. 
 
Synergistic Regulation of Glutamatergic Transmission by Serotonin and Norepinephrine Reuptake Inhibitors in Prefrontal Cortical Neurons*
 
We found that low dose SNRIs, by acting on 5-HT1A and α2-adrenergic receptors, synergistically reduced AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents and AMPAR surface expression in prefrontal cortex pyramidal neurons via a mechanism involving Rab5/dynamin-mediated endocytosis of AMPARs.  Moreover, the depression of AMPAR-mediated excitatory postsynaptic currents by SNRIs required p38 kinase activity, which was increased by 5-HT1A and α2-adrenergic receptor co-activation in an activator of G protein signaling 3-dependent manner. These results have revealed a potential mechanism for the synergy between the serotonin and norepinephrine systems in the regulation of glutamatergic transmission in cortical neurons.
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Int J Clin Exp Pathol. 2015; 8(11): 15454–15461. 
 
Effects of duloxetine on microRNA expression profile in frontal lobe and hippocampus in a mouse model of depression
 
A significant upregulation of miR-132 and miR-18a in hippocampus in the duloxetine treatment group compared with model group, whereas the levels of miR-134 and miR-124a were significantly downregulated. Furthermore, miR-18a showed significant upregulation in frontal lobe in the duloxetine treatment group relative to model group. Our data showed that miRNA expression profile in frontal lobe and hippocampus was affected by duloxetine in mice model of depression. The effect was especially pronounced in the hippocampus, suggesting that hippocampus might be the action site of duloxetine, which presumably worked by regulating the expression of miRNA levels.
 
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Phantosmia and SSRI Discontinuation Syndrome A frustrating change of perception
 
There has been research linking phantosmia with a depressed level of the inhibitory GABA in the CNS. In addition, there have been unrelated research projects linking SSRI/SNRI discontinuation with disinhibition of the excitatory glutamatergic system. Discussion of this can get lost in double-negatives, but in essence, from the perspective of many parts of the brain, GABA is a brake and glutamine is an accelerator (a grotesque simplification, but instructive).
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Chronic antidepressants potentiate via sigma-1 receptors the brain-derived neurotrophic factor-induced signaling for glutamate release.
 
BDNF has been shown by us to reinforce excitatory glutamatergic transmission in cultured cortical neurons 
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Mol Neurobiol
2017 Aug;54(6):4683-4695. doi: 10.1007/s12035-016-9992-1. Epub 2016 Jul 21.
 
Duloxetine Reduces Oxidative Stress, Apoptosis, and Ca 2+ Entry Through Modulation of TRPM2 and TRPV1 Channels in the Hippocampus and Dorsal Root Ganglion of Rats
 
Abstract
Overload of Ca2+ entry and excessive oxidative stress in neurons are the two main causes of depression. Activation of transient receptor potential (TRP) vanilloid type 1 (TRPV1) and TRP melastatin 2 (TRPM2) during oxidative stress has been linked to neuronal survival. Duloxetine (DULOX) in neurons reduced the effects of Ca2+ entry and reactive oxygen species (ROS) through glutamate receptors, and this reduction of effects may also occur through TRPM2 and TRPV1 channels. In order to better characterize the actions of DULOX in peripheral pain and hippocampal oxidative injury through modulation of TRPM2 and TRPV1, we tested the effects of DULOX on apoptosis and oxidative stress in the hippocampal and dorsal root ganglion (DRG) neurons of rats. Freshly isolated hippocampal and DRG neurons were incubated for 24 h with DULOX. In whole-cell patch-clamp and intracellular-free calcium ([Ca2+]) concentration (Fura-2) experiments, cumene hydroperoxide and ADP-ribose-induced TRPM2 currents in the neurons were inhibited by N-(p-amylcinnamoyl) anthranilic acid (ACA) and capsaicin-induced TRPV1 currents were inhibited by capsazepine (CPZ) incubations. TRPM2 and TRPV1 channel current densities, [Ca2+] concentration, apoptosis, caspase 3, caspase 9, mitochondrial depolarization, and intracellular ROS production values in the neurons were lower in the DULOX group than in controls. In addition, the above values were further decreased by DULOX + CPZ and DULOX + ACA treatments. In conclusion, TRPM2 and TRPV1 channels are involved in Ca2+ entry-induced neuronal death and modulation of the activity of these channels by DULOX treatment may account for their neuroprotective activity against apoptosis, excessive ROS production, and Ca2+ entry.
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Pharmacol Rep
. 2013;65(4):991-7. doi: 10.1016/s1734-1140(13)71080-6.
 
Involvement of NMDA and AMPA receptors in the antidepressant-like activity of antidepressant drugs in the forced swim test
 
Abstract
Background: The involvement of glutamate system (particularly the NMDA and AMPA receptors) in the mechanism of antidepressant activity was demonstrated in preclinical and clinical studies.
Methods: In the present study, we investigated the effect of NMDA and AMPA receptors' ligands (agonists and antagonists) on the antidepressant-like activity of escitalopram, milnacipran, imipramine and reboxetine in the forced swim test in mice.
Results: Antidepressant activity (reduction in immobility time) of escitalopram and milnacipran but not of imipramine and reboxetine was antagonized by N-methyl-D-aspartate acid. CGP37849 (antagonist of the NMDA receptor) enhanced the antidepressant activity of all examined antidepressants. On the other hand, CX614 (a potentiator/positive allosteric modulator of the AMPA receptor) enhanced the antidepressant activity of imipramine and reboxetine but not of escitalopram and milnacipran in this test. NBQX (the AMPA receptor antagonist) did not influence the antidepressant activity of all tested agents.
Conclusions: The data indicate the complex interactions following the activation or blockade of the NMDA and AMPA receptors with antidepressant drugs. The general phenomenon is the enhancing effect of the NMDA receptor antagonism on the antidepressant activity. Moreover, is can be concluded that the activity of antidepressants with a serotonergic mechanism of action can be inhibited by NMDA activation, while antidepressants with a noradrenergic mechanism of action are dependent on AMPA receptor transmission.
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BMC Neurosci
. 2013 Jul 29;14:75. doi: 10.1186/1471-2202-14-75.
 
Chronic treatment with agomelatine or venlafaxine reduces depolarization-evoked glutamate release from hippocampal synaptosomes
 
Abstract
Background: Growing compelling evidence from clinical and preclinical studies has demonstrated the primary role of alterations of glutamatergic transmission in cortical and limbic areas in the pathophysiology of mood disorders. Chronic antidepressants have been shown to dampen endogenous glutamate release from rat hippocampal synaptic terminals and to prevent the marked increase of glutamate overflow induced by acute behavioral stress in frontal/prefrontal cortex. Agomelatine, a new antidepressant endowed with MT1/MT2 agonist and 5-HT2C serotonergic antagonist properties, has shown efficacy at both preclinical and clinical levels.
Results: Chronic treatment with agomelatine, or with the reference drug venlafaxine, induced a marked decrease of depolarization-evoked endogenous glutamate release from purified hippocampal synaptic terminals in superfusion. No changes were observed in GABA release. This effect was accompanied by reduced accumulation of SNARE protein complexes, the key molecular effector of vesicle docking, priming and fusion at presynaptic membranes.
Conclusions: Our data suggest that the novel antidepressant agomelatine share with other classes of antidepressants the ability to modulate glutamatergic transmission in hippocampus. Its action seems to be mediated by molecular mechanisms located on the presynaptic membrane and related with the size of the vesicle pool ready for release.
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J Affect Disord
. 2013 Apr 5;146(2):262-5. doi: 10.1016/j.jad.2012.06.037. Epub 2012 Jul 25.
 
Cerebrospinal fluid levels of glutamate and corticotropin releasing hormone in major depression before and after treatment
 
Abstract
Background: Glutamate and corticotropin releasing hormone (CRH) are pro-stress neurotransmitters and may be altered in the plasma and cerebrospinal fluid (CSF) of persons with major depressive disorder (MDD). The goal of this study was to compare the CSF levels of glutamate, glutamine and CRH between patients with depression and healthy controls.
Methods: Eighteen patients with MDD and 25 healthy controls underwent a lumbar puncture (LP); CSF samples were withdrawn and assays were done for glutamine, glutamate, and CRH. Patients with MDD underwent 8 weeks of treatment with the antidepressant venlafaxine and then had a repeat LP post treatment.
Results: Patients had higher baseline scores on depression and suicide rating scales and those scales improved significantly post-treatment. Higher suicidal ratings at baseline were correlated with higher glutamate levels (p=0.016). There were no significant differences between the control and patient group in any baseline CSF measures of glutamate (p=0.761), glutamine (p=0.226) or CRH (p=0.675). Despite no significant change in glutamate (p=0.358) and CRH (p=0.331) in the treatment group, there was a post-treatment decrease in glutamine (p=0.045) in patients.
Limitations: There was a small sample size, age discordance between patients and controls, lack of a follow-up LP in controls, absence of dexamethasone suppression testing, and fluctuating sample sizes among various measures.
Conclusion: Although no significant differences were noted between patients and controls at baseline there was an association of high CSF glutamate and suicidal ideation and lower glutamine post-treatment which may be correlated with attenuation of dysfunction in the glutamatergic system after antidepressant treatment.
---------------------------------------------------------------------------------------------------------------------------https://pubmed.ncbi....h.gov/19447293/
 
Neurosci Res
. 2009 Jul;64(3):251-8. doi: 10.1016/j.neures.2009.03.009. Epub 2009 Mar 25.
 
Effects of antidepressants on GluR2 Q/R site-RNA editing in modified HeLa cell line
 
Abstract
Marked reduction of RNA editing at the glutamine (Q)/arginine ® site of the glutamate receptor subunit type 2 (GluR2) in motor neurons may be a contributory cause of neuronal death specifically in sporadic ALS. It has been shown that deregulation of RNA editing of several mRNAs plays a causative role in diseases of the central nervous system such as depression. We analyzed the effects of eight antidepressants on GluR2 Q/R site-RNA editing in a modified HeLa cell line that stably expresses half-edited GluR2 pre-mRNA. We also measured changes in RNA expression levels of adenosine deaminase acting on RNA type 2 (ADAR2), the specific RNA editing enzyme of the GluR2 Q/R site, and GluR2, in order to assess the molecular mechanism causing alteration of this site-editing. The editing efficiency at the GluR2 Q/R site was significantly increased after treatment with seven out of eight antidepressants at a concentration of no more than 10 microM for 24h. The relative abundance of ADAR2 mRNA to GluR2 pre-mRNA or to beta-actin mRNA was increased after treatment with six of the effective antidepressants, whereas it was unchanged after treatment with milnacipran. Our results suggest that antidepressants have the potency to enhance GluR2 Q/R site-editing by either upregulating the ADAR2 mRNA expression level or other unidentified mechanisms. It may be worth investigating the in vivo efficacy of antidepressants with a specific therapeutic strategy for sporadic ALS in view.
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Randomized Controlled Trial J Psychopharmacol
. 2008 Jul;22(5):473-6. doi: 10.1177/0269881107081510. Epub 2008 Jan 21.
 
Differential effects of citalopram and reboxetine on cortical Glx measured with proton MR spectroscopy
 
Abstract
The pharmacological effects of monoamine potentiating antidepressants are likely to be expressed ultimately on cortical pyramidal neurones that use glutamate as a neurotransmitter. However, there are few data on the effects of antidepressant treatment on cortical glutamate levels in humans. The aim of the present study was to use proton magnetic resonance spectroscopy (MRS) to assess the effects of short-term administration of the selective serotonin re-uptake inhibitor, citalopram and the selective noradrenaline re-uptake inhibitor, reboxetine, on a composite measure of glutamate and glutamine (Glx) in occipital cortex in healthy volunteers using a parallel group, placebo-controlled design. We found that relative both to placebo and reboxetine, seven days treatment with citalopram significantly increased cortical Glx. Our data suggest that short-term treatment with citalopram, but not reboxetine, increases occipital Glx in healthy subjects. Further studies are needed to find out if similar effects occur in anterior brain regions and whether they reflect changes in glutamate or glutamine or both.
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And many more similar articles. I you decide you want to see more articles let me know.

#33 invalidusername

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Posted 17 November 2021 - 07:24 PM

Well there is another few pages for the next eBook update :)


#34 Troypants

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Posted 18 November 2021 - 02:46 AM

Also, do you guys still recommend ashwaghanda? No bad withdrawal? Dosages?

#35 Troypants

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Posted 18 November 2021 - 02:59 AM

Yeh there ya go! Thanks for those articles, they would be a good addition to the book!

So, instead of the usual GABA desensitisation which happens in benzo withdrawal, with SSRIs we are talking about a sensitisation of glutamate activity, and particularly the AMPAR is affected by SNRIs.

#36 Troypants

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Posted 18 November 2021 - 03:23 AM

In effect, it is a similar result I guess?

#37 Troypants

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Posted 19 November 2021 - 05:52 AM

https://www.scienced...006322312009900

Another good study on glutamate and antidepressants

#38 invalidusername

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Posted 20 November 2021 - 07:47 PM

Also, do you guys still recommend ashwaghanda? No bad withdrawal? Dosages?

 

Covered somewhere in the eBook, but no withdrawals at all. Always better to opt for the finest which is KSM-66 variant. 

 

Much like anything else, dose varies from person to person. I found around 1000mg was my sweet spot. One thing to remember with Ashwagandha is that you need to take a tolerance break as the system gets used to it quite quickly. Again, it varies, but as a guide, it is recommended to take 2-3 days off every couple of weeks to maintain potency. 


#39 Troypants

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Posted 24 November 2021 - 06:39 AM

Thanks IUN, I might buy some powder.

I have been using 50mg l-theanine 2ce a night along with 300-400 NAC, seems to cut the edge off the horribleness of the evening anxiety. I take my doses during the day and by the end of the day I get worse anxiety and other crappy sensations.

I have had my hormones checked, my e2 is normal but my testosterone is below the lowest level.... 120 when it should be 150-600.

Do any of you have experience supplementing testosterone?

#40 fishinghat

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Posted 24 November 2021 - 08:35 AM

Cymbalta shut down my testosterone production and I have been on testosterone replacement therapy since 2013. Do you have some questions I can help with?


#41 Troypants

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Posted 24 November 2021 - 05:28 PM

Hey hat, yeah I was just wondering if testosterone replacement made your withdrawal easier or harder?

I wasn't sure whether the low test was from previous AAS use or from the cymbalta, but it looks more like its from the cymbalta.

#42 invalidusername

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Posted 24 November 2021 - 07:17 PM

Quite likely the cymbalta, but it will be difficult to know the true culprit.

 

Best just to keep check of it. I found that Maca root helped me a lot before opting for the allopathic route.


#43 fishinghat

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Posted 25 November 2021 - 08:59 AM

It definitely made it harder Troy. Low testosterone causes depression and too high causes a stimulation effect, higher energy, which can aggravate anxiety. It can take testosterone levels 6 weeks to stabilize after a dose change so definitely makes things harder to control.


#44 Troypants

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Posted 25 November 2021 - 06:39 PM

So you recommend just waiting till I'm off the cymbalta and see how I go? Still holding at 16 beads until I feel normal.

Might be quite a while

#45 fishinghat

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Posted 26 November 2021 - 08:40 AM

Then data my drs gave me was that testosterone usually rebounded to near normal levels within 3 months after the last dose. I emphasize "usually". Obviously that didn't happen in my case. I am sure age can play an important part as well as to whether or not you recover testosterone production or not. In addition, if the depression it may cause gets too bad you might have no choice but to go ahead with replacement therapy. If you can, I would wait until Cymbalta withdrawal was over and keep measuring your testosterone levels every 6 months. Something else you may want to do is try some supplements to increase production. I looked at that when my levels collapsed and will see if I have any research saved on my computer. I will let you know.


#46 fishinghat

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Posted 26 November 2021 - 08:43 AM

Unluckily I did not save any of my research on what supplements to use. Sorry.


#47 Troypants

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Posted 26 November 2021 - 06:06 PM

All good thanks for having a look, I just hope the lowered test isn't going to cause me to be more withdrawn. I don't want to be around people at the moment, I get foreign ideas and feelings and anxious and I hate the hypersensitivity which makes me put off signals to people that aren't me.

It took me a long time to get social, motivated, and comfortable after recreational drug rehabilitation and now I'm going through it all over again, and its not from rec drug use, its from the shit my "trusted doctor" put me on.

Isolation and lack of motivation causes depression which causes isolation and lack of motivation and on and on the cycle goes until you can't go outside... Its a scary prospect.



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