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Discussion Starter · #1 ·
I have found tianeptine to be a useful drug, and take it as needed for when i expect to have a period of anxiety (like when i started my new job, id take one before work and get through pretty good.)

Any theories as to why tianeptine works as good as/better than SSRIs?

I mean serotonin turnover is supposed to be already INCREASED in despressives, and tianeptine increases serotonin turnover.

My theory is increased uptake leads to increased release later on. Any thoughts?
 

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I read about it at google, sounds interesting, Ive tried many antidepressants for depression with no success, dont know if it would work taken only as needed, remember that we SA sufferers usually get a strong placebo effect
 

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I just started this med a few days ago for depression. if it does anything for anxiety that would be great.
i will report back.
 

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I'm taking tianeptine (coaxil) 12,5 mg x 3. It's good med for people who don't tolerate SSRI (like me).
 

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Today I have taken 25mg so far and I notice the effect of the med feels similar to amphetamines.

It has a slight tranquilizing aspect to it but also slightly activating. No side effects to speak of.
 

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Discussion Starter · #7 ·
does downregulation occur with "good" receptors when using agonists like Remeron?
 

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3) It would be upregulation, not downregulation, as mirtazapine is an antagonist.
Are you saying that mirtazapine is upregulating the 5HT2a, 5HT2c and 5HT3 receptors? or am I reading that wrong. Because today my doctor was saying something about how the selective 5HT antagonsim is actually stimulatory to serotonin, through some feedback loop, or something that didn't make a whole lot of sence.
 

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does downregulation occur with "good" receptors when using agonists like Remeron?
Remeron blocks specific serotonin receptors. Most of those it blocks are considered bad for mood, hence its antidepressant effects. Serotonin antagonism isn't the only thing it does, however.

As for downregulation, I vaguely remember reading that it downregulates 5-HT2A and 2C, but other sources say it's not as simple as that. I don't really know. You'd normally expect receptors to upregulate in the presence of an antagonist, to preserve homeostasis.

Because today my doctor was saying something about how the selective 5HT antagonsim is actually stimulatory to serotonin, through some feedback loop, or something that didn't make a whole lot of sence.
Research suggests 5-HT2C receptors are involved in this:

http://www.ncbi.nlm.nih.gov/pubmed/15138437

"...the nonselective 5-HT2 receptor antagonist ketanserin was observed to produce a robust augmentation of citalopram-, fluoxetine-, and sertraline-induced elevations of hippocampal extracellular serotonin levels. Similar effects were also observed in cortex. The potentiation of SSRI-induced increases in hippocampal serotonin levels was reproduced by the 5-HT(2C) receptor-selective antagonists SB 242084 and RS 102221, but not by the 5-HT(2A) receptor-selective antagonist MDL 100 907. Although 5-HT(2C) receptor antagonists augmented the actions of SSRIs, they had no effect on extracellular serotonin levels or tail suspension responses when administered alone. [...]"

This implies SSRIs normally self-inhibit via 5-HT2C, until it downregulates.

There's also this:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2129095

"...A single pre-testing injection of the SSRIs citalopram or fluoxetine significantly increased fear expression. There was no effect of the antidepressant tianeptine, or the norepinephrine reuptake inhibitor, tomoxetine, indicating that this effect is specific to SSRIs. The SSRI induced enhancement in fear expression was not blocked by tropisetron, a 5-HT3 receptor antagonist, but was blocked by SB 242084, a specific 5-HT2C receptor antagonist. [...]"

In agreement with this, SSRI & mirtazapine combos are said to produce significantly less anxiety/depression initially, and start working sooner than SSRIs alone. 5-HT2C blockade may augment SSRI-induced 5-HT increase, but it is also known to have other effects such as boosting dopamine & noradrenaline in certain areas of the brain. 5-HT2C probably isn't the only player in SSRI adjustment periods though, 5-HT1A autoreceptors are already proven to be of importance here, and who knows what else...
 

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Basically, if those studies are correct in their hypotheses, it's like this: SSRI increases serotonin which hits 5-HT2C receptors, resulting in 5-HT2C receptors decreasing the level of serotonin somehow (along with other negative effects) and ultimately limiting the efficacy of SSRIs. Over time, this "indirect agonism" of 5-HT2C by SSRIs downregulates these receptors and their negative effects diminish, allowing the SSRI to operate [relatively] unimpeded. This isn't likely to be the only process necessary in the "adaptation phase", but definitely an important one.

The first article I quoted shows that 5-HT2C antagonists alone didn't increase serotonin, but greatly potentiate the increase caused by SSRIs when taken together. This suggests that the SSRI is limiting its increase in serotonin levels through the 5-HT2C receptor, and this can be blocked by antagonists of that receptor (or by completely removing the gene for it).

The second article demonstrates how taking an SSRI alone increases levels of fear, but this effect is fully blocked by a 5-HT2C antagonist. We can assume fear correlates with levels of anxiety / depression / negative emotion in general, which are all things encountered in SSRI initiation. Based on this it's fair to say a 5-HT2C antagonist would eliminate a large amount of SSRI initiation side-effects such as anxiety & depression.

I'd assume that even though 5-HT2C downregulates with SSRIs, it will still be limiting their benefits to some extent even in chronic treatment. Evidence for this is in the highly effective "Rocket Fuel" type combos, which block that receptor.
 

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Discussion Starter · #12 ·
I'd assume that even though 5-HT2C downregulates with SSRIs, it will still be limiting their benefits even in chronic treatment. Evidence for this is in the highly effective "Rocket Fuel" type combos.
"Rocket Fuel" combos???

Please enlighten me
 

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I've tried an NRI with mirtazapine, and didn't feel any different than just mirtazapine alone. Remeron is highly effective at dealing with depression, but I'm not sure how efficacious the California Rocket Fuel combo is on top of that...
 

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"Rocket Fuel" combos???

Please enlighten me
I was referring to any combination of mirtazapine and an SSRI/SNRI. "California Rocket Fuel" itself means what Medline said, but the benefits of such a combination aren't limited to just those two meds.

I've tried an NRI with mirtazapine, and didn't feel any different than just mirtazapine alone. Remeron is highly effective at dealing with depression, but I'm not sure how efficacious the California Rocket Fuel combo is on top of that...
That's because you were missing out the crucial increase of serotonin. You need to use an SSRI or SNRI with mirtazapine to achieve the same kind of results Rocket Fuel delivers.

On the face of it venlafaxine + mirtazapine would seem to give a large boost to noradrenaline, being that both drugs target this neurotransmitter. However, venlafaxine is stronger on serotonin than noradrenaline, making its classification of SNRI somewhat vague. Mirtazapine also has relatively weak adrenergic effects. For these reasons, I'd say be careful extrapolating expectations of a venlafaxine + mirtazapine combo to other SNRI drugs like duloxetine, or even NRIs. They may be a lot more stimulating than Californian Rocket Fuel.
 

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I was referring to any combination of mirtazapine and an SSRI/SNRI. "California Rocket Fuel" itself means what Medline said, but the benefits of such a combination aren't limited to just those two meds.

That's because you were missing out the crucial increase of serotonin. You need to use an SSRI or SNRI with mirtazapine to achieve the same kind of results Rocket Fuel delivers.

On the face of it venlafaxine + mirtazapine would seem to give a large boost to noradrenaline, being that both drugs target this neurotransmitter. However, venlafaxine is stronger on serotonin than noradrenaline, making its classification of SNRI somewhat vague. Mirtazapine also has relatively weak adrenergic effects. For these reasons, I'd say be careful extrapolating expectations of a venlafaxine + mirtazapine combo to other SNRI drugs like duloxetine, or even NRIs. They may be a lot more stimulating than Californian Rocket Fuel.
I was on Celexa, Strattera and Remeron......
 

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However, venlafaxine is stronger on serotonin than noradrenaline, making its classification of SNRI somewhat vague.
I'm guessing it's a bit decieving due to it's double metabolism, I think venlafaxine itself only has a 5HT:NE ratio of 1:30, however it's active metabolite desvenlafaxine has a ratio of 1:10, and I think something like 70% of the benefit comes from it's metabolism into desvenlafaxine.
 
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