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Total serotonin activity vs. downregulation concerning longterm SSRIs

Cotcha Yankinov

Cotcha Yankinov

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I was wondering if anybody had any thoughts as to whether or not chronic SSRI use would always result in increased serotonin activity throughout a lifespan or if at some point serotonin receptors would down regulate enough to result in less serotonin activity than before ever starting SSRIs? I want to make sure that SSRIs are sustainable before I consider starting them.

Do we still see increased serotonergic metabolites (increased compared to before SSRIs) many years into SSRI therapy?
 
Cotcha Yankinov said:
I was wondering if anybody had any thoughts as to whether or not chronic SSRI use would always result in increased serotonin activity throughout a lifespan or if at some point serotonin receptors would down regulate enough to result in less serotonin activity than before ever starting SSRIs? I want to make sure that SSRIs are sustainable before I consider starting them.

Do we still see increased serotonergic metabolites (increased compared to before SSRIs) many years into SSRI therapy?
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Chronic SSRIs produce neurochemical changes that can ameliorate the symptoms of depression. But their effects on the serotonergic system begin to wear off once use is discontinued. They are not intended to alter serotonergic activity for the remainder of your lifetime.

A discontinuation syndrome can occur in some patients taking SSRIs that have short half-lives. Dizziness and electric-shock sensations happen in about 30% of patients taking paroxetine who discontinue use without tapering. But those effects can be avoided in by slow tapering or by switching to a longer-acting SSRIs such as fluoxetine.
 
I guess this over simplified scenario might illustrate my question better: let's pretend for a moment that a serotonin synapse has 10 molecules of serotonin and 10 receptors - so currently a 1:1 ratio. Now if you administered SSRIs chronically, we can assume that the serotonin concentration in the synapse will rise, but my question is will the receptors ever down regulate to out-pace the increase in synaptic serotonin (resulting in less serotonergic activity than there was before starting SSRIs) or will end result of ssri administration always be an increased ratio of synaptic serotonin to receptors and hence more serotonergic activity than there was before starting SSRIs regardless of compensatory receptor down regulation or other possible compensatory changes?
 
Cotcha Yankinov said:
I guess this over simplified scenario might illustrate my question better: let's pretend for a moment that a serotonin synapse has 10 molecules of serotonin and 10 receptors - so currently a 1:1 ratio. Now if you administered SSRIs chronically, we can assume that the serotonin concentration in the synapse will rise, but my question is will the receptors ever down regulate to out-pace the increase in synaptic serotonin (resulting in less serotonergic activity than there was before starting SSRIs) or will end result of ssri administration always be an increased ratio of synaptic serotonin to receptors and hence more serotonergic activity than there was before starting SSRIs regardless of compensatory receptor down regulation or other possible compensatory changes?
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Wouldn't downregulation of postsynaptic 5HT receptors mean being more sensitised to 5HT (since there are less receptors). Is the term you mean upregulation of postsynaptic 5HT receptors?

Also, one needs to consider autoreceptor downregulation, which I believe is the mode by which these drugs act.
 
You're also going to want to look into the other areas of the brain that some of these antidepressants work on.
Im not sure which specific drug youre looking into trying though
 
Cotcha Yankinov said:
I guess this over simplified scenario might illustrate my question better: let's pretend for a moment that a serotonin synapse has 10 molecules of serotonin and 10 receptors - so currently a 1:1 ratio. Now if you administered SSRIs chronically, we can assume that the serotonin concentration in the synapse will rise, but my question is will the receptors ever down regulate to out-pace the increase in synaptic serotonin (resulting in less serotonergic activity than there was before starting SSRIs) or will end result of ssri administration always be an increased ratio of synaptic serotonin to receptors and hence more serotonergic activity than there was before starting SSRIs regardless of compensatory receptor down regulation or other possible compensatory changes?
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The therapeutic effects of SSRIs are believed to involve 5-HT receptor downregulation. Initially, when SERT is blocked, there is increased activation of 5-HT1A and 5-HT1B/1D autoreceptors, which tends to inhibit the firing of 5-HT neurons and reduces the amount of 5-HT released in response to firing. Gradually the autoreceptors desensitize and 5-HT transmission increases. There is also eventually some desensitization of 5-HT2A, which also may play a role in the therapeutic response.

aced126 said:
Wouldn't downregulation of postsynaptic 5HT receptors mean being more sensitised to 5HT (since there are less receptors). Is the term you mean upregulation of postsynaptic 5HT receptors?
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If the receptors downregulate, then there would be fewer receptors, hence postsynaptic neurons would be less sensitive to 5-HT.
 
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So with the auto receptor down regulation in mind, do you think that the end result of SSRIs will be increased firing of serotonergic cells and that the down regulation of post synaptic receptors (compensation for increased serotonin concentrations) will never cause there to be less serotonin activity than before starting SSRIs? In other words if there was a metabolite that was made only when a serotonin cell fired, would we still find more of this metabolite in someone who has been on SSRIs for 50 years than we would find before that individual started SSRIs?

Also, are you a fan of any particular anti-depressants? Prozac increased my insomnia and just about caused a manic switch, I was thinking Citalopram would be good to try. Fingers crossed it doesn't cause insomnia but it seems both the studies and anecdotal reports show that they all cause insomnia. Thanks for any advice.
 
Mirtazapine is known to help insomniac with depression. Its not an SSRI, its an norandrenergic and specific serotonergic antidepressant that also has strong affinity for H1 (histamine) receptors which is what causes the sleepiness.
 
Cotcha Yankinov said:
So with the auto receptor down regulation in mind, do you think that the end result of SSRIs will be increased firing of serotonergic cells and that the down regulation of post synaptic receptors (compensation for increased serotonin concentrations) will never cause there to be less serotonin activity than before starting SSRIs? In other words if there was a metabolite that was made only when a serotonin cell fired, would we still find more of this metabolite in someone who has been on SSRIs for 50 years than we would find before that individual started SSRIs?
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I think the question you are asking is whether SSRIs cause the serotonergic system to be permenantly altered, so that you are less likely to be depressed even after they are discontinued? That isn't how they work, nor is it the intent of prescribing them. The mechanism for the antidepressant effects is downstream from the serotonergic system. Some of those downstream changes may persist for some time, but the effects on the serotonergic system start to reverse as soon as the SSRI is discontinued and SERT is no longer blocked. Some of the changes may take some time to reverse (SSRI induced sexual dysfunction can persist for some time) but they are not permenant.

Cotcha Yankinov said:
Also, are you a fan of any particular anti-depressants? Prozac increased my insomnia and just about caused a manic switch, I was thinking Citalopram would be good to try. Fingers crossed it doesn't cause insomnia but it seems both the studies and anecdotal reports show that they all cause insomnia. Thanks for any advice.
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Good luck!
 
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There's definitely something weird about SSRIs one should strongly investigate before trying SSRIs if you ask me. I can't give references for now, have to search again about the current state of knowledge but my own experiences were very bad on the long run, I have permanent changes from just around 2 years of venlafaxine (okay, and DXM, but I don't think that one is special in terms of being a SNRI), it has finally messed my 5-HT up. I get these horrible brain zaps all the time, just 1 single day of something serotonergic is enough currently to get a multiple of days of withdrawal symptoms. Using NMDA antagonists solves this, but on the rebound they come back - there is evidence for SSRIs to cause downstream changes in glutamate and it probably contributed to my general over-excitation - nothing one would want. Can't say if it's about gene changes or dysregulated receptors.

Of course there are many out there for which the SSRIs work. Just that I'd say the chance to catch long term effects might be as high as 50% - some get positive changes (they won't complain of course), some negatives. Would give about 25% and think this matches with what we read and hear from users. Many just stay on the SSRI for a long or infinite time or live with the symptoms, thinking it was the underlying 'disease' which I don't believe, at least not completely. Things change. You trade something for something else, unknown. In German we say to this 'you buy the cat in a bag', meaning you pay for something you can't know unless you've already paid.

I really don't know what to think about the SSRIs for now. If it's about the downstream changes, then we better make them happen directly (e.g. memantine).

Also one point might be the initial, acute reaction. Maybe we can track this down by reading reports. I think that if one gets hypomanic in the first days or weeks then it's a sign not to use SSRIs, or a weaker one. Paroxetine is very bad in this regard. Venlafaxine is a good one (acutely), but it is strongly prone to nasty long-term effects and withdrawals. Important for us males are the sexual side effects, I think they are still under-rated. So many get them, and they hardly go away.

We really should have more selective 5-HT agents available, even if they failed in the trials I'm sure they will work for some of us. 5-HT1a agonists, 5-HT2a inverse agonists, you know ...
 
My specific pondering was that in light of the possibility that MDMA abusers have increased excitability of the cortex that might be related to how serotonin is no longer inhibiting the cortex, that increased serotonergic tone might help inhibit the cortex and improve sleep.

I'm pretty sure we both indeed had the same sort of hypomanic reaction with an ssri before too... My chief reason for taking an ssri wouldn't be necessarily for depression but rather on the off chance that it might improve my sleep, which by all accounts it will not do unfortunately :( Maybe Ill just try memantine instead...
 
The combination of memantine and clonidine (as little as 50-75mcg) has been very effective for me in regards of sleep. Intend to go back on them, but I'm on Malta at the moment and they are so strict with off-label prescriptions... the doctor told me memantine is scheduled here and he needs more documents and to fill a special request for it. WTF!? Thought things were easier in the south..

Other question to the experts: Is it possible to reverse the effects of SSRI use somehow if one has them already seemingly permanent?
 
My undestanding is that long term use of SSRIs causes long term changes in the brain. Including an increased probability of repeated instances of major depression.

'We really should have more selective 5-HT agents available, even if they failed in the trials I'm sure they will work for some of us. 5-HT1a agonists, 5-HT2a inverse agonists, you know ..'
Developing a product, getting it approved and marketing is associated with very high costs. Drugs that will only work for few people won't make it to the market, unless they are for serious diseases and very high prices can be fetched.

dopamimetic,

What is the logic of taking both memantine and clonidine for sleep ? How does it work ?

'Other question to the experts: Is it possible to reverse the effects of SSRI use somehow if one has them already seemingly permanent?'
I'm not an expert but I don't think you can, except allowing for the passage of time. Some other drugs might work, but only up to a point. The brain never returns to a past state, you can only move forward. If that makes sense. Try to enjoy a healthy and normal, natural life ... easier said than done.
 
i never took the combination but memantine and clonidine are both agonist for the alpha 2 presynaptic receptor and decrease the release of noradrenaline and other neurotransmitters so they will potentiate each other
 
Do you have a source for this? To my best knowledge memantine doesn't affect norepinephrine. Also didn't notice any potentiation, it's just that memantine calms the overexcitation some people like have and thus one also sleeps better.
 
I wonder if some of the long term effects of SSRIs that people consider bad are really things such as increased hippocampal neuron density, once thought to be therapeutic for depressed people but maybe it doesn't always work out well, especially if decreased neurogenesis wasn't the cause of the depression in the first place.

You know what dopa I think I will try memantine/Clonidine for sleep... Clonidine works very well for me too but I am just limited in dose by low blood pressure. Right now I'm taking Risperidone and a couple other things and I've been meaning to get off the anti psychotics anyways... Thanks for the help guys
 
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