<p>I am wondering about this for a long time now and would like to better understand the impact of longterm SSRI usage when there's a natural deficit of Serotonin availability.</p>
<p>To understand my question better, I am also interested in what conditions may cause a natural deficiency of Serotonin availability.</p>
<p>As far as I understand homeostasis optimizes neural signalling by controlling the sensitivity of receptors as well as the release and reuptake of neurotransmitters.</p>
<p>Is it possible that the Raphe Nuclei may not produce sufficient Serotonin to be released and homeostatic regulation of presynaptic release has no effect because there's not enough Serotonin being produced?</p>
<p>Is it possible that there's a condition like increased SERT or MAOA levels, or something that causes available Serotonin to get reuptaken or broken down too fast?</p>
<p>e.g. SLC6A4 variations like 5-HTTLPR polymorphism with a long allele?</p>
<p>Suppose there's a natural deficiency of Serotonin availability.</p>
<p>As far is I understand it, homeostasis would cause 5HT to upregulate to balance the lower availability and probably increase presynaptic release. If SERT expression is faulty, homeostasis won't be effective at regulating it. Another option may be that supply is the limiting factor (e.g. Tryptophan deficiency). If the release rate is higher than the production rate this might cause homeostasis to be ineffective and not able to fully compensate increased reuptake activity or reduced production.</p>
<p>This would probably lead to further upregulation of 5HT which in my opinion might be an ill condition which might cause secondary symptoms like depression, anxiety or fatigue, as signalling is probably far below optimum with upregulated receptors and deficient availability.</p>
<p>Wouldn't the use of SSRIs be able to block the effect of increased SERT levels, leading to a <strong>normalized</strong> Serotonin availability?
With normalized availability, homeostasis should balance release rate and sensitivity/density of 5HT yielding overall improved Serotonin signalling.</p>
<p>In this specific scenario, would longterm SSRI use still eventually cause a 5HT desensitization even if the use of SSRIs would negate a natural abnormality of SERT levels?</p>
<p>I hope this makes sense.</p>

CC BY-SA 4.0
2024-11-25T21:34:46.460Z
SSRI interactions with serotonin levels are complex and not entirely well-understood, but likely include desensitization at particular synapses and not others. "Deficit of serotonin" is not an accurate description of depression, etc. There are a lot of questions in this post but I don't feel like any of them can be answered without starting over completely from scratch and that sort of answer could fill a textbook.
Bryan Krause
CC BY-SA 4.0
2024-11-25T22:14:30.707Z
Is this desensitization regulated by homeostasis or a direct effect of SSRIs? I didn't mean to state that Serotonin deficit describes depression. My hypothesis is that poor 5HT signalling due to deficit and upregulation might cause **symptoms of** depression, anxiety or fatigue. Not saying, that *MDD = Serotonin deficit*, albeit [MDD is implicating alterations of the serotonergic system in its etiology](https://www.sciencedirect.com/science/article/abs/pii/S1569733910700989).
Moritz Roessler
CC BY-SA 4.0
2024-11-25T22:15:14.277Z
@BryanKrause I understand, although I'd love to read that textbook answer. Do you have any suggestion what to read to get a better picture?
Moritz Roessler
<neuroscience><serotonin>
Can longterm SSRI use improve homeostasis, given a natural SERT overactivity, or does it necessarily cause a downregulation of 5HT?
Moritz Roessler
# Can longterm SSRI use improve homeostasis, given a natural SERT overactivity, or does it necessarily cause a downregulation of 5HT?

(Asked by: username_0 on 2024-11-25)

I am wondering about this for a long time now and would like to better understand the impact of longterm SSRI usage when there's a natural deficit of Serotonin availability.

To understand my question better, I am also interested in what conditions may cause a natural deficiency of Serotonin availability.

As far as I understand homeostasis optimizes neural signalling by controlling the sensitivity of receptors as well as the release and reuptake of neurotransmitters.

Is it possible that the Raphe Nuclei may not produce sufficient Serotonin to be released and homeostatic regulation of presynaptic release has no effect because there's not enough Serotonin being produced?

Is it possible that there's a condition like increased SERT or MAOA levels, or something that causes available Serotonin to get reuptaken or broken down too fast?

e.g. SLC6A4 variations like 5-HTTLPR polymorphism with a long allele?

Suppose there's a natural deficiency of Serotonin availability.

As far is I understand it, homeostasis would cause 5HT to upregulate to balance the lower availability and probably increase presynaptic release. If SERT expression is faulty, homeostasis won't be effective at regulating it. Another option may be that supply is the limiting factor (e.g. Tryptophan deficiency). If the release rate is higher than the production rate this might cause homeostasis to be ineffective and not able to fully compensate increased reuptake activity or reduced production.

This would probably lead to further upregulation of 5HT which in my opinion might be an ill condition which might cause secondary symptoms like depression, anxiety or fatigue, as signalling is probably far below optimum with upregulated receptors and deficient availability.

Wouldn't the use of SSRIs be able to block the effect of increased SERT levels, leading to a **normalized** Serotonin availability?
With normalized availability, homeostasis should balance release rate and sensitivity/density of 5HT yielding overall improved Serotonin signalling.

In this specific scenario, would longterm SSRI use still eventually cause a 5HT desensitization even if the use of SSRIs would negate a natural abnormality of SERT levels?

I hope this makes sense.

**Tags:** neuroscience, serotonin

> **Comments:**
> **username_1**: SSRI interactions with serotonin levels are complex and not entirely well-understood, but likely include desensitization at particular synapses and not others. "Deficit of serotonin" is not an accurate description of depression, etc. There are a lot of questions in this post but I don't feel like any of them can be answered without starting over completely from scratch and that sort of answer could fill a textbook.  
> **username_0**: Is this desensitization regulated by homeostasis or a direct effect of SSRIs? I didn't mean to state that Serotonin deficit describes depression. My hypothesis is that poor 5HT signalling due to deficit and upregulation might cause **symptoms of** depression, anxiety or fatigue. Not saying, that *MDD = Serotonin deficit*, albeit [MDD is implicating alterations of the serotonergic system in its etiology](https://www.sciencedirect.com/science/article/abs/pii/S1569733910700989).  
> **username_0**: @BryanKrause I understand, although I'd love to read that textbook answer. Do you have any suggestion what to read to get a better picture?  

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## 0 answers

