<p><strong>Short answer</strong><br />
The delayed effect of serotonin-specific reuptake inhibitors can be explained, at least in part, because of their actions on the downregulation of presynaptic 5HT1A receptors.</p>
<p><strong>Background</strong><br />
When serotonin (5HT) uptake is inhibited by SSRIs, 5HT diffuses away from the synaptic cleft of the cells that release 5HT diffusely in the brain (Fig. 1). It is believed that eventually 5HT disperses in the extracellular space and reaches the dendritic regions of the cells releasing 5HT (Fig. 2).</p>
<p>The delayed action (say, 2 weeks) can be explained by 5HT's action on 5HT<sub>1</sub>A receptors in the dendritic region. After continuous activation of 5HT1A receptors, they start to downregulate, which in turn changes the firing pattern of the serotonergic neuron into a more fluttering mode over time. This mode of firing tends to release a lot more 5HT <a href="http://www.sciencedirect.com/science/article/pii/S089662730700623X" rel="nofollow noreferrer">(Lucas et al., 2007)</a>, in turn increasing postsynaptic 5HT<sub>2</sub>A activation. Downregulation of 5HT<sub>1</sub>A receptors takes time, explaining the few weeks delayed onset (Fig. 2)<sup>*</sup></p>
<p><sub><strong>References</strong><br />
<strong>-</strong> <a href="http://www.sciencedirect.com/science/article/pii/S089662730700623X" rel="nofollow noreferrer">Duman, <em>Neuron</em> 2007;<strong>55</strong>:679-81</a><br />
<strong>-</strong> <a href="https://www.researchgate.net/publication/318726288_Association_of_5-HT1A_Receptors_with_Affective_Disorders/figures?lo=1" rel="nofollow noreferrer">Fregozo <em>et al</em>., <em>Serotonin - A Chemical Messenger Between All Types of Living Cells</em>, InTech Open (2017)</a><br />
<strong>-</strong> <a href="https://www.researchgate.net/publication/339755837_Molecular_imaging_of_the_human_emotion_circuit" rel="nofollow noreferrer">Numennaa <em>et al</em>., <em>How can social and affective neuroscience explain various aspects of human everyday interaction? – From theory to methodology</em>. Sao Paulo: Hogrefe, 2020</a></sub></p>
<p><sub><strong>Note</strong><br />
The <a href="https://www.researchgate.net/publication/318726288_Association_of_5-HT1A_Receptors_with_Affective_Disorders/figures?lo=1" rel="nofollow noreferrer">frogozo <em>et al</em>. (2017)</a> reference and extracted open access image in Fig. 2 are kind of dodgy, but the image, despite the typos (hiperpolarization should be hyperpolarization <em>etc</em>.), clearly depicts what I mean to convey here</sub></p>
<p><a href="https://i.sstatic.net/x6vP9.png" rel="nofollow noreferrer"><img src="https://i.sstatic.net/x6vP9.png" alt="Raphe" /></a><br />
<sup>Fig. 1. Raphe nuclei release 5HT throughout the brain. source: <a href="https://www.researchgate.net/publication/339755837_Molecular_imaging_of_the_human_emotion_circuit" rel="nofollow noreferrer">Nummenmaa <em>et al.</em>, 2020</a></sup></p>
<p><a href="https://i.sstatic.net/jSmtc.png" rel="nofollow noreferrer"><img src="https://i.sstatic.net/jSmtc.png" alt="5HT1A signalling" /></a><br />
<sup>Fig. 2. SSRIs block 5HT reuptake, causing presynaptic increases in 5HT. Direct effects are an increase of postsynaptic 5HT2A activation. Over time, say a few weeks, this buildup of 5HT causes a downregulation of inhibitory presynaptic 5HT1A receptors, in turn causing more flooding of the brain with 5HT. This point is where the real effects of SSRIs start to kick in. source: <a href="https://www.researchgate.net/publication/318726288_Association_of_5-HT1A_Receptors_with_Affective_Disorders/figures?lo=1" rel="nofollow noreferrer">Fregozo <em>et al</em>. (2017)</a></sup></p>

CC BY-SA 4.0
2022-09-19T00:35:44.767Z
". Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n = 1002)"
Tony Stewart EE75
CC BY-SA 4.0
2022-09-17T09:27:56.697Z
2022-09-17T09:27:56.697Z
AliceD
<p>What is it about SSRIs that they require 2-4 weeks for their long-term effect to become present?</p>
<p>Is this the result of small accumulations over time in some aspect of the brain?</p>
<p>Are there other medicines which are known to have a delayed onset of effect like this?</p>

CC BY-SA 4.0
2022-09-19T00:32:49.680Z
https://www.nature.com/articles/s41380-022-01661-0.pdf  Is this accurate?
Tony Stewart EE75
CC BY-SA 4.0
2022-09-19T00:40:55.620Z
@TonyStewartEE75 Did you want to post that as a separate question, and expand a bit on a single point you'd like to know about as the whole paper/metastudy seems a bit much to deconstruct in one question/answer thread.
Jiminy Cricket.
CC BY-SA 4.0
2022-09-19T00:53:49.970Z
Perhaps I may, but it certainly challenges the 20 yr old assumptions that Serotonin levels  are the chief cause and have a high probability of being inaccurate.  The 2-4wk duration ought to read 2-4 months considering that titration is 2-4 wks.  Perhaps the reasons won't fit on a page. https://i.sstatic.net/hQHSW.png  Yet SSRI's, SNRI's and  MAOI's do have many positive and some negative effects..
Tony Stewart EE75
<neuroscience><neurophysiology><psychopharmacology><neuro-transmitters>
Why do SSRIs take multiple weeks to reach their full effect?
Julius Hamilton
# Why do SSRIs take multiple weeks to reach their full effect?

(Asked by: username_0 on 2022-09-17)

What is it about SSRIs that they require 2-4 weeks for their long-term effect to become present?

Is this the result of small accumulations over time in some aspect of the brain?

Are there other medicines which are known to have a delayed onset of effect like this?

**Tags:** neuroscience, neurophysiology, psychopharmacology, neuro-transmitters

> **Comments:**
> **username_1**: https://www.nature.com/articles/s41380-022-01661-0.pdf  Is this accurate?  
> **username_2**: @TonyStewartEE75 Did you want to post that as a separate question, and expand a bit on a single point you'd like to know about as the whole paper/metastudy seems a bit much to deconstruct in one question/answer thread.  
> **username_1**: Perhaps I may, but it certainly challenges the 20 yr old assumptions that Serotonin levels  are the chief cause and have a high probability of being inaccurate.  The 2-4wk duration ought to read 2-4 months considering that titration is 2-4 wks.  Perhaps the reasons won't fit on a page. https://i.sstatic.net/hQHSW.png  Yet SSRI's, SNRI's and  MAOI's do have many positive and some negative effects..  

---

## 1 answers

### Answer by username_3 on 2022-09-17. Score: 2 | Accepted answer

**Short answer**  
The delayed effect of serotonin-specific reuptake inhibitors can be explained, at least in part, because of their actions on the downregulation of presynaptic 5HT1A receptors.

**Background**  
When serotonin (5HT) uptake is inhibited by SSRIs, 5HT diffuses away from the synaptic cleft of the cells that release 5HT diffusely in the brain (Fig. 1). It is believed that eventually 5HT disperses in the extracellular space and reaches the dendritic regions of the cells releasing 5HT (Fig. 2).

The delayed action (say, 2 weeks) can be explained by 5HT's action on 5HT1A receptors in the dendritic region. After continuous activation of 5HT1A receptors, they start to downregulate, which in turn changes the firing pattern of the serotonergic neuron into a more fluttering mode over time. This mode of firing tends to release a lot more 5HT [(Lucas et al., 2007)](http://www.sciencedirect.com/science/article/pii/S089662730700623X), in turn increasing postsynaptic 5HT2A activation. Downregulation of 5HT1A receptors takes time, explaining the few weeks delayed onset (Fig. 2)\*

**References**  
**-** [Duman, *Neuron* 2007;**55**:679-81](http://www.sciencedirect.com/science/article/pii/S089662730700623X)  
**-** [Fregozo *et al*., *Serotonin - A Chemical Messenger Between All Types of Living Cells*, InTech Open (2017)](https://www.researchgate.net/publication/318726288_Association_of_5-HT1A_Receptors_with_Affective_Disorders/figures?lo=1)  
**-** [Numennaa *et al*., *How can social and affective neuroscience explain various aspects of human everyday interaction? – From theory to methodology*. Sao Paulo: Hogrefe, 2020](https://www.researchgate.net/publication/339755837_Molecular_imaging_of_the_human_emotion_circuit)

**Note**  
The [frogozo *et al*. (2017)](https://www.researchgate.net/publication/318726288_Association_of_5-HT1A_Receptors_with_Affective_Disorders/figures?lo=1) reference and extracted open access image in Fig. 2 are kind of dodgy, but the image, despite the typos (hiperpolarization should be hyperpolarization *etc*.), clearly depicts what I mean to convey here

[![Raphe](https://i.sstatic.net/x6vP9.png)](https://i.sstatic.net/x6vP9.png)  
Fig. 1. Raphe nuclei release 5HT throughout the brain. source: [Nummenmaa *et al.*, 2020](https://www.researchgate.net/publication/339755837_Molecular_imaging_of_the_human_emotion_circuit)

[![5HT1A signalling](https://i.sstatic.net/jSmtc.png)](https://i.sstatic.net/jSmtc.png)  
Fig. 2. SSRIs block 5HT reuptake, causing presynaptic increases in 5HT. Direct effects are an increase of postsynaptic 5HT2A activation. Over time, say a few weeks, this buildup of 5HT causes a downregulation of inhibitory presynaptic 5HT1A receptors, in turn causing more flooding of the brain with 5HT. This point is where the real effects of SSRIs start to kick in. source: [Fregozo *et al*. (2017)](https://www.researchgate.net/publication/318726288_Association_of_5-HT1A_Receptors_with_Affective_Disorders/figures?lo=1)

> **Comments:**
> **username_1**: ". Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n = 1002)"  

---

