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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 10 of 10. This is the beginning of the thread.
Posted by farshad on February 15, 2018, at 17:19:57
if people with anxiety have too much serotonin in the amygdala then how does an SSRI that increase serotonin normalise the activity in the amygdala?
Results
Amygdala responses to fearful facial expressions were significantly greater in depressed patients compared to healthy controls. However, this response was normalised in patients receiving 7 days treatment with escitalopram. There was no significant difference in clinical depression ratings at 7 days between the escitalopram and placebo-treated patients.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488813/
https://www.sciencedaily.com/releases/2015/06/150617115327.htm
Posted by linkadge on February 15, 2018, at 17:48:58
In reply to How do SSRIs normalise the amygdala?, posted by farshad on February 15, 2018, at 17:19:57
Because SSRIs don't actually increase serotonin neurotransmission.
Posted by farshad on February 15, 2018, at 20:34:05
In reply to Re: How do SSRIs normalise the amygdala?, posted by linkadge on February 15, 2018, at 17:48:58
> Because SSRIs don't actually increase serotonin neurotransmission.
>
>
>
>what u mean? care to explain
Posted by SLS on February 15, 2018, at 22:23:32
In reply to Re: How do SSRIs normalise the amygdala?, posted by linkadge on February 15, 2018, at 17:48:58
> Because SSRIs don't actually increase serotonin neurotransmission.
Hi Linkadge.
I am inclined to agree with you.
How do you think SSRIs work?
Sometimes, I think the inhibition of serotonin reuptake leads to a reregulation of receptors and negative feedback loops such that neural activity more approximates a normal dynamic as opposed to an amplified one. Maybe not.
- Scott
Posted by Christ_empowered on February 16, 2018, at 10:19:41
In reply to Re: How do SSRIs normalise the amygdala?, posted by SLS on February 15, 2018, at 22:23:32
ssri drugs are like the old school goofballs...part tranquilizer, part stimulant. you have the apathy-inducing component, and the stimulating component.
they don't 'normalize' anything. sometimes, the alterations in brain chemistry help. sometimes, its a disaster.
Posted by linkadge on February 16, 2018, at 18:33:29
In reply to Re: How do SSRIs normalise the amygdala?, posted by Christ_empowered on February 16, 2018, at 10:19:41
When given in the short term, SSRIs do appear to increase serotonin in the synapse. However, this activates autoreceptors which in turn reduces the subsequent release of serotonin. Also, many antidepressants have anti-inflammatory effects. Reducing inflammation also tends to reduce serotonin release. Also, chronic activation of 5-ht1b autoreceptors can reduce serotonin synthesis.
Here is a study in which mice lacking Tph2 (i.e. mice who are already low in serotonin) given SSRIs experienced a further lowering of serotonin levels.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547473/
"Thus, it is reasonable to expect that the ability of chronic reuptake inhibitors to induce monoamine depletions could be exacerbated under conditions of deficient monoamine synthesis machinery."
Here is another study in which citalopram administration resulted in reduced serotonin synthesis.
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0006797
"Chronic Citalopram Administration Causes a Sustained Suppression of Serotonin Synthesis in the Mouse Forebrain"
They hypothesize "Although SSRI treatment produces robust increases in extracellular 5-HT, there is evidence that SSRI administration can actually deplete brain stores of 5-HT and of its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA) [64], [69][77], as would be predicted if 5-HT synthesis were suppressed and serotonergic neurons were unable to effectively recapture released 5-HT."
Another interesting excerpt, from the book "Neurobiology of Depression", which references over 50 additional studies...
"In contrast to this prevailing hypothesis of antidepressant mechanism of action, we found that half of the approximately 50 studies that have been carried out using in vivo microdialysis fail to report increases in extracellular serotonin levels in response to chronic antidepressant administration in mice and rats"
As far as the amygdala, I'm not sure. It could be that with chronic administration the SSRI is actually reducing serotonin (or at least normalizing serotonin). It could also be that other targets of the drugs have an impact on the amygdala. For example, many SSRIs increase the level of a neurosteroid called allopregnanalone. This substance increases gaba signaling, and could be reducing amygdala activity.
Serotonin is actually a stress hormone of sorts. Anxiety is often seen as a high serotonin state. Many anti-anxiety medications actually lower serotonin release (i.e. benzodiazapines, buspar) or block specific serotonin receptors (5-ht2a/c, 5-ht3). Even activating 5-ht1a receptors increases cortisol (i.e. the cortisol response) although the receptors can become desensitized to this effect.
It's probably a cop out answer to say that its the right amount of serotonin, at the right receptors, for the right length of time which causes the ideal level of stress needed to respond and adapt behaviorally to stressful situations.
But, it's way, way, way more complicated than I can grasp.Linkadge
Posted by farshad on February 16, 2018, at 19:42:54
In reply to Re: How do SSRIs normalise the amygdala?, posted by linkadge on February 16, 2018, at 18:33:29
> When given in the short term, SSRIs do appear to increase serotonin in the synapse. However, this activates autoreceptors which in turn reduces the subsequent release of serotonin. Also, many antidepressants have anti-inflammatory effects. Reducing inflammation also tends to reduce serotonin release. Also, chronic activation of 5-ht1b autoreceptors can reduce serotonin synthesis.
>
> Here is a study in which mice lacking Tph2 (i.e. mice who are already low in serotonin) given SSRIs experienced a further lowering of serotonin levels.
>
> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547473/
>
> "Thus, it is reasonable to expect that the ability of chronic reuptake inhibitors to induce monoamine depletions could be exacerbated under conditions of deficient monoamine synthesis machinery."
>
> Here is another study in which citalopram administration resulted in reduced serotonin synthesis.
>
> http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0006797
>
> "Chronic Citalopram Administration Causes a Sustained Suppression of Serotonin Synthesis in the Mouse Forebrain"
>
> They hypothesize "Although SSRI treatment produces robust increases in extracellular 5-HT, there is evidence that SSRI administration can actually deplete brain stores of 5-HT and of its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA) [64], [69][77], as would be predicted if 5-HT synthesis were suppressed and serotonergic neurons were unable to effectively recapture released 5-HT."
>
> Another interesting excerpt, from the book "Neurobiology of Depression", which references over 50 additional studies...
>
> https://books.google.ca/books?id=XWhcpz0CGyAC&pg=PA156&lpg=PA156&dq=chronic+ssri+%2B+serotonin+levels&source=bl&ots=0aQD_bBJe7&sig=gA4urdi4e5v35_rnXgh0LJ2yQEk&hl=en&sa=X&ved=0ahUKEwjc7anF1KvZAhVC0YMKHYiGAS84KBDoAQg-MAQ#v=onepage&q=chronic%20ssri%20%2B%20serotonin%20levels&f=false
>
> "In contrast to this prevailing hypothesis of antidepressant mechanism of action, we found that half of the approximately 50 studies that have been carried out using in vivo microdialysis fail to report increases in extracellular serotonin levels in response to chronic antidepressant administration in mice and rats"
>
> As far as the amygdala, I'm not sure. It could be that with chronic administration the SSRI is actually reducing serotonin (or at least normalizing serotonin). It could also be that other targets of the drugs have an impact on the amygdala. For example, many SSRIs increase the level of a neurosteroid called allopregnanalone. This substance increases gaba signaling, and could be reducing amygdala activity.
>
> Serotonin is actually a stress hormone of sorts. Anxiety is often seen as a high serotonin state. Many anti-anxiety medications actually lower serotonin release (i.e. benzodiazapines, buspar) or block specific serotonin receptors (5-ht2a/c, 5-ht3). Even activating 5-ht1a receptors increases cortisol (i.e. the cortisol response) although the receptors can become desensitized to this effect.
> It's probably a cop out answer to say that its the right amount of serotonin, at the right receptors, for the right length of time which causes the ideal level of stress needed to respond and adapt behaviorally to stressful situations.
> But, it's way, way, way more complicated than I can grasp.
>
> Linkadgethe 5-ht3 is involved in anxiety?
Posted by linkadge on February 18, 2018, at 13:01:54
In reply to Re: How do SSRIs normalise the amygdala?, posted by farshad on February 16, 2018, at 19:42:54
>the 5-ht3 is involved in anxiety?
I think it can be. 5-ht3 receptors are expressed abundantly in the GI tract. When you first take an SSRI, it can cause nausia which is believed to be due to activation of 5-ht3 receptors. Odansetron is an anti-nausia drug which blocks 5-ht3 receptors.
In the brain, they are conencted with glutamate release. Taking 5-ht3 antagonist either alone, or alongside SSRIs seems to produce / boost antidepressant effects.
5-ht3 antagonists also appear to have antianxiety effects in animal models of anxiety.
Mirtazapine is also a 5-ht3 antagonist, which is why it doesn't cause nausia, and may reduce the nausia associated with SSRIs.
Posted by Tony P on March 28, 2018, at 1:03:48
In reply to Re: How do SSRIs normalise the amygdala?, posted by linkadge on February 16, 2018, at 18:33:29
A lot of meat here - thank you, linkadge. I'm bookmarking this for later reading when I'm less hypomanic!
I've thought for a long time that there must be long-term (structural) changes in the brain in response to SSRIs & other A/Ds. Otherwise how to account for the long lag in them taking full effect? When I take diazepam or Ritalin, I feel the effects within minutes, or an hour at most. Why are antidepressants different? In a few cases, (Wellbutrin/bupropion) the 7-10 days is accounted for by the buildup of its principal metabolite, hydroxybupropion. But how to explain that Prozac may take _months_ to be effective.
I'm also concerned about recent reports that long-term use of SSRIs may lead to exacerbated depression & possibly permanent changes in brain chemistry. Makes sense in terms of homeostasis, the body's tendency to rebalance -- the only question is what is the (new?) balance point.
Posted by Ruuudy on March 28, 2018, at 23:13:03
In reply to Re: How do SSRIs normalise the amygdala? » linkadge, posted by Tony P on March 28, 2018, at 1:03:48
> I'm also concerned about recent reports that long-term use of SSRIs may lead to exacerbated depression & possibly permanent changes in brain chemistry."
Hi Tony,
If you could, would you provide links or info on those reports?
I'm what you'd call a "long-term user", having taking Prozac/Fluoxetine for nearly 28 years now.As I have just read your post, I have another tab open with search results from "long-term SSRI use". Surely there has to be more data and info on these drugs, as they have been around for more than 30 years now!
Thanks!
Rudy
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