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If SSRIs increase hippocampal growth...

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#1 Starchild1337

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Posted 29 August 2014 - 09:38 AM


would it make sense to use a light dosage just for the nootropic benefits?

 

I think it's now well known that SSRIs lead to hippocampal growth. http://www.ncbi.nlm....les/PMC3121947/

 

Do they just restore your hipocampus to normal size or they increase it in normal non-depressed individuals too?


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#2 Area-1255

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Posted 29 August 2014 - 05:15 PM

SSRI's are not nootropic, on the contrary, most of them are anti-cognitive - with only a  few exceptions, which are the ones that act on neurosteroid pathways and / or inhibit PDE4. I believe it was fluvoxamine (Luvox) that acts as a sigma-1-receptor agonist in addition to being an SSRI.

 

 

 


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#3 tolerant

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Posted 29 August 2014 - 11:41 PM

This study is fascinating for another reason altogether: as far as I'm aware it was always thought that glucocorticoids are harmful to the hippocamus, i.e. they are over-produced in stress and depression and kill hippocampal cells. This study suggests the opposite, namely that they are required for neurogenesis to occur. Any comments?

 

Edit: grammar


Edited by tolerant, 29 August 2014 - 11:43 PM.

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#4 Area-1255

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Posted 30 August 2014 - 02:01 AM

This study is fascinating for another reason altogether: as far as I'm aware it was always thought that glucocorticoids are harmful to the hippocamus, i.e. they are over-produced in stress and depression and kill hippocampal cells. This study suggests the opposite, namely that they are required for neurogenesis to occur. Any comments?

 

Edit: grammar

High Cortisol suppreses neurite growth - but ironically serotonin 5-HT1A signaling enhances it - but yet is the primary neuroendocrine signaler of the serotonin family. 



#5 tolerant

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Posted 30 August 2014 - 04:02 AM

 

This study is fascinating for another reason altogether: as far as I'm aware it was always thought that glucocorticoids are harmful to the hippocamus, i.e. they are over-produced in stress and depression and kill hippocampal cells. This study suggests the opposite, namely that they are required for neurogenesis to occur. Any comments?

 

Edit: grammar

High Cortisol suppreses neurite growth - but ironically serotonin 5-HT1A signaling enhances it - but yet is the primary neuroendocrine signaler of the serotonin family. 

 

 

Sorry, I'm finding it a bit hard to follow the scientific stuff. And you seem to be pretty knowledgeable about it. So what is your verdict. Lowering cortisol too much is counter-productive? 



#6 Area-1255

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Posted 30 August 2014 - 09:27 AM

 

 

This study is fascinating for another reason altogether: as far as I'm aware it was always thought that glucocorticoids are harmful to the hippocamus, i.e. they are over-produced in stress and depression and kill hippocampal cells. This study suggests the opposite, namely that they are required for neurogenesis to occur. Any comments?

 

Edit: grammar

High Cortisol suppreses neurite growth - but ironically serotonin 5-HT1A signaling enhances it - but yet is the primary neuroendocrine signaler of the serotonin family. 

 

 

Sorry, I'm finding it a bit hard to follow the scientific stuff. And you seem to be pretty knowledgeable about it. So what is your verdict. Lowering cortisol too much is counter-productive? 

 

 

Lowering Cortisol is a good thing for overall health, this includes neurite growth - as does maintaining healthy levels of serotonin (but not high).



#7 William Sterog

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Posted 30 August 2014 - 09:41 AM

I take Hypericum Perforatum for that reason. I find myself chill and willing to work without distractions.



#8 StevesPetRat

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Posted 30 August 2014 - 10:09 AM

... It would make more sense to take NSI-189
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#9 X_Danny_X

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Posted 30 August 2014 - 01:13 PM

... It would make more sense to take NSI-189

 

 

Does it permanently increase cognitive enhancement, memory?      or it is just for depression?  



#10 Nemo888

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Posted 30 August 2014 - 03:26 PM

Serotonin levels do not correlate well to relief from conditions like depression. They also don't work on the majority of patients. But they do work on a subset. Testing has revealed the same number of subjects with positive treatment outcomes even in mice have their serotonin(5ht) system genetically knocked out. This may be the actual method of action that is therapeutic.

 

This is good because there are many better neuronal growth factors.


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#11 Area-1255

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Posted 30 August 2014 - 03:28 PM

Serotonin levels do not correlate well to relief from conditions like depression. They also don't work on the majority of patients. But they do work on a subset. Testing has revealed the same number of subjects with positive treatment outcomes even in mice have their serotonin(5ht) system genetically knocked out. This may be the actual method of action that is therapeutic.

 

This is good because there are many better neuronal growth factors.

Generally, quality of life goes down when artificially increasing serotonin. 


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#12 blood

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Posted 31 August 2014 - 07:46 AM

SSRI's are not nootropic, on the contrary, most of them are anti-cognitive...


Feel free to provide references for controversial assertions.

Edited by blood, 31 August 2014 - 07:48 AM.

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#13 Tom_

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Posted 01 September 2014 - 03:05 PM

SSRI along with nearly all antidepressants increase hippocampus size and density. However the hippocampus is a large and busy area and the effects of antidepressants tend to be quite specific in areas of the hippocampus. As such they don't tend to have a neurotropic effect as the the areas they effect don't play a huge part in cognition. That being said in depressed individuals where the damage tends to be much more significant they do often have a neurotropic effect in there is clear neuro-cognitive decline (seen in moderate-severe or worse depression).

 

Someone mentioned that SSRI's tend not to help people. This isn't true. They tend to lead to a 50% improvement or remission in around 60% of people, who have moderate or worse depression, with more efficacy the severer the depression. However the placebo effect seems to be particularly pronounced and up to 40% of people with depression responding to a placebo.

 

With regards to cortisol to much is a bad thing and to little is equally as bad. Depression has both been linked to much and to little cortisol, although its generally suggested symptoms are different with to much leading to insomnia, significant psychomotor involvement, increased risk of psychotic symptoms, severe dysphoria, very pronounced cognitive problems and a loss of appetite. To little seems to lead to liable mood, hypersomnia, increased appetite, fatigue, higher risk of suicide and irritability.

 

 


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#14 Area-1255

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Posted 01 September 2014 - 04:45 PM

SSRI along with nearly all antidepressants increase hippocampus size and density. However the hippocampus is a large and busy area and the effects of antidepressants tend to be quite specific in areas of the hippocampus. As such they don't tend to have a neurotropic effect as the the areas they effect don't play a huge part in cognition. That being said in depressed individuals where the damage tends to be much more significant they do often have a neurotropic effect in there is clear neuro-cognitive decline (seen in moderate-severe or worse depression).

 

Someone mentioned that SSRI's tend not to help people. This isn't true. They tend to lead to a 50% improvement or remission in around 60% of people, who have moderate or worse depression, with more efficacy the severer the depression. However the placebo effect seems to be particularly pronounced and up to 40% of people with depression responding to a placebo.

 

With regards to cortisol to much is a bad thing and to little is equally as bad. Depression has both been linked to much and to little cortisol, although its generally suggested symptoms are different with to much leading to insomnia, significant psychomotor involvement, increased risk of psychotic symptoms, severe dysphoria, very pronounced cognitive problems and a loss of appetite. To little seems to lead to liable mood, hypersomnia, increased appetite, fatigue, higher risk of suicide and irritability.

Serotonin is an emotionally blunting substance, high levels can CAUSE depression or in people with increased sensitivity to serotonin increases, such as with overmethylation or those who have the MAO-L gene. If they don't cause depression at high levels, they will numb you out and make you feel like an emotionless zombie with no desire to do anything.

 

Ever read about serotonin syndrome?

How about just high serotonin? -High Serotonin Symptoms-

 

 

 

 

 

The following are symptoms of elevated serotonin in the brain:

 

 

 

Depression
Apathy
Passivity
Loss of motivation
Nasal stuffiness or congestion
Allergic-type symptoms and allergies
Cold or flu-like symptoms
Acne and other skin disorders
Insomnia and other sleep problems
Impaired intellectual functioning
Difficulty concentrating and learning
Poor memory; amnesia
Difficulty making decisions and acting on them
Difficulty making plans and implementing them
Procrastination

Muddled thinking; brain fog
Lack of desire or interest 
Emotional flatness or dullness
Sexual dysfunction
Hearing loss or 
noises in the ears
Altered sense of smell; strange smell in nose


 

 

The depression associated with high serotonin is of a different variety from the 

classical depression, which is most familiar. The typical symptoms of anxiety, low mood, pessimism, sadness, emotional instability, etc. are missing. For that reason it often overlooked, and nothing is done about it. 

High serotonin lowers acetylcholine, norepinephrine, and dopamine in the brain and prevents the release of those neurotransmitters. Because of this, too much serotonin relative to the other brain chemicals results in a type of depression, albeit a different kind. Serotonin is a natural tranquilizer and pain reliever. It has a relaxing, calming,
anti-anxiety effect in the brain. However, too much serotonin causes excessive nervous system inhibition (depression) with the above symptoms. 

In addition, high serotonin is associated with age-related decline of health and increased susceptibility to disease, such as high blood pressure, diabetes, cardiovascular disease and cancer, because of a decrease of growth hormone (and other hormones), which depend on norepinephrine and dopamine in the hypothalamus of the brain for normal pituitary function: http://www.ncbi.nlm....les/PMC2686323/

Once recognized, a high serotonin condition can be alleviated by stopping the use of a medication, a supplement, or food that increases serotonin in the brain. It may take awhile, but serotonin should gradually return to more normal levels. There are, however, instances when the amounts of serotonin in certain parts of the brain may remain elevated, and this can create long-term problems. In general, whenever norepinephrine and dopamine are depleted (I.e., as occurs with continual use of stimulants) the potential for serotonin to become too high increases.



Supplements that increase serotonin: tryptophan, 5-HTP, SAMe, St. John’s Wort, Gingko biloba, B-complex vitamins (esp. megadoses), theanine, vitamin D, zinc, magnesium

Foods that increase serotonin: protein, turkey, sugar and other carbohydrates, eggs, bananas, sunflower seeds, yogurt, chocolate, vitamin-fortified cereals (and other products), onions, garlic, flaxseed, yeast, coffee, green tea, white tea, alcohol (initially; decrease with long-term use) 

Other things that increase serotonin: sunlight exposure, sleep deprivation, medications.

 

 

----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

 

ImHo, SSRI's are a toxic drug family with many unannounced effects and a black box warning to be noted; May cause increased risk of suicidal behavior in adolescents.

 

Just Knowing the NeuroEndocrine systems, one can see why serotonin really is not all that and more.

 

If the majority of all serotonin receptors tend to either,

1.) Increase Cortisol,ACTH,Prolactin   (5-HT1A,2A,2C,3,4 and 7)

 

or

 

2.) Decrease dopaminergic neurotransmission and / or glutamate and acetylcholine..probably histamine too.

 

Then this alone should draw alarm to people, who wants excessive cortisol, ACTH and prolactin release? I certainly wouldn't, hormones are delicate things, and causing a release of stress hormones and stress mediated effects (even if not apparent immediately) over time causes neuroendocrine disruption. This is inevitable with artifically elevated serotonin levels, especially.

 

Now to be clear I am not saying that people don't derive benefit from them, and that SSRI's don't have antidepressent or anxiolytic effects - they certainly do. It's a paradoxical effect however, and only by positive psychology and a relaxing of excessive excito-transmitter firing, are any feasible anti-depressant effects achieved.

 

Also the side-effects are often quite terrible, as is the half-life and withdrawal syndrome.

 

The problem is we never really know for sure, because many SSRI's also take other actions in the brain, at first being seen as selective SRI, then some later found to work through neurosteroid pathways (namely sigmareceptors;progesterone, pregnenoline etc)


Edited by Area-1255, 01 September 2014 - 04:50 PM.


#15 Nemo888

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Posted 01 September 2014 - 08:47 PM

It seems depression has multiple etiologies. SSRI's are a shot in the dark. I am not saying they are useless, but by your own admission only have significant therapeutic effect in 20% of individuals. I may put their efficacy at half your estimate due to research bias. They look closer to astrology than hard science.

Until the etiology is understood the treatments will not be effective. The new model of inflammatory cytokines as a specific cause for some mental disorders looks infinitely more promising that the serontogenic model or the rather forced models of neurotransmitter imbalances. In 50 years I have yet to see a diagnostic test that didn't involve a chat. The field is still in it's infancy. It's chemistry without the electron or periodic table. Hopefully we will live to see it become an effective science.

Edited by Nemo888, 01 September 2014 - 08:48 PM.

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#16 Tom_

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Posted 02 September 2014 - 03:30 PM

Area-1255, I may reply in full later.

 

I do however want to point out and make it very clear that excess serotonin is a disorder of primarily CNS activation. Excess Serotonin causes hyperthemia, clonus and when moderate to severe full blown seizure activity. Behavioral symptoms revolve around delirium, hypomania (full blown mania can appear - although typically the person is to ill to exhibit signs by this point) and agitation. Taychycardia, hyperpnea and vasoconstriction are all also common. This clearly shows CNS activation and also clearly shows behavioral activation rather than your suggestion of it causing depression. It isn't until the DIC, hyperthermia, low O2 sats and renal injury become severe that the patient will eventually end up in a coma. Additionally you can take the examples of SSRI administration to Bi-polar patients (often leading to mania or more commonly mixed episodes) and its potensity to cause mixed like episodes in under 25's (leading to the increased suicidal behavior) as clearly showing some antidepressant effect. Another indicator being that currently non-depressed bi-polar and unipolar sufferers can have depression induced by the administration of a serotonin antagonist.

 

Where ever you got this list from (down below) is absolutely tripe.

Depression
Apathy
Passivity
Loss of motivation
Nasal stuffiness or congestion
Allergic-type symptoms and allergies
Cold or flu-like symptoms
Acne and other skin disorders
Insomnia and other sleep problems
Impaired intellectual functioning
Difficulty concentrating and learning
Poor memory; amnesia
Difficulty making decisions and acting on them
Difficulty making plans and implementing them
Procrastination

 

Only certain Serotonin receptors are shown to play any significant part in depression the most salient being (5ht1a and 5ht2c (by no means the only ones)). The SSRI over some weeks (starts by week 1-2) down-regulate these receptors which are over-active and as such reduce there activity. The down-regulated 5ht2c receptor for example with cause dis inhibit the release of dopamine and nor-adrenaline in the pre-frontal cortex. It would also explain the fact that OCD tends to respond better to larger doses (one part of OCD eitology is clearly a lack of serotoniergic activity in the orbito-frontal cortex), suggesting doses need to be so large that receptor down-regulation is overpowered by the sheer amount of serotonin.

 

You also seemed to have missed a vital point. Overall activity &/or quantity of a single neurotransmitter has very little to do with a single disorder (not true of some neurodegenerative and genetic diseases). Its receptor mediated and receptors tend to be in larger quantities in the brain. Different receptors have different effects on different neurotransmitters in different areas of the brain. As such an SSRI with its longer term downregulation effects tend to increase dopamine and noradrenaline in parts of the brain related to depression. It decreases acetlycholine (studies have shown administration of Achinerase inhibitors reduce severity of mania and worsen depression) and glutemate (NDMA antagonists have shown effiacy in depression). You marked these as bad things, as you can see they are a mixed blessing. The problem with SSRI's is not that they don't theoretically work, its that their mechanism of action is very wide and they have additional unwanted effects (side effects) as well as taking time to down-regulate receptors. Drugs like Mirtazapine which act as antagonists of specific serotonin and noradrenaline receptors tend to work much quicker and are of at least equal efficacy. However they also have a multiude of other actions which can cause side effects, although with certain presentations (insomnia and loss of apetite) these side effects can be put to good use.

 

Certain supplements do increase serotonin. Food is inconsequential in the equation. You would have to eat an entire turkey to take in 500mg of tryptophan for example.

 

Nemo,

 

I agree mostly with you. They appear to have an effect in 20% (you argue 10%, i disagree with the figure but its not a big problem). However if you look at a lot of the studies they are given very short times to work. Normally 6 weeks. However most guidelines suggest a minimum of 8 weeks. Taking a look at these longer studies you start to see a significant increase in remission and in particular response rates. Now I agree that 8 weeks is a long time but at the moment its the best we have. When looking at a swap to a second SSRI you find a significant increase in effiacy and I propose that is simply due to the increase in time taking the SSRI. The modest effect I would say has a clear link to time taking the SSRI. Also those chosen for studies have often been depressed for a long time or have other risk factors for TRD (or in fact are already treatment resistant).

 

As it is, I agree SSRI's aren't great drugs but I would not agree that we don't have a reasonable arsenal at our disposal. I think, although if there is any evidence of it i'm not aware of it that prescribing for symptoms is a more effective way to manage disorders (I don't mean willy nilly prescribing but Mirtazapine would be the best first line for insomniac, anorexic (lack of appetite not the disorder) depressives, while something like bupropion might appear to be best for hypersomnia with excessive appetite. An SSRI might be best used for very mixed depression or as an adjunctive to other drugs.

 

I'd like to point out that while I agree the Monoaminergic hypothesis is dead in the new models (cytokine/inflamation is a good model but yet again not the whole story) the monoamines play one of the central parts in depressive illnesses and while more effective medications may not directly act on the monoamines they will still be significantly changed by such medication. I don't think psychiatry is in its infancy. I'd compare it very much more to a very conflicted teen who has a hundred and one different ideas and is slowly beginning to collate them into a few more reasonable and well thought out positions.

 

The idea of a biological test i think will never happen. Certain Bio-markers might eventually come into clinical practice but people can present with such a dizzying array of symptoms different biomarkers that now firm diagnosis could be based off it (the same can be said from a interview).


Edited by Tom_, 02 September 2014 - 04:00 PM.

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#17 Area-1255

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Posted 02 September 2014 - 04:24 PM

Area-1255, I may reply in full later.

 

I do however want to point out and make it very clear that excess serotonin is a disorder of primarily CNS activation. Excess Serotonin causes hyperthemia, clonus and when moderate to severe full blown seizure activity. Behavioral symptoms revolve around delirium, hypomania (full blown mania can appear - although typically the person is to ill to exhibit signs by this point) and agitation. Taychycardia, hyperpnea and vasoconstriction are all also common. This clearly shows CNS activation and also clearly shows behavioral activation rather than your suggestion of it causing depression. It isn't until the DIC, hyperthermia, low O2 sats and renal injury become severe that the patient will eventually end up in a coma. Additionally you can take the examples of SSRI administration to Bi-polar patients (often leading to mania or more commonly mixed episodes) and its potensity to cause mixed like episodes in under 25's (leading to the increased suicidal behavior) as clearly showing some antidepressant effect. Another indicator being that currently non-depressed bi-polar and unipolar sufferers can have depression induced by the administration of a serotonin antagonist.

 

Where ever you got this list from (down below) is absolutely tripe.

Depression
Apathy
Passivity
Loss of motivation
Nasal stuffiness or congestion
Allergic-type symptoms and allergies
Cold or flu-like symptoms
Acne and other skin disorders
Insomnia and other sleep problems
Impaired intellectual functioning
Difficulty concentrating and learning
Poor memory; amnesia
Difficulty making decisions and acting on them
Difficulty making plans and implementing them
Procrastination

 

Only certain Serotonin receptors are shown to play any significant part in depression the most salient being (5ht1a and 5ht2c (by no means the only ones)). The SSRI over some weeks (starts by week 1-2) down-regulate these receptors which are over-active and as such reduce there activity. The down-regulated 5ht2c receptor for example with cause dis inhibit the release of dopamine and nor-adrenaline in the pre-frontal cortex. It would also explain the fact that OCD tends to respond better to larger doses (one part of OCD eitology is clearly a lack of serotoniergic activity in the orbito-frontal cortex), suggesting doses need to be so large that receptor down-regulation is overpowered by the sheer amount of serotonin.

 

You also seemed to have missed a vital point. Overall activity &/or quantity of a single neurotransmitter has very little to do with a single disorder (not true of some neurodegenerative and genetic diseases). Its receptor mediated and receptors tend to be in larger quantities in the brain. Different receptors have different effects on different neurotransmitters in different areas of the brain. As such an SSRI with its longer term downregulation effects tend to increase dopamine and noradrenaline in parts of the brain related to depression. It decreases acetlycholine (studies have shown administration of Achinerase inhibitors reduce severity of mania and worsen depression) and glutemate (NDMA antagonists have shown effiacy in depression). You marked these as bad things, as you can see they are a mixed blessing. The problem with SSRI's is not that they don't theoretically work, its that their mechanism of action is very wide and they have additional unwanted effects (side effects) as well as taking time to down-regulate receptors. Drugs like Mirtazapine which act as antagonists of specific serotonin and noradrenaline receptors tend to work much quicker and are of at least equal efficacy. However they also have a multiude of other actions which can cause side effects, although with certain presentations (insomnia and loss of apetite) these side effects can be put to good use.

 

Certain supplements do increase serotonin. Food is inconsequential in the equation. You would have to eat an entire turkey to take in 500mg of tryptophan for example.

 

Nemo,

 

I agree mostly with you. They appear to have an effect in 20% (you argue 10%, i disagree with the figure but its not a big problem). However if you look at a lot of the studies they are given very short times to work. Normally 6 weeks. However most guidelines suggest a minimum of 8 weeks. Taking a look at these longer studies you start to see a significant increase in remission and in particular response rates. Now I agree that 8 weeks is a long time but at the moment its the best we have. When looking at a swap to a second SSRI you find a significant increase in effiacy and I propose that is simply due to the increase in time taking the SSRI. The modest effect I would say has a clear link to time taking the SSRI. Also those chosen for studies have often been depressed for a long time or have other risk factors for TRD (or in fact are already treatment resistant).

 

As it is, I agree SSRI's aren't great drugs but I would not agree that we don't have a reasonable arsenal at our disposal. I think, although if there is any evidence of it i'm not aware of it that prescribing for symptoms is a more effective way to manage disorders (I don't mean willy nilly prescribing but Mirtazapine would be the best first line for insomniac, anorexic (lack of appetite not the disorder) depressives, while something like bupropion might appear to be best for hypersomnia with excessive appetite. An SSRI might be best used for very mixed depression or as an adjunctive to other drugs.

 

I'd like to point out that while I agree the Monoaminergic hypothesis is dead in the new models (cytokine/inflamation is a good model but yet again not the whole story) the monoamines play one of the central parts in depressive illnesses and while more effective medications may not directly act on the monoamines they will still be significantly changed by such medication. I don't think psychiatry is in its infancy. I'd compare it very much more to a very conflicted teen who has a hundred and one different ideas and is slowly beginning to collate them into a few more reasonable and well thought out positions.

 

The idea of a biological test i think will never happen. Certain Bio-markers might eventually come into clinical practice but people can present with such a dizzying array of symptoms different biomarkers that now firm diagnosis could be based off it (the same can be said from a interview).

That's funny, because years ago when I had documented high serotonin levels, I felt everything on that list. Before even reading it.

Coincidence? No, this is because high serotonin levels artificially get locked into the wrong area's, it's like the concept of using NMDA blockers for their dopamine reuptake inhibition - but did you stop to think (and search) that the vast majority of G protein coupled receptors, actually enhance dopamine production by means of Tyrosine Hydroxylase?

 

You seem intelligent as well, now let me elaborate on serotonin receptors.

Yes, you are right that they (SSRI) do cause 5-HT2A downregulation...but the issue I have is through all others.

5-HT1A activation, has a lot of benefits - yet it is a presynaptic auto receptor in most regions of the brain tested.

This means ultimately, the reduction of serotonin synthesis by inevitable, negative feedback.

The postsynaptic forms however do NOT act as autoreceptors, but instead have neuroendocrine effects (such as with beta endorphin, oxytocin and prolactin).

 

http://www.ncbi.nlm....pubmed/10462127

http://faculty.virgi...3F/Untitled.pdf

http://www.ncbi.nlm....pubmed/10503938

 

Though the 5-HT1A,1B,1D,5A receptors tend to be inhibitory, it also should be noted that not all of these receptors are present throughout the brain; and area's differ. With 5-HT1A's seemingly having the most preferable actions in the prefrontal cortext, which helps determine behavior. 5-HT1A activation at low to moderate levels produces inhibition, altered state, anxiolysis (relief of anxiety) and helps improve quality of life. However, 5-HT1A OVERACTIVATION..as seen with not just serotonin syndrome, but also in cases where all other serotonin subtypes were blocked, actually diminishes quality of life by over inhibiting the HPTA - and this serotonin overactivation can cause substantial memory problems, especially in the elderly.

 

Hence why 5-HT1A antagonists like LECOZOTAN are being proposed and tested for Alzheimiers'.

 

Lecozotan (SRA-333): a selective serotonin 1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive-enhancing properties.

 

 

Recent data has suggested that the 5-hydroxytryptamine (5-HT)(1A) receptor is involved in cognitive processing. A novel 5-HT(1A) receptor antagonist, 4-cyano-N-{2R-[4-(2,3-dihydrobenzo[1,4]-dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide HCl (lecozotan), which has been characterized in multiple in vitro and in vivo pharmacological assays as a drug to treat cognitive dysfunction, is reported. In vitro binding and intrinsic activity determinations demonstrated that lecozotan is a potent and selective 5-HT(1A) receptor antagonist. Using in vivo microdialysis lecozotan, (0.3 mg/kg s.c.) antagonized the decrease in hippocampal extracellular 5-HT induced by a challenge dose (0.3 mg/kg s.c.) of 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT) and had no effects alone at doses 10-fold higher. Lecozotan significantly potentiated the potassium chloride-stimulated release of glutamate and acetylcholine in the dentate gyrus of the hippocampus. Chronic administration of lecozotan did not induce 5-HT(1A) receptor tolerance or desensitization in a behavioral model indicative of 5-HT(1A) receptor function. In drug discrimination studies, lecozotan (0.01-1 mg/kg i.m.) did not substitute for 8-OH-DPAT and produced a dose-related blockade of the 5-HT(1A) agonist discriminative stimulus cue. In aged rhesus monkeys, lecozotan produced a significant improvement in task performance efficiency at an optimal dose (1 mg/kg p.o.). Learning deficits induced by the glutamatergic antagonist MK-801 [(-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] (assessed by perceptually complex and visual spatial discrimination) and by specific cholinergic lesions of the hippocampus (assessed by visual spatial discrimination) were reversed by lecozotan (2 mg/kg i.m.) in marmosets. The heterosynaptic nature of the effects of lecozotan imbues this compound with a novel mechanism of action directed at the biochemical pathologies underlying cognitive loss in Alzheimer's disease.

 

http://jpet.aspetjou...3/1274.abstract

 

 

 


Edited by Area-1255, 02 September 2014 - 04:30 PM.






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