[Neuroscience] Re: SSRIs bind to post-synaptic 5-HT receptors and function as competitive antagonists?

Glen M. Sizemore via neur-sci%40net.bio.net (by gmsizemore2 from yahoo.com)
Fri Jan 9 18:09:25 EST 2009


"John Hasenkam" <johnh from goawayplease.com> wrote in message 
news:0_ednaYTzJUf0vrUnZ2dnUVZ8srinZ2d from westnet.com.au...
>
> 1. Recent controversy:
>
> I've just finished reading Prozac Backlash(2000) by Glenmullen, a Harvard 
> based psychiatrist who claims SSRIs carry all sorts of risks. There are 
> some risks involved but generally quite slight, though the issue of Redux 
> is worrying. It was an SSRI for appetite suppression but was found to 
> destroy serotonergic axons.

GS: I had not heard about this, but I only follow such topics when the need 
arises. Strange that an SSRI would kill 5-HT neurons...by hyperstimulation?

>Interesting given the known neurotoxicity of Ecstasy and that it is a 
>strong serotonin agonist.

GS: Well...X is an indirect agonist - it is an uptake inhibitor (I don't 
know its specificity for serotonin, dopamine, and norepinephrine), and it 
probably does a lot of the things that amphetamines do in terms of release 
("leaking") of monoamines directly from the cell.  But there are a bunch of 
psychostimulatnts (other amphetamines included) that don't - as far as I 
know - lead to destruction of 5-HT neurons. Am I missing something? Are we 
on the same page here, John?



>In addition recent studies on mice found that mice raised on prozac grow up 
>displaying depressive like symptoms.

GS: It is easy - too easy! - to come up with a story here. Downregulation of 
the "5-HT system" could occur in a number of ways in response to 
hyperstimulation. Then, there is the whole issue of evaluating the cogency 
and quality of the behavioral studies you reference (I assume that you are 
referring to behavior here...if not...never mind!).

>I think Glenmullen is way over the top but still have serious concerns 
>about the widespread use of SSRIs in children. I am not against 
>antidepressants, in fact I consider these drugs to be a great benefit, but 
>I have concerns about the excessive reliance on these drugs. Effexor can 
>induce serious withdrawal symptoms, I don't care what the authorities say 
>I've heard enough people describe their SSRI as a "security blanket" to 
>wonder if this is not a manifestation of dependency. In fact the general 
>advice now is that one should never abruptly stop taking these drugs 
>because of potential withdrawal problems. Whoops, that should read ... 
>because of a potential "antidepressant discontinuation syndrome". Ha!

GS: I don't have much of an opinion on "whether or not anti-depressants 
actually work," but that does not mean that I am disinterested. The topic, 
quite frankly, overwhelms me. It overwhelms me because we are ultimately 
talking about complex human behavior and ALL of the conceptual issues that 
pertain when that is the subject matter under consideration. How much of 
what you read really appears to take these conceptual issues into 
consideration?   Anyway...I have stressed this issue before...but I'm just 
ramblin' here.

>
> What is now being discovered is that CBT\psychotherapy is not only just as 
> effective in treating depression but appears to be much better at 
> preventing relapses. In fact SSRI's can only prevent relapses if one stays 
> on the drugs, which might explain why so many patients are on these for 
> life. Additionally, even strategies like insight meditation, exercise, and 
> dietary changes can be very helpful in dealing with depression. Even 
> vitamin D status may be of slight value because it inhibits 
> pro-inflammatory cytokine production. Then there is the Lancet study which 
> found slight increases in serotonin levels from sunshine exposure, this 
> probably relating to the changes in the melatonin - serotonin balance. Mt 
> is produced from serotonin, Mt production is rapidly stopped by sunlight 
> exposure(amacrine cells in retina, circadians, all that jazz), and Mt can 
> induce drowsiness and fatigue. That brings us to circadians, loss of 
> circadian stability is an intrinsic stressor, you can see the increase in 
> pro-inflammatory cytokines and for some depressives the loss of circadian 
> stability and hence sleep patterns is the straw that makes one rush for a 
> pill. Not surprising, even short periods of sleep deprivation can 
> significantly enhance the production of pro-inflammatory cytokines and 
> this has serious implications not just for depression but for cancer, 
> dementia, cardiovascular disease and what else??? The most remarkable 
> result I have read on the circadian issue was in relation to airline staff 
> who crossed timelines and experienced persistent circadian disruption but 
> without sleep deprivation. 5 year study found differences in temporal lobe 
> volumes and cognitive scores.

Yes...you are simultaneously raising conceptual issues as well as alleged 
(not meant pejoratively) complex cascades of biochemical variables. I've 
already implied that I don't have much to offer - but I am interested in 
what you are saying.
>
> 2.
>
> I'm also wondering if the "competitive antagonist" = inverse agonist. 
> These ligands bind the receptor, change its conformation, and thereby 
> prevent second messenger\adaptor proteins coming into play when a agonist 
> ligand attaches to the receptor.

GS: I don't know what you are referring to when you say " "these ligands." 
The difference between "competitive antagonists" (CAnt) and "inverse 
agonist" (IA) in my, admittedly, amateurish  understanding, is that IAs 
reduce the basal level of spontaneous 2nd messanger stuff, as well as 
competing in the CAnt sense.

>I haven't had time to look into this but the 5HT2c receptor appears to 
>activate production of arachidonic acid(need to find quantifiers for the 
>degree of production), a known pro-inflammatory mediator because it paves 
>the way for pge 2, which in turns helps maintain the expression of 
>pro-inflammatory cytokines(eg. il1, tnfa, il6 is tricky, can work both 
>ways). What is not that well known is that depression can involve 
>substantial increases in pro-inflammatory cytokines and it appears that 
>trying to understand depression by sole reference to the CNS is doomed to 
>fail. Keynote article: Cytokines and Depression: the need for a new 
>paradigm. I have this buried in my archives. We must consider endocrine and 
>immunological impacts as well. In regard to this Sapolsky et al has a great 
>review article, I need to read that again ... . The reason omega 3 intake 
>can help in depression, and possibly some other neuro disorders, is that 
>EPA inhibits A. acid production, diverting the pathways to 
>anti-inflammatory prostaglandins. What I have not looked into is how 
>serotonin impacts on immunological function, many immune cells have 5HT 
>receptors.
>
> For a very different perspective on these matters look up the ideas of 
> David Horrobin, I have a seminal article of his in my archives, that would 
> be a good starting point. If you so wish, give me some time, I'll email 
> you some of these articles.

GS: This is all beyond my understanding. You're claiming that SSRIs work via 
some very roundabout mechanisms? I can't say...more power to you John.

>
> PS: haven't looked too closely at depression for many years now so I'm 
> rusty. I have a small mountain of data in my archives though so if you any 
> specific queries email me and I'll see what I can do to help.
>
> Be well,
>
> John.

GS: Be well also, John. Trying to tackle so-called "psychiatric disorders" 
is a thankless task. I have talked about the conceptual problems that plague 
any discussion of complex human behavior, and you have alluded to potential 
biochemical issues that are independent of usual CNS considerations. And you 
have mentioned behavioral sorts of interventions. I simply don't have a 
strong opinion. I'm in an odd position...I think that our understanding of 
behavior (even in rats) is rudimentary, and any discussion of human 
"psychiatric disorders" is necessarily...errr...premature...yet...talk about 
them we must! Anyway...now I'm really rambling!  Oh! Dang! I was going to 
give you a reference concerning SSRIs and direct 5-HT effects...I brought 
the damn paper home but can't find it right now! Anyway...I'll  get it to 
you...

G.



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