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

John Hasenkam via neur-sci%40net.bio.net (by johnh from goawayplease.com)
Fri Jan 9 22:15:33 EST 2009

In severe depression antidepressants are wonderful and vital. ECT can also 
provide remarkably fast and powerful benefits. ECT itself is a huge mystery, 
it can rapidly, within 24 hours, reduce depressive symptoms. Recently I came 
across a clue as to why: ECT rapidly boosts BDNF. BDNF is strongly 
implicated in depression. In my studies years ago I found a striking set of 
processes involving GABA, BDNF, il1, GCs, and NMDA in the hippocampus. A 
direct infusion of BDNF can also ameliorate depressive behavior in animal 
studies. This is very significant because in sustained major depression 
hippocampal atrophy can be very marked. There is also the suggestion that 
SSRIs boost neurogenesis and the processes I just mentioned also appear 
fundamental in promoting neurogenesis in the dentate gyrus, which provides 
neural progenitors to the hippocampus. As a general rule it appears that 
growth factors like BDNF tend to reduce inflammation, both processes appear 
to be mutually antagonistic. If I remember correctly SSRIs can reduce 
inflammation. It may be the case in severe depression that the SSRIs allow 
the reduction of inflammation to the extent that there is a resetting of 
neurotransmitter levels so allowing neurogenesis to recommence at stronger 
levels. Hence it can take some weeks for the effects to come through. 
Sapolsky argues that the hippocampal atrophy is arising from excessive 
glucocorticoid activation in the hippocampus. Interesting given that it was 
once thought that a biomarker for depression was the Dex suppression test. 
ie. depressives often have high levels of cortisol, which likes killing 
neurons. Over time high CORT can lead to glucocorticoid resistance. Thus, 
the inflammation suppressing effects of GCs are eliminated and so 
inflammation continues to rise, particularly given that ACTH and CRH can act 
as inflammatory mediators. So it is not that surprising that sustained major 
depression is also associated with increased risks for cancer, heart 
disease, and dementia.

I must finish Katharine because my arms are getting really tired ...


"KATHARINE LEAH DICKSON" <kldickson from wisc.edu> wrote in message 
news:mailman.1364.1231531375.29717.neur-sci from net.bio.net...
> I'm curious as to why SSRIs are most effective in the severely depressed - 
> at what point do antidepressants become more effective than talk therapy, 
> if indeed for all but the most extreme depressions CBT is more effective, 
> which seems to be the case?  Is there a point where the neurochemical 
> milieu in the brain necessitates antidepressant intervening?
> Katharine Leah Dickson
> kldickson from wisc.edu
> ----- Original Message -----
> From: John Hasenkam <johnh from goawayplease.com>
> Date: Friday, January 9, 2009 11:45 am
> Subject: [Neuroscience] Re: SSRIs bind to post-synaptic 5-HT receptors and 
> function as competitive antagonists?
> To: neur-sci from magpie.bio.indiana.edu
>>  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. Interesting given the known neurotoxicity of
>> Ecstasy and
>>  that it is a strong serotonin agonist. In addition recent studies on
>> mice
>>  found that mice raised on prozac grow up displaying depressive like
>>  symptoms. 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!
>>  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.
>>  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. 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.
>>  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.
>>  "How many economists does it take to change a lightbulb?
>>  None, the invisible hand will do it."
>>  Citation: Mean markets and Lizard Brains.
>>  "Glen M. Sizemore" <gmsizemore2 from yahoo.com> wrote in message
>>  news:49672529$0$24851$ed362ca5 from nr5c.newsreader.com...
>>  >
>>  > "John Hasenkam" <johnh from goawayplease.com> wrote in message
>>  > news:-f-dnT--Crq0jPvUnZ2dnUVZ8tPinZ2d from westnet.com.au...
>>  >> Hey Glen,
>>  >>
>>  >> Would you mind posting your provisional answer? Depression is a
>> hobby
>>  >> horse of mine and given recent controversy over just how SSRIs do
>> what
>>  >> they do I'm interested.
>>  >>
>>  >> Trust the musical marvel is doing well.
>>  >>
>>  >>
>>  >> John.
>>  >
>>  > Hi John,
>>  > I am trying to get to the bottom of this alleged binding of some
>> SSRIs to
>>  > the 5-HT2c receptor - I may have spoken too soon! I'll get back to
>> you on
>>  > this. I am going to have to become educated on this topic since I
>> am going
>>  > to be involved in the pre-clinical anti-depressant business. What
>> are you
>>  > referring to when you talk about the "recent controversy"?
>>  >
>>  > Yes, Mike is doing well - he's become sort of good on the sax (just
>> a
>>  > hobby though). He went to see Perlman the other night - he was
>> supposed to
>>  > get to meet him before the performance, but Perlman was not up to
>> meeting
>>  > people. Mike spends a lot of time watching Perlman and old tapes of
>>  > Heifetz - that's in between times when he is teaching himself to
>> play
>>  > drums along with an old Little Feat LP we have.
>>  >
>>  > Hope you are well.
>>  >
>>  > Regards,
>>  > Glen
>>  >
>>  >
>>  >>
>>  >>
>>  >>> I can now answer my own question, but I'll post the provisional
>> answer
>>  >>> for those that might be interested, and I'll provide a reference
>> for
>>  >>> those that are interested. Some SSRIs do, indeed, bind at the
>> 5-HT2c
>>  >>> receptor, and function as competitive antagonists.
>>  >>
>>  >>
>>  >>
>>  >> "Glen M. Sizemore" <gmsizemore2 from yahoo.com> wrote in message
>>  >> news:4924ad7c$0$28062$ed362ca5 from nr5.newsreader.com...
>>  >>>
>>  >>> "r norman" <r_s_norman from _comcast.net> wrote in message
>>  >>> news:1f38i4ptqiifib4vmg6d6elrrm30t0t6s0 from 4ax.com...
>>  >>>> On Wed, 19 Nov 2008 05:26:55 -0500, "Glen M. Sizemore"
>>  >>>> <gmsizemore2 from yahoo.com> wrote:
>>  >>>>
>>  >>>>>
>>  >>>>>"Glen M. Sizemore" <gmsizemore2 from yahoo.com> wrote in message
>>  >>>>>news:49234c1f$0$26361$ed362ca5 from nr5.newsreader.com...
>>  >>>>>> Someone I know claims that SSRIs bind at post-synaptic serotonin
>>  >>>>>> receptors, and function as competitive antagonists. Anyone
>> know
>>  >>>>>> anything
>>  >>>>>> about this? Thanks ahead of time...
>>  >>>>>>
>>  >>>>>> G.
>>  >>>>>
>>  >>>>>Correction: SOME SSRIs
>>  >>>>
>>  >>>> Could (s)he be thinking of the action of pindolol which is 
>> sometimes
>>  >>>> used in conjunction with SSRIs?
>>  >>>
>>  >>> Hi  Dr. Norman,
>>  >>>
>>  >>> I can now answer my own question, but I'll post the provisional
>> answer
>>  >>> for those that might be interested, and I'll provide a reference
>> for
>>  >>> those that are interested. Some SSRIs do, indeed, bind at the
>> 5-HT2c
>>  >>> receptor, and function as competitive antagonists.
>>  >>>
>>  >>> Cordially,
>>  >>> Glen
>>  >>
>>  >>
>>  >
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