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
>>>>>
