From: zorrilla@cattell.psych.upenn.edu (Eric Zorrilla)
Newsgroups: sci.med
Subject: Re: How do antidepressants work (was: Re: anxiety drugs)
Date: 11 Nov 92 03:58:34 GMT
Organization: University of Pennsylvania

In article <werner-101192134958@128.32.157.31> werner@soe.berkeley.edu (John Werner) writes:

>In article <1992Nov10.030016.0909188@locus.com>, Bob Yazz wrote:

>> | If so, is there a simple description of the mechanism
>> | by which they are effective?

>> Both of these work, in substantial measure, by increasing the effectiveness
>> of the brains natural serotonin "messages".

>We know what the drugs do: inhibit serotonin reuptake, for example.  But
>does anyone really know yet why altering serotonin levels helps alleviate
>depression/ocd/whatever?  I'm curious.

Lest we oversimplifiy, it should be emphasized that some cases of depression
do not respond to serotonin reuptake inhibitors (such as Prozac and Zoloft).
Similarly, a large proportion of OCD cases don't respond to Prozac,
clomipramine, etc. and even those that do "respond" don't unanimously have
large response rates.

That said, for depression (where more research has been done), animal models
suggest that serotonin reuptake inhibitors may have thir therpaeutic effects
on a class of serotnin receptors (the 5-HT1A autoreceptors) that are involved
in delievering negative feedback to the presynaptic cleft.  It *appears*
that these autoreceptors, which, when activated, reduce secretion of serotonin
at the synapse, downregulate (both in number and, possibly sensitivity) with
prolonged exposure to increased serotnin levels as is seen with reuptake
inhibitors.  The net effect of this is that the presynaptic cell is less
sensitive to negative feedback and, consequently, can maintain higher levels
of seronin secretion.  This downregulation process appears to correspond
roughly with the time it take to see clinical improvement with pharmacothera-
peutic intervention.

One probable locus of the curative effects of these drugs is the raphe
nucleus, a serotonin-rich part of the brain stem that projects widely
to other brain regions.  The question, I suppose, is what was wrong with
serotonin transmission before (if anything), and how did it get that way.
Neither of these are adequately answered at the moment by biological or
cognitive psychologists/psychiatrists.

All that said, however, I must differ with something Bob Yazz said in a pre-
vious post.  After withdrawing medication from depression, reported relapse
rates of depression (40-50%) are almost as high as relapse rates for
patients who remitted spontaneouly with no treatment (around 60%).  Cognitive
therapy for depression and maintained drug regimens have comparable relapse
rates or possibly better for cognitive therapy.  The *BEST* treatment
for depression, however, appears to be a combination of cognitive therapy
and pharmacotherapy (and the medication can be removed) with still relatively
low relapse rates (15-20%).

The curative effects of serotonin reuptake inhibitors are associated with
metabolic changes in the basal ganglia (specifically, the caudate nucleus
of the basal ganglia) and the orbitofrontal precortex as revealed by PET
scans.  Specifically, metabolism in these areas tends to go down.  Moreover,
metabolism between these two areas becomes uncorrelated (as is found in
normals) whereas it was correlated during OCD.  Similar metabolic changes
are observed with behavioral interventions in the same brain regions.  The
basal ganglia has some serotnin receptors, though,as far as I know, its
projections to the orbitofrontal precortex are glutamatergic and it's
not clear why they should have SUCH profound effects on the circuit.


-- 
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| Eric Zorrilla - Dept. of Psychology  | zorrilla@cattell.psych.upenn.edu     |
| University of Pennsylvania           | 3815 Walnut, Philadelphia, PA 19104  |
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Newsgroups: sci.med