Serotonin and Depression

dag.stenberg at helsinki.nospam.fi dag.stenberg at helsinki.nospam.fi
Fri Oct 9 02:57:06 EST 1998


John Hasenkam <johnhkm at logicworld.com.au> wrote:
> ..., I'm doubtful that serotonin levels alone can explain
> depression. Does anyone know of  studies indicating how relative levels of
> serotonin, Dopamine, and norepinephrine that might explain why depression
> can occur; particularly since severe depressives can often suffer various
> visceral disorders, indicating a more global neural dysfunction.

If depression is related to malfunction of serotonin at a synaptic level
(a hypothesis I still like), this could of course be due to any of: 
- deficient substrate/tryptophan/ in neurons, 
- deficient synthesis and activation of enzymes needed for subsequent steps, 
- deficient synthesis, storage and release of serotonin,
- deficient postsynaptic mechanisms both at membrane level and
   intracellularly.

Serotonin "levels" related to depression must refer to the synaptic levels,
and an increased amount of substrate may not correct the disturbances
leading to lower serotonin release, if, for example, the deficiency is
in the expression of the tryptophan hydroxylase gene, in the
vesicular transporter gene, in MAO, or in any of the proteins expressed
by these genes. Also, adequate or increased serotonin levels in synapses
are of no consequence if the postsynaptic actions cannot be achieved.

Thus, I believe that much of the serotonin-depression research up to now
has been quite superficial. A relationship is certainly indicated by:
- SSRIs often relieve depression
- SSRIs combined with serotonin autoreceptor block shortens the delay to
clinical result
- the explanation is evident: during initial SSRI treatment, the
elevated synaptic serotonin will inihibit its own release through
autoreceptors, and it takes time (weeks) for these to be downregulated.

The fact you pointed out, that serotonin has both excitatory and
inhibitory postsynaptic effects in different places and cases, is surely
an additional difficulty for research, but that is normal in
neuroscience, isn't it?

To find out more about the serotonin-depression relationship, I feel
that correlational evidence from blood or CSF samples from patients
cannot be enough. One has to find out about dysfunction at the molecular
level. I think there is very much work to do before we dare give an
answer to whether depression is expressed mainly as a result of a 
disturbance in serotonergic function or not.
  I would like to see 
- studies of relevant gene and gene product types in depressives 
as compared to "normals". 
- more transgenic studies than have been emerging during the last few years. I
- in vivo animal monitoring of serotonergic function parameters,
possibly in conjunction with known "models of depression" (which I
recognize as being far from perfect).
- perhaps human imaging studies in relation to focussed experiments
after we have some idea about where in the brain to look and what to
look for.

Dag Stenberg
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Dag Stenberg     MD PhD                    stenberg at cc.helsinki.fi
Institute of Biomedicine		   tel: (int.+)358-9-1918532
Department of Physiology                   fax: (int.+)358-9-1918681
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