Serotonin theory of depression flipped on its head
Serotonin cell discoveries mean rethink of depression
* 22 July 2010 by Linda Geddes </search?rbauthors=Linda+Geddes>
* Magazine issue 2770 </issue/2770> . Subscribe and save
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* For similar stories, visit the Mental Health </topic/mental-health>
and The Human Brain </topic/brain> Topic Guides
IF YOU thought depression was caused by low serotonin levels, think
again. It looks as if the brain chemistry of a depressed person is much
more complex, with mounting evidence suggesting that too much serotonin
in some brain regions is to blame.
If correct, it might explain some of the negative side-effects
associated with selective serotonin re-uptake inhibitors (SSRIs),
antidepressants like Prozac
</article/dn13375-prozac-does-not-work-in-majority-of-depressed-patients\
.html> which increase the amount of the neurotransmitter serotonin in
some parts of the brain.
The traditional view of depression was largely based on the observation
that SSRIs boost mood- although why they do so is unknown. "Because
antidepressants increase serotonin in some parts of the brain, people
assumed that depression must be the result of low serotonin levels,"
says Christopher Lowry
<http://www.colorado.edu/intphys/faculty/lowry.html>
of the University
of Boulder in Colorado. But the discovery of multiple types of
serotonin-releasing neurons in the brain, along with high levels of
serotonin recorded in people with depression, is prompting a rethink.
"What's more likely is that there are subgroups of serotonin neurons
that are overactive in depressed patients, rather than underactive as we
have all been assuming," says Lowry.
One of the first clues that something might be amiss with the
traditional theory came three years ago, when Murray Esler at the Baker
Heart Research Institute in Melbourne, Australia, and colleagues found
that the level of serotonin in the brains of people with panic disorder
was four times higher than in healthy volunteers (Stress, DOI:
10.1080/10253890701300904 <http://dx.doi.org/10.1080/10253890701300904>
), and in depressed people who were not receiving treatment it was two
times higher than in volunteers (Archives of General Psychiatry, vol 65,
p 38
<http://archpsyc.ama-assn.org/cgi/content/abstract/65/1/38?maxtoshow=&hi\
ts=10&RESULTFORMAT=1&andorexacttitle=and&andorexacttitleabs=and&andorexa\
ctfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&volume=65&firs\
tpage=38&resourcetype=HWCIT> ). They also showed that long-term use of
SSRIs in people with depression and panic disorder seemed to decrease
serotonin levels through an as yet unidentified mechanism.
Now, in studies of rats and mice, Lowry has found that there are
multiple types of serotonin neurons that can be independently regulated.
He presented his results at the Forum of European Neuroscience in
Amsterdam, the Netherlands, last week.
This fits well with findings from other groups that there are two types
of serotonin receptor in the amygdala, a brain region linked to emotion
and anxiety: 5-HT2A receptors that inhibit anxiety, and 5-HT2C receptors
that promote it. The roles of the receptors were identified by injecting
drugs that either stimulated or inhibited each receptor and observing
the animals' behavioural response.
Together, the findings might mean that while high levels of serotonin in
some brain regions like the prefrontal cortex can lead to improved mood,
high serotonin in other regions could have negative effects.
Evidence for this idea comes from Gina Forster at the University of
South Dakota in Vermillion and colleagues, who injected a stress-related
molecule into the brains of rats and found that it triggered two phases
of serotonin release. An initial wave of serotonin appeared to increase
fear-like behaviour in the rats, while a second wave decreased this
behaviour, possibly because it activated a brain region called the
medial prefrontal cortex, which is associated with calming of fears
(Neuroscience, vol 141, p 1047
<http://dx.doi.org/10.1016/j.neuroscience.2006.04.006>
).
The new findings have implications for how SSRI drugs work. In the
long-term, SSRIs do tend to have a calming effect, although more
research is needed to understand how they do this.
However, in the short-term some people taking SSRIs report feeling
increased anxiety. This is "almost certainly due to the activation of
one of these groups of serotonin neurons", says Lowry. The suicidal
thoughts some people taking SSRIs claim to experience may also be linked
to boosting serotonin, as suicide is thought to be associated with
increased impulsivity. "It may be that certain types of SSRI are
affecting these impulsivity circuits in the brain," says Lowry.
Learning more about these different groups of serotonin neurons could
lead to better treatments for depression and anxiety disorders. "It
might be possible to design very specific drugs that can turn on or off
specific groups of neurons that are deregulated in anxiety or
depression," says Lowry.