Serotonin deficiency may not cause depression after all - Salon.com

Serotonin deficiency may not cause depression after all - Salon.com

New research may lead to a more direct and
effective treatment than common SSRIs

Jeanene Swanson, Scientific American

Topics:
Scientific American,
depression,
World Health Organization,
Serotonin,
SSRI, Technology News, News

(Credit: hikrcn/Shutterstock)

Depression strikes
some 35 million people worldwide, according to the World Health
Organization, contributing to lowered quality of life as well as an
increased risk of heart disease and
suicide. Treatments typically include psychotherapy, support groups and
education as well as psychiatric medications. SSRIs, or selective
serotonin reuptake inhibitors, currently are the most commonly
prescribed category of antidepressant drugs in the U.S., and have become
a household name in treating depression.

The action of these
compounds is fairly familiar. SSRIs increase available levels of
serotonin, sometimes referred to as the feel-good neurotransmitter, in
our brains. Neurons communicate via neurotransmitters, chemicals which
pass from one nerve cell to another. A transporter molecule recycles
unused transmitter and carries it back to the pre-synaptic cell. For
serotonin, that shuttle is called SERT (short for “serotonin
transporter”). An SSRI binds to SERT and blocks its activity, allowing
more serotonin to remain in the spaces between neurons. Yet, exactly how
this biochemistry then works against depression remains a scientific
mystery.

In fact, SSRIs fail to work for mild cases of depression,
suggesting that regulating serotonin might be an indirect treatment
only. “There’s really no evidence that depression is a
serotonin-deficiency syndrome,” says Alan Gelenberg, a depression and
psychiatric researcher at The Pennsylvania State University. “It’s like
saying that a headache is an aspirin-deficiency syndrome.” SSRIs work
insofar as they reduce the symptoms of depression, but “they’re pretty
nonspecific,” he adds.

Now, research headed up by neuroscientists
David Gurwitz and Noam Shomron of Tel Aviv University in Israel supports
recent thinking that rather than a shortage of serotonin, a lack of
synaptogenesis (the growth of new synapses, or nerve contacts) and
neurogenesis (the generation and migration of new neurons) could cause
depression. In this model lower serotonin levels would merely result
when cells stopped making new connections among neurons or the brain
stopped making new neurons. So, directly treating the cause of this
diminished neuronal activity could prove to be a more effective therapy
for depression than simply relying on drugs to increase serotonin
levels.

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Evidence
for this line of thought came when their team found that cells in
culture exposed to a 21-day course of the common SSRI paroxetine (Paxil
is one of the brand names) expressed significantly more of the gene for
an integrin protein called ITGB3 (integrin beta-3). Integrins are known
to play a role in cell adhesion and connectivity and therefore are
essential for synaptogenesis. The scientists think SSRIs might promote
synaptogenesis and neurogenesis by turning on genes that make ITGB3 as
well as other proteins that are involved in these processes. A
microarray, which can house an entire genome on one laboratory slide,
was used to pinpoint the involved genes. Of the 14 genes that showed
increased activity in the paroxetine-treated cells, the gene that
expresses ITGB3 showed the greatest increase in activity. That gene,ITGB3,
is also crucial for the activity of SERT. Intriguingly, none of the 14
genes are related to serotonin signaling or metabolism, and, ITGB3 has never before been implicated in depression or an SSRI mode of action.

These results, published October 15 in Translational Psychiatry,
suggest that SSRIs do indeed work by blocking SERT. But, the bigger
picture lies in the fact that in order to make up for the lull in SERT,
more ITGB3 is produced, which then goes to work in bolstering
synaptogenesis and neurogenesis, the true culprits behind depression.
“There are many studies proposing that antidepressants act by promoting
synaptogenesis and neurogenesis,” Gurwitz says. “Our work takes one big
step on the road for validating such suggestions.”

The research is
weakened by its reliance on observations of cells in culture rather
than in actual patients. The SSRI dose typically delivered to a
patient’s brain is actually a fraction of what is swallowed in a pill.
“Obvious next steps are showing that what we found here is indeed viewed
in patients as well,” Shomron says.

The study turned up additional drug targets for treating depression—two
microRNA molecules, miR-221 and miR-222. Essentially, microRNAs are
small molecules that can turn a gene off by binding to it. The
microarray results showed a significant decrease in the expression of
miR-221 and miR-222, both of which are predicted to target ITGB3,
when cells were exposed to paroxetine. So, a drug that could prevent
those molecules from inhibiting the production of the ITGB3 protein
would arguably enable the growth of more new neurons and synapses. And,
if the neurogenesis and synaptogenesis hypothesis holds, a drug that
specifically targeted miR-221 or miR-222 could bring sunnier days to
those suffering from depression.