CHEMISTRY OF THE BRAIN: MOLECULES, MOOD, AND MENTAL ILLNESS - Chemistry: Notable Research and Discoveries - page 88

not show improvement until two or three weeks after beginning Prozac
treatment, yet the drug begins to affect serotonin much sooner. Kazufumi
Hirano and Shizuo Yamada at the University of Shizuoka in Japan, along
with their colleagues, showed that SSRIs begin to act on serotonin trans-
porters within hours. The report, “Relationship Between Brain Serotonin
Transporter Binding, Plasma Concentration and Behavioural Effect of
Selective Serotonin Reuptake Inhibitors,” was published in 2005 in the
British Journal of Pharmacology.
One explanation for this delay is that the brain adjusts to the pres-
ence of SSRIs, and this adjustment is the mechanism by which the drug
works. The brain may change the number of serotonin transporters,
receptors, or other molecules, a process that would require time as the
proteins are made and inserted in the correct positions.
Another explanation is that the monoamine hypothesis is not the
whole story. In the search for alternative ideas, some researchers have
noticed that new neurons generated in a brain structure known as the
hippocampus may affect depression. Once thought not to occur at all
in the brain of mammals, the generation of new neurons—neurogen-
esis—has been shown, in the 1990s by Elizabeth Gould of Princeton
University in New Jersey and her colleagues, to take place in rats and
primates. In 1998, Fred Gage of the Salk Institute for Biological Studies
in California and his colleagues found evidence that the same is true in
humans.
Testing for a possible relationship between antidepressant activity
and neurogenesis, a research team led by René Hen at Columbia Uni-
versity in New York used mice as models. Under certain conditions,
mice exhibit behavior and neural properties similar to depression in
humans. Hen and his colleagues found that antidepressants, including
fluoxetine, did not work if neurogenesis was blocked. This 2003 report,
“Requirement of Hippocampal Neurogenesis for the Behavioral Effects
of Antidepressants,” published in Science by Luca Santarelli, Hen, and
their colleagues, offers evidence of a role of neurogenesis in antidepres-
sant activity, though no one knows if this result is also true in humans.
The time required for neurogenesis could account for the delay in the
effectiveness of the medications. In their report, the researchers note,
“Our results suggest that strategies aimed at stimulating hippocampal
neurogenesis could provide novel avenues for the treatment of anxiety
and depressive disorders.”