The beneficial effects of a widely used class of
antidepressants might be the result of increased
nerve-fiber growth in key parts of the brain, according to
a Johns Hopkins study being published in the January 2006
issue of the Journal of Neurochemistry.
The study on rats, led by Vassilis E. Koliatsos, a
neuropathologist at the
School of Medicine, found that selective serotonin
reuptake inhibitors, known as SSRIs, increase the density
of nerve-impulse-carrying axons in the frontal and parietal
lobes of the neocortex and part of the limbic brain that
control the sense of smell, emotions, motivation and organs
that work reflexively, such as the heart, intestines and
stomach. "It appears that SSRI antidepressants rewire areas
of the brain that are important for thinking and feeling,
as well as operating the autonomic nervous system,"
Axons are long filament-shaped extensions of neurons
that, together with myelin, are the main constituents of
nerves. Axons conduct chemically driven nerve impulses away
from the cell body toward a narrow gap known as a synapse.
Among the chemicals involved are such monoamines as
norepinephrine and serotonin, which, at the synapse, are
transferred to another neuron.
Antidepressants, such as Prozac, Zoloft and Paxil,
have long been thought to exert their clinical effects by
increasing synaptic concentrations of serotonin and
norepinephrine, enhancing or stimulating their
"But our findings — that serotonin reuptake
modulators increase the density of nerve synapses,
especially in the front part of the brain — may offer
a better explanation of why antidepressants are effective
and why they take time to work," Koliatsos said.
For example, antidepressants increase synaptic
monoamines within hours, and the regulatory effects on
receptors are complete within a few days, yet clinically
meaningful results from antidepressants usually require a
two- to four-week delay.
"This disparity between simple pharmacological effects
and clinical experience might be due to the time it takes
for serotonin axons to grow," Koliatsos said. "For the
patient, this hypothesis provides more tangible evidence of
a real effect in the brain."
In the Johns Hopkins study, Koliatsos and his team
gave either the selective serotonin reuptake inhibitor
fluoxetine (Prozac), the selective serotonin reuptake
enhancer tianeptine (a drug approved for human use only in
France) or the selective norepineprine reuptake inhibitor
desipramine, a so-called tricyclic antidepressant, to
groups of rats for four weeks and studied anatomical
patterns of serotonin stimulation on various parts of the
brain. The results showed that fluoxetine and tianeptine,
but not desipramine, increased the density of serotonin
axons in the frontal and parietal neocortex and certain
limbic cortical and subcortical areas.
One possible explanation for this action is the
brain-derived growth factor. BDNF is regulated by levels of
serotonin and is known to be a prime candidate for causing
serotonin axon growth, Koliatsos said.
In general, the relationships between brain serotonin
concentrations and BDNF expression are very complex, but
previous studies have suggested that both higher (such as
caused by serotonin reuptake inhibitors) and lower (such as
effected by tianeptine) concentrations of free serotonin
might induce BDNF expression in such brain regions as the
frontal and parietal cortex.
The researchers caution that since a previous study
failed to show a correlation between tianeptine treatment
and BDNF levels, further investigation of the complex
regulations of BDNF by antidepressants is needed.
Funding for this study came from the National
Institute of Mental Health.