Beneficial effects of selective serotonin reuptake inhibitors might be at least partly due to increased axonal density in the frontal and parietal cortex and part of the limbic system, according to an article in the January 2006 issue of the Journal of Neurochemistry.

The study on rats, led by Vassilis E. Koliatsos, MD, a neuropathologist at the Johns Hopkins University School of Medicine, found that selective serotonin reuptake inhibitors (SSRIs) increase the density of axons in the frontal and parietal cortex and part of the limbic brain, which 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,” said Koliatsos.

Koliatsos added, “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.”

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.

In the study, researchers gave fluoxetine, the selective serotonin reuptake enhancer tianeptine, or the selective norepineprine reuptake inhibitor desipramine 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 that brain-derived growth factor (BDNF) is regulated by levels of serotonin and is known to be a prime candidate for causing serotonin axon growth.