23 Dec 2005

The beneficial effects of serotonin reuptake inhibitor (SSRI)
antidepressants may be due to increased nerve-fiber growth in certain parts of the brain, study findings suggest.

SSRIs have long been thought to exert their clinical effects by increasing
synaptic concentrations of serotonin and norepinephrine to enhance their
transference across the synapse.

However, the current research findings in rats suggest that this class of
antidepressants increases the density of nerve-impulse-carrying axons in areas
of the brain that control sense of smell, emotions, motivation, and in organs
operating the autonomic nervous system.

For their study, Vassilis Koliatsos, from the Johns Hopkins University
School of Medicine in Baltimore, Maryland, USA, and colleagues studied the effects of three compounds on the structure of central serotonin pathways in the brains of rats over a 4-week period.

The compounds were the SSRI fluoxetine, the SSR enhancer tianeptine, and the selective norepinephrine reuptake inhibitor desipramine.

The results, published in the Journal of Neurochemistry, showed that fluoxetine and tianeptine, but not desipramine, increased the density of serotonin and serotonin transporter (SERT)-immunoreactive axons in the neocortical layer IV and in certain forebrain limbic areas.

The researchers note that these changes occurred in the absence of a significant effect of serotonin antidepressants on the expression of tryptophan hydroxylase (TPH-2), which is the rate-limiting enzyme for serotonin and SERT biosynthesis at the messenger RNA level.

Commenting on their findings, the researchers say that the changes may provide a plausible explanation for why there is a delay in the onset of the clinical effects of SSRI antidepressants.

Antidepressants result in the increase in synaptic monoamines within hours, yet the onset of an antidepressant effect can take 2 to 4 weeks.

This disparity in pharmacological effects and clinical experience may be due to the time it takes for serotonin axons to grow, Koliatsos and team suggest.

"Our findings suggest that antidepressants may exert very selective structural effects on their cognate monoamine systems in normal animals and raise the possibility that neurotrophic mechanisms may play a roe in their clinical efficacy," the researchers conclude.

Source: J Neurochem 2006; 96: 396–406