More on SSRIs and BDNF

HD Lighthouse Contributing Editor's Comment: Since so many people with the HD gene are on SSRIs, the Lighthouse follows research of this type of antidepressant. A new study from Johns Hopkins shows that serotonin reuptake inhibitors like fluoxetine (Prozac) stimulate nerve fiber growth in the areas of the brain associated with thoughts, emotions, and autonomic functions. The most probable mechanism is through their ability to increase BDNF (brain derived neurotrophic factor) which is known to be reduced with HD.
--Marsha L. Miller, Ph.D.
Posted to the HDL: 20 Dec 2005

Vassilis E. Koliatsos, M.D., Associate Professor of Pathology, Department of Neuropathology, Johns Hopkins University, School of Medicine

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, M.D., a neuropathologist at the Johns Hopkins University School of Medicine, found that selective serotonin reuptake inhibitors (SSRIs) increase the density of nerve-impulse-carrying axons in the frontal and parietal lobes of the neocortex 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.

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 transference.

"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," according to Koliatsos.

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," he added.

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 only for human use 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). 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.

The Abstract

The mechanism of action of commonly used antidepressants remains an issue of debate. In the experiments reported here we studied the effects of three representative compounds, the selective serotonin reuptake inhibitor fluoxetine, the selective serotonin reuptake enhancer tianeptine and the selective norepinephrine reuptake inhibitor desipramine on the structure of central serotonin pathways after a 4-week administration. We found that the serotonin modulators fluoxetine and tianeptine, but not desipramine, increase the density of 5-HT and serotonin transporter (SERT)-immunoreactive axons in the neocortical layer IV and certain forebrain limbic areas, such as piriform cortex and the shell region of nucleus accumbens. These changes were noted in the absence of a significant effect of serotonin antidepressants on the expression of tryptophan hydroxylase (TPH-2), i.e. the rate-limiting enzyme for 5-HT biosynthesis and of SERT at the mRNA level. In addition, we found that anterogradely filled terminal axons from injections of biotinylated dextran amine into the dorsal raphe showed significantly more branching in animals treated with fluoxetine compared with animals treated with liposyn vehicle. 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 role in their clinical efficacy.

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Source: Journal of Neurochemistry Volume 96 Page 396 - January 2006

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