Antidepressant fluoxetine suppresses neuronal growth. What do you think, Dr. M?

[Cappa]

And to what extent does this generalize to other SRI antidepressants?

Eur J Neurosci. 2010 Mar;31(6):994-1005. Epub 2010 Mar 8.

Antidepressant fluoxetine suppresses neuronal growth from both vertebrate and invertebrate neurons and perturbs synapse formation between Lymnaea neurons.

Xu F, Luk C, Richard MP, Zaidi W, Farkas S, Getz A, Lee A, van Minnen J, Syed NI.

Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Alberta T2N 4N1, Canada.

Abstract

Current treatment regimes for a variety of mental disorders involve various selective serotonin reuptake inhibitors such as Fluoxetine (Prozac). Although these drugs may ‘manage’ the patient better, there has not been a significant change in the treatment paradigm over the years and neither have the outcomes improved. There is also considerable debate as to the effectiveness of various selective serotonin reuptake inhibitors and their potential side-effects on neuronal architecture and function. In this study, using mammalian cortical neurons, a dorsal root ganglia cell line (F11 cells) and identified Lymnaea stagnalis neurons, we provide the first direct and unequivocal evidence that clinically relevant concentrations of Fluoxetine induce growth cone collapse and neurite retraction of both serotonergic and non-serotonergic neurons alike in a dose-dependent manner. Using intracellular recordings and calcium imaging techniques, we further demonstrate that the mechanism underlying Fluoxetine-induced effects on neurite retraction from Lymnaea neurons may involve lowering of intracellular calcium and a subsequent retardation of growth cone cytoskeleton. Using soma-soma synapses between identified presynaptic and postsynaptic Lymnaea neurons, we provide further direct evidence that clinically used concentrations of Fluoxetine also block synaptic transmission and synapse formation between cholinergic neurons. Our study raises alarms over potentially devastating side-effects of this antidepressant drug on neurite outgrowth and synapse formation in a developing/regenerating brain. Our data also demonstrate that drugs such as Fluoxetine may not just affect communication between serotonergic neurons but that the detrimental effects are widespread and involve neurons of various phenotypes from both vertebrate and invertebrate species.

PMID: 20377614 [PubMed – in process]

[DrMariano2]

@Cappa 2689 wrote:

And to what extent does this generalize to other SRI antidepressants?

The study you quote is very very flawed. They studied isolated neurons in petri dishes.

This is NOT how the brain is structured. In the brain, neurons are ALWAYS connected to glial cells. They cannot survive without their glial cells. Neurons are contained, arranged, connected, and controlled by astroglia and oligodendrocytes and microglia. Synapses cannot form without signaling from astroglia. The astroglia lay down the signal (cholesterol) which guides neuron axons to grow toward the desired area for synapse formation with another neuron. The astroglia send signals (such as glutamate) to neurons to cause the neurons to disengage from the synapse with one neuron, and guide the neuron to connect to another neuron.

In studies of REAL, intact brains, studies after studies show that antidepressants increase brain cell growth. Antidepressants actually work by blocking reuptake transporters on astroglia. This can lead to an increase in Brain-Derived Neurotrophic Factor (BDNF), which is one of the signals that stimulates the transformation of stem-cell astrocytes into new neurons and other glial cells ; and stimulates the growth of new connections.

Here are some articles:

http://www.scientificamerican.com/article.cfm?id=prozac-spurs-neuron-growt

Prozac Spurs Neuron Growth
Scientific American Mind
August 2006
Recent work with mice has revealed that the antidepressant Prozac spurs growth of new neurons in the brain. Prozac, or fluoxetine, is thought to ease depression by raising the level of the neurotransmitter serotonin in the brain. But now researchers have learned that the drug also causes more neurons to form than normally would. In mice, blocking this growth nullifies the drug’s effects on behavior, suggesting that neuron formation may be part of the mechanism that alleviates depression.
How exactly fluoxetine boosts neuron formation, called neurogenesis, is unclear. Neurogenesis con-sists of several rounds of cell division that create many neurons from a few stem cells. To pinpoint fluoxetine’s effect on this pathway, a group at Cold Spring Harbor Laboratory on Long Island, N.Y., created a strain of mouse with neural stem cells that contained a green fluorescent protein in their nuclei, making the cells easy to track under a microscope. They found that fluoxetine works on the second stage of neurogenesis, causing cells called amplifying neural progenitors to reproduce at a 50 percent greater rate than usual. This step is therefore “a clear target for the action of an antidepressant,” which may help in designing better antidotes, says study leader Grigori Enikolopov.–JR Minkel

http://www.sciencedaily.com/releases/2008/04/080417142449.htm

Antidepressants Enhance Neuronal Plasticity In The Visual System
ScienceDaily (Apr. 21, 2008)
Scientists from the Scuola Normale Superiore in Pisa, Italy and the Neuroscience Centre at the University of Helsinki, Finland have provided new information about the mechanism of action of antidepressant drugs. In addition, the study suggests that antidepressants could also be used for the treatment of amblyopia. However, to produce a functional effect, antidepressant treatment also seems to require environmental stimuli, such as rehabilitation or therapy.

According to Professor Eero Castrén at the University of Helsinki, the original objective of the study was to learn more about why the antidepressant effect of fluoxetine (also known as Prozac) and other selective serotonin reuptake inhibitors develops so slowly, many weeks after starting treatment.
Castrén’s research group has approached this question by examining the growth factor, brain-derived neurotrophic factor (BDNF), which influences plasticity of the nervous system or in other words, the ability of brain cells to change their structure or function in response to stimuli. Antidepressants seem to act through BDNF, thus enhancing the plasticity of the nervous system, at least in certain brain areas. However, it has been unclear how antidepressant-induced increases in BDNF could relieve depression.

http://www.biopsychiatry.com/antidepressants/index.htm

Sustained Use Of Anti-Depressants Increases
Cell Growth And Protects Cells In The Brain
Source: Yale University
Date: 15 December 2000

Continued use of anti-depressants leads to new cell growth in an area of the brain known to suffer cell death and atrophy as a result of depression and stress, a study by Yale researchers shows.
********Depression affects an estimated 12 percent to 17 percent of the population at some point during their lifetime. Anti-depressants are commonly prescribed for depression and other affective disorders, but the drugs’ therapeutic effects on the molecular and cellular level are not clearly understood.
********”The findings of our study are that chronic administration of anti-depressants increases the number of neurons in the adult hippocampus ,” said Ronald Duman, M.D., professor of psychiatry and pharmacology. “This could explain in part how anti-depressants produce their therapeutic response.” Duman was senior author of the study published Dec. 15 in The Journal of Neuroscience.
********The hippocampus is part of the limbic brain that is involved in learning, memory, mood and emotion. It is one of only a few regions of the brain where production of neurons occurs in the adult brain of animals, including humans. Several studies have demonstrated that stressful experiences, both physical and psychological, lead to neuronal loss or atrophy in the hippocampus. Other studies show that anti-depressants can block this cell loss.
********”In humans, brain imaging studies demonstrate that in patients with depression or post traumatic stress syndrome there is a decrease in volume of the hippocampus that is thought to be related to the neuronal atrophy and loss,” Duman said. “The results of our study demonstrate that anti-depressants can reverse or block further loss of neurons in the hippocampus by increasing neurogenesis (new cell growth).”
********Duman’s laboratory has been studying the mechanism of action of anti-depressants in rodents for over 15 years. The researchers have focused on cellular actions of anti-depressants, looking at the role of the intracellular signal transduction pathways that control neuronal function. They have identified several actions of anti-depressants which indicate that anti-depressants influence the survival or the number of neurons in the hippocampus.
********This study was intended to look at whether the anti-depressants increased the birth of neurons in the hippocampus. The researchers tested several different classes of anti-depressant drugs, as well as electroconvulsive seizure therapy (ECS), and an anti-psychotic medication.
********ECS is clinically the most effective treatment for cases of depression that are resistant to available drug treatments. As expected, chronic, or repeated, administration of ECS increased the number of neurons in the hippocampus of the brain by 50 percent. The chemical anti-depressants tested increased the number of neurons in the same area by 20 percent to 40 percent.
********The anti-depressants that were administered included a monoamineoxidase inhibitor (tranlcypromine), a serotonin-selective reuptake inhibitor (fluoxetine), and a norepinephrine-selective reuptake inhibitor (reboxetine).
********However, brief or “acute” (one to five days) administration of the anti-depressants did not lead to any significant cell change. Results were seen after 14 to 28 days of administration, which is consistent with treatment regimens for the therapeutic response to anti-depressants.
********Administration of the anti-psychotic drug haloperidol, which is a non-antidepressant psychotropic drug, also did not produce any significant cell change in this area of the brain. In addition, the researchers recently have demonstrated that morphine, another non-antidepressant psychotropic drug, decreases the number of cells in the hippocampal area.

Co-authors of the study were Jessica Malberg and Amelia Eisch, both postdoctoral fellows in psychiatry, and Eric Nestler, formerly a professor of psychology, pharmacology and neurobiology at Yale.

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