International Journal of General Medicine

Effects of selective serotonin reuptake inhibitors on motor neuron survival

Authors: Lily B Anderson, Phaedra B Anderson, Thea B Anderson, Amy Bishop, et al.
Published Date May 2009 , Volume 2009:2
Journal: International Journal of General Medicine

Lily B Anderson1, Phaedra B Anderson, Thea B Anderson, Amy Bishop, James Anderson

Cherokee Labsystems, Huntsville, AL USA; Department of Biology, University of Alabama in Huntsville, Huntsville, AL, USA

Abstract: Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and paroxetine are prescribed to relieve clinical depression and a variety of other disorders. Recently tardive dyskinesia, as well as other movement disorders, have been found to be a clinical side effect of SSRIs. In light of these emerging side effects, we asked if motor neurons were affected by SSRI. Motor neurons were challenged with fluoxetine and paroxetine at clinically relevant doses as well as at lesser and greater doses. Ethanol was used as a negative control and another group of cells was left untreated. As expected, in alcohol-treated cells, there was significant decrease in cell survival and neurite outgrowth. In untreated cells there was no effect in either cell survival or neurite outgrowth. In fluoxetine-treated motor neurons there was ∼52% cell death while in paroxetine-treated cells there was 14% cell survival and both SSRIs caused significant loss of the percentage of neurite-bearing cells. Both SSRIs decreased cell survival in a dose-dependent manner. This study is provocative enough to call for further in vivo studies.

Keywords: fluoxetine, paroxetine, motor neurons, NSC34, neurotoxicity, SSRI

Background
Selective serotonin reuptake inhibitors (SSRIs) are prescribed for disorders such as clinical depression and more recently for obsessive–compulsive disorder (OCD), premenstrual dysphoric disorder (PMDD), eating disorders, social anxiety, and panic disorders. SSRIs are also approved for the treatment of major depressive disorder and OCD inpediatric patients, both preadolescent and adolescent.1The two most prescribed SSRIs are fluoxetine hydrochloride and paroxetine hydrochloride.2 Fluoxetine hydrochloride is the most widely prescribed antidepressant medication in history. Since its introduction it has been prescribed to over 54 million patients worldwide.2
The mechanisms of action of SSRIs are presumed to be linked to its inhibition of central nervous system (CNS) neuronal uptake of serotonin. Studies at clinically relevant doses have demonstrated that fluoxetine and paroxetine block the uptake of serotonin in human platelets, rodent neurons, and other systems.1,2 However, the mechanism of action has not been fully elucidated and there may be other processes at work. Recently, a variety of side effects of SSRI therapy have come to light, specifically muscle twitches and tardive dyskinesia, all indicative of neuron damage. In one key study it was found that SSRIs affect development of the projection of thalamocortical fibers which has implications for development of afferent (sensory) pathways.3 Another key study found that SSRIs induced cell death in a hippocampal cell line and PC12 cell line, although the mechanism of neurotoxicity is still unknown which has implications for both the CNS and peripheral nervous system (PNS).

Results
Here we report the effects of SSRIs on motor neuron
health, as compared to untreated controls and ethanol treated
negative controls. The four panels of micrographs displayed in Figure 1A are from one exemplar experiment chosen from multiple experiments (n = 4). In Figure 1A we see that the untreated cells look healthy with a high percentage of neurite-bearing cells while we see some toxicity in the ethanol-treated cells, while in the fluoxetine and paroxetine-treated cells there is profound toxicity as evidenced by the loss of cells and loss of neurite-bearing cells…..

Discussion
This experiment is an Ames Test utilizing CNS cells to
assay for cellular toxicity. This is a study of possible
neurotoxicity exhibited of the two most commonly
presribed SSRI drugs. It is a straightforward experiment
that tells us that the two SSRIs we assayed are profoundly toxic to motor neurons at the levels seen in serum of adolescent patients who are undergoing SSRI therapy.
What is most interesting is that fluoxetine is very much
less toxic than is paroxetine.
Although it is clear that treatment with SSRIs is toxic to
motor neurons, we have to remember the blood–brain barrier
and we have assumed that 100% of the serum concentration
ends up in the CNS when we treated our cultures. What
this study does do is alert us in the medical community that
there appears to be SSRI-induced neurotoxicity and that
a full exploration of the degree and mechanisms of this
neurotoxicity needs to be assayed in whole animal models.
And since it has been well established that the CNS of rodents
do differ from humans in a variety of ways, most important
of which is increased resistance to both cellular toxicity,
oxidative stress, and carcinogenesis, the model that we may
need to use is a primate.

Well, at least the primates may be safe now. We are already using a primate model, anyway: just not a non-human one. We know there are risks to SSRI’s by now.  Some neuron death seems necessary to escape depression.  (Suicide kills more than a few brain cells – all of them, in fact.)   Sure, it would be nice to know which drugs are riskiest at what doses, and why some individuals handle them better than others.  But getting that kind of detail could lead to other knowledge that could be used as evidence that would stand up in civil actions. Also, some of those homicides linked to SSRI use might lead to insanity verdicts.  (And to drug companies getting dragged into civil actions.)

So non-human primates are safe from unnecessary SSRI treatments and subsequent dissections. The rest of us primates are on our own.  (Just don’t ever stop SSRI’s without your doctor’s guidance.  That is very dangerous!)