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What's the Connection? SSRI's, Pregnancy and Autism

SSRIBy Teresa Conrick

A few months back, I wrote about a calcium-binding protein, S100B, as it had been implicated as a possible biomarker in Autism -- "Autistic children had significantly higher serum S100B protein levels than healthy controls."  From that article -- S100B is a calcium-binding protein that is produced primarily by astrocytes. Increased serum S100B protein levels reflect neurological damage.

In my reading and researching, I came upon this sentence- "an increase of serotonin levels by fluoxetine [PROZAC] administration increased S100B concentrations....." which made me wonder if it could be possible that S100B might be a player in research showing that SSRI use in pregnancy might cause Autism.  This is not fact -- it is a hypothesis but let's take a look at some points.

July 2011 Antidepressant Use During Pregnancy and Childhood Autism Spectrum Disorders 

."...we found a 2-fold increased risk of ASD associated with treatment with selective serotonin reuptake inhibitors by the mother during the year before delivery.. with the strongest effect associated with treatment during the first trimester ..No increase in risk was found for mothers with a history of mental health treatment in the absence of prenatal exposure to selective serotonin reuptake inhibitors.........no association was seen for the small group of women who were prescribed a non-SSRI antidepressant only.......we found no association between ASD and a history of depression or a history of any mental health disorder..."

 

The underlining is from me, as emphasis, so you can see a contradiction presented on some sites.  First from an Autism Speaks Blog:

"In fact, it’s not clear whether the autism risk associated with taking antidepressants during pregnancy is, in fact, related to the women’s depression rather than the drugs themselves.

I think it's important to emphasize that the writer of this Autism Speaks blog is appearing to state a fact -- that is just not true.  She was not the only one.  Here from an FDA site:

"This study does not prove that exposure to an antidepressant can cause autism. It is possible that depression, not the medicine, was related to autism risk."  Are we seeing a pattern here where blame is being placed on the mother rather than the pharmaceutical product?

Now I think the authors of the SSRI study were clear:

- No association was seen for the small group of women who were prescribed a non-SSRI antidepressant only.

- No association between ASD and a history of depression or a history of any mental health disorder

So it seems that the use of an SSRI [ Fluoxetine hydrochloride -Prozac, Paroxetine hydrochloride -Paxil,

Sertraline hydrochloride - Zoloft and Fluvoxamine maleate - Luvox ] during pregnancy might influence an Autism diagnosis -- but how?

When I read that Prozac, not unlike Risperdal, could cause an increase in S100B, I wondered if  SSRI use and S100B could be involved. Let's be clear that this is a small piece to the autism numbers, as the authors state:  "The fraction of cases of ASD that may be attributed to use of antidepressants by the mother during pregnancy is less than 3% in our population, and it is reasonable to conclude that prenatal SSRI exposure is very unlikely to be a major risk factor for ASD. Although these findings indicate that maternal treatment with SSRIs during pregnancy may confer some risk to the fetus with regard to neurodevelopment, this potential risk must be balanced with the risk to the mother or fetus of untreated mental health disorders. We recommend that our findings be considered as preliminary and treated with caution, pending results from further studies...."  

Here are some connecting dots that I would like to add:

- Experimental studies in rodents show that administration of SSRIs during a key developmental window creates changes in brain circuitry and maladaptive behaviors that persist into adulthood.


- Secretion of S100B, an astrocyte-derived neurotrophic protein, is stimulated by fluoxetine via a mechanism independent of serotonin
 

- Secreted glial S100B exerts trophic or toxic effects depending on its concentration.

- ....overexpression of S100B has been shown to accelerate Alzheimer disease-like pathology with enhanced astrogliosis and microgliosis (12). Because of these observations, the concept has emerged that S100B, when present in the brain extracellular milieu in relatively high amounts, might act as an unconventional cytokine and/or a damage-associated molecular pattern molecule playing a role in the pathophysiology of neurodegenerative disorders and inflammatory brain diseases..

- studies implicating S-100 in both Down's syndrome and Alzheimer's disease

- the expression of S100B is increased in trisomy-21 foetuses; it also constitutes a prerequisite basis for a possible involvement of the protein in pathogenic processes associated with trisomy-21 

- Protein S-100B: a serum marker for ischemic and infectious injury of cerebral tissue.

- Methylmercury increases S100B content in rat cerebrospinal fluid ; "The present data show, for the first time, increased S100B levels in CSF after exposure to a neurotoxic metal."

- Autistic children have acute-phase systemic inflammation, as demonstrated by elevated levels of serum C-reactive protein (CRP) and S100 proteins, which most likely precedes inflammation of the brain.

- ...data suggest that S100B pairs with RAGE for anti– and pro–inflammatory activities, a feature consistent with the unique ability of S100B to exhibit opposite effects depending on doses ........  an inherent risk of autoimmunity associated with S100B. Incidentally, elevated levels of S100B have been observed in certain immuno–mediated diseases [12]

- Inflammation [42}, glutamate [43]. and oxidative stress [44]. are considered as important stimulants for S-100B production.

- The observed increase in plasma levels of S100B may reflect increased BBB permeability [30]. However, increased plasma levels of S100B may also be due to increased production and/or active secretion from glia cells, or to their destruction [40, 41]..

Those were appetizers.  Here's the meat and potatoes - a Pediatrics Study from 2009,  Neonatal S100B Protein Levels After Prenatal Exposure to Selective Serotonin Reuptake Inhibitors  This study is NOT about Autism. I pulled out the important pieces as they relate to the above SSRI-Autism paper:

1- This study adds new evidence that prenatal SSRI exposure alters serotonin-related neurodevelopment in human infants.

2- In nanomolar concentrations, S100B stimulates glial cell proliferation 20and neuronal survival18,21 and can induce neurite outgrowth.18 In micromolar concentrations, however, S100B can be cytotoxic. As a biomarker, S100B may reflect neurodevelopmental vulnerability.11,23

3-Apgar scores at 1 minute were significantly lower for infants with prenatal SSRI exposure (F1,56 = 9.141; P = .004), and the frequency of jitteriness within the first 48 hours after birth was significantly higher for infants exposed prenatally to SSRIs.

4- (SSRI) exposure increases the risk for altered newborn behavior,5 congenital anomalies,6,7 and persistent pulmonary hypertension.8

5- Our findings suggest that different antidepressants may influence S100B levels in specific ways (Table 4); however, links between infant  neurodevelopment and pharmacologic variables remain to be studied.

6- Levels of depression, as measured with the EPDS, during pregnancy were significantly higher in the SSRI-treated group than in the nontreated group

7- Maternal serum S100B levels at delivery among SSRI-exposed mothers were significantly higher than levels among nonexposed mothersInfants exposed prenatally to SSRI medications had significantly lower cord S100B protein levels, controlling for third-trimester maternal mood and gestational age

Some caveats:

It appears that there is data showing both physical and behavioral issues with infants from SSRI use. Note that this is a study on THIRD trimester data when the above SSRI-Autism study was stressing FIRST trimester.  Alarming that depression levels among the SSRI users "were significantly higher" than in the nontreated group. MOST INTERESTING, take a look at number 7- significantly lower cord S100B protein levels for infants who received SSRI vs Maternal serum S100B levels at delivery among SSRI-exposed mothers were significantly higher  Again, this is THIRD TRIMESTER, not FIRST.  But how is it possible that these infants had such low levels and the mothers so high?  Does it mean that S100B does not accumulate in the fetus?  Here is a possible explanation that would highlight S100B still as a culprit in the chain of events:

The intriguing hypothesis  was raised that the particular properties of S100B (low molecular weight) could lead to the protein crossing the placenta and being transported from the fetal to the maternal bloodstream. Thus, an extra aliquot of fetal S100B could be detectable in maternal blood when high levels of the protein are present in the fetus in concomitance with pathological conditions. In fact, high maternal blood S100B concentrations have been shown to be a reliable tool (sensitivity 100%; specificity 99.3%; positive and negative predictive values 100% and 93%, respectively) to identify newborns at risk of IVH in pregnancies complicated by intrauterine growth retarded fetuses (Gazzolo et al 2006).  These findings support the hypothesis that the monitoring of fetal well-being/stress by evaluating a fetus-derived biomarker in the maternal bloodstream may become possible.

So it appears that it may be possible for maternal levels of S100B to actually be the way to gauge the fetal levels.

One aspect that has not been addressed adequately in this equation is breast milk - "After delivery, when the lactation starts, S100B is secreted in human milk at a level 80–100 times that in mother plasma, but the function of S100B content in colostrums is still unknown."  Could SSRI use and then S100B in breast milk then also be a concern? Remember, S100B appears to be a double-edged sword -- "Secreted glial S100B exerts trophic or toxic effects depending on its concentration." 

The manufacturer recommends that fluoxetine not be used by nursing mothers in accordance with a 1994 FDA advisory [23].....The American Academy of Pediatrics has classified fluoxetine as a drug "for which the effect on nursing infants is unknown but may be of concern" [24]. 

Possible association between fluoxetine hydrochloride and colic in an infant. 

"...increased crying, decreased sleep, increased vomiting, and watery stools when fluoxetine hydrochloride was transmitted through breast feeding or breast milk in bottle."  -- connection to the gut?

S100B protein in the gut: The evidence for enteroglial-sustained intestinal inflammation

"Glial cells in the gut represent the morphological and functional equivalent of astrocytes and microglia in the central nervous system (CNS). In recent years, the role of enteric glial cells (EGCs) has extended from that of simple nutritive support for enteric neurons to that of being pivotal participants in the regulation of inflammatory events in the gut. Similar to the CNS astrocytes, the EGCs physiologically express the S100B protein that exerts either trophic or toxic effects depending on its concentration in the extracellular milieu. In the CNS, S100B overexpression is responsible for the initiation of a gliotic reaction by the release of pro-inflammatory mediators, which may have a deleterious effect on neighboring cells. S100B-mediated pro-inflammatory effects are not limited to the brain: S100B overexpression is associated with the onset and maintenance of inflammation in the human gut too."

"...members of the S100 family have important roles in inflammation and may also be useful markers of gut inflammation. Furthermore, these proteins may have functional roles in gut defense or in the pathogenesis of inflammatory bowel disease."

Pathogen and Probiotic Bacteria Differentially Stimulate Nitric Oxide Production and S100B Protein Expression in Human Enteroglial Cells

It appears that there is ample evidence that may implicate SSRI use in pregnancy as a route to an Autism diagnosis in a very small piece of the Autism epidemic and S100B may be a culprit.  S100B seems to have many connections to the prominent aspects in research regarding Autism causation -- mercury, infections, inflammation and autoimmunity.  One final question to consider -  Where is the research on the effects of prenatal mercury flu shots?

Teresa Conrick is Contributing Editor for Age of Autism.

Comments

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Benedetta

Milnacipran (Ixel, Savella, Dalcipran, Toledomin) is a serotonin–norepinephrine reuptake inhibitor (SNRI)

I just watched a lecture on something the other day that talked about the role of epinephrihrine on the metabolism.

I can't remember it is all running together.

Benedetta

I spent all day yesterday - from the moment I opened my eyes and jumped out of bed dealing with my husband having intense pain in his chest, jaws - after going from one place to another - he refused to go to our local ER - we went to his doctor-- who insisted we get him to the ER in Lexington to a well known heart specialist hospital.

By the time we got there he was runnig a 103 temp, turned red, had painful red mouth, when he breathed deep he was in pain, rapid heart rate (he usually has below normal heart rate, and he slept all day in the ER.

Cultures came back negative, nothing showed up in the x rays or cat scan in the lungs.

I have woke up at three this morning with clarity. I thought it had a familiar feel to all of this. I reminded me of my kids when they had Kawasaskis. But not Kawasakis - he is an adult man000 vasculitis!!

This is something I thing every last one of us here do not appreciate what it really is!!!!

I think the Savella or other name is milnacipran caused it. He started this new drug a few days ago. It came in a nice new packet with one pill the first day - two pills the second through the seventh day then dosage is increased after that.

I see he has taken 8 of these pills -

prozac is in the water all over the country

I hate to say this but you do not have to be pregnant to be taking prozac, your just taking MORE prozac. It is a known fact that prozac is excreted essentially unchanged in the urine. Since we now recycle and drink from our sewers, anyone who is drinking city water or even many/most bottled water, is drinking prozac! Never mind the other stuff they do not know how do eliminate.

Our government knows this, they just do not know what to do. There was even an article in The Scientist about Autistic Fish from the increased amount of prozac found in the water of the fish tested....

Benedetta

http://www.youtube.com/watch?v=iPWe9y7K5I8&feature=related

This guy is teaching doctors about oxidation phosphorylation.

He says 10;30 - 10 percent of the SIDS is caused by CoA Coenzyme A.

This Coenzyme A is made not at the end of the energy pathway which is oxidation phoshorylation -- but at the very beginning of the energy cycle - glycolysis - breaking down of carbohydrates.

We have spent tons of money on Co enyzyme Q 10 that is used on the end of the energy pathway oxidation phosphorylation/electron transfer system.

Benedetta

Linda;
I am so sorry.
I am sure you were not taking Paxill for candy.
Why were you depressed?
I blame the vaccines for that, I really do. Because young people of child bearing age and teenagers are not suppose to be depressed and have to take medicine in the first place

MotherofPossibility

Nice article. I've also wondered about immune suppressing drugs taken by mothers, such as birth control pills for example...i'm not knocking women using birth control, jus another example though of medicines we put in our bodies without really knowing the effects on our future babies. And absolutely want some intergenerational studies on mothers' and fathers' vaccine schedules related to Autism. Are any of these things really known or studied even?

Linda Higgins

So, not only did that Paxil I was taking while not planning to bemome pregnant caused my daughter's serious heart condition, it also likely caused her Autism. Lovely. And that would explain why so many of the kids that I know who have Down syndrome and Tetralogy of Fallot (the heart condition caused by Paxil - not a normal heart condition associated with Down syndrome) have Autism. Thank you FDA for your concern for our children and their health. And if when reading this you don't see the sarcasm you missed something - because my thank you is entirely sarcastic. Damn bureaucrats!

R Edems

http://davidhealy.org/a-new-epidemic/

From A New Epidemic, by Adam Urato, MD, director of obstetrics at Tufts University Medical Center

"What is particularly concerning in this area is the issue of possible long term effects on the developing brains of exposed babies. Developing embryos and fetuses are loaded with serotonin receptors and the serotonergic system plays a crucial role in fetal development. What happens to human development of the brain and behavior when we alter this system? We simply have no idea and we are currently witnessing what amounts to a large uncontrolled experiment on human development. The current research data is not reassuring. Animal data clearly shows that fetal exposure to antidepressants can lead to changes in the development of the brain and changes in behavior (15, 16). Studies are available that demonstrate effects on the branching of neurons–the basic cell in the nervous system (17). Human studies have shown that children who were exposed to antidepressant in utero have changes in motor development and behavior (18, 19). Last July (2011) researchers at Kaiser in California showed a doubling of the risk of autism with prenatal exposure to antidepressants (20). And this doesn’t appear to be a “chance” finding. For decades serotonin has been implicated in the etiology of autism (21)."

Adriana

So interesting, Teresa. I swear the key is in the overlapping mechanisms of damage between causes the mainstream does concede and the ones they refuse to. If the substances cause the same cellular damage and the denied substance is more ubiquitous, what does that say?

The review on Depakote induced autism that I read in 2007 discussed a *compounding* of damaging effects in a child who received chemo at age two and a half and then was plunged into full blown autism at age 7 after receiving the drug Depakote (valproic acid). The author Grace Jackson showed about half a dozen overlaps between the damaging effects of chemo and Depakote. All of these effects turned out to be linked to mercury as well. It appears valproate also impacts expression of S100b (http://rgd.mcw.edu/rgdweb/report/annotation/main.html?id=3615&term=CHEBI:39867) and a quick look at the literature and it seems vincristine and other chemo agents do as well.

So now I wonder what would be seen in a review of subjects who'd been exposed to SSRIs in the first trimester and then split into two groups-- those who were exposed to vaccines (including maternal flu shots in pregnancy and while nursing) and those who weren't. I suspect there would still be cases of autism in the unvaccinated group but not as many and not as severe as in the vaccinated group.

Great work, Teresa. I have a feeling you've hit an artery.

Benedetta

P.S.
My husband has been given a new drug.
Watch out for those side effects like sucidial thoughts if you are under 24 - well he is older so all we have to worry about is getting mad???

It is savella or milnacipran - someone should hold pharma's feet to the fire when it comes to naming drugs.

But it has something to do with domomine/serotonin and S100B

Benedetta

I put a comment on the article "Unfriend" by Lisa Goes last night that really did not belong there.
But she was telling us that there is now a mitro test that just requires rubbing a swab inside the cheek instead of muscle biospy.

THe muscle biospy for my husband was a big ordeal.
We had it done in Lousiville, Kentucky and it left two long scars on his shoulder and thigh. It was shipped on ice by express mail to Emory (not sure if that was the place they sent it to, but I think so). The biospy if muscle arrrived not fresh enough, so it was useless.

Next he actually went down to Emory clinic, and had it done there. Another set of scars are now on the other side of his body.

My husband came out just like Hannah Poling
Problems showed up in the "electron transfer/oxidation phosphoralaton" system that occurs on the inter membrane of the mitochondria.
THe complex I and Complex III part of the electron transfer system.

This energy cycle is a chain of events. So,how do they know it really all starts is in the Complex I of the "electron transfer system/Oxidation phosphorylation"?

If the complex I in the electron transfer system is messed up --- then the Complex III will darn well be messed up too.

Complex two by the way is "NOT" in the chain of events - it
is another event coming in making energy - sort of joining in the electron transfer system.

Like a branch or creek flows into an existing river and makes it bigger.

But way further up the that river begins is glycolysis - glucose is broken up to make a "few" of those things that are suppose to grab ahold of electrons -as well as electrons to grab ahold of later.

I don't understand;
if not eating carbs helps and it does
or eating few carbs helps and oh - it -- does

Then why in the heck are they telling us that the problem is in the complex I and III of the electron transfer system?

It looks like to me it is up at the very beginning of the whole process where the carbohydrates are first being broken up in that part called Glycolysis.

S100B plays a role in glycoylsis. When I looked it up to see what role it played -- at least in a few of the websites there was a big only (?) in the drawings

I admit I love drawings on this stuff.

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