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

Posted Aug 01 2012 12:00am

SSRI By 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 . with the strongest effect associated with treatment .. in risk was found for mothers with a history of mental health treatment in the absence of prenatal exposure to selective serotonin reuptake inhibitors.........was seen for the small group of women who were prescribed a non-SSRI antidepressant only.......we found 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, whether the autism risk associated with taking antidepressants during pregnancy is, in fact, " 

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."  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:

- was seen for the small group of women who were prescribed a non-SSRI antidepressant only.

- 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 than levels among nonexposed mothersInfants exposed prenatally to SSRI medications 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 cord S100B protein levels for infants who received SSRI vs Maternal serum S100B levels at delivery among SSRI-exposed mothers were significantly   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.

Posted by Age of Autism at August 20, 2012 at 5:45 AM in Teresa Conrick Permalink

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