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The Catalyst

Researcher links citalopram use during pregnancy to birth defects

By Mikie Hayes
Public Relations

Craniofacial phenotype after in utero treatment with citalopram. A: Differences in shape variation between those exposed in utero to citalopram and those from untreated dam, at 15 days postnatal. B,D: Lateral and superior views of the shape variation associated with the untreated mice. C,E: Lateral and superior views exposed to citalopram. F–K: examples of anomalies found among the citalopram exposed mice. F: 3-D reconstruction of a citalopram exposed mouse with an ectopic suture dividing the parietal bone. G: Parietal defect from the same mouse. H: 3D reconstruction of one of two mice born with a single maxillary incisor. I: Absence of the left maxillary incisory root. J: Citalopram exposed mouse with a deviated snout. K: 45-degree frontal view of same animal shown in J. image provided

MUSC’s James Cray, Ph.D., who specializes in head and facial birth defects research, has associated the use of citalopram during pregnancy with birth defects such as a reduction in the size of the skull and other facial deformities.

Over the course of the 1990s, a then–new class of antidepressant drugs, known as selective seratonin reuptake inhibitors (SSRIs), became household words, and since that time, both their popularity and potency have continued to increase, according to Cray, making many of them among the most prescribed drugs today.

SSRIs work by increasing levels of a brain chemical called serotonin, which is linked to mood, sleep regulation and emotions. Dubbed “happy pills,” names like Prozac, Zoloft, Paxil, Celexa, Effexor and Lexapro went from obscurity to the subject of everyday discussion at the office and at cocktail parties.

The National Center for Health Statistics report that approximately 10 percent of Americans take an antidepressant. And by their calculations, these antidepressants are the third most common prescription medication taken by Americans.

In a recent report, the Centers for Disease Control Birth Defects Prevention study identified the use of SSRIs in pregnant mothers as increasing the odds of having a child with a birth defect, specifically craniofacial and cardiac malformations. The drug citalopram was cited as particularly concerning, since a significant number of reports linked birth defects in babies born to mothers who were on the drug while pregnant. From a public health perspective, these findings, as well as other known related side effects, were great cause for concern for Cray, an assistant professor in the Department of Oral Health Sciences.

Cray stated that women are 2 ½ times more likely to be taking an antidepressant than men, and further, that SSRIs are currently the most commonly prescribed drugs for the treatment of depression and routinely prescribed during pregnancy.

It is known that SSRIs pass the placental barrier, meaning the fetus is not only exposed to the drug, but accumulations can be found in the fetus’s blood stream and tissues: Effectively, the baby is born already on an anti-depressant.

Cray and his team focused their work on the drug citalopram, as a result of the CDC study, which implicated citalopram as greatly increasing the odds of having a child with craniosynostosis, a condition characterized by the premature fusion of the sutures of the skull, with an estimated prevalence of 1 in 1,800 to 2,500 live births.

In the U.S., citalopram is marketed by Forest Laboratories as Celexa, which is in the same class as Prozac and Zoloft. Celexa was approved by the Food and Drug Administration in 1998, and according to IMS Health, a global information and technology services company, Celexa was the third highest prescribed psychiatric drug in 2013 with nearly 39.5 million prescriptions having been dispensed. Zoloft, number two on the list, was the only anti-depressant ahead of Celexa. 

While poorly understood, there is evidence to suggest that serotonin may play a significant role in early craniofacial development. SSRIs, which block the reuptake of serotonin, have been shown to impact overall craniofacial development.  Serotonin has been detected during the earliest phases of fetal development, and it is important to the process of cell differentiation and normal bone development.

Preclinical studies report a reduction in cranial size in offspring after the administration of SSRIs to pregnant mice, and there are similar reports in humans. Given the frequency of SSRI use during pregnancy, Cray stated that more studies must be conducted. “It is imperative that any potential teratogenic  effects be investigated. There is now convincing evidence that at least some SSRIs are capable of disrupting the normal function and maintenance of the craniofacial development in the fetus, resulting in an elevated risk for specific birth defects. However, almost nothing is known about the mechanisms underlying this phenomenon.”

In his research, he and his team set out to determine what effects citalopram in particular would have on the developing craniofacial skeleton in mice. Cray’s team examined the effects of citalopram administration at two levels. First they conducted tests in vitro — a biological process which occurs in a controlled laboratory setting, using test tubes and petri dishes rather than within a living organism. To accomplish this, they used cells that are responsible for building the skull as markers of bone formation, craniofacial development and serotonin synthesis. Subsequently, they conducted tests in vivo — studies that are conducted on living organisms such as animals or humans — after in utero administration of a clinical dose of citalopram.

The team hypothesized that in vitro exposure would result in altered expression of those biological factors related to both the serotonin and craniofacial growth pathways. They also predicted that they would see changes in craniofacial development in mice exposed to citalopram in utero, akin to those observed in humans.

Ultimately, some of the craniofacial changes observed corresponded to known craniofacial syndromes involving the genes that showed significant alterations in expression following the SSRI exposure. Excessive flattening of the midface, a depressed nasal bridge, major reduction in the prominence of the upper jaw, and inward bending of the nasal bones were evident. Other possible negative effects in the cranium and midface include altered regulation of the molecules known to be important for proper growth and cranial suture stability — the fibrous bands of tissue that connect the bones of the skull.

Cray said, “We observed morphological alterations similar to those previously reported in human epidemiological and cohort studies, such as altered cranial vault shape and decreased growth. There were also several craniofacial anomalies in the fetally exposed mice, suggesting that clinical use of citalopram during pregnancy has the potential to cause craniofacial birth defects.”

Cray and his team appreciate the implications of these findings which are being published in Birth Defects Research. “Our results,” he said, “provide confirmatory evidence that citalopram exposure is associated with cellular and morphological alterations of the craniofacial complex, which may have important implications for use during pregnancy.”

Cray hopes to be able to continue studying how SSRIs affect pregnancy. He plans to look at other SSRI drugs, hone the pathways and mechanism, and in particular investigate the potential of window of susceptibility. “The most clinical translative aspect of this research would be to identify a dose threshold or less safe time to be on these drugs during pregnancy.  It is not likely a ubiquitous effect and may not affect every patient.”

The FDA categorizes citalopram as a pregnancy class C drug. Paxil, or paroxetine, on the other hand, has already been reclassified for pregnancy risk from a class C to a class D, indicating its potential risks to the developing fetus. This type of research aids in the proper classification of drugs.

In addition, research is bearing out that SSRIs have other harmful drawbacks. Cray said, “The realization that SSRIs have more systemic effects are now finally coming into focus. We now have a population of long–term users. Data is beginning to suggest long–term SSRI use may exacerbate or even cause osteoporosis. There are also some indications SSRI use may impair bone healing particularly as it relates to dental implants.

While there are clearly side effects related to the use of citalopram in pregnancy, Cray is very clear that a pregnant patient diagnosed with depression should not simply stop taking her prescribed medication. He hopes his studies will point to how best to prescribe medication during pregnancy to reduce side effects. “Depression is a disorder with varied physiological effects. It is very difficult to ascertain from human population studies what might be an effect of depression, a drug to treat depression or a combinatory effect.”

November 7, 2014



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