Effects of Drugs on Babies Exposed Via Pregnancy and Breastfeeding

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T01-4P4NPGN-1&_user=10&_coverDate=07%2F07%2F2007&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=f6d5a09cf544b66a9526277a6e021e57

Review

Developmental effects of SSRIs: lessons learned from animal studies

Xenia Borue^a^, ^b, John Chen^a^, ^b and Barry G. Condron^b^, ^,
^aUniversity of Virginia Medical Scientist Training Program and University of Virginia Neuroscience Graduate Program, Charlottesville, VA 22904, United States
^bUniversity of Virginia, Department of Biology, Charlottesville, VA 22904, United States
Received 1 June 2007; accepted 19 June 2007. Available online 7 July 2007.

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are utilized in the treatment of depression in pregnant and lactating women. SSRIs may be passed to the fetus through the placenta and the neonate through breastfeeding, potentially exposing them to SSRIs during peri- and postnatal development. However, the long-term effects of this SSRI exposure are still largely unknown. The simplicity and genetic amenability of model organisms provides a critical experimental advantage compared to studies with humans. This review will assess the current research done in animals that sheds light on the role of serotonin during development and the possible effects of SSRIs. 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. Similar changes result from the inhibition of the serotonin transporter or monoamine oxidase, implicating these two regulators of serotonin signaling in developmental changes. Understanding the role of serotonin in brain development is critical to identifying the possible effects of SSRI exposure.

Keywords: Serotonin; Neurotransmitter; CNS development

Corresponding author at: University of Virginia, Department of Biology, Gilmer Hall 071, Box 400328, Charlottesville, VA 22904, United States. Tel.: +1 434 243 6794; fax: +1 434 243 5315.

8. Conclusions

In this review, we have presented the major steps of serotonin signaling: serotonin synthesis and packaging,

reuptake, and degradation. We have stressed the effects that each of these processes has on the regulation of

serotonin levels and the developing brain. Animal studies have shown the importance of serotonin signaling in

modulating neuronal circuitry, 5HT receptor level, and behavior. Regardless of the method employed, increased

extracellular serotonin levels during the perinatal period can cause subtle changes in brain circuitry and

maladaptive behaviors, such as increased anxiety, aggression, or depression, that are maintained into

adulthood. These effects are thought to occur through excessive activation of certain serotonin receptors as

evidenced by the rescue of these phenotypes by pharmacological or genetic means.

Serotonin signaling is highly conserved, and therefore many of these animal model finding are relevant to

humans. This is highlighted by the discovery of human polymorphisms in SERT and MAO that are associated

with maladaptive behaviors that are very similar to the behaviors seen in knockout mice lacking these serotonin

signaling genes. Altogether these findings stress the importance of regulating levels of extracellular serotonin

during critical developmental windows. SSRIs blockage during this time could have subtle effects on the

developing brain that may not become apparent until adulthood. Very little is known about the timing or number

of such critical periods in human development. It is clear that more studies in both animals and humans will

need to be done to fully understand the effects of SSRIs on the developing brain.

While much of our current knowledge of serotonin signaling comes from mouse models, more basic animal

systems may be necessary to tease out some of the fundamental rules governing serotonin signaling. For

example, the fruit fly with its conserved serotonin signaling pathway, provides a simpler model to study the

serotonergic system at the single neuron level. Studies done in the fruit fly, where excess serotonin has been

shown to cause compensatory changes in the structure of the serotonergic neurons, have provided evidence for

an autoregulatory role of serotonin. Further work in this simple model may yield more insight into the

serotonergic signaling and its role in the developing brain.

(To see the entire study, click here.)

Citalopram and breast-feeding: serum concentration and side effects in the infant.
Schmidt K, Olesen OV, Jensen PN.
Biol Psychiatry Jan 2000; 47(2):164-5

Affiliation
Department A, Psychiatric University Hospital, Aarhus, Risskov, Denmark.

Abstract
BACKGROUND: During treatment of postpartum depression with antidepressant drugs, the mothers often strongly wish to continue breast-feeding although the long-term safety of exposing infants to low doses of antidepressants has not been established. METHODS: Citalopram in breast milk and in the serum of a nursing mother and her infant was determined by high-performance liquid chromatography. RESULTS: During treatment with 40 mg/day of citalopram, the concentration of the drug in milk and serum was 205 ng/mL and 98.9 ng/mL, respectively. Her infant obtained 12.7 ng/mL of citalopram in serum and uneasy sleep was observed. Sleep was normalized when the dose was halved and two breast-feedings were replaced with artificial nutrition. CONCLUSION: The amount of citalopram and other selective serotonin inhibitors (SSRIs) passed to breast milk and delivered to the child correlates to the serum concentration of the mother. The lowest possible effective serum concentration should be used and breast-feeding during the drug absorption phase may be avoided.

Risks of congenital malformations and perinatal events among infants exposed to antidepressant medications during pregnancy.
Davis RL, Rubanowice D, McPhillips H, Raebel MA, Andrade SE, Smith D, Yood MU, Platt R, .
Pharmacoepidemiol Drug Saf Oct 2007; 16(10):1086-94

Affiliation
Center for Health Studies, Group Health Cooperative, Seattle, WA, USA.

Abstract
PURPOSE: To evaluate risks for perinatal complications and congenital defects among infants exposed in utero to antidepressants. METHODS: We identified 2201 women who were prescribed an antidepressant during pregnancy and who delivered an infant within one of five large managed care organizations (HMO). Prescription drug dispensings and inpatient and outpatient diagnoses were obtained from automated databases at each HMO. Antidepressants were categorized into tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs), and medication timing was assessed by trimester. Rates of congenital anomalies or perinatal complications were compared to infants whose mothers were not prescribed antidepressants during pregnancy. RESULTS: Infants exposed to SSRIs or TCAs during pregnancy had a significant increase in preterm delivery risk. Fullterm infants exposed to SSRIs during the third trimester had an increased risk for respiratory distress syndrome, endocrine and metabolic disturbances, hypoglycemia, temperature regulation disorders, and convulsions. Third-trimester exposure to TCAs was also associated with an increased risk for respiratory distress syndrome, endocrine and metabolic disturbances, and temperature regulation disorders. There were 182 infants exposed to Paroxetine, and these infants did not have an increased risk of cardiac septal defects. CONCLUSIONS: SSRIs and TCAs did not show a consistent link with congenital anomalies. Paroxetine exposure was not linked with an increased risk for cardiovascular anomalies, although our study power to detect a moderate increase in risk was limited. Infants exposed to antidepressants were at increased risk for preterm delivery. Both SSRIs and TCAs used during the third trimester appeared to increase the risk for perinatal complications and their use should be managed carefully among pregnant women with depression. Copyright (c) 2007 John Wiley & Sons, Ltd.

Distribution and excretion of sertraline and N-desmethylsertraline in human milk.
Kristensen JH, Ilett KF, Dusci LJ, Hackett LP, Yapp P, Wojnar-Horton RE, Roberts MJ, Paech M.
Br J Clin Pharmacol May 1998; 45(5):453-7

Affiliation
Department of Pharmacy, King Edward Memorial Hospital, Subiaco, Western Australia.

Abstract
AIMS: To characterise milk/plasma (M/P) ratio and infant exposure, for sertraline and N-desmethylsertraline, in breast-feeding women taking sertraline for the treatment of depression. METHODS: Eight women (mean age 28 years) taking sertraline (1.05 mg kg(-1) day(-1)) and their infants (mean age 5.7 months) were studied. Sertraline and N-desmethylsertraline in plasma and milk were measured by high-performance liquid chromatography over a 24 h dose interval at steady-state. M/P values were estimated from area under the plasma and milk concentration-time curves. All milk produced was collected over the dose interval. Infant exposure was estimated as the product of actual or estimated milk production, and average drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. RESULTS: Mean milk production was 321 ml day(-1) (range 34-974 ml). Mean M/P values of 1.93 and 1.64 were calculated for sertraline and N-desmethylsertraline respectively. Infant exposure estimated from actual milk produced was 0.2% and 0.3% of the weight-adjusted maternal dose for sertraline and N-desmethylsertraline (as sertraline equivalents) respectively. When calculated from estimated milk production (0.15 l kg(-1) day(-1)), infant exposure was significantly greater (P<0.0001) at 0.90% and 1.32% for sertraline and N-desmethylsertraline respectively. Neither sertraline nor its N-desmethyl metabolite could be detected in plasma samples from the four infants tested. No adverse effects were observed in any of the eight infants and all had achieved normal developmental milestones. CONCLUSIONS: Irrespective of the method of calculation of infant exposure, the mean total dose of sertraline and its N-desmethyl metabolite transmitted to infants via breast-feeding is low and unlikely to cause any significant adverse effects.

The pharmacokinetics of sertraline excretion into human breast milk: determinants of infant serum concentrations.
Stowe ZN, Hostetter AL, Owens MJ, Ritchie JC, Sternberg K, Cohen LS, Nemeroff CB.
J Clin Psychiatry Jan 2003; 64(1):73-80

Affiliation
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta GA, USA.

Abstract
BACKGROUND: The purpose of this study was to attain a new landmark in the area of selective serotonin reuptake inhibitor therapy during lactation by establishing a basis for interpreting infant serum concentrations and for minimizing infant exposure in the absence of treatment-emergent side effects. METHOD: Breast milk and paired maternal and infant sera were collected following maternal treatment with sertraline monotherapy (25-200 mg/day) administered once daily. Sertraline and its major metabolite were measured in breast milk and serum samples using high-performance liquid chromatography with UV detection (limit of detection = 2 ng/mL). RESULTS: Twenty-six nursing women with DSM-IV major depressive disorder participated in the study; the mean (SD) daily sertraline dose was 123.9 (62.8) mg/day. Fifteen women submitted 182 breast milk samples for analysis of gradient (foremilk to hindmilk) and time course of medication excretion. The milk/plasma ratio was highly variable (range, 0.42-4.81). A significant gradient and time course of excretion for both sertraline (p <.001 for both) and desmethylsertraline (p <.001 for gradient and p <.046 for time course) were observed, with the highest concentrations observed in the hindmilk 8 to 9 hours after maternal ingestion. Mathematical modeling of sertraline and desmethylsertraline excretion revealed that discarding breast milk 9 hours after maternal dose decreased the infant daily dose of sertraline by a mean of 17.1% (1.8%). Twenty-two mother/infant sera pairs were obtained. Sertraline was detectable in 4 infants (18% of sample), and desmethylsertraline was found in 11 infants (50% of sample). The mean (SD) maximum calculated nursing infant dose of sertraline, 0.67 (0.61) mg/day, and desmethylsertraline, 1.44 (1.36) mg/day, represented 0.54% (0.49%) of the maternal daily dose. The maximum infant dose of desmethylsertraline (p <.002) significantly correlated with infant serum desmethylsertraline concentrations (ng/mL). In contrast, maternal daily dose, duration of medication exposure, and infant age and weight at sampling did not correlate with either detectability (< 2 ng/mL vs. > or = 2 ng/mL) or absolute concentrations (ng/mL) in infant serum. No adverse events were reported or documented in any infant. CONCLUSION: These results extend previous studies by demonstrating the utility of breast milk analysis in interpreting infant serum concentrations and minimizing infant exposure.

First, in case you aren't familiar, this is olanzapine:

Olanzapine (Zyprexa, Zyprexa Zydis, or in combination with fluoxetine Symbyax) is an atypical antipsychotic, approved by the FDA in 1996^[1] for the treatment of schizophrenia, acute manic episodes in bipolar disorder, acute agitation associated with both these disorders, maintenance treatment in bipolar disorder, and, as the Symbyax formulation, for the treatment of depressive episodes associated with bipolar disorder. Off-label uses are listed below.
Olanzapine is manufactured and marketed by the pharmaceutical company Eli Lilly and Company, whose patent for olanzapine proper ends in 2011.

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Transfer of olanzapine into breast milk, calculation of infant drug dose, and effect on breast-fed infants.
Gardiner SJ, Kristensen JH, Begg EJ, Hackett LP, Wilson DA, Ilett KF, Kohan R, Rampono J.
Am J Psychiatry Aug 2003; 160(8):1428-31

Affiliation
Department of Clinical Pharmacology, Christchurh Hospital, New Zealand. sharon.gardiner@ cdhb.govt. nz

Abstract
OBJECTIVE: This study characterized infant drug doses and breast-milk-to-plasma area-under-the- curve ratios for olanzapine and determined plasma concentrations and effects of this drug on breast-feeding infants. METHOD: Seven mother-infant nursing pairs were studied. Olanzapine was measured in plasma and milk with high-performance liquid chromatography over a dose interval (for six patients) or at a single time after dose ingestion (for one patient) at steady state. Infant drug exposure was estimated as the product of an assumed milk production rate and average drug concentration in milk, normalized to body weight, and expressed as a percentage of maternal drug dose, normalized to body weight. RESULTS: The median infant dose of olanzapine ingested through milk was 1.02% of the maternal dose; the median milk-to-plasma area-under-the- curve ratio was 0.38 for the six patients with data collected over the dose interval. Corresponding values in the patient with single-point data were 1.13% and 0.75. Olanzapine was not detected in the plasma of the six infants with an evaluable plasma sample. All of the infants were healthy and experienced no side effects. CONCLUSIONS: Breast-fed infants were exposed to a calculated olanzapine dose of approximately 1%-well below the 10% notional level of concern. In infant plasma, olanzapine was below the detection limit; there were no adverse effects on the infants. These data support the use of olanzapine during breast-feeding. However, the authors recommend that breast-fed infants be monitored closely and the decision to breast-feed be made after individual risk-benefit analysis.