Serotonin Reuptake Inhibitor Exposure Research Articles

Effects of periadolescent fluoxetine and paroxetine on elevated plus-maze, acoustic startle, and swimming immobility in rats while on and off-drug

RationaleWhether selective serotonin reuptake inhibitors (SSRIs) exposure during adolescent brain development causes lasting effects remains unresolved.ObjectiveAssess the effects of fluoxetine and paroxetine 60 days after adolescent exposure compared with when on-drug.MethodsMale Sprague-Dawley littermates (41 litters) were gavaged on postnatal days 33-53 with fluoxetine (3 or 10 mg/kg/day), paroxetine (3, 10 or, 17 mg/kg/day), or water; half were tested while on-drug (21 litters) and half after 60 days off-drug (20 litters).ResultsThe highest dose of the drugs reduced body weight gain during treatment that rebounded 1 week post-treatment. On-drug, no significant group differences were found on elevated plus maze time-in-open, zone entries, or latency to first open entry; however, the high dose of paroxetine significantly reduced head-dips (N = 20/group). No significant effects were found on-drug for acoustic startle response/prepulse inhibition (ASR/PPI) although a trend (p < 0.10) was seen, which after combining dose levels, showed a significant increase in ASR amplitude for both fluoxetine and paroxetine (N = 20-21/group). No differences on immobility time were seen in the Porsolt forced swim test or in plasma corticosterone at the end of forced swim (N-19-21/group). Off-drug, no effects were seen in the elevated plus maze (N = 16/group), ASR/PPI (N = 20/group), forced swim (N = 19-20/group), or plasma corticosterone (N = 19/group). At the doses tested, fluoxetine and paroxetine induced minor effects with drug on-board but no residual, long-term adverse effects in rats 60 days after drug discontinuation.ConclusionsThe data provide no evidence that fluoxetine or paroxetine have long-term adverse effects on the behaviors measured here after adolescent to young adult exposure.

Selective Serotonin Reuptake Inhibitor Exposure In Utero and Pregnancy Outcomes

Selective Serotonin Reuptake Inhibitor Exposure In Utero and Pregnancy Outcomes

Antidepressants in pregnancy: a systematic review.

Part of three systematic reviews on the effects of psychotropic medication exposure in pregnancy, this paper critically reviews the literature on adverse effects of antidepressant use during pregnancy, and derives recommendations for clinical practice. Electronic databases were searched for original research studies examining the effects of gestational exposure to antidepressants on pregnancy, neonatal and longer-term developmental outcomes. Most results were derived from cohort (prospective and retrospective) and casecontrol studies. There were no randomized controlled trials. Congenital malformations: 35 studies identified, 12 demonstrated a significant association between antidepressant use in early pregnancy and congenital malformations. Pregnancy outcomes: 35 articles identified, outcomes measured rates of spontaneous abortion (4 out of 7 studies reporting elevated risk), preterm birth (15 out of 19 reporting elevated risk) and abnormal birth weight (8 out of 23 reporting elevated risk). Neonatal outcomes: 17 controlled studies including one meta-analysis were identified concerning neonatal adaptation. 15 studies showed an association between gestational exposure to antidepressants and neonatal adaptation difficulties. Three studies examined an association between selective serotonin reuptake inhibitor (SSRI) exposure and persistent pulmonary hypertension in the neonate with conflicting results. Longer-term developmental outcomes: 6 of 7 studies comparing developmental outcomes of children exposed to antidepressants in utero with non- exposed children reported no significant differences. Most of these medications remain relatively safe in pregnancy, but some significant areas of concern exist, particularly some evidence of higher risk of preterm birth, neonatal adaptation difficulties and congenital cardiac malformations (with paroxetine). The impact of these findings on the risk-benefit analysis when treating pregnant women with antidepressants is discussed.

Impact of antenatal selective serotonin reuptake inhibitor exposure on pregnancy outcomes in mice

This study investigates fluoxetine (FLX) exposure as an etiology for altered gestational length and adverse pregnancy outcomes. Two experiments were performed exposing mice to drinking water (H(2)O) or H(2)O+FLX. Primary outcomes included gestational length, litter size, and live birth rate. In experiment 1, time-mated dams were monitored for spontaneous birth, and gestational length was calculated. In experiment 2, dams were dissected on day 14 to verify litter size and qualities of embryo implantation. There was no difference in gestational length between H(2)O dams (480.7 ± 13.2 hours) and H(2)O+FLX dams (483.5 ± 10.1 hours), P = .70. Mean litter size was decreased in H(2)O+FLX dams (4.1 ± 1.3/litter) compared to H(2)O dams (5.5 ± 1.9/litter), P = .04. H(2)O+FLX dams were less likely to have live births (25.4%) compared to H(2)O dams (49.3%), P = .01. Antenatal FLX exposure did not statistically alter gestational length, but did affect litter size and spontaneous loss in mice. This warrants further investigation.

A register study of the impact of stopping third trimester selective serotonin reuptake inhibitor exposure on neonatal health

To determine whether risk for adverse neonatal outcomes are reduced by stopping SSRI use before the end of pregnancy. Using population health data, maternal health and prenatal SSRI prescriptions were linked to neonatal birth records (N = 119,547) (1998-2001). Neonates SSRI-exposed in the last 14 days (L14) of gestation were compared with infants who had gestational exposure, but not during the last 14 days (NL14). Propensity score matching was used to control for potential confounders (total exposure, maternal health characteristics). Increased risk for neonatal respiratory distress was present where L14 exposure occurred compared with risk where exposure stopped before L14. However, controlling for potential maternal and neonatal confounders, differences disappeared. Controlling for maternal illness severity, reducing exposure to SSRI's at the end of pregnancy had no significant clinical effect on improving neonatal health. These findings raise the possibility that some adverse neonatal outcomes may not be an acute pharmacological condition such as toxicity or withdrawal.

Selective Serotonin Reuptake Inhibitor Exposure in Pregnancy and Neonatal Adverse Events

Selective Serotonin Reuptake Inhibitor Exposure in Pregnancy and Neonatal Adverse Events

Selective Serotonin Reuptake Inhibitor Exposure in Pregnancy and Neonatal Adverse Events—Reply

Selective Serotonin Reuptake Inhibitor Exposure in Pregnancy and Neonatal Adverse Events—Reply

99: Pregnancy outcomes in mice following antenatal selective serotonin reuptake inhibitor exposure

Conflicting data exist linking selective serotonin reuptake inhibitor (SSRI) use to spontaneous pregnancy loss. This study investigates the effect of antenatal SSRI exposure as an etiology for altered embryo implantation, litter size, and birth rate.

Error in Table in: Selective Serotonin Reuptake Inhibitor Exposure In Utero and Pregnancy Outcomes

Error in Table in: Selective Serotonin Reuptake Inhibitor Exposure In Utero and Pregnancy Outcomes

707: Impact of antenatal selective serotonin reuptake inhibitor exposure on length of gestation and pregnancy loss in mice

Fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI), is the most commonly prescribed antidepressant in pregnancy. Some human literature suggests that SSRIs both shorten the length of gestation and increase the likelihood of spontaneous abortion. This study aims to determine the impact of antenatal FLX exposure on length of gestation in a mouse model.

Selective Serotonin Reuptake Inhibitor Exposure In Utero and Pregnancy Outcomes

To investigate the effect of intrauterine selective serotonin reuptake inhibitor (SSRI) exposure on pregnancy outcomes. Prospective cohort study. Department of Obstetrics, Aarhus University Hospital, Aarhus, Denmark. Pregnant women receiving prenatal care in our hospital from 1989 to 2006. Maternal SSRI use during pregnancy. Gestational age, birth weight, head circumference, 5-minute Apgar score, and admission to the neonatal intensive care unit. Three hundred twenty-nine pregnant women reported treatment with SSRIs, 4902 were not treated with SSRIs but had a history of psychiatric illness, and 51 770 reported no history of psychiatric illness. Gestational age was 5 days (95% confidence interval [CI], -6 to -3) shorter and the odds ratio (OR) for preterm birth was 2.0 (95% CI, 1.3-3.2) in the women exposed to SSRIs compared with women with no history of psychiatric illness. In utero-exposed newborns had increased risk of admission to the neonatal intensive care unit (OR, 2.4; 95% CI, 1.7-3.4) and of 5-minute Apgar scores of less than 8 (OR, 4.4; 95% CI, 2.6-7.6) compared with those not exposed. Head circumference and birth weight did not differ between infants in the exposed and unexposed groups. The results were similar when compared with infants of women with a psychiatric history. Exposure to SSRIs during pregnancy was associated with an increased risk of preterm delivery, a low 5-minute Apgar score, and neonatal intensive care unit admission, which was not explained by lower Apgar scores or gestational age. The study justifies increased awareness to the possible effects of intrauterine exposure to antidepressants.

Neonatal S100B Protein Levels After Prenatal Exposure to Selective Serotonin Reuptake Inhibitors

This study investigated neonatal S100B levels as a biomarker of prenatal selective serotonin reuptake inhibitor (SSRI) exposure. Maternal (delivery; N = 53) and neonatal (cord; N = 52) serum S100B levels were compared between prenatally SSRI-exposed (maternal, N = 36; neonatal, N = 37; duration: 230 +/- 71 days) and nonexposed (maternal, N = 17; neonatal, N = 15) groups. Measures of maternal depression and anxiety symptoms were assessed during the third trimester (33-36 weeks), and neonatal outcomes, including Apgar scores, birth weight, gestational age at birth, and symptoms of poor neonatal adaptation, were recorded. S100B levels were significantly lower in prenatally SSRI-exposed neonates than in nonexposed neonates, controlling for gestational age and third-trimester maternal mood (P = .036). In contrast, SSRI-exposed mothers had significantly higher maternal serum S100B levels, compared with nonexposed mothers (P = .014), even controlling for maternal mood in the third trimester. S100B levels were not associated with maternal or neonatal drug levels, duration of prenatal exposure, demographic variables, or risk for poor neonatal adaptation. Prenatal SSRI exposure was associated with decreased neonatal serum S100B levels, controlling for prenatal maternal mood. Neonatal S100B levels did not reflect neonatal behavioral outcomes and were not related to pharmacologic indices. These findings are consistent with prenatal alcohol and cocaine exposures, which also alter central serotonin levels.

Selective Serotonin Reuptake Inhibitor Exposure During Early Pregnancy and the Risk of Fetal Major Malformations

To analyze all studies reporting primary data on the rate of fetal malformations after early in utero exposure to paroxetine, investigated either specifically or jointly with other antidepressant medications. Medical literature was identified through searches of MEDLINE/PubMed, TOXNET, EMBASE, and The Cochrane Library (1980 through September 2008). Search terms were pregnancy, antidepressants, SSRIs, paroxetine, and fetal malformations. Additional studies were identified from the reference lists of published articles. Twenty-five articles reporting primary data on the rate of fetal structural malformations following exposure to paroxetine or selective serotonin reuptake inhibitors as a group during the first trimester of pregnancy were electronically or manually selected. Studies on the teratogenic risk of paroxetine show a high degree of heterogeneity. Moreover, research studies performed with the same methodology and thus showing the same level of evidence report conflicting results. Given the inconsistency of the findings and limitations of the methodology of the published studies, the teratogenic potential of paroxetine that has been reported in some studies remains unproven. This relevant safety question is likely to remain unanswered until large, prospective studies are conducted. Such studies should be designed to include a control group of untreated mothers with similar psychiatric diagnosis so as to differentiate effects of drug exposure from impact of underlying mental disorder on the fetus. Moreover, further experimental studies are warranted to definitively assess clinical consequences of the impact on fetal development related to physiologic effects of prenatal paroxetine exposure on different maternal and fetal parameters.

Effects of timing and duration of gestational exposure to serotonin reuptake inhibitor antidepressants: Population-based study

Late-gestational serotonin reuptake inhibitor (SRI) exposure has been linked to adverse neonatal outcomes; however, the impact of timing and duration of exposure is unknown. To determine whether late-gestational exposure to an SRI is associated with increased risk of adverse neonatal outcome relative to early exposure. Population-based maternal and neonatal health records were linked to prenatal maternal prescription records for an SRI medication (n=3500). After controlling for maternal illness and duration of exposure, using propensity score matching, neonatal outcomes did not differ between late and early exposure (P>0.05). After controlling for maternal illness, longer prenatal exposure increased the risks of lower birth weight, respiratory distress and reduced gestational age (P<0.05). Using population health data, length of gestational SRI exposure, rather than timing, increased the risk for neonatal respiratory distress, lower birth weight and reduced gestational age, even when controlling for maternal illness and medication dose. These findings highlight the importance of distinguishing the specific impact of medication exposure from exposure to maternal illness itself.

Poor Neonatal Adaptation After in Utero Exposure to Duloxetine

Back to table of contents Previous article Next article Letters to the EditorFull AccessPoor Neonatal Adaptation After in Utero Exposure to DuloxetineROY EYAL M.D.DEBORAH YAEGER M.D.,ROY EYAL M.D.Search for more papers by this authorDEBORAH YAEGER M.D.Search for more papers by this author,Published Online:1 May 2008https://doi.org/10.1176/appi.ajp.2008.07071194AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To The Editor: Risk-benefit analysis is central when forming a treatment plan for pregnant women with mental illness. This task is further complicated by limited data pertaining to the effects of antidepressants on the fetus, neonate, and child. To our knowledge, this is the first case report of in utero exposure to duloxetine.“Ms. A” was a 36-year-old Caucasian female with a history of recurrent major depression, anorexia, and chronic neck pain. When she sought psychiatric consultation at 34 weeks’ gestation, she was 1) in complete remission, 2) being treated by an anesthesiologist, 3) and receiving monotherapy duloxetine (90 mg/day). She was educated about neonatal behavioral syndrome, and duloxetine was subsequently decreased to 60 mg/day.The child was delivered without complication at 38 weeks. Upon delivery, she was blue, with minimal respiratory effort and oxygen saturations in the 80s. Her Apgar scores were 7 and 9. After birth, she was transferred to the neonatal intensive care unit because she continued to require oxygen. The child was started on antibiotics while possible causes of transient tachypnea were assessed. Basic laboratory examination, blood gas, echocardiogram, and chest and abdominal x-rays were all normal on day 1. Breast feeding was discouraged because of concerns of exposure to duloxetine, and the mother was advised to switch to sertraline. Antibiotic treatment was discontinued after blood cultures remained negative.On day 3, the child was weaned to room air but developed “jerky rhythmic movements,” or “twitchiness.” An electroencephalogram (EEG) showed nonspecific encephalopathic findings. The child did have episodes of shaking, and the EEG revealed no correlated changes. Phenobarbital was started, and despite a high blood level the following day, the child continued to experience occasional twitching. Head computed tomography, magnetic resonance imaging, and lumbar puncture were all normal. A repeat EEG conducted at 7 days was suggestive of subclinical seizures. A follow-up EEG at 7 weeks was normal. Phenobarbital was discontinued, and the child was diagnosed with tremors and neonatal seizures associated with neonatal behavior syndrome. At age 2, the child is healthy with consistently normal neurobehavioral development. This case demonstrates the syndrome referred to as poor neonatal adaptation or neonatal behavioral syndrome, characterized by jitteriness, poor muscle tone, weak cry, respiratory distress, hypoglycemia, low Apgar score, and seizure (1) . These symptoms start within hours, generally require only supportive care, and end within 1 to 2 weeks. The syndrome may occur in up to 30% of infants with selective serotonin reuptake inhibitor exposure (2) , with a risk ratio of approximately 3.0 (3) or higher for premature infants (4) . The mechanism underlying the syndrome is unclear. A dose of fluoxetine or nursing may decrease symptoms assuming they stem from withdrawal. Reports indicate a higher risk with exposure to paroxetine and venlafaxine, agents with the shortest half-lives, but data are very limited pertaining to newer antidepressants such as duloxetine, mirtazapine, and bupropion. Better characterization of poor neonatal adaptation and its etiology could reduce invasive procedures and inform the difficult decisions in treating mental illness during pregnancy. Los Angeles, Calif.The authors report no competing interests.This letter (doi: 10.1176/appi.ajp.2008.07071194) was accepted for publication in January 2008.

Infant serotonin transporter (SLC6A4) promoter genotype is associated with adverse neonatal outcomes after prenatal exposure to serotonin reuptake inhibitor medications

Reduced Apgar scores and birth weight, increased risk of respiratory distress, jitteriness and increased tone have been reported in up to 30% of neonates with prenatal exposure to serotonin reuptake inhibitor (SRI) antidepressant medications. In adults, effects of these medications may be related to the genotype for the serotonin transporter (SLC6A4) promoter. In this study we investigated whether SLC6A4 genotype influences the risk for adverse outcomes in neonates with prenatal SRI exposure. Neonatal outcomes including Apgar scores, birth weight, gestational age at birth, symptoms of poor neonatal adaptation and genotype for SLC6A4 were determined in 37 prenatally SRI exposed neonates and compared with 47 non-exposed neonates. Reduced 5 min Apgar scores were observed in exposed neonates and this was moderated by the ss genotype (P<0.001). Birth weight was lower in exposed ls neonates (P=0.008). Risk for respiratory symptoms (respiratory distress and rapid breathing) was higher in exposed neonates with the ll genotype compared to non-exposed neonates (P<0.05) and risk for neuromotor symptoms increased in exposed ss neonates (P<0.026). These relationships remained when controlling for maternal mood during pregnancy, length of gestational medication exposure and gestational age at birth and cesarean section rate. Prenatal SRI exposure was associated with adverse neonatal outcomes and these effects were moderated by infant SLC6A4 genotype. Relationships between polymorphisms and specific outcomes varied during the neonatal period, suggesting that beyond apparent gene-medication interactions, multiple mechanisms contribute to adverse neonatal outcomes following prenatal SRI exposure.

A Pilot Study of Antidepressant-Induced Mania in Pediatric Bipolar Disorder: Characteristics, Risk Factors, and the Serotonin Transporter Gene

Antidepressant-induced mania (AIM) has been described in bipolar disorder (BD) and has been associated with the short-allele of the serotonin transporter gene (5-HTT). We wished to investigate the frequency of and risk factors for AIM in pediatric patients with or at high risk for BD. Fifty-two children and adolescents (30 with BD and 22 with subthreshold manic symptoms, 15.1 +/- 3.4 years old), all with a parent with BD, were interviewed with their parents for manic/depressive symptoms occurring before and after past antidepressant treatment. The 47 subjects with serotonin reuptake inhibitor (SSRI) exposure were genotyped for the 5-HTT polymorphism. Fifty percent of subjects were AIM+ and 25.5% had new onset of suicidal ideation. The AIM+ and AIM- groups did not differ significantly in relation to allele (p = .36) or genotype (p = .53) frequencies of the 5-HTT polymorphism. The AIM+ subjects were more likely to have more comorbidities (3.2 vs. 2.4; p = .02) and be BD type I (p = .04) than AIM- subjects. Youth with or at high risk for BD may be particularly vulnerable to SSRI AIM and thus should be monitored if given SSRIs. In this preliminary study, we did not find that the 5-HTT polymorphism significantly influenced vulnerability to AIM.

Internalizing Behaviors in 4-Year-Old Children Exposed in Utero to Psychotropic Medications

Internalizing behaviors in children between 4 and 5 years of age who had been prenatally exposed to psychotropic medications were investigated. The authors had previously reported the effects of prenatal medication exposure in this same cohort when they were newborns and infants at 3 and 8 months of age. Parental/teacher reports and a clinical measure of mother and child interactions were used to assess levels of internalizing behaviors (e.g., depression, anxiety, withdrawal). Outcomes were compared between children with prenatal selective serotonin reuptake inhibitor (SSRI) exposure (N=22) and nonexposed children of healthy, nondepressed, nonmedicated mothers (N=14). Measures of maternal mood were obtained. Ordered logistic regressions, independent-sample t tests, and univariate ANOVAs were used to compare outcomes between groups. Pearson correlations were used to determine associations between maternal mood and child behaviors. Levels of internalizing behaviors did not differ significantly between children with prenatal psychotropic medication exposure and those not exposed. However, as symptoms of maternal anxiety and depression increased, so did reported internalizing behaviors in their children. Prenatal exposure to psychotropic medications was not associated with increased reports of internalizing behaviors at 4 years of age, whereas impaired maternal mood did have an identified impact on child behavior. Further study of complex associations between maternal psychiatric disorders, prenatal SSRI exposure, and childhood internalizing behaviors is required to understand if the child outcome is affected by the illness, medications, or a combination of both.

Internalizing Behaviors in 4-Year-Old Children Exposed in Utero to Psychotropic Medications

Internalizing behaviors in children between 4 and 5 years of age who had been prenatally exposed to psychotropic medications were investigated. The authors had previously reported the effects of prenatal medication exposure in this same cohort when they were newborns and infants at 3 and 8 months of age.Parental/teacher reports and a clinical measure of mother and child interactions were used to assess levels of internalizing behaviors (e.g., depression, anxiety, withdrawal). Outcomes were compared between children with prenatal selective serotonin reuptake inhibitor (SSRI) exposure (N=22) and nonexposed children of healthy, nondepressed, nonmedicated mothers (N=14). Measures of maternal mood were obtained. Ordered logistic regressions, independent-sample t tests, and univariate ANOVAs were used to compare outcomes between groups. Pearson correlations were used to determine associations between maternal mood and child behaviors.Levels of internalizing behaviors did not differ significantly between children with prenatal psychotropic medication exposure and those not exposed. However, as symptoms of maternal anxiety and depression increased, so did reported internalizing behaviors in their children.Prenatal exposure to psychotropic medications was not associated with increased reports of internalizing behaviors at 4 years of age, whereas impaired maternal mood did have an identified impact on child behavior. Further study of complex associations between maternal psychiatric disorders, prenatal SSRI exposure, and childhood internalizing behaviors is required to understand if the child outcome is affected by the illness, medications, or a combination of both.

Neonatal Signs After Late In Utero Exposure to Serotonin Reuptake Inhibitors

A neonatal behavioral syndrome linked to in utero serotonin reuptake inhibitor (SRI) exposure during the last trimester of pregnancy has been identified. The US Food and Drug Administration (FDA) and drug manufacturers have recently agreed to a class labeling change for SRIs, which include selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), to include information about potential adverse events in neonates exposed in utero. Integration of data about the neonatal behavioral syndrome into the management of pregnancy in women who take SRIs is a current challenge for physicians. To review evidence regarding the SRI-related neonatal syndrome and to help clinicians guide their patients in a risk-benefit decision-making process. We searched MEDLINE (1966-February 2005) and PsycINFO (1974-February 2005). All articles related to neonatal signs after in utero SRI exposure were acquired, as well as unpublished data on this topic from the FDA advisory committee meeting of June 2004. References cited in case reports and studies were reviewed. Foreign-language literature was included and translated to English. Studies were included if they had clearly identified maternal SRI exposure for a minimum of the final trimester of pregnancy through delivery and assessed neonatal outcomes. We identified 13 case reports describing a total of 18 cases. Nine cohort studies met criteria. When not included in the published article, relative risks and 95% confidence intervals (CIs) were computed from raw data and summary risk ratios and 95% CIs were determined with Mantel-Haenszel estimates. Compared with early gestational SRI exposure or no exposure, late SRI exposure carries an overall risk ratio of 3.0 (95% CI, 2.0-4.4) for a neonatal behavioral syndrome. The most SRI-related neonatal case reports involved fluoxetine and paroxetine exposures. Neonates primarily display central nervous system, motor, respiratory, and gastrointestinal signs that are usually mild and disappear by 2 weeks of age. Medical management has consisted primarily of supportive care in special care nurseries. A severe syndrome that consists of seizures, dehydration, excessive weight loss, hyperpyrexia, or intubation is rare in term infants (1/313 quantifiable cases). There have been no reported neonatal deaths attributable to neonatal SRI exposure. Available evidence indicates that in utero exposure to SRIs during the last trimester through delivery may result in a self-limited neonatal behavioral syndrome that can be managed with supportive care. The risks and benefits of discontinuing an SRI during pregnancy need to be carefully weighed for each individual patient. Development and validation of assessment methods and clinical management strategies are critical to advancing this research.