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1.  Use of selective serotonin-reuptake inhibitors during early pregnancy and risk of congenital malformations: updated analysis 
Clinical Epidemiology  2010;2:29-36.
Background:
Data on the safety of selective serotonin-reuptake inhibitors (SSRIs) in pregnancy are inconsistent. We examined associations between SSRI use during early pregnancy and risk of congenital malformations in infants.
Methods:
Set in Northern Denmark, our population-based prevalence study included 216,042 women who had a live birth after the 20th week of gestation. We compared the prevalence of malformation in infants born to women who redeemed at least one SSRI prescription during early pregnancy with the prevalence in infants born to women who redeemed no SSRI prescriptions during their pregnancies. Drug use data were extracted from prescription databases, while data on congenital malformations were obtained from the National Registry of Patients.
Results:
The 2,062 women with SSRI prescriptions during early pregnancy gave birth to 105 (5.1%) infants with malformations, while the 213,712 women with no SSRI prescriptions gave birth to 7,449 (3.5%) infants with malformations. SSRI use was associated with an increased risk of malformations overall (odds ratio [OR] = 1.3; 95% confidence interval (CI): 1.1–1.6) and cardiac malformations (OR = 1.7; 95% CI: 1.1–2.5). For specific SSRIs, we found an increased risk for septal defects associated with sertraline.
Conclusions:
We found little overall association between use of SSRIs during pregnancy and congenital malformations, but our findings suggest an association between maternal SSRI use in early pregnancy and cardiac malformations which could be causal.
PMCID: PMC2943182  PMID: 20865100
antidepressants; drug safety; pregnancy; congenital malformations; epidemiology
2.  Increased risk of severe congenital heart defects in offspring exposed to selective serotonin-reuptake inhibitors in early pregnancy – an epidemiological study using validated EUROCAT data 
Background
Previous studies suggest a possible association between maternal use of selective serotonin-reuptake inhibitors (SSRIs) during early pregnancy and congenital heart defects (CHD). The purpose of this study was to verify this association by using validated data from the Danish EUROCAT Register, and secondary, to investigate whether the risk differs between various socioeconomic groups.
Methods
We conducted a cohort study based on Danish administrative register data linked with the Danish EUROCAT Register, which includes all CHD diagnosed in live births, fetal deaths and in pregnancies terminated due to congenital anomalies. The study population consisted of all registered pregnancies (n = 72,280) in Funen, Denmark in the period 1995–2008. SSRI-use was assessed using The Danish National Prescription Registry, information on marital status, maternal educational level, income, and country of origin from Statistics Denmark was used as indicators of socioeconomic situation, and the CHD were studied in subgroups defined by EUROCAT. Logistic Regression was used to investigate the association between redeemed prescriptions for SSRIs and CHD.
Results
The risk of severe CHD in the offspring of the 845 pregnant women who used SSRIs during first trimester increased four times (AOR 4.03 (95% CI 1.75-9.26)). We found no increased risk of septal defects. Socioeconomic position did not modify the association between maternal SSRI-use during pregnancy and severe CHD.
Conclusion
This study, which is based on data with high case ascertainment, suggests that maternal use of SSRIs during first trimester increases the risk of severe CHD, but does not support findings from previous studies, based on administrative register data, regarding an increased risk of septal defects. The study was unable to document an interaction between socioeconomic status and maternal SSRI-use on the risk of severe CHD.
doi:10.1186/1471-2393-14-333
PMCID: PMC4183770  PMID: 25258023
SSRI drugs; Antidepressant; Congenital heart defects; Socioeconomic status; EUROCAT; Cohort study
3.  Exposure to selective serotonin reuptake inhibitors and the risk of congenital malformations: a nationwide cohort study 
BMJ Open  2012;2(3):e001148.
Objectives
To analyse the relation between selective serotonin reuptake inhibitor (SSRI) use and major congenital malformations, with focus on malformations of the heart.
Design
Register-based retrospective nationwide cohort study, using the Danish Medical Birth Registry.
Setting
Denmark.
Participants
Pregnant women in Denmark between 1997 and 2009 and their offspring.
Primary outcome measures
For each SSRI, ORs for major congenital malformations were estimated using multivariable logistic regression models for women exposed to an SSRI during the first trimester and for women with paused exposure during pregnancy.
Results
The authors identified 848 786 pregnancies; 4183 were exposed to an SSRI throughout the first trimester and 806 pregnancies paused exposure during pregnancy. Risks of congenital malformations of the heart were similar for pregnancies exposed to an SSRI throughout the first trimester, adjusted OR 2.01 (95% CI 1.60 to 2.53), and for pregnancies with paused SSRI treatment during pregnancy, adjusted OR 1.85 (95% CI 1.07 to 3.20), p value for difference: 0.94. The authors found similar increased risks of specific congenital malformations of the heart for the individual SSRIs. Furthermore, the authors found no association with dosage.
Conclusions
The apparent association between SSRI use and congenital malformations of the heart may be confounded by indications. The moderate absolute risk increase combined with uncertainty for causality still requires the risk versus benefit to be evaluated in each individual case.
Article summary
Article focus
Relationship between SSRIs and congenital malformations.
Focus on malformations of the heart.
Focus on women with paused treatment during pregnancy.
Key messages
Risks of congenital malformations of the heart are increased for infants whose mothers were exposed to an SSRI during the first trimester.
Risks of congenital malformations of the heart are not different for pregnancies exposed during the first trimester as for pregnancies with paused treatment during pregnancy.
The found risk increases are moderate in absolute terms.
Strengths and limitations of this study
Observational study—no causal relations.
Nationwide study, including all live births in the study period.
Register-based study—no recall bias.
doi:10.1136/bmjopen-2012-001148
PMCID: PMC3378942  PMID: 22710132
4.  Antidepressant Use in Pregnancy and the Risk of Cardiac Defects 
The New England journal of medicine  2014;370(25):2397-2407.
Background
There is controversy regarding whether the use of selective serotonin reuptake inhibitors (SSRIs) and other antidepressants in pregnancy is associated with increased risks for congenital cardiac defects. In particular, concerns exist about a possible association between paroxetine and right ventricular outflow tract obstruction (RVOTO), and between sertraline and ventricular septal defects (VSD).
Methods
We performed a cohort study nested in the 2000–2007 nationwide Medicaid Analytic eXtract. The study included 949,504 pregnant women enrolled in Medicaid from three months before conception through one month post delivery, and their live-born infants. We compared the risk of major cardiac defects in women with antidepressant medication use during the first trimester versus no use, restricting the cohort to women with depression and using propensity score adjustment to control for depression severity and other potential confounders.
Results
64,389 women (6.8%) used antidepressants during the first trimester. Overall, 6,403 infants not exposed to antidepressants were born with a cardiac defect (72.3 per 10,000), compared with 580 infants exposed (90.1 per 10,000). Associations between antidepressant use and cardiac defects were attenuated with increasing levels of adjustment for confounding. For SSRIs, relative risks for any cardiac defect were 1.25 (95%CI, 1.13–1.38) unadjusted, 1.12 (1.00–1.26) depression-restricted, and 1.06 (0.93–1.22) depression-restricted and fully-adjusted. We found no significant associations between the use of paroxetine and RVOTO (1.07, 0.59–1.93), or the use of sertraline and VSD (1.04, 0.76–1.41).
Conclusions
Results of this large population-based cohort study suggest no substantial increased risk of cardiac malformations attributable to SSRIs.
doi:10.1056/NEJMoa1312828
PMCID: PMC4062924  PMID: 24941178
5.  Increasing the risk of spontaneous abortion and major malformations in newborns following use of serotonin reuptake inhibitors during pregnancy: A systematic review and updated meta-analysis 
Selective serotonin reuptake inhibitors (SSRIs) are the most frequently used antidepressants during pregnancy. There are conflicting results about their influence on pregnancy outcomes. The goal of this study was to update our previous meta-analysis about pregnancy outcomes following exposure to SSRIs. For this purpose, all relevant databases were searched from 1990 to March 2012 for studies investigating the pregnancy outcomes following exposure to any therapeutic dosage of any SSRI (fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine) during pregnancy. Types of outcome investigated were spontaneous abortion, major malformations, cardiovascular malformations, and minor malformations. A total of 25 studies met our criteria and were included in the meta-analysis. The odds ratio (OD) values are 1.87 (95% CI: 1.5 to 2.33, P< 0.0001) for spontaneous abortion, 1.272 (95% CI: 1.098 to 1.474, P = 0.0014) for major malformations, 1.192 (95% CI: 0.39 to 3.644, P= 0.7578) for cardiovascular malformations, and 1.36 (95% CI: 0.61 to 3.04, P= 0.4498) for minor malformations. The results demonstrated that SSRIs increase the risk of spontaneous abortion and major malformations during pregnancy while they don’t increase the risk of cardiovascular malformations and minor malformations. Our previous meta-analysis only showed an increase in the risk of spontaneous abortion following the use of SSRIs during pregnancy. This might be due to increase in the number of studies included or addition of two new SSRIs (citalopram and escitalopram). The message to researchers is to try considering SSRIs individually during pregnancy to reduce heterogeneity, although all are aware of inevitable limitations to study on pregnant mothers.
doi:10.1186/2008-2231-20-75
PMCID: PMC3556001  PMID: 23351929
Selective serotonin reuptake inhibitors (SSRIs); Pregnancy outcome; Meta-analysis; Evidence-based medicine; Malformation; Systematic review
6.  Maternal depression, antidepressant prescriptions, and congenital anomaly risk in offspring: a population-based cohort study 
Bjog  2014;121(12):1471-1481.
Objective
To estimate risks of major congenital anomaly (MCA) among children of mothers prescribed antidepressants during early pregnancy or diagnosed with depression but without antidepressant prescriptions.
Design
Population-based cohort study.
Setting
Linked UK maternal–child primary care records.
Population
A total of 349 127 singletons liveborn between 1990 and 2009.
Methods
Odds ratios adjusted for maternal sociodemographics and comorbidities (aORs) were calculated for MCAs, comparing women with first-trimester selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) and women with diagnosed but unmedicated depression, or women without diagnosed depression.
Main outcome measures
Fourteen system-specific MCA groups classified according to the European Surveillance of Congenital Anomalies and five specific heart anomaly groups.
Results
Absolute risks of MCA were 2.7% (95% confidence interval, 95% CI, 2.6–2.8%) in children of mothers without diagnosed depression, 2.8% (95% CI 2.5–3.2%) in children of mothers with unmedicated depression, and 2.7% (95% CI 2.2–3.2%) and 3.1% (95% CI 2.2–4.1%) in children of mothers with SSRIs or TCAs, respectively. Compared with women without depression, MCA overall was not associated with unmedicated depression (aOR 1.07, 95% CI 0.96–1.18), SSRIs (aOR 1.01, 95% CI 0.88–1.17), or TCAs (aOR 1.09, 95% CI 0.87–1.38). Paroxetine was associated with increased heart anomalies (absolute risk 1.4% in the exposed group compared with 0.8% in women without depression; aOR 1.78, 95% CI 1.09–2.88), which decreased marginally when compared with women with diagnosed but unmedicated depression (aOR 1.67, 95% CI 1.00–2.80).
Conclusions
Overall MCA risk did not increase with maternal depression or with antidepressant prescriptions. Paroxetine was associated with increases of heart anomalies, although this could represent a chance finding from a large number of comparisons undertaken.
doi:10.1111/1471-0528.12682
PMCID: PMC4232879  PMID: 24612301
Antidepressants; congenital anomaly; depression; SSRIs; TCAs
7.  Counseling pregnant women treated with paroxetine 
Canadian Family Physician  2006;52(5):593-594.
QUESTION
I have always reassured my patients that taking selective serotonin reuptake inhibitors (SSRIs) during pregnancy would not increase their risk of having children with major malformations. A recent warning from Health Canada, based on results of a study from GlaxoSmithKline, stated that infants exposed to paroxetine might be at higher risk of congenital malformations, specifically cardiovascular defects. Some of my pregnant patients who are taking paroxetine heard the warning and asked me whether they should stop taking it. What should I tell them?
ANSWER
The new warning is based on unpublished, non–peer-reviewed studies. It ignored 2 published studies that failed to show any association between exposure to paroxetine and cardiovascular malformations, and no association with cardiovascular malformations has been shown by SSRIs as a class. Even if there is risk, it is minimal, and the warning does not disclose details of the cardiovascular malformations. Many cases of ventricular septal defect, the most common cardiac malformation, resolve spontaneously. Concerned pregnant women should know that, if taken after the first trimester, drugs cannot cause cardiac malformations. Failure to treat depression during pregnancy can have severe consequences for both mothers and babies and is the strongest predictor of postpartum depression.
PMCID: PMC1531721  PMID: 16739830
8.  Sertraline exposure leads to small left heart syndrome in adult mice 
Pediatric research  2012;73(3):286-293.
Background
Sertraline, a selective serotonin reuptake inhibitor (SSRI), is the most commonly prescribed therapy for maternal depression. Epidemiologic studies have linked SSRI exposure with decreased fetal growth, altered autonomic regulation, and cardiac malformations. We hypothesized SSRI exposure decreases left ventricular volumes and increases adult sympathetic nervous system activation, resulting in increased adult heart rates.
Methods
C57BL/6 mice received saline or sertraline (5 or 15 mg/kg/day i.p.) on postnatal days 1–14. Adult phenotypes were assessed at 5 months.
Results
Sertraline-exposed mice had smaller left ventricular internal diameters in diastole (control 4.0 ± 0.1 mm, SSRI 3.7 ± 0.1 mm, p < 0.05), decreased stroke volumes (control 46 ± 2.6 μL, SSRI 37 ± 2.3 μL, p < 0.05), higher heart rates (control 530 ± 13 beats per minute (bpm), SSRI 567 ± 6 bpm, p <0.05) and increased urinary excretion of noradrenaline (control 174 ± 29.4 ng/mL, SSRI 276 ± 35.1 ng/mL, p<0.05). These changes were associated with increased cerebral serotonin transporter (5-HTT) expression.
Conclusion
Neonatal sertraline exposure causes long term changes in cardiac morphology and physiology. We speculate that early life SSRI exposure impairs cardiomyocyte growth and central serotonin signaling, leading to a small left heart syndrome in adult mice.
doi:10.1038/pr.2012.183
PMCID: PMC3607080  PMID: 23232669
9.  Modeling of the Temporal Patterns of Fluoxetine Prescriptions and Suicide Rates in the United States 
PLoS Medicine  2006;3(6):e190.
Background
To study the potential association of antidepressant use and suicide at a population level, we analyzed the associations between suicide rates and dispensing of the prototypic SSRI antidepressant fluoxetine in the United States during the period 1960–2002.
Methods and Findings
Sources of data included Centers of Disease Control and US Census Bureau age-adjusted suicide rates since 1960 and numbers of fluoxetine sales in the US, since its introduction in 1988. We conducted statistical analysis of age-adjusted population data and prescription numbers. Suicide rates fluctuated between 12.2 and 13.7 per 100,000 for the entire population from the early 1960s until 1988. Since then, suicide rates have gradually declined, with the lowest value of 10.4 per 100,000 in 2000. This steady decline is significantly associated with increased numbers of fluoxetine prescriptions dispensed from 2,469,000 in 1988 to 33,320,000 in 2002 (rs = −0.92; p < 0.001). Mathematical modeling of what suicide rates would have been during the 1988–2002 period based on pre-1988 data indicates that since the introduction of fluoxetine in 1988 through 2002 there has been a cumulative decrease in expected suicide mortality of 33,600 individuals (posterior median, 95% Bayesian credible interval 22,400–45,000).
Conclusions
The introduction of SSRIs in 1988 has been temporally associated with a substantial reduction in the number of suicides. This effect may have been more apparent in the female population, whom we postulate might have particularly benefited from SSRI treatment. While these types of data cannot lead to conclusions on causality, we suggest here that in the context of untreated depression being the major cause of suicide, antidepressant treatment could have had a contributory role in the reduction of suicide rates in the period 1988–2002.
An association has been shown between the introduction of the antidepressant fluoxetine in the USA in 1988 and a reduction in the number of suicides.
Editors' Summary
Background.
Depression is very common. For example, in the US, an estimated 10% of men and 20% of women will suffer from major depression at some stage in their lives. One way of treating the condition is with drugs. Several types of antidepressant drugs are available, and in many countries they are among the most commonly prescribed medicines. However, all antidepressants have side effects.
One family of antidepressants, called selective serotonin uptake inhibitors (SSRIs), was introduced in the late 1980s. The name of these drugs comes from their effect, which is to prevent the removal (reuptake) from the nerve endings of one type of chemical (serotonin) that is important for transmitting nerve impulses between brain cells. SSRIs are claimed to be more effective and to have fewer side effects than older antidepressants, and many brands of SSRI are now on the market. However, in recent years there have been claims that some people taking SSRIs have committed suicide as a result of the drugs. Whether the SSRIs are the cause of the suicide is hard to know, because people who are depressed do sometimes feel like killing themselves; so if a depressed person taking an SSRI commits suicide, it is hard to tell whether this is a result of the depression or a side effect of the treatment (the SSRI). The drug regulatory authorities in some countries are now carefully studying the issue of suicides and antidepressant use, both in adults and in children. The US Federal Drug Administration has issued what it calls a “black box warning” on the use of these drugs.
Why Was This Study Done?
The researchers wanted to discover whether the number of suicides in the US had increased or decreased since treatment with the first widely used SSRI (fluoxetine, also known as Prozac) began in 1988. Any difference in the number of suicides found before and after that date would not necessarily be the result of the introduction of this antidepressant, or other SSRIs, but the information would provide helpful information about the effects of these drugs.
What Did the Researchers Do and Find?
They looked at annual suicide rates between 1960 and 1988 and compared them with annual rates in the period 1988 to 2002. They used several sources of data, including the Centers of Disease Control and the US Census Bureau. The researchers found that from the early 1960s until 1988, in the entire US population, between 12.2 and 13.7 people in every 100,000 committed suicide each year. After that time, the numbers of suicides gradually declined, with the lowest figure (10.4 people per 100,000) reached in 2000. The researchers did mathematical tests, which demonstrated that the steady decline was statistically associated with the increased number of fluoxetine prescriptions—that is, the more prescriptions there were, the fewer suicides there were. (There were around two-and-a-half million prescriptions of the drug in 1988, increasing to over 33 million in 2002.)
What Do These Findings Mean?
In all scientific research, it is an important principle that finding an association between two events does not prove that one caused the other to occur. However, the authors of this paper suggest that the use of this drug could have contributed to the reduction of suicide rates in the US in the period 1988 to 2002. Several other SSRIs are also now in common use, but they were not considered in this study, nor were other antidepressants, or other treatments for depression.
Additional Information.
As depression is such a common condition—and because there are so many ways of treating it, including counseling and psychotherapy—there are many Web sites devoted to the subject. We have given a small selection below. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030190.
• From the American Academy of Family Physicians (AAFP), general advice on depression
• Also from the AAFP, advice specifically about antidepressant drugs
• MedlinePlus brings together authoritative information about depression from the US National Library of Medicine, National Institutes of Health, and other government agencies and health-related organizations
• Health pages of the BBC on depression
• Information about depression from other UK health advice sites: Patient UK and NetDoctor.co.uk
doi:10.1371/journal.pmed.0030190
PMCID: PMC1475655  PMID: 16768544
10.  SSRIs and SNRIs: A review of the Discontinuation Syndrome in Children and Adolescents 
Objective
To review the occurrence, clinical relevance and characteristics of the discontinuation syndrome in children and adolescents who have been on a selective serotonin reuptake inhibitor (SSRI) or a serotonin/norepinephrine re-uptake inhibitor (SNRI) for various conditions as an update for physicians prescribing these medications in this population.
Method
An on-line literature search was done using MEDLINE, PubMed, CINAHL, PsychARTICLES, and PsychINFO with the following key words: selective serotonin reuptake inhibitors or SSRIs, serotonin/norepinephrine re-uptake inhibitors or SNRIs, discontinuation syndrome, pediatric or children or adolescents, occurrences and characteristics.
Results
Not a single randomized placebo-controlled trial was found that addresses this condition solely in the child and adolescent population. A couple of papers written by the same authors indicate that children and adolescents taking an SSRI definitely experience discontinuation reactions that can be mild, moderate or severe when the medication is stopped suddenly or high doses are reduced substantially. Among the SSRIs paroxetine seems to be the worst offender and fluoxetine the least while sertraline and fluvoxamine tend to be intermediate. However, the most serious discontinuation reactions came from the SNRI venlafaxine. There was no study or reports found on citalopram, another SSRI that is commonly prescribed in children and youth. While the adult literature abounds with papers describing the different aspects of this condition including clinical features, diagnostic criteria, management and prevention, the limited information available to-date in children and adolescents indicate that the essential features of the discontinuation syndrome may not be significantly different than in adults. There were no specific characteristics identified relating to the child population.
Conclusion
In considering the use of an SSRI in children, physicians must seriously weigh the not so clear benefits against the risks of adverse reactions including the discontinuation syndrome. The frequency and severity of this reaction seem dependent on the SSRI half-life and although children metabolize drugs much faster than adults the reactions to-date have been reported as similar. The use of fluoxetine with its long half-life appears safer in this respect with paroxetine and venlafaxine causing the most concerns. Patients and their families should be well informed of the risks of stopping the medication abruptly and instructed not to do so without consulting their physician. Physicians in Canada who are using these medications off-label in children need to be knowledgeable and vigilant about such adverse reactions. These could be avoided through adequate follow ups which will also ensure better adherence. They may benefit from this review even though the information comes mostly form the adult literature. More prospective studies are needed to clarify this issue and identify any specific features relating to the pediatric population.
PMCID: PMC3024727  PMID: 21286371
selective serotonin reuptake inhibitor; serotonin/norepinephrine re-uptake inhibitor; children; adolescents; discontinuation; adverse effects
11.  Early Morbidity and Mortality Following In Utero Exposure to Selective Serotonin Reuptake Inhibitors 
CNS Drugs  2012;26(7):e1-e14.
Background
The early years of life have a profound effect on a child’s developmental pathway. The children born to mothers suffering from depression may be at risk of increased morbidity and mortality in the first years of life.
Objective
The objective of this study was to investigate the hospital admissions and mortality of children whose mothers were dispensed a selective serotonin reuptake inhibitor (SSRI) during their pregnancy.
Methods
This was a population-based study of all pregnancy events in Western Australia (WA) from 2002 to 2005. The study used linkable state health administrative data from the WA Data Linkage System (WADLS) and the national Pharmaceutical Benefits Scheme (PBS), enabling birth outcomes, hospital admissions and deaths to be ascertained for the children of women dispensed an SSRI during their pregnancy.
Results
There were 3764 children born to 3703 women who had been dispensed an SSRI during their pregnancy (3.8% of all pregnancies in WA, 2002–5), and 94 561 children born to 92 995 women who had not been dispensed an SSRI. Mean birth weight, length and APGAR score at 5 minutes were significantly lower in children of women dispensed an SSRI, regardless of whether the SSRI was dispensed in trimester 1, or, trimester 2 or 3 only. 0.9% of the live born children in the SSRI group had died before the age of 1 year compared with 0.5% of the non-SSRI group (odds ratio [OR] 1.8; 95% CI 1.3, 2.6). Before the age of 2 years, 42.9% of the children in the SSRI group had been admitted to hospital after their birth admission, compared with 34.1% of the non-SSRI group (OR 1.4; 95% CI 1.3, 1.6). The most common reason for admission to hospital was acute bronchiolitis (OR 1.6; 95% CI 1.3, 1.8), with an increased risk seen in children of mothers who did not smoke during their pregnancy (OR 1.7; 95% CI 1.4, 2.0).
Conclusions
The children in the SSRI group were more likely to be admitted to hospital in the first years of life, and this may reflect their prenatal exposure to SSRIs, be related to maternal depression, or SSRI use may be a proxy for an environmental exposure such as smoking, or a combination of these factors. Although the numbers of deaths in the first year of life were small, the increased risk of death in the first year of life in the SSRI group (OR 1.8; 95% CI 1.3, 2.6) is a new finding and should be investigated further.
doi:10.2165/11634190-000000000-00000
PMCID: PMC3585696  PMID: 22712699
12.  Congenital Heart Disease Associated With Selective Serotonin Reuptake Inhibitor Use During Pregnancy 
Mayo Clinic Proceedings  2009;84(1):23-27.
OBJECTIVE: To determine the risk of congenital cardiac abnormalities associated with use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy.
PATIENTS AND METHODS: We conducted a retrospective review of the medical records of all pregnant women presenting at Mayo Clinic's site in Rochester, MN, from January 1, 1993, to July 15, 2005, and identified 25,214 deliveries. A total of 808 mothers were treated with SSRIs at some point during their pregnancy. We reviewed the medical records of the newborns exposed to SSRIs during pregnancy to analyze their outcomes, specifically for congenital heart disease and persistent pulmonary hypertension of the newborn.
RESULTS: Of the study patients, 808 (3.2%) took an SSRI at some point during the antenatal period. Of the 25,214 deliveries, 208 newborns (0.8%) were diagnosed as having congenital heart disease. Of the 808 women exposed to SSRI during pregnancy, 3 (0.4%) had congenital heart disease compared with 205 (0.8%) of the 24,406 women not exposed to an SSRI (P=.23). Of the total number of deliveries, 16 newborns were diagnosed as having persistent pulmonary hypertension of the newborn, none of whom had exposure to SSRIs (P>.99).
CONCLUSION: Our data are reassuring regarding the safety of using SSRIs during pregnancy.
Of the 808 women who took a selective serotonin reuptake inhibitor during pregnancy, 3 (0.4%) had congenital heart disease; of the 25,214 deliveries, 208 newborns (0.8%) were diagnosed as having congenital heart disease; these findings reconfirm the safety of these drugs for pregnant women.
PMCID: PMC2664566  PMID: 19121250
13.  Combined use of selective serotonin reuptake inhibitors and sedatives/hypnotics during pregnancy: risk of relatively severe congenital malformations or cardiac defects. A register study 
BMJ Open  2013;3(2):e002166.
Objectives
To investigate the proposed synergistic teratogenic effect of use of selective serotonin receptor inhibitors (SSRI) together with sedatives or hypnotics, primarily benzodiazepines, during pregnancy.
Design
Cohort study of congenital malformations after maternal use of SSRI, sedatives/hypnotics or the combination of the two drug categories.
Setting
Swedish national health registers.
Participants
A total of 10 511 infants born of women who had used SSRI drugs but no other central nervous system (CNS)-active drug, 1000 infants born of women who had used benzodiazepines and no other CNS-active drug, and 406 infants whose mothers had used both SSRI and benzodiazepines but no other CNS-active drug.
Results
None of the three groups showed a higher risk for any relatively severe congenital malformation or any cardiac defect when comparison was made with the general population risk (adjusted risk ratio (RR) for the combination of SSRI and benzodiazepines and a relatively severe malformation=1.17 (95% CI 0.70 to 1.73). Similar results were obtained for the combination of SSRI with other sedative/hypnotic drugs.
Conclusions
The previously stated increased risk associated with the combined use of these drug categories, notably for a cardiac defect, could not be replicated.
doi:10.1136/bmjopen-2012-002166
PMCID: PMC3586083  PMID: 23427202
EPIDEMIOLOGY
14.  Assessing the Comparative-Effectiveness of Antidepressants Commonly Prescribed for Depression in the US Medicare Population 
Background
Depression is among the most common chronic illnesses in the US elderly Medicare population, affecting approximately 11.5% of beneficiaries with estimated costs of about US$65 billion annually. Patients with depression are typically treated with antidepressants - most commonly the Selective Serotonin Reuptake Inhibitors (SSRIs). SSRIs vary substantially in their costs, side effect profiles and convenience of use. All these factors might affect medication adherence and subsequently down-stream medical costs.
Aims of Study
To assess the comparative-effectiveness of three antidepressants (escitalopram, citalopram, sertraline) commonly-prescribed for depression in Medicare.
Methods
We used pharmacy and medical claims data for a 5 percent national random sample of Medicare beneficiaries who were diagnosed with depression in 2008 and followed until 12/31/2009. Key measures included drug spending, medication adherence to antidepressants, down-stream non-drug medical costs at three levels: all, psychiatric and depression related costs. Three methods were conducted to test robustness: generalized linear regression (GLM), propensity score matching, and instrumental variables (IV) approach. For the instrumental variables approach, we used a two-stage residual inclusion model, using geographic variation in the use of the various drugs as instruments. Specifically, we calculated the ratio of the number of individuals who used each drug to the total number of individuals using any antidepressants at the 306 Dartmouth hospital-referral regions.
Results
The regression and the propensity score matching method each showed that patients using escitalopram had significantly worse adherence, higher drug costs, and higher medical costs than patients using either citalopram or sertraline. However, our IV analysis yielded different results. While drug costs remained significantly higher for escitalopram patients, we found that escitalopram users had lower non-drug medical spending than patients who used citalopram, which was enough to offset the higher drug costs. The instrumental variables results also suggested that sertraline users had lower non-drug medical costs than citalopram users. The differences between sertraline and escitalopram were not statistically significant for medical spending, but sertraline users had lower drug costs and better adherence than escitalopram users.
Discussion
The IV method yielded somewhat different results than the GLM regressions and the propensity score matching methods. Once we controlled for selection bias using the instrumental variables, we found that escitalopram is actually associated with lower medical spending. One interpretation is that the IV approach mitigates selection biases due to unobserved factors that are not controlled in regular regressions. However, one conclusion remains the same: in every model, we found that sertraline was at least as cost-effective as or more cost-effective than the other drugs.
Limitations
Potential unobserved factors affecting the choice of three antidepressants are possible.
Implications for Health Policies
All methods indicated that sertraline is the most cost-effective drug to treat depression. Substantial savings to Medicare could be realized by using more cost-effective antidepressants such as sertraline.
Implications for Further Research
Geographic variation in the use of prescription drugs has been underutilized as an instrumental variable in comparative-effectiveness research. Our study demonstrates that it can help to control for selection biases in observational data.
PMCID: PMC3608926  PMID: 23525835
Medicare; comparative-effectiveness research; depression; costs
15.  Use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy and disorganized infant-mother attachment 
Objective
Examine the quality of infant-mother attachment in a prospective case series of infants whose mothers took selective serotonin reuptake inhibitors (SSRIs) during pregnancy.
Background
SSRIs are prescribed to 2 to 6% of pregnant women (National Collaborating Centre for Mental Health, 2007; Stewart, 2011). Recent articles on the use of SSRIs during pregnancy note the increased risk for problematic infant-mother relationships among mothers with untreated postpartum depression (Gentile, 2011; Stewart, 2011). However, little is known about the quality of infant-mother relationships among mothers who took SSRIs during pregnancy.
Methods
Five mothers who took SSRIs during pregnancy were recruited from a community study of infant development. Mothers completed ratings of postpartum depression symptoms (Beck Depression Inventory) 4 to 6 times between 1 month and 1 year following the infant’s birth. At 1 year postpartum, quality of infant-mother attachment was assessed using the strange situation procedure.
Results
Four of the 5 infant-mother dyads (80%) were classified as disorganized, a rate considerably higher than in postpartum depression samples.
Conclusion
These results are used to raise questions about the clinical implications of research on in utero exposure to SSRIs, perinatal depression, and disorganized attachment. Specifically, this case series raises questions about using research on the link between postpartum depression and infant-mother attachment as a rationale for the use of SSRIs during pregnancy. Current research indicates use of SSRIs during pregnancy may: 1) increase risk for disorganized attachment, 2) decrease risk for disorganized attachment, or 3) have no effect on disorganized attachment.
doi:10.1080/02646838.2012.717263
PMCID: PMC3598596  PMID: 23509416
16.  Trends in Depression and Antidepressant Prescribing in Children and Adolescents: A Cohort Study in The Health Improvement Network (THIN) 
PLoS ONE  2012;7(3):e33181.
Background
In 2003, the Committee on Safety of Medicines (CSM) advised against treatment with selective serotonin reuptake inhibitors (SSRIs) other than fluoxetine in children, due to a possible increased risk of suicidal behaviour. This study examined the effects of this safety warning on general practitioners' depression diagnosing and prescription behaviour in children.
Methods and Findings
We identified a cohort of 1,502,753 children (<18 y; registered with GP for >6 m) in The Health Improvement Network (THIN) UK primary care database. Trends in incidence of depression diagnoses, symptoms and antidepressant prescribing were examined 1995–2009, accounting for deprivation, age and gender. We used segmented regression analysis to assess changes in prescription rates. Overall, 45,723 (3%) children had ≥1 depression-related entry in their clinical records. SSRIs were prescribed to 16,925 (1%) of children. SSRI prescription rates decreased from 3.2 (95%CI:3.0,3.3) per 1,000 person-years at risk (PYAR) in 2002 to 1.7 (95%CI:1.7,1.8) per 1,000 PYAR in 2005, but have since risen to 2.7 (95%CI:2.6,2.8) per 1,000 PYAR in 2009. Prescription rates for CSM-contraindicated SSRIs citalopram, sertraline and especially paroxetine dropped dramatically after 2002, while rates for fluoxetine and amitriptyline remained stable. After 2005 rates for all antidepressants, except paroxetine and imipramine, started to rise again. Rates for depression diagnoses dropped from 3.0 (95%CI:2.8,3.1) per 1,000 PYAR in 2002 to 2.0 (95%CI:1.9,2.1) per 1,000 PYAR in 2005 and have been stable since. Recording of symptoms saw a steady increase from 1.0 (95%CI:0.8,1.2) per 1,000 PYAR in 1995 to 4.7 (95%CI:4.5,4.8) per 1,000 PYAR in 2009.
Conclusions
The rates of depression diagnoses and SSRI prescriptions showed a significant drop around the time of the CSM advice, which was not present in the recording of symptoms. This could indicate caution on the part of GPs in making depression diagnoses and prescribing antidepressants following the CSM advice.
doi:10.1371/journal.pone.0033181
PMCID: PMC3302807  PMID: 22427983
17.  What happens next?: a claims database study of second-line pharmacotherapy in patients with major depressive disorder (MDD) who initiate selective serotonin reuptake inhibitor (SSRI) treatment 
Background
The objective of this research was to examine treatment patterns and health-care costs associated with second-step pharmacotherapy in patients with major depressive disorder (MDD) who initiated monotherapy with a selective serotonin reuptake inhibitor (SSRI) in 2010.
Methods
This claims database study analyzed patients diagnosed with MDD who were prescribed a monotherapy SSRI, with the first prescription identified as the index date. Patients were required to be ≥18 years old, to have continuous insurance coverage from 1 year prior (pre-index) through 1 year post (post-index) from the index date, and to have not received an antidepressant in the pre-index period. The analyses are descriptive of the patient characteristics, initial SSRI prescribed, most commonly prescribed second-step therapies, and annualized health-care costs.
Results
The identified patients (N = 5,012) were predominantly female (65.2%) with a mean age of 41.9 years. The most frequent index SSRIs were citalopram (30.1%) and sertraline (27.5%), and 52.9% of patients were prescribed a second-step pharmacotherapy during the post-index period. Add-on therapy occurred twice more frequently than switching treatments, with either anxiolytics (40.2%) or antidepressants (37.1%) as the most common classes of add-on pharmacological therapies. Patients who added a second medication or switched therapies had higher annualized medical costs compared with patients who continued their index SSRI or discontinued treatment.
Conclusions
For patients who were initially treated with an SSRI therapy, approximately half were prescribed a second-step treatment. In this comprehensive claims analysis, many of these patients experienced the addition of second medication, rather than switching to a new therapy. Given the type of medications used, it is possible that second-step interventions were targeted toward resolution of residual symptoms; however, this work is limited by the use of claims data without information on dosing or clinical symptoms, side effects, or response. Findings from this study set the expectation that physicians and patients will most likely need to partner for additional interventions in order to achieve remission.
doi:10.1186/1744-859X-13-8
PMCID: PMC3994945  PMID: 24645830
Treatment; SSRI; Prescription; Major depressive disorder
18.  Association between Prenatal Exposure to Antiretroviral Therapy and Birth Defects: An Analysis of the French Perinatal Cohort Study (ANRS CO1/CO11) 
PLoS Medicine  2014;11(4):e1001635.
Jeanne Sibiude and colleagues use the French Perinatal Cohort to estimate the prevalence of birth defects in children born to HIV-infected women receiving antiretroviral therapy during pregnancy.
Please see later in the article for the Editors' Summary
Background
Antiretroviral therapy (ART) has major benefits during pregnancy, both for maternal health and to prevent mother-to-child transmission of HIV. Safety issues, including teratogenic risk, need to be evaluated. We estimated the prevalence of birth defects in children born to HIV-infected women receiving ART during pregnancy, and assessed the independent association of birth defects with each antiretroviral (ARV) drug used.
Methods and Findings
The French Perinatal Cohort prospectively enrolls HIV-infected women delivering in 90 centers throughout France. Children are followed by pediatricians until 2 y of age according to national guidelines.
We included 13,124 live births between 1994 and 2010, among which, 42% (n = 5,388) were exposed to ART in the first trimester of pregnancy. Birth defects were studied using both European Surveillance of Congenital Anomalies (EUROCAT) and Metropolitan Atlanta Congenital Defects Program (MACDP) classifications; associations with ART were evaluated using univariate and multivariate logistic regressions. Correction for multiple comparisons was not performed because the analyses were based on hypotheses emanating from previous findings in the literature and the robustness of the findings of the current study. The prevalence of birth defects was 4.4% (95% CI 4.0%–4.7%), according to the EUROCAT classification. In multivariate analysis adjusting for other ARV drugs, maternal age, geographical origin, intravenous drug use, and type of maternity center, a significant association was found between exposure to zidovudine in the first trimester and congenital heart defects: 2.3% (74/3,267), adjusted odds ratio (AOR) = 2.2 (95% CI 1.3–3.7), p = 0.003, absolute risk difference attributed to zidovudine +1.2% (95% CI +0.5; +1.9%). Didanosine and indinavir were associated with head and neck defects, respectively: 0.5%, AOR = 3.4 (95% CI 1.1–10.4), p = 0.04; 0.9%, AOR = 3.8 (95% CI 1.1–13.8), p = 0.04. We found a significant association between efavirenz and neurological defects (n = 4) using the MACDP classification: AOR = 3.0 (95% CI 1.1–8.5), p = 0.04, absolute risk +0.7% (95% CI +0.07%; +1.3%). But the association was not significant using the less inclusive EUROCAT classification: AOR = 2.1 (95% CI 0.7–5.9), p = 0.16. No association was found between birth defects and lopinavir or ritonavir with a power >85% for an odds ratio of 1.5, nor for nevirapine, tenofovir, stavudine, or abacavir with a power >70%. Limitations of the present study were the absence of data on termination of pregnancy, stillbirths, tobacco and alcohol intake, and concomitant medication.
Conclusions
We found a specific association between in utero exposure to zidovudine and heart defects; the mechanisms need to be elucidated. The association between efavirenz and neurological defects must be interpreted with caution. For the other drugs not associated with birth defects, the results were reassuring. Finally, whatever the impact that some ARV drugs may have on birth defects, it is surpassed by the major role of ART in the successful prevention of mother-to-child transmission of HIV.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
AIDS and HIV infection are commonly treated with antiretroviral therapy (ART), a combination of individual drugs that work together to prevent the replication of the virus and further spread of the infection. Starting in the 1990s, studies have shown that ART of HIV-infected women can substantially reduce transmission of the virus to the child during pregnancy and birth. Based on these results, ART was subsequently recommended for pregnant women. Since 2004, ART has been standard therapy for pregnant women with HIV/AIDS in high-income countries, and it is now recommended for all HIV-infected women worldwide. Several different antiviral drug combinations have been shown to be effective and are used to prevent mother-to-infant transmission. However, as with any other drugs taken during pregnancy, there is concern that ART can harm the developing fetus.
Why Was This Study Done?
Several previous studies have assessed the risk that ART taken by a pregnant woman might pose to her developing fetus, but the results have been inconsistent. Animal studies suggested an elevated risk for some drugs but not others. While some clinical studies have reported increases in birth defects in children born to mothers on ART, others have shown no such increase.
The discrepancy may be due to differences between the populations included in the studies and the different methods used to diagnose birth defects. Additional large studies are therefore necessary to obtain more and better evidence on the potential harm of individual anti-HIV drugs to children exposed during pregnancy. So in this study, the authors conducted a large cohort study in France to assess the relationship between different antiretroviral drugs and specific birth defects.
What Did the Researchers Do and Find?
The researchers used a large national health database known as the French Perinatal Cohort that contains information on HIV-infected mothers who delivered infants in 90 centers throughout France. Pediatricians follow all children, whatever their HIV status, to two years of age, and health statistics are collected according to national health-care guidelines. Analyzing the records, the researchers estimated the rate at which birth defects occurred in children exposed to antiretroviral drugs during pregnancy.
The researchers included 13,124 children who were born alive between 1994 and 2010 and had been exposed to ART during pregnancy. Children exposed in the first trimester of pregnancy, and those exposed during the second or third trimester, were compared to a control group (children not exposed to the drug during the whole pregnancy). Using two birth defect classification systems (EUROCAT and MACDP—MACDP collects more details on disease classification than EUROCAT), the researchers sought to detect a link between the occurrence of birth defects and exposure to individual antiretroviral drugs.
They found a small increase in the risk for heart defects in children with exposure to zidovudine. They also found an association between efavirenz exposure and a small increase in neurological defects, but only when using the MACDP classification system. The authors found no association between other antiretroviral drugs, including nevirapine (acting similar to efavirenz); tenofovir, stavudine, and abacavir (all three acting similar to zidovudine); and lopinavir and ritonavir (proteinase inhibitors) and any type of birth defect.
What Do These Findings Mean?
These findings show that, overall, the risks of birth defects in children exposed to antiretroviral drugs in utero are small when considering the clear benefit of preventing mother-to-child transmission of HIV. However, where there are safe and effective alternatives, it might be appropriate to avoid use by pregnant women of those drugs that are associated with elevated risks of birth defects.
Worldwide, a large number of children are exposed to zidovudine in utero, and these results suggest (though cannot prove) that these children may be at a slightly higher risk of heart defects. Current World Health Organization (WHO) guidelines for the prevention of mother-to-child transmission no longer recommend zidovudine for first-line therapy.
The implications of the higher rate of neurological birth defects observed in infants exposed to efavirenz in the first trimester are less clear. The EUROCAT classification excludes minor neurological abnormalities without serious medical consequences, and so the WHO guidelines that stress the importance of careful clinical follow-up of children with exposure to efavirenz seem adequate, based on the findings of this study. The study is limited by the lack of data on the use of additional medication and alcohol and tobacco use, which could have a direct impact on fetal development, and by the absence of data on birth defects and antiretroviral drug exposure from low-income countries. However, the findings of this study overall are reassuring and suggest that apart from zidovudine and possibly efavirenz, other antiretroviral drugs are not associated with birth defects, and their use during pregnancy does not pose a risk to the infant.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001635.
This study is further discussed in a PLOS Medicine Perspective by Mofenson and Watts
The World Health Organization has a webpage on mother-to-child transmission of HIV
The US National Institutes of Health provides links to additional information on mother-to-child transmission of HIV
The Elizabeth Glaser Pediatric AIDS Foundation also has a webpage on mother-to-child transmission
The French Perinatal Cohort has a webpage describing the cohort and its main publications (in French, with a summary in English)
doi:10.1371/journal.pmed.1001635
PMCID: PMC4004551  PMID: 24781315
19.  A drug utilisation study of antidepressants in children and adolescents using the General Practice Research Database 
Archives of Disease in Childhood  2004;89(12):1098-1102.
Aims: To characterise prescribing patterns of antidepressants (ATDs) to children and adolescents aged ⩽18 years in the UK.
Methods: Subjects issued at least one ATD prescription between 1 January 1992 and 31 December 2001 were identified from the UK General Practice Research Database. Prescribing patterns, annual prevalence, morbidity patterns, and time to discontinuation of ATD use were identified.
Results: A total of 24 976 subjects received 93 091 prescriptions; 51 868 (55.7%), 38 429 (41.3%), and 2708 (2.9%) prescriptions were for tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and other ATDs respectively. ATD prevalence increased 1.7-fold from 1992 to 2001. TCA prevalence decreased by 30% from 3.6 to 2.5 per 1,000; SSRI prevalence increased 10 times from 0.5 to 4.6 per 1,000. In new ATD users aged ⩽10 years, the most common diagnosis associated with TCA use was nocturnal enuresis (75.1%); in those aged ⩾15 years, it was depression (45.8%). Depression was also associated with SSRI use (69.0%). For new users with depression, the median treatment durations for TCAs and SSRIs were 30 and 58 days respectively. TCA users were more likely to terminate treatment than SSRI users (TCAs v fluoxetine: 1.40, 95% CI 1.32 to 1.47; non-fluoxetine SSRIs v fluoxetine: 1.01, 95% CI 0.96 to 1.07).
Conclusions: SSRIs have gained popularity for the treatment of depression compared with TCAs. TCAs are still used despite their lack of efficacy in prepubertal depression and their moderate effect in adolescents. However, >50% of subjects discontinue treatment after two months, with TCA users stopping earlier than SSRI users.
doi:10.1136/adc.2004.064956
PMCID: PMC1719765  PMID: 15557040
20.  Suicide-related events in young people following prescription of SSRIs and other antidepressants: a self-controlled case series analysis 
BMJ Open  2013;3(9):e003247.
Objectives
We aimed to examine the temporal association between selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressant (TCA) prescriptions and suicide-related events in children and adolescents.
Design
Self-controlled case series.
Setting
Electronic health records were used from 479 general practices in The Health Improvement Network (THIN) UK primary care database from 1995 to 2009.
Participants
81 young people aged 10–18 years with a record of completed suicide, 1496 who attempted suicide, 1178 with suicidal ideation and 2361 with intentional self-harm.
Main outcome measures
Incidence Rate Ratios (IRRs) for completed and attempted suicide, suicidal ideation and intentional self-harm.
Results
For non-fatal suicide-related behaviour, IRRs were similar for the time the person was prescribed either SSRIs or TCAs: IRRs increased during pre-exposure, peaked on prescription day, were stable up to the fourth prescription-week, and decreased after the prescriptions were stopped. For both types of antidepressants, IRRs were lower or similar to pre-exposure levels during the period of prescription. For SSRIs, there was an increase in the IRR for completed suicide on the day of prescription (N=5; IRR=42.5, 95% CI 4.5 to 403.4), and during the fourth week of SSRI prescription (N=2; IRR=11.3, 95% CI 1.1 to 115.6).
Conclusions
We found that a very small number of young people were prescribed antidepressants and that there was an absence of a sustained increase in rates of suicide-related events in this group. There were no systematic differences between the association of TCAs and SSRIs and the incidence risk ratios for attempted suicide, suicidal ideation or intentional self-harm and, apart from the day of prescription, rates did not exceed pre-exposure levels. The pattern of IRR for suicide for SSRIs was similar to that found in non-fatal suicide-related events. Our results warrant a re-evaluation of the current prescription of SSRIs in young people. We recommend the creation of a pragmatic registry for active pharmacovigilance.
doi:10.1136/bmjopen-2013-003247
PMCID: PMC3780295  PMID: 24056479
Epidemiology; Mental Health; Suicide & Self-Harm < Psychiatry; Depression & Mood Disorders < Psychiatry
21.  Are SSRIs safe for pregnant and breastfeeding women? 
Canadian Family Physician  2000;46:626-633.
OBJECTIVE: To summarize the literature on use of the selective serotonin reuptake inhibitor (SSRI) class of antidepressants for pregnant and breastfeeding women. DATA SOURCES AND STUDY SELECTION: MEDLINE was searched over the past 9 years. An examination of the literature over the last 8 years was included in this review. Primary studies consist of prospective investigations and case studies. Evidence for the safety of SSRIs is limited, but some good studies describe the effects of untreated depression. SYNTHESIS: All studies report that infants are exposed to SSRIs; the drugs can be measured in their plasma and urine. Some evidence shows an increase in minor perinatal complications among infants exposed to SSRIs late in gestation or while nursing. No studies, however, have found an increase in major fetal malformations or pregnancy-related complications. The only investigation of long-term neurodevelopmental outcomes found no negative outcomes among infants exposed to SSRIs during pregnancy. Data are scarce, and readers are cautioned to take into consideration the limitations of the studies reviewed before making definite treatment decisions. CONCLUSIONS: Major fetal malformations and exposure to SSRIs during pregnancy and lactation do not appear to be associated. Some minor perinatal complications have been reported. Data on the long-term developmental outcomes of children exposed to SSRIs in utero and during breastfeeding are limited.
PMCID: PMC2144975  PMID: 10752001
22.  Central nervous system effects of prenatal selective serotonin reuptake inhibitors: sensing the signal through the noise 
Psychopharmacology  2013;227(4):10.1007/s00213-013-3115-8.
Rationale
Women are increasingly prescribed selective serotonin reuptake inhibitors (SSRIs) during pregnancy, with potential implications for neurodevelopment. Whether prenatal SSRI exposure has an effect on neurodevelopment and behavior in the offspring is an important area of investigation.
Objectives
The aim of this paper was to review the existing preclinical and clinical literature of prenatal SSRI exposure on serotonin-related behaviors and markers in the offspring. The goal is to determine if there is a signal in the literature that could guide clinical care and/or inform research.
Results
Preclinical studies (n = 4) showed SSRI exposure during development enhanced depression-like behavior. Half of rodent studies examining anxiety-like behavior (n = 13) noted adverse effects with SSRI exposure. A majority of studies of social behavior (n = 4) noted a decrease in sociability in SSRI exposed offspring. Human studies (n = 4) examining anxiety in the offspring showed no adverse effects of prenatal SSRI exposure. The outcome of one study suggested that children with autism were more likely to have a mother who was prescribed an SSRI during pregnancy.
Conclusions
Preclinical findings in rodents exposed to SSRIs during development point to an increase in depression- and anxiety-like behavior and alteration in social behaviors in the offspring, though both the methods used and the findings were not uniform. These data are not robust enough to discourage use of SSRIs during human pregnancy, particularly given the known adverse effects of maternal mental illness on pregnancy outcomes and infant neurodevelopment. Future research should focus on consistent animal models and prospective human studies with larger samples.
doi:10.1007/s00213-013-3115-8
PMCID: PMC3838633  PMID: 23681158
Perinatal depression; Perinatal SSRI; Serotonin; Anxiety; Social behavior; Pain reactivity; Psychomotor development; S100B; HPA axis
23.  Selective serotonin reuptake inhibitors in pregnancy and infant outcomes 
Paediatrics & Child Health  2011;16(9):562.
Adequate treatment of depression during pregnancy is very important for maternal, fetal and neonatal health. Selective serotonin reuptake inhibitors (SSRIs) are commonly used antidepressants. According to one American study, approximately 7% of pregnant women were prescribed an SSRI in 2004–2005. First trimester use of SSRIs, as a group, is unlikely to increase the risk of congenital malformations. Paroxetine may be associated with a small increased risk of cardiac malformations, but evidence remains inconclusive. Fetal exposure to SSRIs closer to time of birth may result in respiratory, motor, central nervous system and gastrointestinal symptoms in about 10% to 30% of newborns (SSRI neonatal behaviour syndrome). These symptoms are usually mild and transient. Persistent pulmonary hypertension of the newborn is an extremely rare consequence of fetal exposure. This information should be used to make individual risk-benefit decisions when considering the treatment of depression during pregnancy. Newborns with late-pregnancy exposure to SSRIs should be observed in hospital for at least 48 h.
PMCID: PMC3223895  PMID: 23115498
Depression in pregnancy; Neonatal abstinence; Neonatal behaviour syndrome; Selective serotonin reuptake inhibitors
24.  Breast cancer recurrence risk related to concurrent use of SSRI antidepressants and tamoxifen 
Background
Up to one-quarter of breast cancer patients suffer clinically significant depression in the year after diagnosis, which may respond to intervention. About half may be prescribed a psychotropic medication, such as a selective serotonin reuptake inhibitor (SSRI), while completing breast cancer therapy. Cytochrome P-450 2D6 (CYP2D6) metabolizes SSRIs and also metabolizes tamoxifen to more active forms. Therefore, concurrent use of SSRIs may reduce tamoxifen’s effectiveness at preventing breast cancer recurrence. The SSRI citalopram has limited potency to inhibit CYP2D6 activity, so has been recommended for breast cancer patients taking tamoxifen. This study provides epidemiologic evidence to support this recommendation.
Material and methods
We conducted a case-control study of breast cancer recurrence nested in the population of female residents of Denmark who were diagnosed with non-metastatic estrogen-receptor positive breast cancers between 1994 and 2001 and who took tamoxifen for at least one year. We ascertained complete prescription histories by linking cases’ and controls’ civil registration numbers to the Danish national prescription registry. We estimated the association between SSRI use while taking tamoxifen and risk of recurrent breast cancer.
Results
About the same proportion of recurrent cases (37 of 366) and matched controls (35 of 366) received at least one prescription for citalopram or its s-stereoisomer while taking tamoxifen (adjusted odds ratio = 1.1, 95% confidence interval =0.7, 1.7). Breast cancer patients taking other SSRIs were also at no increased risk of recurrence (adjusted odds ratio = 0.9, 95% confidence interval = 0.5, 1.8).
Discussion
Breast cancer patients with indications for an SSRI may be prescribed citalopram — and possibly other SSRI — without adversely affecting the outcome of adjuvant therapy with tamoxifen.
doi:10.3109/02841860903575273
PMCID: PMC2892037  PMID: 20156115
breast neoplasms; pharmacology and therapeutic use; tamoxifen; antagonists and inhibitors; serotonin uptake inhibitors; cytochrome P-450 2D6
25.  Cost-effectiveness evaluation of escitalopram in major depressive disorder in Italy 
Background
Depression has a lifetime prevalence of 10%–25% among women and 5%–12% among men. Selective serotonin reuptake inhibitors (SSRIs) are the most used and the most cost-effective treatment for long-term major depressive disorder. Since the introduction of generic SSRIs, the costs of branded drugs have been questioned. The objective of this study was to assess the cost-effectiveness (€ per quality-adjusted life year [QALY]) of escitalopram (which is still covered by a patent) compared with paroxetine, sertraline, and citalopram, the patents for which have expired.
Methods
A decision analytic model was adapted from the Swedish Dental and Pharmaceutical benefits agency model to reflect current clinical practice in the treatment of depression in Italy in collaboration with an expert panel of Italian psychiatrists and health economists. The population comprised patients with a first diagnosis of major depressive disorder and receiving for the first time one of the following SSRIs: escitalopram, sertraline, paroxetine, and citalopram. The time frame used was 12 months. Efficacy and utility data for the original model were validated by our expert panel. Local data were considered for resource utilization and for treatment costs based on the Lombardy region health service perspective. Several scenario simulations, oneway sensitivity analyses, and Monte Carlo simulations were performed to test the robustness of the model.
Results
The base case scenario showed that escitalopram had an incremental cost-effectiveness ratio (ICER) of €4395 and €1080 per QALY compared with sertraline and paroxetine, respectively. Escitalopram was dominant over citalopram, which was confirmed by most one-way sensitivity analyses. The escitalopram strategy gained 0.011 QALYs more than citalopram, 0.008 more than paroxetine, and around 0.007 more than sertraline. Monte Carlo simulations indicated that ICER values for escitalopram were centered around €1100 and €4400 per QALY compared with paroxetine and sertraline, respectively. Although there is no official cost-effectiveness threshold in Italy, the value of €25,000 per QALY could be acceptable. All ICER values retrieved in all analyses were lower than this threshold.
Conclusion
The findings from this cost-effectiveness analysis indicate that escitalopram could be accepted as a cost-effective strategy for the Lombardy region health service compared with the other SSRIs studied. The present assessment is based on ICER values resulting from this analysis, which are lower than the thresholds proposed by health care authorities in other European Union countries. These benefits are driven by the effectiveness of escitalopram, which result in an improved health-related quality of life, a higher probability of sustained remission, and better utilization of health care resources. The study results are robust and in line with other pharmacoeconomic analyses comparing escitalopram with other SSRIs.
doi:10.2147/CEOR.S39492
PMCID: PMC3570079  PMID: 23413176
CEA; depression; escitalopram; Lombardy; ICER; SSRI

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