Maternal Depression, Prenatal SSRI Exposure, and Brain Trajectories in Childhood

Talati, Ardesheer

doi:10.1001/jamapsychiatry.2023.2664

Cited by 4 publications

(4 citation statements)

References 12 publications

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“…This disconnect-avoiding stating any causal intent yet providing conclusions embedded with implied causality-has been found to be widespread in many high-profile medical journals. 2,3 But here, it can be especially harmful given the magnitude of the reported associations, as they can be misconstrued to have important causal implications by research consumers and policymakers, which can lead to erroneous decision-making and ineffective policies (eg, if individuals with SSD use cannabis because of their condition, then intervening on cannabis use will not reduce the risk of SSD).…”

Section: …The Elevated Risk Associated With Cannabis…has Implications...mentioning

confidence: 99%

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SSRIs in Pregnancy—What Offspring Brain Volumes Can and Cannot Tell Us

Ceulemans,

Damkier,

Panchaud

2024

JAMA Psychiatry

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To the Editor We read with great interest the publication of Koc and colleagues on prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) and offspring brain trajectories. 1 We applaud the authors for their innovative and well-executed study using data from a prospective population-based cohort, adjusting for confounders, including different comparator groups, and applying advanced neuroimaging techniques and statistical modeling. The authors showed that prenatal SSRI exposure was associated with about 3% reduced brain volumes of regions involved in emotional regulation in offspring. They also demonstrated minor reduced volumes of specific brain regions among offspring of women with depressive symptoms in the prenatal and postnatal life.In their Key Points and conclusion, however, the authors refer only to the findings linked to prenatal SSRI use and not to those linked to depressive symptoms. From a clinical perspective, we are concerned that clinicians or patients may jump to preemptive conclusions and consider these findings discouraging to prescribing or taking SSRIs in pregnancy. We have listed several considerations.First, the clinical relevance of the altered brain volumes is unknown. Second, despite differences in absolute brain volumes across groups, the developmental trajectories of various brain volumes followed similar trends during the follow-up period, regardless of SSRI or depression exposure. Third, the advanced statistical model demonstrating the trajectory of brain volumes following prenatal SSRI exposure is based entirely on 80 data points in 41 participants over a span of 8 years. Overadjustment is a risk and in their illustration, the y-axis starts at 700 000 mm 3 . Fourth, the observations are subject to residual confounding by indication as women receiving SSRIs in pregnancy likely experience more severe disease than any of the comparators. Fifth, some volumetric brain differences did not persist until early adolescence, suggesting adaptability and plasticity of the brain morphology and protective environmental factors during the postnatal life. Sixth, discontinuing prenatal antidepressant treatment is associated with an increased risk of psychiatric emergency and postpartum relapse. 2,3 Seventh, depression is common in pregnancy and associated with important short-and long-term risks if treated insufficiently. 4,5 Although we applaud the authors for not suggesting clinical implications, we remain concerned that these findings will be framed as signals mitigating SSRI use in pregnancy and cause uncertainty and guilt among pregnant women with depression. We do agree that more research on the functional implications and clinical impact of the differences in brain volumes on the developing infant is pivotal.

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Section: …The Elevated Risk Associated With Cannabis…has Implications...mentioning

confidence: 99%

“…One of the interesting findings that certainly requires further exploration is the clinical relevance of differences in brain volume trajectories. As highlighted in the accompanying Editorial, 3 the clinical significance of the observed changes in brain volume remains unclear. Interestingly, key limbic regions tend to normalize over time.…”

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SSRIs in Pregnancy—What Offspring Brain Volumes Can and Cannot Tell Us

Ceulemans,

Damkier,

Panchaud

2024

JAMA Psychiatry

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“…In the past 12 years, antidepressant usage during pregnancy has increased 3% in Europe and 8% in the US [ 7 ]. Complex perinatal mood disorders, manifesting in various forms such as anxiety, bipolar affective disorder, and depression, have emerged amongst the most prevalent complications associated with pregnancy, [ 8 ]. The incidence of perinatal depressive disorder (PND) in the US is notably high, affecting approximately one in 7 to 10 pregnant women.…”

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confidence: 99%

Selective serotonin re-uptake inhibitors affect craniofacial structures in a mouse model

Saluan,

Bauer,

Vyas

et al. 2024

PLoS ONE

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Selective serotonin re-uptake inhibitors (SSRI) widely used in the treatment of depression, anxiety, obsessive compulsive disorder, fibromyalgia, and migraine are among the most heavily prescribed drug class in the United States (US). Along with an overall rise in SSRI use, these medications are increasingly used by pregnant individuals and recent preclinical and clinical studies have indicated that SSRIs may increase the prevalence of congenital abnormalities and birth defects of the craniofacial region. Our group has developed pre-clinical models of study, including those that mimic the clinical use of SSRI in mice. Here we designed a study to interrogate a commonly prescribed SSRI drug, Citalopram, for its effects on craniofacial and dental development when introduced in utero. Pre-natal exposure to a clinically relevant dose of citalopram resulted in changes in craniofacial form identified by an increase in endocast volume in SSRI exposed postnatal day 15 mouse pups. More specifically, cranial length and synchondrosis length increased in SSRI exposed pups as compared to control pups of the same age. Additionally, growth center (synchondrosis) height and width and palate length and width decreased in SSRI exposed pups as compared to control un-exposed pups. Effects of SSRI on the molars was minimal. Craniofacial growth and development continue to be an area of interest in the investigation of in utero pharmaceutical drug exposure. Altogether these data indicate that prenatal SSRI exposure affects craniofacial form in multiple tissues and specifically at growth sites and centers of the skull.

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“…One of the interesting findings that certainly requires further exploration is the clinical relevance of differences in brain volume trajectories. As highlighted in the accompanying Editorial, the clinical significance of the observed changes in brain volume remains unclear. Interestingly, key limbic regions tend to normalize over time.…”

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confidence: 99%

SSRIs in Pregnancy—What Offspring Brain Volumes Can and Cannot Tell Us—Reply

Koc,

Tiemeier,

El Marroun

2024

JAMA Psychiatry

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COMMENT & RESPONSEIn Reply We appreciate Ceulemans and colleagues' response. We share their concern regarding the potential for misinterpretation and preemptive clinical implications of our study of selective serotonin reuptake inhibitor (SSRI) use during pregnancy. 1 We also agree that discontinuing prenatal SSRI treatment can increase the risk of psychiatric emergencies and postpartum relapse. We certainly did not advocate against SSRI treatment during pregnancy or recommend discontinuation of treatment. At the same time, we recognize that there are effective alternatives to SSRI treatment and that most women taking SSRIs during pregnancy are taking maintenance treatment. 2 In our study, all women had initiated SSRI treatment before conception. Thus, the results should not be generalized to women who consider commencing treatment in pregnancy. We propose further research and discussion of possible risks and unwanted effects of discontinuing or continuing treatment. Our vision is a more personalized treatment, eg, for asymptomatic women on maintenance therapy who are planning a pregnancy.We readily acknowledge that the association between exposure to maternal prenatal depressive symptoms and brain structural differences in offspring should have been mentioned in the key findings despite word count limitations. Several points raised by Ceulemans and colleagues would have deserved more discussion. The sample size concerns are valid and discussed only briefly, although the number of SSRI-exposed participants (partly due to repeated imaging assessment) was sufficient to detect an association with offspring brain morphology.One of the interesting findings that certainly requires further exploration is the clinical relevance of differences in brain volume trajectories. As highlighted in the accompanying Editorial, 3 the clinical significance of the observed changes in brain volume remains unclear. Interestingly, key limbic regions tend to normalize over time. Ideally, we would have been able to incorporate mediation models linking brain trajectories to behavioral and cognitive outcomes. However, in this cohort, Generation R, data that allow careful temporal modeling are not available yet.We certainly recognize the significance of the postnatal environment in shaping the neurodevelopment of the offspring, but we consider it as a downstream factor and not as an antecedent or possible confounder of the effects of prenatal SSRI use. The postnatal environment could mediate the association between intrauterine exposures and brain development; exploring such mechanisms was beyond the scope of our study.

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Maternal Depression, Prenatal SSRI Exposure, and Brain Trajectories in Childhood

Cited by 4 publications

References 12 publications

SSRIs in Pregnancy—What Offspring Brain Volumes Can and Cannot Tell Us

SSRIs in Pregnancy—What Offspring Brain Volumes Can and Cannot Tell Us

Selective serotonin re-uptake inhibitors affect craniofacial structures in a mouse model

SSRIs in Pregnancy—What Offspring Brain Volumes Can and Cannot Tell Us—Reply

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