SSRI Exposure in Utero Linked to Higher Adolescent Depression
Abstract
Researchers and reviewers both stress the importance of treating maternal depression. Future work will consider whether dosage, titration schedules, and timing of treatment may provide new guidance for treating pregnant women with depression.
Prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) was associated with increased rates of depression diagnoses in early adolescence, according to a report published online on March 2 in the Journal of the American Academy of Child and Adolescent Psychiatry.
The study is the first to investigate the incidence of psychiatric diagnoses in offspring prenatally exposed to SSRIs as far out as adolescence. Researchers and those who reviewed the study alike emphasized that the findings are preliminary and should not be construed to change clinical practice. They underscored the vital importance of treating maternal depression, which can have significant adverse effects on offspring.
The leader of the project and second author of the paper, Alan S. Brown, M.D., M.P.H., told Psychiatric News that untreated maternal depression has been shown to increase risks of several perinatal outcomes including preterm birth, delivery by C-section, and bleeding during delivery.
“Untreated depression also has substantial adverse effects to the mother including relapse or worsening of depression, greater risk of suicide, and less adequate prenatal care,” he said. “The association between maternal SSRI use and offspring depression also requires replication before these findings are considered as possible recommendations for clinical care. Hence, these findings must be viewed with considerable caution by clinicians and patients regarding the risks and benefits of use of SSRIs in pregnant women.”
He is a professor of psychiatry and epidemiology at Columbia University.
The findings, which received widespread coverage in the national press, are striking. The study was based on previous animal studies by Jay Gingrich, M.D., Ph.D., of Columbia that suggested SSRIs have an adverse effect on the developing fetal brain. He told Psychiatric News that further research will try to pinpoint antidepressant medications, dosages, titration schedules, and periods during pregnancy when treatment might be more or less safe (see box).
Animal Research Raises Troubling Questions About SSRIs
In 2004 psychiatrist Jay Gingrich, M.D., who trained as a molecular biologist, began working with mice on an experiment that would have troubling findings.
Those findings would lay the basis for an epidemiologic study appearing in the Journal of the American Academy of Child and Adolescent Psychiatry showing that there are higher rates of depression in adolescent offspring of mothers who used SSRIs during pregnancy.
Gingrich and colleagues at the New York State Psychiatric Institute engineered mice with a genetic knockout of the serotonin transporter, thereby mimicking the effect of lifelong exposure to SSRIs. “The behavior of the offspring mice pups as they matured was anything but what we would have expected,” he told Psychiatric News. “They were clearly more anxious in new environments, less exploratory, and more depressed.”
The same results were found when Gingrich and colleagues administered SSRIs to mice pups at early stages of life equivalent to the second and third trimester in humans. “These medications may have a very different effect on the fetal brain than on the adult brain, and the mice research appears to confirm that something very different may be happening in the fetal brain exposed to SSRIs that is setting them up for depression later.”
Gingrich emphasized that like all preliminary research, the results require replication. And he stressed that treatment of maternal depression is vital to the health of offspring as well as the mother. “I know that for most people with whom I share this work, it is very paradoxical because the recommendation to treat maternal depression is intended to mitigate the risk to the child,” he said.
Gingrich emphasized that the findings relate only to SSRIs, and other antidepressants do not appear to have the same risks found in the JAACAP study. He and epidemiologist Myrna Weissman, Ph.D., emphasized that dose, titration, and timing may also be crucial and can be manipulated to safely treat maternal depression.
“Ideally, what we will try to do in the next three years is gain enough new information so we can really help clinicians and their patients have some concrete data,” he said. “We know dose and mechanism of action matter, and timing [during pregnancy] matters a lot. Hypothetically, for instance, we might be able to show that some drugs are safer and or that medication be tapered in the second trimester, eliminated in the third trimester, and begun again immediately after delivery. But that remains to be determined.”
He added, “Nothing we are finding here is mitigating the need to aggressively treat depression postpartum.”
Echoing the importance of treating maternal depression, epidemiologist Myrna Weissman, Ph.D., a lead author of the study, also emphasized the value of psychotherapy and other nonpharmaceutical interventions. She and Gingrich said follow-up research would include meta-analyses of evidence-based psychotherapies for perinatal treatment of depression.
(Other lead authors of the JAACAP study were Heli Malm, M.D., Ph.D., of Helsinki University, and Andre Sourander, M.D., Ph.D., of Columbia University and the New York State Psychiatric Institute.)
Brown and colleagues used Finnish national birth registry data to determine the cumulative incidence of depression, anxiety disorders, autism spectrum disorder, and attention-deficit/hyperactivity disorder in the offspring of four groups of mother-offspring dyads: mothers exposed to SSRIs during pregnancy (n=15,729), mothers exposed to psychiatric disorder but not to antidepressants (n=9,651), mothers who used SSRIs only before pregnancy (n=7,980), and children of mothers unexposed to either antidepressants or psychiatric disorders (n=31,394).
They found the cumulative incidence of depression among offspring exposed prenatally to SSRIs was 8.2 percent by age 14.9 years, compared with 1.9 percent in the psychiatric disorder/no medication group and 2.8 percent in the SSRI-discontinued group. In contrast, SSRI prenatal exposure was not associated with an increased risk of autism spectrum disorder, ADHD, or anxiety.
Psychiatrists who reviewed the report for Psychiatric News cautioned that—as with all epidemiological associations—correlation is not causation, and several raised severity of maternal depression as a factor that may have influenced rates of depression in adolescent offspring. Brown, Gingrich, Weissman, and colleagues did in fact seek to control for maternal severity using “proxies” such as history of previous hospitalization and use of multiple prescriptions.
Bonnie T. Zima, M.D., M.P.H., a member of the APA Council on Quality Care, said the study raises awareness about an important debate for women’s health and their children.
She noted that among the mothers with any history of SSRI exposure or depressive disorder and no SSRI exposure during pregnancy, the proportion of mothers with other risk factors was generally higher than mothers who did not have a history of exposure to an SSRI during pregnancy or depressive disorder.
“Roughly 24 to 30 percent of the mothers in this group also had a history of smoking,” she said. “Psychiatric comorbidity, including substance abuse, was also higher among these groups. Roughly 13 to 26 percent of the mothers had a history of other psychiatric diagnoses compared with only 2 percent in the unexposed group, and roughly 7 to 12 percent of mothers had a history of substance abuse compared with less than 1 percent in the unexposed group. Among mothers with exposure to an SSRI during pregnancy, almost 19 percent of mothers had a least one paid prescription for an anxiolytic or sedative medication.
“These data alone suggest that clinical awareness for other risk factors should be raised when providing prenatal care to mothers with a history of SSRI prescription, during or one year prior to pregnancy.”
At the same time, Zima acknowledged the power of the results. “Even when limiting the sample to mothers with exposure to only SSRI monotherapy, the risk of depression during early adolescence remained significantly higher than for offspring in the comparison groups.”
What the study does not account for are effects of the postnatal environment. “The strength of this study is the capacity to include children aged 0 to 14.9 years, but the trade-off was that it also expanded the time window for child and youth exposure to other risk and protective factors that may have influenced their risk for developing early-onset depression,” Zima said.
“By concluding with an ongoing debate, it powerfully reminds the clinical reader of the trade-offs we must make and share with our patients when considering medication treatment for affective disorders among women during their child-bearing years.”
Past APA President Nada Stotland, M.D., emphasized the stigma surrounding depression, especially for expectant mothers who are concerned about the welfare of their offspring.
“It is impossible to ignore the likelihood that it was women with more severe and intractable depression who received medication,” she said. “Therefore, it is likely that the adolescents exposed to SSRIs in utero had mothers who suffered from some degree of depression while the children were growing up, and that the children had a higher genetic loading for depression than the other subject groups. A great deal happens to a child between the uterus and adolescence.
“Despite repeated attempts to formulate an algorithm, there is no way to get beyond the need to make treatment decisions on a case-by-case basis, taking into account past history of depression and response to treatment, current severity of depression, access to quality psychotherapy, and the patient’s concerns and preferences,” Stotland said. “Somehow we hear far less, if anything, about medications needed during pregnancy to treat nonpsychiatric medical conditions. Women depressed during pregnancy are already anxious about causing harm to their babies.
“Most people hearing about the study will not get beyond the headline or will assume that there is a causal connection,” Stotland said. ■
An abstract of “Gestational Exposure to Selective Serotonin Reuptake Inhibitors and Offspring Psychiatric Disorders: A National-Registry Study” can be accessed here.
