Experts Caution More Research Is Needed to Understand Link Between Maternal SSRI Use, Depression in Offspring

Prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) was associated with increased rates of depression diagnoses in early adolescence, according to a report online 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.

Finnish and American researchers used Finnish national birth registry data to determine the cumulative incidence of depression and other mental illnesses in the offspring of four groups of mother-offspring dyads: those exposed to SSRIs during pregnancy (n=15,729); those exposed to psychiatric disorder but not to antidepressants (n=9,651); mothers who used SSRIs only before pregnancy (n=7,980); and those 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% by age 14.9 years, compared with 1.9% in the psychiatric disorder/no medication group and to 2.8% in the SSRI-discontinued group.

Authors and reviewers of the study emphasized in interviews with Psychiatric News the importance of treating maternal depression. “…Until either confirmed or refuted, these findings must be balanced against the substantial adverse consequences of untreated maternal depression,” the authors wrote.

The study was based on previous animal studies by Jay Gingrich, M.D., Ph.D., of Columbia, that suggested that 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.

“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.”

Past APA President Nada Stotland, M.D. (pictured above), emphasized the stigma surrounding depression, especially for expectant mothers who are concerned about the welfare of their offspring. “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,” she said. “Somehow we hear far less, if anything, about medications needed during pregnancy to treat non-psychiatric medical conditions. Women depressed during pregnancy are already anxious about causing harm to their babies.”

Lead authors were Heli Malm, M.D., Ph.D., of Helsinki University, and Andre Sourander, M.D., Ph.D., Alan S. Brown, M.D., and Myrna Weissman, Ph.D., of Columbia University and the New York State Psychiatric Institute.

For related information, see the Psychiatric News article “Study Reports Risks, Benefits of SSRIs Taken During Pregnancy.”

Study Supports Raising SSRI Doses in Patients Who Do Not Respond to Low-Dose Treatment

Using a higher dose of selective serotonin reuptake inhibitors (SSRIs) for major depressive disorder appears to be associated with an increased likelihood of response, according to a meta-analysis published today in AJP in Advance. This benefit, which is somewhat offset by decreased tolerability of SSRIs at high doses, appears to plateau at about 50 mg of fluoxetine (250 mg imipramine-equivalent dose).

A team of researchers in the United States and London searched PubMed for randomized, placebo-controlled trials that examined the efficacy of SSRIs for treating adults with major depressive disorder and assessed improvement in depression severity at multiple time points. Additional data were collected on treatment response and all-cause and side effect-related discontinuation. All medication doses were transformed into imipramine-equivalent doses.

Based on an analysis of 40 studies involving 10,039 participants, the investigators found a statistically significant positive association between SSRI dose and measured efficacy of SSRIs in reducing depression severity, with the greatest measured efficacy of SSRIs observed in the dosing range of 200–250 imipramine equivalents. The analysis also revealed that higher doses of SSRIs were associated with an increased likelihood of dropouts due to side effects but a decreased likelihood of all-cause dropout, which the authors noted “is likely attributable to their greater efficacy.”

“Our meta-analysis provides evidence to support clinical guidelines that recommend raising SSRI dose in adults with major depressive disorder who do not respond to SSRI medications at or below the lower end of the therapeutic dose range,” the study authors wrote.

For related information, see the Psychiatric News article “Study to Answer What Comes Next When MDD Patients Don’t Respond.”

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Study Reports on Risks, Benefits of Taking SSRIs During Pregnancy

Treatment of maternal psychiatric disorders with selective serotonin reuptake inhibitors (SSRIs) during pregnancy was related to a lower risk of preterm birth and cesarean section but a higher risk of neonatal complications, according to an analysis of results from a large national birth cohort published Tuesday in AJP in Advance.

Finnish, American, and Swedish researchers analyzed data from Finnish national registries to compare outcomes for pregnant women exposed to SSRIs (N=15,729) with those who had a psychiatric diagnosis but did not use any SSRIs (N=9,652) and those who had no psychiatric diagnosis and no exposure to SSRIs (N=31,394).

The outcomes of interest were diagnoses related to pregnancy and delivery, including hypertension of pregnancy/preeclampsia, vaginal delivery or cesarean section, and bleeding during or after delivery. The researchers also looked at neonatal outcomes, including late preterm (32 to 36 gestational weeks) and very preterm birth (less than 32 weeks), small for gestational age, and neonatal problems, including a five-minute Apgar score less than 7, neonatal breathing problems, monitoring in a neonatal intensive care unit, and hospital stay at 7 days of age.

Women in the SSRI group had a lower risk of cesarean section, emergency or urgent cesarean section, and bleeding compared with women who had a psychiatric diagnosis but no medication (but a higher risk of cesarean section than women with no exposure and no diagnosis). Moreover, compared with the psychiatric diagnosis/no medication group, the SSRI group had a 16% lower risk of late preterm birth and a 48% lower risk of very preterm birth.

However, in SSRI-treated mothers, the risk was higher for offspring neonatal complications, including low Apgar score and monitoring in a neonatal intensive care unit.

AJP Editor Robert Freedman, M.D., told Psychiatric News that because both groups of women with psychiatric diagnoses in the study experienced problems, it suggests the illnesses themselves may be a major contributor to the risks previously ascribed to SSRIs. “However, the post-birth reaction of the baby to withdrawal from the maternal SSRI lowers Apgar scores and requires neonatal monitoring, sometimes for as long as a week. These babies are then discharged home with no known further consequences,” he added.

Freedman noted that the CDC and similar agencies in other countries monitor drug side effects and report them, even if they are rare, to alert clinicians and their patients of the existence of such side effects and their approximate frequency, but the CDC and other agencies do not generally conduct a risk-benefit analysis to directly guide clinical decisions.

“Prenatal depression is associated with a number of ill effects, not only on the health of the mother, but also on the fetus. These include shorter gestation with its attendant decrease in fetal development, poorer maternal-infant bonding, and slight but significant increase in the long-term risk for psychiatric illnesses ranging for autism spectrum disorder to schizophrenia,” he said. “If a mother has major depressive disorder or a similar serious anxiety disorder during pregnancy, generally treatment with appropriate medication and psychotherapy should be part of her regimen, but she and the father need to be fully aware of the calculus of risks and benefits of treatment versus no treatment that inform this decision.” 

For related information, see the Psychiatric News article “SSRI Use in Late Pregnancy May Slightly Increase Risk of Newborn Respiratory Disease.

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Birth Weight May Impact Brain Development

Even after controlling for age, gender, household income, and genetic ancestry, children with higher birth weights were found to have a greater brain surface in numerous regions and a greater brain volume than children who had weighed less at birth. Kristine Beate Walhovd, Ph.D., of the University of Oslo in Norway and her colleagues reported these findings today in the Proceedings of the National Academy of Sciences Online Early Edition. The study included 628 healthy American children.

This is one of several notable brain-development studies whose results have been reported recently. Preliminary imaging findings suggested, for example, that a distinct and pervasive course of white-matter development characterizes high-risk infants who then eventually develop autism symptoms. Read about that study in Psychiatric News. And in another study rat pups perinatally exposed to the SSRI antidepressant citalopram exhibited impaired social behavior and impaired response to novelty situations. See Psychiatric News to read more about that study as well.

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