By Deborah Borfitz
March 10, 2022 | Perinatal depression is an understudied and underappreciated mood disorder, but a group of researchers in Michigan are moving the field forward with the discovery of predictive biomarkers of the condition that could one day be used for the routine screening of high-risk women. Nearly one in five new mothers experience severe depression and an estimated 14% have suicidal thoughts—and pregnancy itself, being a major inflammatory event, can be the inducer, according to Lena Brundin, M.D., Ph.D., a behavioral medicine professor at the Van Andel Institute and a senior author on the study.
Many correlative studies have been done in the past identifying markers that track with depression during pregnancy, but this is the first one that has identified a set of biomarkers with predictive ability, says co-senior study author Eric Achtyes, M.D., staff psychiatrist at Pine Rest Christian Mental Health Services and an associate professor at Michigan State University. The discovery of a causal link opens the possibility of diagnosing future major depressive episodes early in pregnancy and eventually testing anti-inflammatory drugs to treat those symptoms or prevent it from occurring in the first place.
It has been known since the 1990s that inflammation can cause depressive symptoms, as first evidenced in cancer patients being treated with cytokine-based drugs such as interferon, says Brundin, who has been studying the body-mind connection for the last 15 years. Most people also experience “sickness behavior,” including the type of sleeping and eating difficulties seen in patients with depression, when they get the flu.
Since the placenta generates a lot of inflammatory changes in a woman’s body during pregnancy, Brundin continues, it seems logical that these inflammatory mechanisms are particularly important in peripartum depression—defined as depression with onset during and up to four weeks after delivery. The results of that investigation recently published in Translational Psychiatry (DOI: 10.1038/s41398-022-01801-8).
Researchers measured 15 biomarkers of inflammation—six cytokines, four kynurenine metabolites, tryptophan, and serotonin, plus three derivative ratios—but four of them had the best predictive capacity. Ultimately, “perhaps we can use even fewer in the clinic,” says Brundin. The current top candidates are interleukin 6, tumor necrosis factor, kynurenine, and quinolinic acid, which showed strong individual accuracy in predicting depression risk and severity at future timepoints.
The full panel of biomarkers predicted significant depressive symptoms with 83% accuracy. But the four-marker subset may serve as a basis for an even better risk prediction tool that incorporates other clinical factors, adds Achtyes, much as the Framingham Heart Study informed the development of risk calculators for heart disease.
The pilot confirmation cohort in the study, 12 women who developed perinatal depression, suggests the utility of the biomarkers as a diagnostic tool. The four biomarkers, by themselves, succeeded in identifying during pregnancy almost every one of those confirmed cases of depression, says Brundin.
“Pregnancy is really the ideal situation if you want to track somebody with a predictive biomarker because a high percentage of women are coming in for regular visits, usually at least once in each trimester,” she says. As was seen in the study, a blood sample could best pick up impending depression between the second and third trimester (three months of advance warning) but some signs could be detected as early as the first trimester (six months prior to diagnosis via a structured clinical interview).
The biomarker panel was not strongly predictive of post-delivery depression, Brundin notes, suggesting other mechanisms are coming into play that may be related to the hormonal changes that accompany labor and birth. “Our best prediction model is during the actual pregnancy.”
When depression strikes during pregnancy where the mother may be caring for multiple children and perhaps other family members, it can have “devastating effects” on her and everyone else within the family unit, says Achtyes.
But for mothers, “pregnancy is a time when it might be particularly difficult to talk about depressive symptoms and even more so suicidal symptoms because family and friends, everybody, is expecting it to be the best time in their life,” adds Brundin. “It can be really difficult for some women to talk about how they are really feeling.”
This is also why the researchers felt fortunate to find women willing to participate in their study, which involved the collection of biological samples and speaking about any symptoms they may be experiencing, Achtyes says. Study participants were recruited from obstetrics and gynecology clinics of partner hospital Spectrum Health, a significant proportion of whom were single women with low incomes.
The study cohort was probably more diverse than the general pregnant population in the community, he adds, and social determinants of health are likely why so many of them (roughly one-third of the 114 women) experienced depression at one or more timepoints. “As you add stress after stress, your chance of inflammation just goes up and up.”
Some studies suggest inflammation might be higher during pregnancy in African American women, Brundin says. They are also at increased risk not only for depression but other adverse pregnancy outcomes that could be related to inflammation—diabetes and pre-term delivery, for example.
Now that the research team has identified risk intervals for each of the depression biomarkers, the next step is to test their predictive power in a larger population of pregnant women using the same lab tests and equipment, says Brundin. The plan is to identify partner hospitals around the country and conduct a multi-center clinical trial to confirm this standardized panel of markers, perhaps tapping federal funding sources available for biomarker development.
Countering depression in pregnancy won’t necessarily require anti-inflammatory medications, most of which have yet to be confirmed safe for mothers-to-be and their fetuses, she says. Prevention would be the easiest starting point, including dietary and exercise changes to reduce inflammation.
But marketed medications with anti-inflammatory properties exist across many drug classes, adds Achtyes. Some of them could be safety-tested for possible repurposing in treating perinatal depression.