Women who go on to develop postpartum depression (PPD) may have characteristic levels of neuroactive steroids, molecules derived from the hormone progesterone, in their blood during the third trimester of pregnancy, according to a new study by researchers at Weill Cornell Medicine and the University of Virginia. These molecules influence the brain's stress response and emotional regulation.
The findings, published XX in Neuropsychopharmacology, suggest that this may provide a way to identify women at risk of PPD before symptoms start, allowing doctors to intervene earlier. Postpartum depression, severe depression that happens after giving birth, affects 10-15% of new mothers, causing emotional struggles that can impact both the parent and child for years. Symptoms include difficulty bonding with the baby, feelings of hopelessness and sadness, fatigue, loss of appetite, difficulty sleeping, to name a few.
"Postpartum is the only time in people's lifespans when we know there is a biological trigger which guarantees that a certain percentage of people will become ill," said Dr. Lauren Osborne , associate professor of obstetrics and gynecology and of psychiatry at Weill Cornell Medicine, who co-led the study. "If we can untangle this biology and find predictors for it, not only will we be helping women, but it may give us a step up in trying to find predictors for other psychiatric illnesses also."
Co-lead on this research, Dr. Jennifer Payne, professor and vice chair of research in psychiatry and neurobehavioral sciences at the University of Virginia, has also spent years searching for the biological basis that leads to major clinical depression. "Studying postpartum depression gives us a way to identify biological changes that occur before someone becomes depressed because the timing of postpartum depression is predictable," she added.
Neuroactive Steroid Levels May Provide a Warning Sign
"Many papers have compared averages of neuroactive steroid levels with averages of mood across time, which just tells us there is some biological correlation but doesn't help us clinically," said Dr. Osborne.
To address this gap, the researchers restricted their study to 136 women who were not depressed during pregnancy and measured neuroactive steroid levels in their blood samples at specific timepoints during the second and third trimesters. They also followed up with clinical data for up to nine months after birth. Thirty-three participants developed symptoms of depression in the postpartum period. "While depression can manifest at different times throughout and after pregnancy, that early-on, 4-to-6 weeks onset is a biologically distinct entity," Dr. Osborne explained.
The study focused on the hormone progesterone and its metabolic pathway as potential suspects in postpartum depression. Two neuroactive steroids derived from progesterone that seem to affect the risk of developing PPD are pregnanolone and isoallopregnanolone. Pregnanolone acts on the GABA-A receptor to provide calming effects and reduce stress. Conversely, isoallopregnanolone interacts with the GABA-A receptor to increase stress.
The study determined that in the third trimester, individuals who developed PPD had a lower pregnanolone/progesterone ratio and a higher isoallopregnanolone/pregnanolone ratio compared with those who did not. Elevated progesterone levels in late pregnancy were also associated with a higher risk of PPD, pointing to decreased metabolism of progesterone into its beneficial downstream products.
"If we were able to replicate these results, then this could reasonably become a clinical test that could predict the development of future illness," said Dr. Osborne.
Though it isn't clear why some women develop PPD, these findings suggest that there may be an imbalance in the metabolism of progesterone. When this resulted in either too much progesterone or preferentially metabolizing to isoallopregnanolone instead of positive metabolites, those women were four times more likely to develop PPD. This could be related to the relative activity of two enzymes (3α-HSD and 3β-HSD) that help convert progesterone to pregnanolone and isoallopregnanolone.
Toward a Preventive Treatment
Currently, two new treatments, brexanolone and zuranolone, can be prescribed once someone is diagnosed with PPD. The findings of the study open the door to a potential preventive treatment for pregnant women whose blood tests reveal neuroactive steroid levels associated with an increased risk of postpartum depression. "We don't know if these drugs would work as a preventive measure for people who are at risk of developing postpartum depression, but based on our findings, they have the potential to prevent the development of postpartum depression," said Dr. Osborne.
The researchers plan to replicate their findings in a larger, more diverse group of patients. In addition, Dr. Osborne, Dr. Payne and their teams will determine what occurs in the progesterone metabolic pathway prior to postpartum depression developing by directly measuring the levels of the two enzymes that convert progesterone into its metabolites.
This work was supported by the National Institutes of Health's Institute of Mental Health, grants R01MH104262 and R01MH112704.
