Research has indicated that women who are likely to develop postpartum depression (PPD) may exhibit specific levels of neuroactive steroids, which are substances derived from the hormone progesterone, in their bloodstream during the third trimester of pregnancy. These steroids play a significant role in regulating emotional responses and the brain’s reaction to stress.
Recent studies from Weill Cornell Medicine and the University of Virginia have shown that women at risk for postpartum depression (PPD) may have distinct levels of neuroactive steroids in their blood during the third trimester. These steroids, which are derived from progesterone, impact the brain’s ability to manage stress and emotions.
The research, published in Neuropsychopharmacology, suggests that this discovery could help identify women who may be predisposed to PPD before they experience any symptoms, enabling earlier intervention by healthcare professionals. PPD is a severe form of depression occurring after childbirth, affecting 10-15% of new mothers, and can have long-lasting emotional effects on both the mother and child. Common symptoms include difficulty bonding with the baby, feelings of despair, fatigue, sleep disruptions, and a decreased appetite.
Dr. Lauren Osborne, an associate professor at Weill Cornell Medicine who co-led the study, noted, “Postpartum is a unique period in life where a biological trigger is evident, leading to a certain percentage of individuals falling ill. If we can understand the biological factors at play and identify predictors, we can not only aid these women but also advance our understanding of other psychiatric conditions.”
Another co-leader, Dr. Jennifer Payne, a professor and vice chair at the University of Virginia, emphasized the importance of studying postpartum depression to uncover the biological changes that happen before depression sets in, as the timing of postpartum depression is relatively predictable.
Warning Signs from Neuroactive Steroid Levels
Dr. Osborne pointed out, “Previous studies have looked at the average neuroactive steroid levels alongside average mood states over time, providing only a correlation without clinical applicability.”
To fill this gap, researchers focused on a group of 136 pregnant women without existing depression and measured their neuroactive steroid levels at specific stages in the second and third trimesters. They continued to collect clinical data for up to nine months post-birth. Out of these participants, 33 exhibited postpartum depression symptoms. “Although depression can emerge at various times during and after pregnancy, its early onset within 4 to 6 weeks post-birth represents a unique biological scenario,” Dr. Osborne clarified.
The study concentrated on progesterone and its metabolic processes as key elements related to postpartum depression risk. Two neuroactive steroids generated from progesterone, pregnanolone and isoallopregnanolone, were specifically investigated. Pregnanolone has calming effects by acting on the GABA-A receptor, while isoallopregnanolone can increase stress through the same receptor.
The researchers found that women who went on to develop PPD had lower ratios of pregnanolone to progesterone and higher ratios of isoallopregnanolone to pregnanolone during the third trimester than those who did not develop PPD. Elevated progesterone levels in late pregnancy were further linked to a greater likelihood of PPD, indicating less effective metabolism of progesterone into its beneficial derivatives.
Dr. Osborne stated, “If we can validate these findings, it could lead to developing a clinical test to predict the onset of postpartum depression.”
Though the reasons for some women developing PPD remain unclear, the study hints at a potential imbalance in progesterone metabolism. If this imbalance manifests as excessive progesterone or an inclination to metabolize to isoallopregnanolone instead of beneficial metabolites, those women faced a fourfold increased risk of developing PPD. This phenomenon could be linked to the activity levels of two enzymes (3α-HSD and 3β-HSD) that convert progesterone into its metabolites.
Paving the Way for Preventive Treatment
Currently, treatments like brexanolone and zuranolone can be administered after a PPD diagnosis. However, the insights from this study suggest the possibility of preventive treatments for pregnant women who show neuroactive steroid levels indicative of higher PPD risk. “While we can’t yet confirm if these drugs would serve as a preventive measure against postpartum depression, our findings indicate they hold potential for such prevention,” said Dr. Osborne.
The research team plans to verify their findings by involving a larger and more diverse population. Additionally, Dr. Osborne, Dr. Payne, and their colleagues aim to analyze the progesterone metabolic pathway prior to the onset of postpartum depression by directly measuring the activity levels of the relevant enzymes.
The study received support from grants R01MH104262 and R01MH112704 from the National Institutes of Health’s Institute of Mental Health.
