Postpartum depression (PPD) affects nearly 20 percent of childbearing people, but just three percent receive treatment until their symptoms resolve (1,2). Lauren Osborne, a reproductive psychiatrist at Weill Cornell Medicine/New York-Presbyterian Hospital said that this is partly because “we aren't good at figuring out who's going to be at risk and getting them into care early.” What if there was a way to better predict and treat people before PPD develops?
Through a multi-institutional collaboration, Osborne and her team sought to find a way to predict PPD during pregnancy based on the levels of neuroactive steroids in the blood (3).
These neuroactive steroids are metabolites of progesterone, a hormone that increases during pregnancy and then decreases rapidly after giving birth. The body normally metabolizes progesterone into four metabolites that either positively or negatively modulate the GABAA receptor, which binds the primary inhibitory neurotransmitter GABA. When stimulated, the GABAA receptor leads to a calm feeling in the brain, Osborne said. Two metabolites, allopregnanolone and pregnanolone, positively modulate that receptor while two other metabolites, isoallopregnanolone and epipregnanolone, have the opposite effect.
“We've known for a long time that the metabolites of progesterone play a major role in the pathophysiology of postpartum depression,” she said. “But it's been unclear exactly what that role is, and whether that's something that happens at the time symptoms develop or before.”
In their study, Osborne and her colleagues took blood samples from 136 pregnant individuals once during each trimester and at five different times postpartum. Study participants also took a self-rating questionnaire to screen for depression symptoms during the second and third trimesters and during the postpartum period. Using gas chromatography/mass spectrometry and high-pressure liquid chromatography, the researchers teased apart and measured the absolute levels of each of the four molecules.
We've known for a long time that the metabolites of progesterone play a major role in the pathophysiology of postpartum depression. … But it's been unclear exactly what that role is, and whether that's something that happens at the time symptoms develop or before.
– Lauren Osborne, Weill Cornell Medicine/New York-Presbyterian Hospital
They found that during the third trimester, blood samples from people who developed PPD contained different signatures from those who did not. These samples had higher levels of progesterone, a lower pregnanolone/progesterone ratio, and a higher ratio of the negative modulator isoallopregnanolone to the positive modulator pregnanolone. This means that in women who develop PPD, GABA signaling becomes dysregulated. While the cause behind these differences is currently unknown, it’s possible that the enzymes responsible for metabolizing progesterone aren’t working properly or that there’s a defect in the GABAA receptor itself in people who will eventually develop PPD.
“There've been a lot of efforts to try to predict which women might suffer from postpartum depression, and it's been incredibly difficult,” said Jamie Maguire, a neuroscientist at Tufts University who was not involved in the study. “I think that this paper is incredibly important because it's starting to make some headway in that area.”
In the future, the level of these neuroactive steroids could be a predictive biomarker of PPD. To do this, Maguire said that further studies would have to establish a threshold level of these metabolites that could identify patients at risk. If there were a blood test for these metabolites, Osborne said, that would help those at risk get care early or receive treatment as a prophylactic.
“[Our work] goes a long way towards showing those biological underpinnings of postpartum depression,” said Osborne. “I hope that means people will start to reduce their stigma about perinatal mental illness and realize that these illnesses are just as important as physical comorbidities of pregnancy.”
References
- Khadka, N. et al. Trends in Postpartum Depression by Race, Ethnicity, and Prepregnancy Body Mass Index. JAMA Netw Open 7, e2446486 (2024).
- Cox, E.Q. et al. The Perinatal Depression Treatment Cascade: Baby Steps Toward Improving Outcomes. J Clin Psychiatry 77, 1189-1200 (2016).
- Osborne, L.M. et al. Neuroactive steroid biosynthesis during pregnancy predicts future postpartum depression: a role for the 3α and/or 3β-HSD neurosteroidogenic enzymes? Neuropsychopharmacol (2025).
