Postpartum depression affects up to 15% of new mothers, creating significant emotional strain on them and their families that can last for years after birth. New findings recently published in Neuropsychopharmacology indicate that alterations in progesterone metabolism during the third trimester of pregnancy may raise the risk of postpartum depression, supporting a biological basis for the disorder.
The research was co-led by Lauren M. Osborne, M.D., a reproductive psychiatrist at NewYork-Presbyterian and Weill Cornell Medicine and vice chair for clinical research for the Department of Obstetrics and Gynecology at Weill Cornell Medicine, with key colleagues Dr. Jennifer Payne at the University of Virginia and Dr. Graziano Pinna at the University of Illinois-Chicago. The study analyzes the entire progesterone metabolic pathway in women who did not have depression during pregnancy, in hopes of pinpointing alterations that could predict a higher risk of postpartum depression.
The findings could eventually lead to the development of a blood test that could be used during pregnancy to predict postpartum depression and identify which patients may benefit from earlier treatment. “There’s a big stigma around mental illness, and one of the reasons I’m excited about this paper is that it shows a clear biological link,” Dr. Osborne says. “I want physicians to see that we can’t underestimate the effect of these illnesses and that there are things we can do to treat them.”
Research Background and Methods
The research team set out to measure levels in pregnancy of neuroactive steroids, which are metabolites of cholesterol that are either produced in the brain or are made in the periphery and have actions on the brain. The neuroactive steroids most closely associated with reproductive psychiatric disorders are descended from progesterone, and these molecules influence stress response and emotional regulation. Several prior studies have compared neuroactive steroid levels with averages of mood across time, indicating there is a biological correlation. Dr. Osborne previously looked at one molecule in the progesterone metabolic pathway as a predictor of disease, but until now, no one had examined the entire pathway in pregnancy and its influence on postpartum depression.
In women without depression who are going to develop postpartum depression, there is a key defect in the progesterone metabolic pathway that may help us predict who's going to develop it later on.
— Dr. Lauren M. Osborne
The trial participants were 136 women who were not depressed during pregnancy. Researchers examined the level of neuroactive steroids in their blood and measured their psychological scales during the second and third trimesters, and up to nine months after birth. Their findings concerned two neuroactive steroids, pregnanolone and isoallopregnanolone. Pregnanolone acts on the GABA-A receptor to provide calming effects and reduce stress, while isoallopregnanolone has the opposite effect, interacting with this receptor to increase stress.
“The GABA receptor undergoes a conformational change during pregnancy and postpartum,” Dr. Osborne says. “The levels of neuroactive steroids affect whether that conformational change occurs appropriately.”
Key Findings and Clinical Implications
Of the 136 participants, 33 developed symptoms of depression in the postpartum period. In their third trimester, the women who developed postpartum depression had a lower pregnanolone-to-progesterone ratio and a higher isoallopregnanolone-to-pregnanolone ratio compared with those who did not develop postpartum depression.
Elevated progesterone levels in late pregnancy were also associated with a higher risk of postpartum depression, indicating decreased metabolism of progesterone into its beneficial downstream products.
“In women without depression who are going to develop postpartum depression, there is a key defect in the progesterone metabolic pathway that may help us predict who's going to develop it later on,” Dr. Osborne says. “This confirms that postpartum depression has a biological cause.”
The findings may be useful in determining which pregnant women could benefit from earlier treatment intervention, opening the possibility of a clinical blood test that could be developed to predict postpartum depression. The newer medications specifically for postpartum depression, such as brexanolone and zuranolone, are very effective after diagnosis, but their safety during pregnancy is unknown. The research suggests it may be beneficial to consider whether those medications can be used prophylactically.
“If we learn that a patient has an elevated risk of postpartum depression, we can prescribe that medication for her as soon as she gives birth,” Dr. Osborne noted. “There are also older medications for depression that are low risk in pregnancy, but some women still choose to go off them during pregnancy. We might suggest to a patient with an elevated risk of postpartum depression that she restarts her medication before the end of pregnancy to protect her during the postpartum period.”
