Exploring the biology behind maternal mental health disorders

Pregnancy and new motherhood transform a woman's body as well as her life. While this is often a joyous time, it can sometime lead to mental health disorders, most often anxiety and depression. These conditions can be detrimental to the mother's health and that of her child, but despite the high stakes, modern medicine often fails to address them. By teasing out the biological mechanisms underlying these pregnancy-related disorders, investigators at Weill Cornell Medicine are laying the groundwork for new ways to detect and treat women at risk. 

The statistics for depression that occurs after delivery, or postpartum, reflect a particularly abysmal reality: Clinicians successfully treat only about three percent of women with this disorder. For those who become depressed before giving birth, that number rises only slightly, to around five percent. 

We do a shockingly bad job in this country of detecting and treating women who have pregnancy-related depression."

Dr. Lauren M. Osborne, associate professor of obstetrics and gynecology at Weill Cornell Medicine and reproductive psychiatrist at NewYork-Presbyterian/Weill Cornell Medical Center

In one effort to ameliorate this problem, she and her colleagues have begun a perinatal wellness program that embeds experts in pregnancy and postpartum mental health into obstetric care. 

Left untreated, anxiety and depression can cause significant harm, potentially negatively affecting a child's development and behavior over time and putting mothers at increased risk of substance abuse and suicide. The low rates of successful treatment reflect a series of shortfalls in the healthcare system's capacity to intervene, beginning with difficulty predicting who is at heightened risk. 

Studies have established that certain psychological and social factors, such as a history of mental illness, low education level, or a lack of support, increase risk for pregnancy-related mental health illnesses. But scientists know less about the biological dimensions of these conditions.

"We have this special window of time, where something makes women vulnerable to mood and anxiety disorders," said Dr. Jonathan Power, an assistant professor of psychiatry at Weill Cornell Medicine, who is tracking women to see how their brain activity changes with pregnancy and into motherhood. "We don't know definitively what that is, but we have some likely candidates."

These potential culprits are changes in the immune system and fluctuations in hormones, according to Dr. Power. By investigating them in detail, he and Dr. Osborne hope, over the long term, to help turn medicine's track record around. 

Spying on immune cell communication

Dr. Osborne's research on the first of these potential culprits has pointed toward the possibility of pre-empting postpartum depression.

During pregnancy, the immune system's complex, defensive network must adapt to tolerate another living being within its perimeter, while still defending against threats from outside. Dr. Osborne's research has offered some clues, such as differences in T-cell activity, linking abnormal immunological activity during pregnancy with anxiety and depression. 

In a study in Molecular Psychiatry, her team identified another key difference, shifts in a particular type of intercellular communication package released by two types of immune cells, macrophages and monocytes. 

Under normal circumstances, cells expel bits of RNA, a relative of DNA, into the bloodstream, bundled within tiny packages. These packages increase in pregnancy, and the RNA found within them may contribute to implantation of the embryo and other processes. 

Dr. Osborne and her colleagues examined the RNA within blood samples taken from women during pregnancy and up to six months after they had delivered. Among the women who were not depressed in pregnancy but went on to develop postpartum depression, the researchers saw a warning sign. During the 2nd and 3rd trimester of their pregnancies, the presence of a certain type of RNA package from the immune cells dropped off — a change not seen among the women who did not become depressed.  

This clear difference could provide the basis for a blood test to predict risk, according to Dr. Osborne.

"If we knew who would become sick, we could direct mental health resources to the people at highest risk early on, so we would be engaging in prevention rather than treatment," she said.

Looking to hormones' effect on the brain

For those women who do develop postpartum depression and anxiety, treatment, including psychotherapy and medication, is currently available. Dr. Osborne notes that anti-anxiety and antidepressant medications, while not risk free, are compatible with pregnancy and breastfeeding. However, pregnant women and mothers are often concerned about the medication's potential effects on their babies.

In her own experience, Dr. Osborne has found that women want medications developed specifically for pregnancy-related conditions. However, until relatively recently, their only options were medications used to treat anxiety and depression in the general populations. A new class of drugs for postpartum depression shows that a more targeted approach is possible. These new medications, brexanolone and zuranolone, rely on a synthetic version of a hormone, allopregnanolone (a metabolite of progesterone produced in the brain), which fluctuates dramatically with pregnancy and delivery.

Shifts in hormone levels are the second likely candidate Dr. Osborne and Dr. Power are pursuing. During pregnancy, levels of estrogen, progesterone and allopregnanolone rise dramatically. Then, within 24 hours of delivery, they plummet. These fluctuations appear to cause problems for certain women. 

With support from a pilot grant, the 1907 Trailblazer Award from the 1907 Foundation, Dr. Power has begun looking for three-way relationships among changes in hormone levels, mood, and brain activity detected by MRI scans. His goal is to track all three from before conception up to a year after delivery. 

To find women before they become pregnant, he has partnered with the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine to recruit those undergoing fertility treatments. Once enrolled, the participants complete daily, roughly one-minute, digital surveys about their mood, sleep, exercise and other activities.

Statistically, some of the women who are trying to become pregnant will go on to struggle with mood or anxiety after they conceive. "So, is there something about the brain scans beforehand that leads to a prediction about who's going to be troubled and who's going to do OK?" Dr. Power said. 

Any such insight remains far off, however. He views the stage of current brain imaging research as similar to the studies in the 1990s that examined the role of hormones, including allopregnanolone, in the brain and so laid the foundation for the recently approved drugs for postpartum depression.

Like that research, the studies he and Dr. Osborne are conducting could — one day — make similar advancements possible.

"This is about understanding why it's happening, which then gradually serves as the basis for developing therapies," he said.  

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