Depression among new mothers is finally getting some attention

On the hormonal roller coaster of life, the ups and downs of childbirth are the Tower of Power. For nine long months, a woman’s body and brain absorb a slow upwelling of hormones, notably progesterone and estrogen. The ovaries and placenta produce these two chemicals in a gradual but relentless rise to support the developing fetus.

With the birth of a baby, and the immediate expulsion of the placenta, hormone levels plummet. No other physiological change comes close to this kind of free fall in both speed and intensity. For most women, the brain and body make a smooth landing, but more than 1 in 10 women in the United States may have trouble coping with the sudden crash. Those new mothers are left feeling depressed, isolated or anxious at a time society expects them to be deliriously happy.
This has always been so. Mental struggles following childbirth have been recognized for as long as doctors have documented the experience of pregnancy. Hippocrates described a woman’s restlessness and insomnia after giving birth. In the 19th century, some doctors declared that mothers were suffering from “insanity of pregnancy” or “insanity of lactation.” Women were sent to mental hospitals.

Modern medicine recognizes psychiatric suffering in new mothers as an illness like any other, but the condition, known as postpartum depression, still bears stigma. Both depression and anxiety are thought to be woefully underdiagnosed in new mothers, given that many women are afraid to admit that a new baby is anything less than a bundle of joy. It’s not the feeling they expected when they were expecting.

Treatment — when offered — most commonly involves some combination of antidepression medication, hormone therapy, counseling and exercise. Still, a significant number of mothers find these options wanting. Untreated, postpartum depression can last for years, interfering with a mother’s ability to connect with and care for her baby.

Although postpartum depression entered official medical literature in the 1950s, decades have passed with few new options and little research.
Even as brain imaging has become a common tool for looking at the innermost workings of the mind, its use to study postpartum depression has been sparse. A 2017 review in Trends in Neurosciences found only 17 human brain imaging studies of postpartum depression completed through 2016. For comparison, more than four times as many have been conducted on a problem called “internet gaming disorder” — an unofficial diagnosis acknowledged only five years ago.
Now, however, more researchers are turning their attention to this long-neglected women’s health issue, peering into the brains of women to search for the root causes of the depression. At the same time, animal studies exploring the biochemistry of the postpartum brain are uncovering changes in neural circuitry and areas in need of repair.

And for the first time, researchers are testing an experimental drug designed specifically for postpartum depression. Early results have surprised even the scientists.

Women’s health experts hope that these recent developments signal a new era of research to help new moms who are hurting.

“I get this question all the time: Isn’t it just depression during the postpartum period? My answer is no,” says neuroscientist Benedetta Leuner of Ohio State University. “It’s occurring in the context of dramatic hormonal changes, and that has to be impacting the brain in a unique way. It occurs when you have an infant to care for. There’s no other time in a woman’s life when the stakes are quite as high.”

Brain drain
Even though progesterone and estrogen changes create hormonal whiplash, pregnancy wouldn’t be possible without them. Progesterone, largely coming from the ovaries, helps orchestrate a woman’s monthly menstrual cycle. The hormone’s primary job is to help thicken the lining of the uterus so it will warmly welcome a fertilized egg. In months when conception doesn’t happen, progesterone levels fall and the uterine lining disintegrates. If a woman becomes pregnant, the fertilized egg implants in the uterine wall and progesterone production is eventually taken over by the placenta, which acts like an extra endocrine organ.

Like progesterone, estrogen is a normal part of the menstrual cycle that kicks into overdrive after conception. In addition to its usual duties in the female body, estrogen helps encourage the growth of the uterus and fetal development, particularly the formation of the hormone-producing endocrine system.

These surges in estrogen and progesterone, along with other physiological changes, are meant to support the fetus. But the hormones, or chemicals made from them, cross into the mother’s brain, which must constantly adapt. When it doesn’t, signs of trouble can appear even before childbirth, although they are often missed. Despite the name “postpartum,” about half of women who become ill are silently distressed in the later months of pregnancy.

Decades ago, controversy churned over whether postpartum depression was a consequence of fluctuating hormones alone or something else, says neuroscientist Joseph Lonstein of Michigan State University in East Lansing. He studies the neurochemistry of maternal caregiving and postpartum anxiety. Lonstein says many early studies measured hormone levels in women’s blood and tried to determine whether natural fluctuations were associated with the risk of postpartum depression. Those studies found “no clear correlations with [women’s] hormones and their susceptibility to symptoms,” he says. “While the hormone changes are certainly thought to be involved, not all women are equally susceptible. The question then became, what is it about their brains that makes particular women more susceptible?”
Seeking answers, researchers have examined rodent brains and placed women into brain scanners to measure the women’s responses to pictures or videos of babies smiling, babbling or crying. Though hormones likely underlie the condition, many investigations have led to the amygdalae. These two, almond-shaped clumps of nerve cells deep in the brain are sometimes referred to as the emotional thermostat for their role in the processing of emotions, particularly fear.

The amygdalae are entangled with many structures that help make mothers feel like mothering, says neuroscientist Alison Fleming of the University of Toronto Mississauga. The amygdalae connect to the striatum, which is involved in experiencing reward, and to the hippocampus, a key player in memory and the body’s stress response. And more: They are wired to the hypothalamus, the interface between the brain and the endocrine system (when you are afraid, the endocrine system produces adrenaline and other chemicals that get your heart racing and palms sweating). The amygdalae are also connected to the prefrontal cortex and insula, involved in decision making, motivation and other functions intertwined with maternal instinct.

Fleming and colleagues have recently moved from studies in postpartum rodents to human mothers. In one investigation, reported in 2012 in Social Neuroscience, women were asked to look at pictures of smiling infants while in a functional MRI, which images brain activity. In mothers who were not depressed, the researchers found a higher amygdala response, more positive feelings and lower stress when women saw their own babies compared with unfamiliar infants.

But an unexpected pattern emerged in mothers with postpartum depression, as the researchers reported in 2016 in Social Neuroscience. While both depressed and not-depressed mothers showed elevated amygdala activity when viewing their own babies, the depressed mothers also showed heightened responses to happy, unknown babies, suggesting reactions to the women’s own children were blunted and not unique. This finding may mean that depressed women had less inclination to emotionally attach to their babies.

Mothers with postpartum depression also showed weaker connectivity between the amygdalae and the insula. Mothers with weaker connectivity in this area had greater symptoms of depression and anxiety. Women with stronger connectivity were more responsive to their newborns.

While there’s still no way to definitely know that the amygdalae are responding to postpartum chemical changes, “it’s very likely,” Lonstein says, pointing out that the amygdalae are influenced by the body’s reaction to hormones in other emotional settings.

Maternal rewards
While important, the amygdalae are just part of the puzzle that seems to underlie postpartum depression. Among others is the nucleus accumbens, famous for its role in the brain’s reward system and in addiction, largely driven by the yin and yang of the neurotransmitters dopamine and serotonin. In studies, mothers who watched films of their infants (as opposed to watching unknown infants) experienced increased production of feel-good dopamine. The women also had a strengthening of the connection between the nucleus accumbens, the amygdalae and other structures, researchers from Harvard Medical School and their collaborators reported in February 2017 in Proceedings of the National Academy of Sciences.

That’s not entirely surprising given that rodent mothers find interacting with their newborn pups as neurologically rewarding as addictive drugs, says Ohio State’s Leuner. Rodent mothers that are separated from their offspring “will press a bar 100 times an hour to get to a pup. They will step across electrified grids to get to their pups. They’ve even been shown in some studies to choose the pups over cocaine.” Mothers find their offspring “highly, highly rewarding,” she says.

When there are postpartum glitches in the brain’s reward system, women may find their babies less satisfying, which could increase the risk for impaired mothering. Writing in 2014 in the European Journal of Neuroscience, Leuner and colleagues reported that in rats with symptoms of postpartum depression (induced by stress during pregnancy, a major risk factor for postpartum depression in women), nerve cells in the nucleus accumbens atrophied and showed fewer protrusions called dendritic spines — suggesting weaker connections to surrounding nerve cells compared with healthy rats. This is in contrast to other forms of depression, which show an increase in dendritic spines.
Unpublished follow-up experiments conducted by Leuner’s team also point to a role for oxytocin, a hormone that spikes with the birth of a baby as estrogen and progesterone fall. Sometimes called the “cuddle chemical,” oxytocin is known for its role in maternal bonding (SN Online: 4/16/15). Leuner hypothesizes that maternal depression is associated with deficits in oxytocin receptors that enable the hormone to have its effects as part of the brain’s reward system.

If correct, the idea may help explain why oxytocin treatment failed women in some studies of postpartum depression. The hormone may simply not have the same potency in some women whose brains are short on receptors the chemical can latch on to. The next step is to test whether reversing the oxytocin receptor deficits in rodents’ brains relieves symptoms.

Leuner and other scientists emphasize that the oxytocin story is complex. In 2017, in a study reported in Depression & Anxiety, women without a history of depression who received oxytocin — which is often given to promote contractions or stem bleeding after delivery — had a 32 percent higher likelihood of developing postpartum depression than women who did not receive the hormone. In more than 46,000 births, 5 percent of women who did not receive the hormone were diagnosed with depression, compared with 7 percent who did.

“This was the opposite of what we predicted,” says Kristina Deligiannidis, a neuroscientist and perinatal psychiatrist at the Feinstein Institute for Medical Research in Manhasset, N.Y. After all, oxytocin is supposed to enhance brain circuits involved in mothering. “We had a whole group of statisticians reanalyze the data because we didn’t believe it,” she says. While the explanation is unknown, one theory is that perhaps the women who needed synthetic oxytocin during labor weren’t making enough on their own — and that could be why they are more prone to depression after childbirth.

But postpartum depression can’t be pinned to any single substance or brain malfunction — it doesn’t reside in one tidy nest of brain cells, or any one chemical process gone haywire. Maternal behavior is based on complex neurological circuitry. “Multiple parts of the brain are involved in any single function,” Deligiannidis says. “Just to have this conversation, I’m activating several different parts of my brain.” When any kind of depression occurs, she says, multiple regions of the brain are suffering from a communication breakdown.

Looking further, Deligiannidis has also examined the role of certain steroids synthesized from progesterone and other hormones and known to affect maternal brain circuitry. In a 2016 study in Psychoneuroendocrinology involving 32 new mothers at risk for postpartum depression and 24 healthy mothers, Deligiannidis and colleagues reported that concentrations of some steroids that affect the brain, also called neurosteroids, were higher in women at risk for developing depression (because of their past history or symptoms), compared with women who were not. The higher levels suggest a system out of balance — the brain is making too much of one neurosteroid and not enough of another, called allopregnanolone, which is thought to protect against postpartum depression and is being tested as a treatment.
Treating pregnancy withdrawal
Beyond mom

CASEZY IDEA/SHUTTERSTOCK
Postpartum depression doesn’t weigh down just mom. Research suggests it might have negative effects on her offspring that can last for years. Risks include:

Newborns
Higher levels of cortisol and other stress hormones
More time fussing and crying
More “indeterminate sleep,” hovering between deep and active sleep
Infants and children
Increased risk of developmental problems
Slower growth
Lower cognitive function
Elevated cortisol levels
Adolescents
Higher risk of depression
Tufts University neuroscientist Jamie Maguire, based in Boston, got interested in neurosteroids during her postgraduate studies in the lab of Istvan Mody at UCLA. Maguire and Mody reported in 2008 in Neuron that during pregnancy, the hippocampus has fewer receptors for neurosteroids, presumably to protect the brain from the massive levels of progesterone and estrogen circulating at that time. When progesterone drops after birth, the receptors repopulate.

But in mice genetically engineered to lack those receptors, something else happened: The animals were less interested in tending to their offspring, failing to make nests for them.

“We started investigating. Why are these animals having these abnormal postpartum behaviors?” Maguire recalls. Was an inability to recover these receptors making some women susceptible? Interestingly, similar receptors are responsible for the mood-altering and addictive effects of some antianxiety drugs, suggesting that the sudden progesterone drop after childbirth could be leaving some women with a kind of withdrawal effect.

Further experiments demonstrated that giving the mice a progesterone-derived neurosteroid — producing levels close to what the mice had in pregnancy — alleviated the symptoms.

Today, Maguire is on the scientific advisory board of Boston area–based Sage Therapeutics, which is testing a formulation of allopregnanolone called brexanolone. Results of an early clinical trial published last July in The Lancet assessed whether brexanolone would alleviate postpartum symptoms in women with severe postpartum depression. The study involved 21 women randomly assigned to receive a 60-hour infusion of the drug or a placebo within six months after delivery.

At the end of treatment, the women who received the drug reported a 21-point reduction on a standard scale of depression symptoms, compared with about 9 points for the women on a placebo. “These women got better in about a day,” says Deligiannidis, who is on the study’s research team. “The results were astonishing.”

In November, Sage Therapeutics announced the results of two larger studies, although neither has been published. Combined, the trials involved 226 women with severe or moderate postpartum depression. Both groups showed similar improvements that lasted for the month the women were followed. The company has announced plans to request approval from the U.S. Food and Drug Administration to market brexanolone in the United States. This is an important first step, researchers say, toward better treatments.

“We are just touching on one small piece of a bigger puzzle,” says Jodi Pawluski, a neuroscientist at the Université de Rennes 1 in France who coauthored the 2017 review in Trends in Neurosciences. She was surprised at the dearth of research, given how common postpartum depression is. “This is not the end, it’s the beginning.”