When Katherine Wisner began studying postpartum mental health in the 1980s, the field barely existed. Relatively little research was focused on psychiatric illness related to pregnancy, and postpartum depression wasn’t yet well understood.
Wisner, now an associate chief of perinatal mental health at Children’s National Hospital in Washington, D.C., recalls a senior male supervisor dismissing a case she flagged of a new mother experiencing severe depression and suicidal thoughts. “You have to be wrong,” she remembers him responding. “Women aren’t depressed in pregnancy, because they’re fulfilled.”
For years, the idea that having a baby is one of the happiest times in a mother’s life persisted despite research indicating that’s not always the case. Over time, though, researchers and physicians began to acknowledge the range of mental health effects a postpartum woman can experience, spurring research into medicines that might help.
Now, doctors in the U.S. have two drugs they can prescribe specifically for postpartum depression, or PPD, a condition that affects an estimated 1 in 8 women following birth and can be severe. Both are from biotechnology company Sage Therapeutics. An intravenous injection called Zulresso was approved in 2019, while a daily oral pill called Zurzuvae got clearance last summer.
Their approvals were many years in the making. Yet both come with risks and limitations, and adoption has been slow — a fact some experts attribute to still-evolving awareness of PPD, and how to treat it.
“We are not recognizing it as a country and as a society,” Wisner said.
Slow recognition
Mental health professionals have relied on a guidebook called the Diagnostic and Statistical Manual of Mental Disorders, or DSM, to diagnose and treat their patients for more than 70 years.
But the DSM didn’t recognize PPD until the 1990s, when its fourth edition codified the condition as a “major depressive disorder occurring within four weeks of giving birth.”
The next edition, in 2013, went a bit further, defining PPD as a major depressive episode occurring during pregnancy or within four weeks after giving birth. The most recent update also highlights possible coexisting symptoms of anxiety and panic.
“Slowly the field grew so that eventually there actually was a formal diagnosis of depression,” said Wisner.
The drawn-out recognition of PPD left women dealing with the condition to fend for themselves for decades. It wasn’t until 2015, for instance, that the American College of Obstetricians and Gynecologists issued its first guidance on screening for symptoms in both pregnant and postpartum women.
The U.S. Preventative Services Task Force and American Psychological Association soon followed with similar recommendations.
“Historically, the messaging was that pregnancy is the greatest time in a woman’s life, and there’s no happier time than after a baby’s delivered,” said Julia Riddle, a reproductive psychiatrist and assistant professor at the University of North Carolina School of Medicine. “And it took a lot to really demonstrate that, maybe, it’s a little more complicated.”
Difficulties in diagnosis
Even with formal screening recommendations, diagnosis can still be challenging. Questionnaires like the Edinburgh Postnatal Depression Scale and the Patient Health Questionnaire are often used by doctors to determine whether new mothers may be experiencing PPD or anxiety.
If PPD is suspected, psychotherapy, or “talk therapy,” is typically the first option. Drug intervention is usually reserved for more severe cases or for women who were previously on medication.
Actually receiving treatment can be a hurdle, too. Michelle Visser, a mother and psychotherapist for pregnant and postpartum women, recalled how few people asked about her mental health after she gave birth.
“A lot of people don’t necessarily know when they need help, because people aren’t talking about it,” Visser said. “You don’t know what you don’t know.”
Partly as a result, PPD is often underdiagnosed and, even when it is, not well treated. According to the Centers for Disease Control and Prevention, approximately 60% of women with symptoms of postpartum depression go undiagnosed, and half of those diagnosed aren’t treated.
“People tend to do the [Edinburgh] scale and then move on,” said Judith Joseph, a psychiatrist at NYU Langone Health and a researcher on trials of Sage’s PPD drugs. “Many times, there’s shame in reporting any type of sadness to the provider because if your baby’s happy and healthy, you should be happy and healthy too.”
Moreover, not every OB-GYN is trained to treat PPD since it has not always been a part of standard care. Access to therapies can also vary depending on a person’s insurance coverage, resources, or other health concerns.
Treatment shortcomings
Before Sage’s drugs were available, physicians treating PPD typically turned to standard antidepressants like selective serotonin reuptake inhibitors, or SSRIs.
These medicines can help, but their effects don’t usually kick in for four to 10 weeks, if at all. The evidence supporting their use in PPD is also limited.
“When people are having depression, that impacts their functioning and their quality of life,” Joseph said. “Telling them they’ll get relief in eight to 10 weeks is very difficult to hear for someone who has a lot of responsibilities, who wants to be able to bond with their child, who wants to be able to get back to the life that they once had.”
Antidepressants can also cause weight gain, gastrointestinal issues, agitation and sleep disturbance.
Doctors need to evaluate prospective patients for bipolar disorder before they prescribe an antidepressant, too. Up to 1 in 5 people screened for PPD may instead have bipolar disorder, a mental illness that causes mood swings and psychosis. Antidepressants can exacerbate bipolar disorder.
Additionally, treatment can be a difficult choice for pregnant or postpartum women, who may feel pressured to go without therapy or fear a drug might affect their child through breastfeeding. (Breastfeeding while on medication doesn’t necessarily present a risk to the infant, however.)
“There is stigma because people assume that motherhood should be inherent to being a woman,” Joseph said. “But [people] don’t necessarily acknowledge the challenges.”
Socioeconomic status, ethnicity and familial support can also affect how someone might view receiving help.
“We treat in the medical system, for the most part, people of color totally different,” Visser said. “Those families are very concerned they’re going to be seen as unfit parents and that action will be taken against them.”
A sparse drug pipeline
Despite a push for better treatments, the development of drugs specifically for PPD has been sluggish. Research has largely centered on psychotherapy and existing antidepressants.
“We weren’t even recognizing these [postpartum] illnesses decades ago, so we weren’t going to do trials trying to find a medication specifically for these illnesses,” said Nancy Byatt, a perinatal psychiatrist and professor at UMass Chan Medical School.
Compounding the difficulty is the fact that clinical studies have historically not always included women, nor have drugmakers focused on illnesses that primarily affect women. Clinical trials frequently exclude pregnant women over concerns an experimental drug may harm a fetus and, as a result, researchers don’t know as much about how different types of drugs can affect pregnant women.
Enrolling postpartum women in trials is complicated, too, as the window of time to test a therapy is small.
“It’s still hard because we’re talking about nine months. People are often not talking about their pregnancy until three months in,” Riddle said. “So you have a very brief time to consent them, get them onto a protocol and follow them into the postpartum. It’s a hard thing to study.”
A box of Sage Therapeutics’ postpartum depression drug Zurzuvae
Permission granted by Sage Therapeutics
Sage has been one of the few biotechnology firms to try. The company set out early last decade to develop the drug that became Zulresso, which was approved in 2019 for moderate-to-severe PPD. Its modest efficacy and 60-hour infusion requirement has kept adoption minimal, however.
Working with Biogen, Sage later developed an oral drug called Zurzuvae that it sought to get approved for both PPD and in major depressive disorder. In 2023, the FDA approved it for PPD, but not MDD — a blow to the company that led to layoffs.
Earlier academic research had set the stage for Sage’s drugs. Studies found that depressive symptoms caused by changes in certain brain chemicals during pregnancy might be alleviated with drugs that act on so-called GABA-A receptors. Both of Sage’s PPD drugs are synthetic versions of a neurosteroid called allopregnanolone, a brain hormone that affects GABA-A receptors. They essentially work similarly to hormone therapy, suggesting the role hormones might play in PPD.
“For a long time, it’s been debated whether postpartum depression is just another form of major depressive disorder or it’s an entity by itself,” said Bassem Maximos, an OB-GYN in League City, Texas and a trial investigator. “A lot of us OB-GYNs believe there has to be a different mechanism because a lot of our patients are different from regular major depressive disorder patients.”
Beyond Sage’s drugs, the pipeline of therapies in development for postpartum depression is thin. Brii Biosciences, another biotechnology company, has a drug in mid-stage testing, but there are few others.
Will PPD drugs succeed?
While Zulresso and Zurzuvae’s approvals were a milestone for PPD drug research, neither has been widely used.
Zulresso’s lengthy administration must take place in a healthcare facility, keeping adoption low, while Sage faced pushback for the drug’s $34,000-per-course price tag. Sales were $6.7 million in Zulresso’s first full year on the U.S. market, and only $10.5 million last year.
The FDA, as well as psychiatrists like Byatt, agreed Zulresso’s “benefits outweigh the negatives.” But the drug’s requirements make it a hard sell, especially for women who lack additional support, or are a single parent.
Zurzuvae, which launched commercially in the U.S. last December, seems more attractive. As an oral medicine, the drug can be shipped to a patient’s home and is taken daily for two weeks. Sage has said psychiatrists, OB-GYNs and primary care physicians have already started prescribing Zurzuvae, with $1.6 million in sales for the fourth quarter of 2023. Results for the first three months of this year will offer a better gauge of demand.
Zurzuvae takes effect rapidly, which could help it stand out compared to other medications, such as SSRIs, that have a slower onset of action. In clinical trials, Sage also found its drug could relieve symptoms of anxiety.
“The fact that this medication works quickly, and also gives [patients] that added relief for sleep and anxiety is beneficial compared to an SSRI that works slower, and may not necessarily relieve sleep and anxiety as rapidly,” Joseph said.
Zurzuvae, which is being co-marketed with Biogen, costs $15,900 at list price for a two-week course — less than Zulresso, but still high enough to raise access concerns.
While Zulresso’s and Zurzuvae’s side effects are modest, both carry black box safety warnings. Zulresso’s warns of excessive sedation and loss of consciousness, while Zuruvae’s cautions of impaired ability to drive. However, Maximos claims the drowsiness was a “positive side effect” for some mothers in the clinical trials who suffered from a lack of sleep and exhaustion.
“It’s exciting that we’re here,” Riddle said “It’s exciting that women have spoken up about their struggles, and that women have taken the time to say, ‘hold on, [motherhood] was actually hard.”
Beyond drug-specific challenges, new mothers face other hurdles that can impact PPD care. Paid maternity leave is not guaranteed in the U.S. and many women are in so-called maternity care deserts, making finding adequate support difficult.
“We always want better treatments that work but the reality is we’re not getting the treatments we have to the people who need it right now,” Wisner said. “That’s where the big gains are going to come from.”
In an effort to make treatment easier, Sage and Biogen have launched a patient support program, and are working with organizations on PPD education initiatives.
Some experts think a bigger change around culture and access is needed, however.
“The main way that we could possibly address mental health — what’s been a crisis for years and is now an emergency — is by supporting resilient and healthy families, and we have to start with perinatal mental health to be able to do that,” Byatt said.
Still, there is some optimism. Joseph sees Sage’s approvals as opening the door to more drug research, for instance.
“This is an opportunity to pave the way for a huge amount of research in this space,” Joseph said. “It’s just the beginning.”
