A New Treatment Could Offer Lasting Relief for Individuals With Postpartum Depression

The arrival of a new child can be an emotional roller coaster for any parent. However, for some individuals, this time marks the beginning of a serious struggle with postpartum depression. The Centers for Disease Control and Prevention (CDC) estimates that 1 in 8 women in the United States experience symptoms of depression in the weeks following childbirth.

A new medication known as zuranolone, expected to become available as early as October 2023 under the brand name Zurzuvae, could offer lasting relief to these patients. The Food and Drug Administration (FDA) granted approval of the medication to manufacturers Sage Therapeutics on August 4, 2023, following two multicenter clinical trials of the drug.

“This drug has the potential to change the way we treat postpartum depression,” says Lisa Boyars, MD, a perinatal and reproductive psychiatrist in both Women’s Reproductive Mental Health of Texas within UT Health Austin’s Mulva Clinic for the Neurosciences and the Comprehensive Fetal Care Center, a clinical partnership between Dell Children’s Medical Center and UT Health Austin.

As a perinatal and reproductive psychiatrist, Dr. Boyars specializes in mood and anxiety disorders that may emerge during pregnancy or shortly after childbirth, a span of time collectively known as the perinatal period.

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<br>Making Hormonal Fluctuations Manageable

Postpartum depression is thought to result from a person’s response to changing hormonal levels before and after childbirth. Beginning in the first trimester, the steroid hormones progesterone and estrogen are produced in high levels to support a healthy pregnancy.

“Once the baby is delivered, the mother’s progesterone and estrogen levels plummet,” explains Dr. Boyars. “While these huge hormonal shifts are a typical part of childbirth, people with a heightened sensitivity to these changes may develop postpartum depression.”

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<br>Zuranolone is designed to counteract the mood-related effects of these hormonal fluctuations. This medication is a synthetic form of allopregnanolone, a naturally occurring byproduct of progesterone that is also in low supply during the postpartum period. Allopregnanolone belongs to a class of steroid-based compounds known as neuroactive steroids, which play a role in nervous system activity.

Allopregnanolone acts on certain neurons (brain cells) known as GABA_A receptors, making them more responsive to a molecule called GABA. As the body’s main inhibitory neurotransmitter, GABA prevents neurons from firing. This reduced signaling can alleviate anxiety. Other drugs that work on the GABA pathway include alcohol and benzodiazepines.

“For some time, scientists have known that allopregnanolone is involved in mood and anxiety,” notes Dr. Boyars. “By helping restore allopregnanolone levels, zuranolone eases the mental and emotional effects of decreased progesterone.”

Participants in the two national clinical trials of zuranolone reported a significant reduction in depression symptoms after taking the medication daily for two weeks, with a marked improvement in symptoms observed after just three days. Additionally, the positive effects of zuranolone were still noted four weeks after participants completed the medication regimen.

Researchers closely monitored trial participants for evidence of any negative health outcomes related to zuranolone, and most side effects reported by participants were either mild or moderate.

Side effects of zuranolone may include:

• Diarrhea
• Dizziness
• Drowsiness
• Headache
• Increased risk of urinary tract infection

Faster, More Convenient Depression Relief

Based on this evidence about zuranolone’s safety and effectiveness, the drug may offer several advantages over existing treatments for postpartum depression. Currently, most people who choose to manage their postpartum depression with medication are prescribed selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, sertraline, citalopram, or paroxetine. SSRIs affect brain signaling pathways involving another inhibitory neurotransmitter called serotonin, which plays a crucial role in mood regulation.

Unfortunately, these medications may not translate to a meaningful improvement in depression symptoms for weeks. Patients often must adjust their medication dose after beginning SSRI treatment, further delaying the optimal effects of these drugs.

“It can take one or two months for someone to achieve symptom remission with an SSRI,” says Dr. Boyars. “For people who are suffering, that’s a long time to wait.”

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<br>The introduction of brexanolone, the first drug specifically approved by the FDA to treat postpartum depression, represented a breakthrough in peripartum psychiatry. Like zuranolone, brexanolone harnesses allopregnanolone to offer rapid improvements in depressive symptoms that last after the treatment regimen is completed. However, brexanalone, which first became available to patients in 2021, must be delivered intravenously over a 60-hour period. “Very few hospitals nationwide offer the treatment, so it is not easily accessible to most persons who may need it,” notes Dr. Boyars.

In contrast, zuranolone is an oral medication taken once a day for two weeks, offering a more convenient experience for both patients and healthcare providers. “The 60-hour brexanalone infusion period is certainly shorter than the 14 days that patient must take zuranolone,” says Dr. Boyars. “However, with zuranolone, a patient does not need to live near or travel to one of the few centers that offer the infusion treatment.”

Balancing Enthusiasm and Uncertainty

While zuranolone presents an attractive option for patients seeking postpartum depression treatment, its overall effect on depression symptoms has not yet been compared directly to that of brexanolone ­or SSRIs. Additionally, the implications of Zuranolone on a parent’s decision to breastfeed are unclear. Small but significant amounts of allopregnanolone were detected in breast milk samples provided by clinical trial participants, who were asked not to breastfeed their children while undergoing the experimental treatment. Further investigation is needed to understand how allopregnanolone intake via breast milk could affect a child’s health.

“Patients considering zuranolone should speak with their provider to determine whether to breastfeed or provide their baby formula on the days they take the medication,” advises Dr. Boyars.

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<br>Questions also remain about the treatment’s accessibility to patients. Before the drug becomes available to the public, the Drug Enforcement Agency (DEA) must classify zuranolone within its five-tier schedule system for controlled substances. A drug’s ranking is determined by its acceptance as a medical treatment and potential for abuse. The placement of zuranolone within the schedule system will determine how prescriptions of the drug are regulated under federal law.

The cost of zuranolone and the extent to which insurance companies will cover this cost are still unknown. “I am a little bit cautious in my excitement for this medication, because I don’t know if it will be affordable for the average patient who needs it,” shares Dr. Boyars.

Broader Implications for Mental Health Care

Alongside further investigation comparing zuranolone with other postpartum depression treatments, researchers are working to determine whether the drug could treat PTSD and major depressive disorder (MDD) in adult and adolescent patients regardless of sex. Although the FDA did not approve zuranolone for MDD alongside its approval for postpartum depression in August 2023, researchers like Dr. Boyars are optimistic about the potential of the drug and other similar compounds.

“I predict that neuroactive steroids will be used to treat an increasing number of conditions in the near future,” says Dr. Boyars. “This is an exciting time not just for perinatal and reproductive psychiatrists, but for the field of psychiatry as a whole.”

For more information or to schedule an appointment with Women’s Reproductive Mental Health of Texas, call 1-833-UT-CARES (1-833-882-2737) or visit here.

For more information or to schedule an appointment with the Comprehensive Fetal Care Center, call 1-512-324-0040 or visit here.