Postpartum depression (PPD) is depression that occurs after giving birth for up to 12 months. It is a serious disorder affecting 10-20% of mothers (Khadka, 2024).

For most cases of mild to moderate postpartum depression, standard treatment with psychotherapy with or without an antidepressant works well. Treating severe PPD is more challenging. Fortunately, there is a new category of medication for PPD that is intended for severe PPD.

The newest one is zuranolone (trade name is Zurzuvae). Currently, “existing efficacy data are limited to individuals with severe postpartum depression, where long-term outcomes need further study” (Miller, 2025). It has a different mode of action than older antidepressants.

How does zuranolone work?

Multiple factors affect GABAa, a nerve receptor in the brain. This receptor is involved in the development of PPD and is a major target for treatment (Sharma, 2024). GABAa is the chief inhibitory neurotransmitter in the brain, which plays a significant role in maintaining balance in the activity of the brain.

Hormonal fluctuations in the brain play a role in the development of PPD. During pregnancy, the female hormones, estrogen and progesterone, rise to very high levels. After giving birth, the hormones drop rapidly because the placenta is their primary source. After birth, when the placenta detaches, the hormonal levels drop, which contributes to PPD (Dukic, 2014). These hormonal fluctuations include a derivative of the hormone progesterone, which may contribute to “symptoms such as depressed mood, irritability, and emotional lability” (Miller, 2025).

Older antidepressants such as SSRIs and SNRIs do not directly target the GABAa receptors. Zuranolone is a novel antidepressant that targets the GABAa receptors, so it plays a unique role in treating PPD. Zuranolone is the only oral antidepressant for PPD that activates GABAa receptors.

Is zuranolone effective for PPD?

Zuranolone was approved by the FDA in 2023 after research trials showed superior relief of depression symptoms compared to a placebo. Researchers compared baseline total scores on the 17-item Hamilton Depression Rating Scale at days 3, 15, 28, and 45. Zuranolone showed improvement as soon as day 3, which is much faster than older antidepressants (Deligiannidis & Meltzer-Brody, 2023).

It is well absorbed when given by mouth and has a half-life that enables it to be taken just once a day. Current guidelines recommend taking a 50 mg dose by mouth in the evening for 14 days. To be properly absorbed, it must be taken with a fatty meal (400 to 1,000 calorie meal with 15% to 50% fat). Zuranolone can be given alone or along with standard antidepressants such as an SSRI, e.g., sertraline.

Zuranolone should not be used along with minor tranquilizers such as alprazolam or with alcohol, as the combination can lead to impaired driving and other complex activities. It should also not be used during pregnancy because animal studies suggest potential fetal harm. This is important because many women who develop PPD have depression while pregnant, and it should not be used until after birth and before a new pregnancy is attempted.

Over time, it has been shown that the more severe the depression, the less effective zuranolone is, and the longer it takes to provide any relief. However, it remains more effective than a placebo.

Is zuranolone safe for breastfeeding?

Breastfeeding mothers with PPD want to know if taking zuranolone is safe for their baby. In one study, it was concluded that “zuranolone transfer into the breast milk of healthy, nonpregnant, lactating adult female participants was low: the estimated RID for 50 mg of zuranolone was < 1%, well below the <10% threshold generally considered compatible with breastfeeding” (Deligiannidis & Bullock, 2024). RID stands for the Relative Infant Dose, which compares the dose the infant receives to the mother’s dose.

What are the side effects?

Although zuranolone is generally well-tolerated, there are potential side effects. These include somnolence (15%), headache (9%), dizziness (8%), upper respiratory tract infection (8%), diarrhea (6%), and sedation (5%) (Richardson, 2025). Infants who are being breastfed should be monitored for sedation. However, there is no loss of consciousness in the mothers (unlike the older IV form of the medication), withdrawal symptoms, or increased suicidal ideation or behavior.

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There are other potential downsides to taking zuranolone. It tends to be sedating in a third of patients; it needs to be taken with a fatty meal before bedtime; and the wholesale cost is $15,900 for a 14-day treatment (Miller, 2025).

Summary

In summary, zuranolone is a novel, rapid-onset, oral antidepressant that is a welcome addition to our treatment options for postpartum depression. It is expensive. However, many insurers and Medicaid providers do cover it. Preauthorization and other restrictions are often required.