ZURZUVAE video library

Dr. Greg Mattingly, MD: Patients in the SKYLARK trial were randomized 1:1 to receive ZURZUVAE or placebo once daily for 14 days. The change from baseline in their total score for the HAMD-17 at day 15, following completion of the treatment course, was the primary endpoint. Change from baseline in HAMD-17 total scores at Days 3, 28, and 45 were among the key secondary endpoints.

ZURZUVAE demonstrated rapid improvement of PPD symptoms, with statistically significant improvement vs placebo at Day 15 and treatment effect seen as early as Day 3.

As you can see on this graph, at day 15, patients taking ZURZUVAE 50 mg had a statistically significant improvement in depressive symptoms as assessed by change from baseline in HAMD-17 total score compared with placebo.

We also saw statistically significant improvements at key secondary endpoints shown here, starting with a rapid improvement of PPD symptoms as early as Day 3.

This separation from placebo continued even after patients stopped taking ZURZUVAE.

Patients in the ZURZUVAE group showed a significant reduction in HAMD-17 total score vs placebo at Day 28 and at Day 45.

What could a 14-day treatment with reduction in depressive symptoms at Day 15, and as early as Day 3, mean for your patients?

Dr. Bessem Maximos, MD, MPH, FACOG: We have all acknowledged that PPD is a serious disease warranting urgent intervention, which is why I find the Day 3 symptom improvement data so compelling.

Dr. Danielle Johnson, MD, MHA, FAPA: An acute, 14-day treatment for PPD is an exciting option. What are your reactions, Dr. Mattingly?

Dr. Mattingly: Having a 14-day oral treatment option that is now FDA approved may offer hope for these patients.

Dr. Greg Mattingly, MD: ZURZUVAE® (zuranolone) is indicated for the treatment of postpartum depression in adults.

ZURZUVAE has a boxed warning related to impaired ability to drive or engage in other potentially hazardous activities.

ZURZUVAE causes driving impairment due to central nervous system, or CNS, depressant effects.

Advise patients not to drive or engage in other potentially hazardous activities until at least 12 hours after administration. Patients may not be able to assess their own driving competence, or the degree of impairment caused by ZURZUVAE.

In addition to driving impairment, ZURZUVAE can cause other CNS depressant effects such as somnolence, dizziness, and confusion, which may require dose reduction or discontinuation.

One case of confusional state was severe, and was also associated with somnolence, dizziness, and gait disturbance.

Patients taking ZURZUVAE may be at greater risk of falls. Other CNS depressants or drugs that increase zuranolone concentration may increase impairment of psychomotor performance or CNS depressant effects in ZURZUVAE-treated patients.

In pooled analyses of chronically administered antidepressant drugs, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 and younger was greater than in placebo-treated patients. Consider changing the therapeutic regimen, including discontinuing ZURZUVAE, in patients whose depression becomes worse or who experience emergent suicidal thoughts and behaviors.

Based on findings from animal studies, ZURZUVAE may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Also, please advise female patients of reproductive potential to use effective contraception while taking ZURZUVAE and for one week after the final dose.

Dr. Bassem Maximos, MD, MPH, FACOG: This table shows the most common adverse reactions occurring in at least 2% of patients with PPD treated with 50 mg of ZURZUVAE and greater than placebo. The most common adverse reactions occurring in greater than or equal to 5% of patients and greater than placebo were somnolence, dizziness, diarrhea, fatigue, and urinary tract infection.

Dose reduction due to adverse reaction occurred in 14% of patients who received ZURZUVAE 50 mg. The adverse reactions most frequently leading to dose reduction were somnolence and dizziness.

Discontinuation due to adverse reactions was 2% with ZURZUVAE 50 mg and 1% with placebo. The most common adverse reaction leading to treatment discontinuation in the ZURZUVAE group was somnolence.

Across the PPD clinical studies at all doses studied, serious adverse reactions included confusional state in 1% of patients.

As a treatment for women in the postpartum period, it is important to talk about lactation and breastfeeding data for ZURZUVAE. Data from a clinical lactation study indicated that ZURZUVAE was present in low levels in breast milk. This study evaluated the presence of ZURZUVAE in breast milk in 14 healthy women treated with ZURZUVAE 30 mg orally once daily for 5 days.

At Day 5, when ZURZUVAE reached steady state, the calculated maximum relative infant dose was <1%.

It is important to note that there was no data on the effects of ZURZUVAE on a breastfed infant and limited data on the effects on milk production.

When discussing the benefits and risks of breastfeeding when taking ZURZUVAE, it’s important to consider the developmental and health benefits of breastfeeding, along with the mother’s clinical need for ZURZUVAE.

It’s also important to consider any adverse effects on the breastfed child from ZURZUVAE or from underlying maternal conditions.

Dr. Mattingly: ZURZUVAE is a Schedule IV controlled substance. Remember to advise patients that ZURZUVAE has potential risks of misuse, abuse, and substance use disorder including addiction, and that ZURZUVAE may produce physical dependence.

Dr. Bassem Maximos, MD, MPH, FACOG: ZURZUVAE is an oral medication that is administered once-daily in the evening for a 14-day treatment course.

The FDA-recommended treatment dose for most patients is 50 mg, given as two, 25-mg capsules. Advise patients to take ZURZUVAE with fat-containing food to ensure adequate exposure to zuranolone. Some examples include cheese, peanut butter, eggs, and avocado, of course taking any food allergies into consideration. 

Some patients may experience CNS-depressant effects within that 14-day treatment course. If your patient experiences these effects, you have the option to reduce the dosage to 40 mg taken as two, 20-mg capsules once daily in the evening for the duration of the treatment course, or discontinue treatment. 

ZURZUVAE may be used alone or as an adjunct to oral therapy.

Dr. Greg Mattingly, MD: This is a treatment paradigm we haven’t seen before. After 14 days, your patients are finished taking ZURZUVAE.

Dr. Maximos: As an OB/GYN, I see those patients for a limited period of time after their delivery and even if treatment is initiated, many of them are lost to follow-up. 

The 14-day course fits within my practice because it is consistent with the timeframe which I'm treating these patients.

Dr. Mattingly: Having a 14-day oral treatment option that is now FDA approved may offer hope for these patients.

Dr. Danielle Johnson, MD, MHA, FAPA: Postpartum depression is unfortunately not uncommon. In fact, the symptoms of PPD are one of the most common medical complications related to pregnancy, so we need to be prepared to address it.

For a woman to meet DSM-5-TR diagnostic criteria for PPD, she must experience 5 or more of the symptoms listed in the manual within the same 2-week period, and the symptoms should represent a change from previous functioning. At least one of the symptoms should be depressed mood or loss of interest or pleasure. Her symptoms should cause significant distress or impairment in social, occupational, or other areas of functioning, and symptoms can’t be attributed to other causes.

PPD can present differently in different women. Women with PPD may experience emotional changes, such as depressed mood, loss of interest in daily activities, or feelings of worthlessness or guilt. They may also have cognitive changes, like challenges with thinking, concentrating, or making decisions. PPD can manifest with physical symptoms, including changes in sleep, weight or appetite, or energy levels. A woman with PPD may also have difficulties bonding with the infant, feel that she is unable to care for the infant, or have thoughts of harming herself or the infant.

These symptoms can be debilitating, and it’s important to address them as soon as we can.

Dr. Greg Mattingly, MD: What do you think are some of the most important things a provider can think about when they’re talking with their patients with PPD?

Dr. Johnson: Patients are relieved to know their symptoms are not uncommon and they are not alone. We need to give them reassurance they're not a bad mother, that it’s OK to ask for help, and that they can get better.

Dr. Mattingly: We want to take away the stigma by making sure our patients know that these symptoms are no one’s fault and that there are multiple treatment options that we can discuss to help get them better.

Dr. Greg Mattingly, MD: PPD can be a “perfect storm” of multiple factors contributing to a patient’s symptoms. Things like stress or a prior history of depression coupled with the rapid changes in hormones during the postpartum period may contribute to the symptoms we see in these patients.

Dr. Danielle Johnson, MD, MHA, FAPA: Stressors and changes in hormone levels have both been connected to changes in GABA signaling. When GABA signaling is thrown off balance, brain network connectivity can become dysregulated. We think this dysregulation could be a contributor to the depressive symptoms seen in PPD, along with a number of other proposed mechanisms.  

Dr. Mattingly: Now let’s talk about how we think ZURZUVAE works. We don’t fully understand the mechanism of action of ZURZUVAE. It is hypothesized that the mechanism of action is related to its positive allosteric modulation of GABA_A receptors.

With ZURZUVAE, we are not directly affecting monoamines.  This is a different way of approaching depressive symptoms.