Zurzuvae: New Miracle Treatment for Postpartum Depression?

Unless you’ve been off the grid these past couple of months, you’re almost certainly aware of Zurzuvae (zuranolone), the new postpartum antidepressant pill recently approved by the FDA. As you might expect, the hype around the pill positions it as a new miracle drug for this serious maternal mental-health problem. Is Zurzuvae a miracle drug for postpartum depression?

In this blog post, I’ll cut through the hype to give you the facts. I’ll start by summarizing the two trials that prompted the FDA to give Zurzuvae the green light so you can see who the researchers studied, how the trials were set up, and what results they got. I’ll follow that with a list of questions I think are raised by the data that articles about the pill—well, all but one or two of them—don’t consider. I’ll end, as usual, with “Your Takeaway”: suggestions for what you can do with what you’ve learned from my discussion.

The Research Used in Determining FDA Approval

The Setup

The drug’s manufacturer conducted two trials in which participants were assigned by chance to either Zurzuvae or a placebo, one of which evaluated taking a 30 mg daily dose (153 participants) and the other a 50 mg dose (196 participants).^{6, 7} Treatment consisted of 14 days of a pill taken daily in the evening with food.

All participants were experiencing major depressive disorder, defined as a score of 26 points or above on the Hamilton Rating Scale for Depression (HAMD), who had onset of depression in the third trimester or within 4 weeks of giving birth. Participants could be taking other antidepressant medication (15% in the 50 mg trial; 19% in the 30 mg trial), and they could not be breastfeeding because Zurzuvae passes into breast milk, and the effects on the baby are unknown.⁸

Improvement was measured by a decrease in the HAMD score as well as score improvements on various other rating scales for depression, anxiety, and health.

Effectiveness

Zurzuvae worked rapidly to reduce depression scores in both trials,^{6, 7} although interesting to note is that participants receiving the placebo pill also had a strong response. Also interesting to note, is that the lower dose was as effective as the higher dose.

Change from baseline as measured on Day 15, the day after the last dose:

• 50 mg dose
  • -15.6 points Zurzuvae
  • -11.6 points placebo
  • difference: -4.0 points
• 30 mg dose
  • -17.8 points Zurzuvae
  • -14.4 points placebo
  • difference: -4.2 points

Change from baseline as measured on Day 45, the last day of follow up:

• 50 mg dose
  • -17.9 points Zurzuvae
  • -14.4 points placebo
  • difference: -3.5 points
• 30 mg dose
  • -19.1 points Zurzuvae
  • -15.0 points placebo
  • difference: -4.1 points

Day 45 percentage of participants achieving remission (HAMD score of 7 or less):

• 50 mg dose
  • 44 percent Zurzuvae
  • 29 percent placebo
  • difference: 15 percentage points
• 30 mg dose
  • 53 percent Zurzuvae
  • 30 percent placebo
  • difference: 23 percentage points

Zurzuvae also improved anxiety scores at both dosages compared with those taking the placebo pill. The 50 mg trial notes a score reduction on Day 15 on the anxiety component of the HAM scale (-12.8 points versus -10.6, difference -2.2),⁷ and a follow-up analysis of the 30 mg trial reports that Zurzuvae reduced anxiety and insomnia according to various scales evaluating these symptoms.⁵

Adverse Effects

Zurzuvae is no lightweight drug as you can see by this table of percentages of participants experiencing adverse effects. Interesting to note here is that in addition to being equally effective, the 30 mg dose was also less likely to produce somnolence (drowsiness), dizziness, or sedation (slower reaction time and impaired performance).^{6, 7}

In light of these adverse effects, the FDA patient information guideline warns:⁸ 

Unanswered Questions

So, after reviewing the trials and the FDA’s Prescribing Information document, here are some questions that occurred to me. Looking first at questions about Zurzuvae’s benefits:

• What would the gap between Zurzuvae and control group have been had the control group also received treatment? The control group received a dummy pill but no other treatment. What if the control group had received a non-drug therapy such as counseling or “listening visits”? Research has shown these to be effective at relieving postpartum depression:¹³

Women with mild to moderate depression should be informed that there is no current evidence to suggest a clear difference between the effectiveness of antidepressants and psychological-psychosocial treatments.

Interestingly, in the discussion section of one of the trials,⁷ the researchers theorize that one reason why recipients of the dummy pill may also have had a strong response is the attention they received because of the high frequency of visits necessitated by participation in the study. How much stronger might the control group’s response have been had those visits not just been for evaluation but had included care?

• What would the gap between Zurzuvae and control group have been had the control group received care that addressed psychological and social factors known to cause postpartum depression and anxiety? Postpartum depression and anxiety can originate in biologic factors (the upheaval in hormones that occurs after birth, genetic predisposition), and it can also arise from the psychosocial stresses of new motherhood (feeling overwhelmed by the demands of parenting, financial worries, needing to return to work before ready, lack of social support).¹⁴ Medical management thinking, however, only acknowledges the biologic factors, although most postpartum depression and anxiety is probably caused by an interaction between the two. This means that Zurzuvae, as do all other antidepressants, treats symptoms by manipulating brain chemistry to reduce depression and anxiety but does nothing to address the causes—or at least not all of the causes—that lead to experiencing those symptoms. How many new mothers wouldn’t develop depression or anxiety, or if they did, would be able to manage their symptoms without medication, were they provided guidance, support, and financial assistance? The predicted cost of a course of treatment with Zurzuvae is $35,000.⁹ What could be done if that money were used to alleviate some of the psychosocial stresses instead?

There’s something else too: postpartum anxiety, like depression, arises from external as well as internal sources. One external source is childbirth-related posttraumatic distress, including full-blown PTSD. Posttraumatic distress is its own entity and is as common as depression in postpartum mothers.² Childbirth-related psychological trauma is linked to treatment during childbirth.^{1, 4, 12} Making anxiety a collateral symptom of depression and ignoring its origins does two things: first, it deprives women and birthing people of a correct diagnosis and therefore appropriate treatment, and second, it renders invisible the culpability of the maternity care system in causing—or contributing to causing—posttraumatic distress.

• What would the gap between Zurzuvae and control group have been had the trials included participants with moderate or mild depression? Zurzuvae has been approved for “postpartum depression,” but the trials included only those experiencing major postpartum depression. These would likely have been people predisposed to depression and therefore particularly vulnerable to the stresses of new parenthood. Considering the improvement in scores in participants with major depression even in the control group, who received no treatment, how much would those with lesser degrees of depression stand to benefit from taking Zurzuvae compared with treatments with lesser or no side effects?
• What are the long- or even medium-term benefits of Zurzuvae treatment? Follow up ended 30 days after taking the last pill. Might depression and anxiety rebound—especially considering that underlying contributors to depression and anxiety were not addressed?

So much for benefits. Now let’s turn to adverse effects:

• What is the potential impact of stopping breastfeeding in order to take this medication? The obvious impact is the lose-lose choice between taking on the additional stress of pumping and discarding the milk during the two-week treatment and risking that the baby will be unwilling to return to the breast when breastfeeding is reintroduced or giving up breastfeeding permanently, thereby depriving both mother and child of its benefits. But there is a less well-known effect as well: breastfeeding and bed sharing have been shown to decrease depression and anxiety and improve sleep duration compared with formula feeding and sleeping apart from the baby.¹⁰ Stopping breastfeeding means ceasing a “treatment,” if you will, that helps to prevent depression, anxiety, and insomnia—the same symptoms Zurzuvae treats—while providing important additional benefits and having no adverse effects.
• What is the potential impact of the 12-hour driving prohibition after taking the pill? The FDA has made the prohibition against driving a “black box” warning in its Prescribing Information document and notes that those taking it may be unable to assess their driving competence.⁸ How might that prohibition increase the stress of carrying out daily life activities?
• What is the potential impact of possibly experiencing, as the FDA’s patient information document stated: “sleepiness, drowsiness, slow thinking, dizziness, confusion, and trouble walking” on the ability to care for a newborn and possibly other children and to carry out household or work responsibilities?⁸ How much might those difficulties add to the stresses of navigating new parenthood?
• What about possible rarer, severe consequences of Zurzuvae treatment or potential problems for which follow up was too short? The trials were too small to provide data on the occurrence of rarer, severe adverse effects. For example, the FDA warns about increased risk of suicidal thoughts.⁸ The FDA also advises doctors that Zurzuvae has the potential for “misuse, abuse, and substance use disorder including addiction” and that its use “is associated with the potential for physical dependence.” We won’t know about these until large numbers of people have taken Zurzuvae, which will take time. In the meantime, how does knowing that these possibilities exist affect consideration of the benefit versus risk ratio in deciding whether to take this drug?
• What might be the unintended consequences of taking a medication that works by modulating a neurotransmitter that is created from progesterone?¹¹ Interference in the complex web of interactions that regulate physiologic processes always has high potential for adverse effects. In the case of major depression not responding to other treatment, interference may be warranted, but what about when this is not the case?

In Conclusion

Medications shouldn’t be the first or only line of treatment for mental health conditions. . . . PPD is not just a biological or an individual issue but a culmination of complex interactions between gender roles, societal expectations, and systemic inequalities. Social cultural and structural factors contribute to women’s overall health experiences, including PPD, and these factors influence the prevalence, diagnosis, presentation, management, and access to treatment for this condition. Before prescribing [Zurzuvae] to a perinatal woman, . . . biopsychosocial factors need to be addressed.³

Your Takeaway

So, what have you learned here that you can put to practical use?

Psychosocial factors as well as biologic factors contribute to the onset of postpartum depression and anxiety. You can’t do much about the biologic contributors, but you can be proactive about the external stressors. What can you plan for and arrange ahead of time that will help minimize the stresses of recovery from childbirth and life with a new baby?

Breastfeeding and bed sharing reduce depression and anxiety and promote better sleep. Get educated about breastfeeding, including how to breastfeed, best practices, and the tips and tricks of the trade for dealing with the difficulties that may crop up. Line up where you will seek help if it turns out you need more expert assistance. As for bed sharing, bed sharing has an undeserved negative reputation. In this blog post, I provide research-based information on bed sharing, breastfeeding, and maximizing sleep.

Zurzuvae is a powerful drug with adverse effects that are problematic for life with a new baby, and taking it may deprive mother and child of the benefits of breastfeeding. If you have decided to take an antidepressant medication, consider the benefits versus risks in making a choice among your options.

According to the trials, the 30 mg dose of Zurzuvae is as effective as the 50 mg dose in treating depression and is less likely to produce adverse effects. If you have decided to take Zurzuvae and your doctor is recommending the 50 mg dose, ask what the advantages are of taking the higher dose.

References

1. Andersen LB, Melvaer LB, Videbech P, et al. Risk factors for developing post-traumatic stress disorder following childbirth: A systematic review. Acta Obstet Gynecol Scand 2012.
2. Beck CT, Gable RK, Sakala C, et al. Posttraumatic stress disorder in new mothers: results from a two-stage U.S. national survey. Birth 2011;38(3):216-27.
3. Blanc J. The new postpartum depression pill is not a panacea. MedPage Today Aug 9, 2023.
4. Carter J, Bick D, Gallacher D, et al. Mode of birth and development of maternal postnatal post-traumatic stress disorder: A mixed-methods systematic review and meta-analysis. Birth 2022;49(4):616-27.
5. Deligiannidis KM, Citrome L, Huang MY, et al. Effect of Zuranolone on Concurrent Anxiety and Insomnia Symptoms in Women With Postpartum Depression. J Clin Psychiatry 2023;84(1).
6. Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, et al. Effect of Zuranolone vs Placebo in Postpartum Depression: A Randomized Clinical Trial. JAMA Psychiatry 2021;78(9):951-9.
7. Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the Treatment of Postpartum Depression. Am J Psychiatry 2023;180(9):668-75.
8. Full Prescibing Information for Zurzuvae. 2023. (Accessed Aug 5, 2023, at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217369s000lbl.pdf.)
9. Howard J. Drugmakers adjusting their ‘thinking on price’ of first postpartum depression pill approved in US. CNN Aug 8, 2023.
10. Kendall-Tackett K. The impact of feeding method and infant sleep location on mother/infant sleep, maternal depression, and mothers’ well-being. Clinical Lactation 2018;9(3):117-23.
11. McNamara D. Experts highlight benefits and offer caveats for first postpartum depression pill. In: Medscape; Aug 9, 2023.
12. Mohamoud YA, Cassidy E, Fuchs E, et al. Vital Signs: Maternity Care Experiences – United States, April 2023. MMWR Morb Mortal Wkly Rep 2023;72(35):961-7.
13. Molyneaux E, Howard LM, McGeown HR, et al. Antidepressant treatment for postnatal depression. Cochrane Database Syst Rev 2014(9):CD002018.
14. Yim IS, Tanner Stapleton LR, Guardino CM, et al. Biological and psychosocial predictors of postpartum depression: systematic review and call for integration. Annu Rev Clin Psychol 2015;11:99-137.