Taken from the March/April 2019 issue of The Women’s Health Activist Newsletter.

Last November, the Food and Drug Administration’s (FDA) Reproductive Health Drugs Advisory Committee voted overwhelmingly in favor of brexanolone, a first-of-its-kind treatment for postpartum depression (PPD).[1] [2] We question whether brexanolone will help mothers or if it’s a misdirected silver bullet for a larger, more insidious problem: lack of support during the postpartum period. Brexanolone, developed by Sage Therapeutics, was initially tested—and failed—as a treatment for a dangerous kind of seizure called status epilepticus.[3] In 2016, the FDA gave brexanolone “breakthrough designation”[4] (which speeds the approval process to address “significant unmet need”[5]) for PPD treatment. Brexanolone’s evaluation by the Advisory Committee indicates, however, that the FDA wasn’t comfortable approving it without external advice.

PPD is characterized by a feeling of hopelessness lasting more than two weeks after giving birth; 1 in 9 new mothers suffers from PPD.[6] Countries with higher rates of income inequality, maternal and infant mortality, or where reproductive-age women work more than 40 hours a week, have higher PPD rates. A systematic review of studies from 56 countries found that PPD’s prevalence internationally was 17.7%, ranging from 3% in Singapore to 38% in Chile.[7] The U.S. rate is 11.5%,[8] although multiple speakers at the FDA hearing erroneously claimed a 20% prevalence rate (a rate also cited in brexanolone’s clinical trial).

Severe PPD is serious and far less common than the “baby blues” (sadness that lasts three to five days after childbirth and affects up to 80% of new mothers).[9] But, many mental health conditions are ripe for “diagnostic creep,”[10] which blurs lines between normal function and pathology, expanding the pool of candidates for medical treatment. The baby blues and PPD are ripe for this subtle erasure of differences between conditions. In 2017, Sage Therapeutics launched a PPD “disease awareness” campaign with the slogan “Silence Sucks,” which showed women sucking on pacifiers and encouraged mothers to talk about PPD.[11] The website has since been removed and is inaccessible.

The current standard of care for PPD is a combination of talk therapy and antidepressants—usually inexpensive, generically available medications that have been used for decades.[12] In contrast, brexanolone has been studied in relatively few women. The efficacy studies tested 2 doses on 226 women with moderate or severe PPD (213 women completed the trial). The studies found modest but significant improvement for brexanolone compared to placebo. The trial actually included two studies, however, with inconsistent results at day 30: one study showed a benefit while the other did not. Sage’s CEO defended brexanolone in a call with investors, stating: “The placebo response was more volatile, which accounted for the inability to show a durable benefit in the moderate study.” In other words, the placebo worked too well, putting the drug at a disadvantage.

Adverse events were more common in the brexanolone group than placebo group, including headaches, dizziness, nausea, infusion site pain, somnolence, and fatigue. Three severe adverse events occurred, including altered state of consciousness, severe headaches, and fainting; two patients terminated treatment due to these adverse effects.[13]

These serious adverse effects explain why women must be hospitalized to receive brexanolone, given through a continuous 60-hour intravenous infusion.[14] [15] The impracticalities are obvious: families with a new baby might struggle with child care and logistics for a three-day hospital stay. The cost of the hospitalization and medication may be tens of thousands of dollars. Further, how much of brexanolone’s benefit stems from three days away from the baby, having meals in bed, and not doing housework?

Sage is currently developing a pill form of brexanolone, but it’s not yet determined if the same adverse events will occur when a woman receives treatment at home.[16] The effect on breastfeeding babies is also unknown; women were not allowed to breastfeed during this study.

Two Advisory Committee members voted against the proposition that SAGE had adequately described brexanolone’s safety for treating PPD, citing concerns about the loss of consciousness events.[17] Most speakers providing public comment had their travel to the meeting funded by Sage. Although these financial relationships were disclosed, disclosure does not erase bias.

When a pharmacologic intervention is touted as the solution for PPD, mothers and advocates alike should consider if the drug is a BandAid on the larger wound of America’s treatment of  mothers. How would PPD rates be affected if we adopted policies that support parents, like subsidized child care, paid parental leave, and health care norms that center mothers’ choices in childbirth and the postpartum period?

Massachusetts has a PPD program that leverages care providers, psychiatric screenings, and community resources.[18] New York and other jurisdictions have set promising precedents by experimenting with public funding for doula services to reduce adverse childbirth outcomes.[19] Expanding access to postpartum doulas[20]—nonmedical professionals trained to help families through the transitional period with a new baby—may not be far behind, as awareness grows about PPD and doula care.

Besides brexanolone’s dubious efficacy, it’s worth considering the hospital costs, adverse effects, and whether we need a specific PPD drug when numerous antidepressants are already available.

More importantly, nonmedical solutions should be considered with equal—or greater—weight than medication. Pegging the complexities of a new mother’s adjustment as a mental illness ignores cultural factors that cause new parents to feel unsupported. Conversations about PPD should be broader than one drug. If brexanolone becomes PPD’s therapeutic norm, the onus of treatment will remain where it’s always been, on individual mothers—hardly a revolution in postpartum care.

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Sophie Krensky is the project manager and Olivia Shannon is a research intern at PharmedOut, a Georgetown University Medical Center project that promotes rational, evidence-based prescribing and conducts research on the pharmaceutical industry’s influence on medicine.

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References

[1] Shoot B, “The FDA Is Poised to Approve the First-Ever Postpartum Depression Drug.” Fortune, November 2, 2018. Online at: fortune.com/2018/11/02/fda-poised-to-approve-zulresso-brexanolone-postpartum-depression-drug/.

[2] Mathis MV, “Psychopharmacologic Drugs Advisory Committee (PDAC) and Drug Safety and Risk Management (DSaRM) Advisory Committee Meeting,” FDA [Food and Drug Administration] Briefing Document, Rockville (MD): FDA, November 2, 2018. Online at: www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM624643.pdf.

[3] MGH Center for Women’s Mental Health, Brexanolone: A New Drug for Postpartum Depression, Boston (MA): Harvard Medical School, June 11, 2018. Online at: www.womensmentalhealth.org/posts/brexanolone_new_drug_postpartum_depression/.

[4] Sage Therapeutics, Sage Therapeutics Submits New Drug Application to U.S. FDA for Intravenous Brexanolone in the Treatment of Postpartum Depression, Cambridge (MA): Sage Therapeutics, Inc., 23 April 23, 2018. Online at: investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-submits-new-drug-application-us-fda.

[5] Sage Therapeutics, Sage Therapeutics Submits New Drug Application to U.S. FDA for Intravenous Brexanolone in the Treatment of Postpartum Depression, Cambridge (MA): Sage Therapeutics, Inc., 23 April 23, 2018. Online at: investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-submits-new-drug-application-us-fda

[6] U.S. Office on Women’s Health (OWH), Postpartum Depression, Rockville (MD): OWH, October 18, 2018. Online at: www.womenshealth.gov/mental-health/mental-health-conditions/postpartum-depression.

[7] Hahn-Holbrook J, Cornwell-Hinrichs T, Anaya I, “Economic and Health Predictors of National Postpartum Depression Prevalence: A Systematic Review, Meta-analysis, and Meta-Regression of 291 Studies from 56 Countries,” Frontiers in Psychiatry 2018; 8(248): 1-23. doi:10.3389/fpsyt.2017.00248.

[8] Ko JY, Rockhill KM, Tong TV, et al., Trends in Postpartum Depressive Symptoms — 27 States, 2004, 2008, and 2012,” Morbidity and Mortality Weekly Report (MMWR) 2017 / 66(6);153–158. Online at: www.cdc.gov/mmwr/volumes/66/wr/mm6606a1.htm.

[9] National Institute of Mental Health (NIMH), Postpartum Depression Facts, Bethesda (MD): NIHM, no date. Online at: www.nimh.nih.gov/health/publications/postpartum-depression-facts/index.shtml.

[10] Moynihan R, “Caution! Diagnosis Creep,” Australian Prescriber 2016; 39(2): 30-1.

[11] Thielking M, “A Campaign to Raise Awareness of Postpartum Depression Hits a Nerve.” STAT, June 14, 2017. Online at: www.statnews.com/2017/06/14/sage-postpartum-depression/.

[12] U.S. Office on Women’s Health (OWH), Postpartum Depression, Rockville (MD): OWH, October 18, 2018. Online at: www.womenshealth.gov/mental-health/mental-health-conditions/postpartum-depression.

[13] MGH Center for Women’s Mental Health, Brexanolone: A New Drug for Postpartum Depression, Boston (MA): Harvard Medical School, June 11, 2018. Online at: https://womensmentalhealth.org/posts/brexanolone_new_drug_postpartum_depression/

[14] Joint Meeting of the Psychopharmacologic Drug Advisory Committee and Drug Safety and Risk Management Advisory Committee, “Brexanolone Injection, for Intravenous Use,” in Brexanolone Injection, IV Briefing Document, Joint Meeting of the Psychopharmacologic Drug Advisory Committee and Drug Safety and Risk Management Advisory Committee, November 2, 2018. Online at: www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM624646.pdf.

[15] Joint Meeting of the Psychopharmacologic Drug Advisory Committee and Drug Safety and Risk Management Advisory Committee, “Brexanolone Injection, for Intravenous Use,” in Brexanolone Injection, IV Briefing Document, Joint Meeting of the Psychopharmacologic Drug Advisory Committee and Drug Safety and Risk Management Advisory Committee, November 2, 2018. Online at: www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM624646.pdf.

[16] Feuerstein A, “Sage Therapeutics Pill Improves Postpartum Depression in Key Clinical Trial.” STAT, January 7, 2019. Online at: www.statnews.com/2019/01/07/sage-therapeutics-pill-improves-postpartum-depression-in-pivotal-clinical-trial/.

[17] Walker M, “FDA Panel Gushes Over Postpartum Depression Tx,” MedpageToday, November 2, 2018. Online at: www.medpagetoday.com/obgyn/pregnancy/76115.

[18] Clark K, Gessner JS, Bombaugh MC, “Massachusetts Postpartum Depression Program a Model for a National Plan,” STAT, January 9, 2017. Online at: www.statnews.com/2017/01/09/postpartum-depression-massachusetts/.

[19] Ferré-Sadurní L, “New York to Expand Use of Doulas to Reduce Childbirth Deaths,” The New York Times, April 22, 2018. Online at: www.nytimes.com/2018/04/22/nyregion/childbirth-death-doula-medicaid.html.

[20] Greenberg Z, “If Only Everyone Had a Postpartum Doula,” The New York Times, October 2, 2018. Online at: www.nytimes.com/2018/10/02/style/postpartum-doula.html.