Zulresso (Brexanolone) First Drug Approved by the FDA Specifically for Postpartum Depression in Adults

Approximately 11% of women in the United States have postpartum depression, a common condition that occurs after giving birth that is associated with serious adverse outcomes for mothers and their infants.¹ Multiple factors are implicated in postpartum psychiatric disorders, including neurotransmitter and neuroendocrine changes, hormonal alterations, genetic and epigenetic features, psychosocial patterns (ie, stressors), and sleep deprivation or disruption.^2,3

Postpartum depression can have a substantial adverse impact on the health of mothers and infants, including inadequate bonding between the mother and her baby and deficient breastfeeding motivation and duration, which can affect the infant’s cognitive and behavioral development.^1,2 For individuals with postpartum depression, feelings of sadness, worthlessness, and anxiety can be extreme, leading to undue anger, poor eating habits, withdrawal from friends and family, and in some cases, self-harm or suicidal ideation.^2,4

Postpartum depression remains undiagnosed in nearly 60% of women with depressive symptoms, and up to 50% of those who are diagnosed with this condition do not receive treatment.¹ Left untreated, post­partum depression can persist for months or years.⁴ Screening for depressive symptoms is crucial to detect patients who are at risk. Recommendations for screening, appropriate treatment, and follow-up have been issued by the American College of Obstetricians and Gynecologists, the US Preventive Services Task Force, and other organizations.^1,5,6

The traditional treatments for postpartum depression may include pharmacologic therapy (antidepressants and, in some cases, mood stabilizers), hormone therapy, and/or interpersonal or behavioral therapy.^4,7 Treatment barriers include the potential effect of medication on breast milk, the patient’s perceived stigma about seeking help (reflection of mothering skills, ability to care for the child), and disparities that limit the patient’s access to effective treatment.^7,8 Recently, a novel therapy became available specifically for the treatment of postpartum depression.

FDA Approves Brexanolone for Postpartum Depression

On March 19, 2019, brexanolone (Zulresso; Sage Therapeutics) became the first drug to be approved by the US Food and Drug Administration (FDA) specifically for the treatment of postpartum depression in adults.⁹

Brexanolone, a neuroactive steroid gamma-amino­butyric acid (GABA)A receptor–positive modulator, was granted a priority review and was designated a breakthrough treatment by the FDA.^9,10 Brexanolone is available only through a Risk Evaluation and Mitigation Strategy (REMS) program and must be administered at a certified healthcare facility; in addition, patients must be monitored continuously during the infusion of the drug because of the risk for serious side effects.⁹

Commenting on the approval of brexanolone, Samantha Meltzer-Brody, MD, MPH, Ray M. Hayworth and Family Distinguished Professor of Mood and Anxiety Disorders; Director, Perinatal Psychiatry Program, University of North Carolina at Chapel Hill Center for Women’s Mood Disorders; and the primary investigator of its clinical trials, stated, “Today’s approval of Zulresso represents a game-changing approach to treating PPD [postpartum depression].” She added, “The potential to rapidly reduce symptoms in this critical disorder is an exciting milestone in women’s mental health. PPD is recognized to have a significant and long-term impact on women and their families, but with Zulresso we may finally have the opportunity to change that.”¹¹

Mechanism of Action

GABA signaling, neuroendocrine factors (ie, hypothalamic-pituitary-adrenal axis and epigenetic changes), and perinatal hormone variations may play a role in the pathophysiology of postpartum depression.^2,3,8 The precise mechanism of action of brexanolone, a GABAA receptor–positive modulator, as a treatment for postpartum depression is not fully understood, but it may be linked to the drug’s positive allosteric modulation of GABAA receptors.¹⁰

Dosing and Administration

Brexanolone injection is available as a 100-mg/20-mL (5-mg/mL) single-dose vial. Dilution is required before brexanolone is administered.¹⁰

For the duration of the brexanolone infusion, a healthcare provider must be on site to monitor the patient continuously and intervene if needed.¹⁰

Brexanolone is administered as a continuous intra­venous infusion over 60 hours (2.5 days). From 0 to 4 hours, the initial dose of brexanolone is 30 mcg/kg per hour; from 4 to 24 hours, the dose is increased to 60 mcg/kg per hour; from 24 to 52 hours, the dose is increased to 90 mcg/kg per hour (or, for patients unable to tolerate the 90-mcg/kg dose, a dose of 60 mcg/kg per hour can be considered). From 52 to 56 hours, the dose is decreased to 60 mcg/kg per hour; and from 56 to 60 hours, the dose is decreased to 30 mcg/kg per hour.¹⁰

Pivotal Clinical Studies

The efficacy of brexanolone was demonstrated in 2 randomized, double-blind, placebo-controlled phase 3 clinical trials—Study 1 (N = 122) and Study 2 (N = 104)—in women with postpartum depression who met the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria for a major depressive episode with the onset of symptoms in the third trimester or within 4 weeks of delivery.^8,10 Eligible patients (aged 18-45 years; median age, 28 years) received a 60-hour continuous intravenous infusion of brexanolone or placebo and were followed for 4 weeks.^8,10 At baseline, 23% of patients were receiving oral antidepressants.¹⁰

The primary efficacy end point in both studies was mean change in depressive symptoms at 60 hours, as measured by the Hamilton Depression Rating Scale.^8,10 Both studies assessed a titration to the recommended target dose of 90 mcg/kg per hour, in which patients received 30 mcg/kg per hour for 4 hours, 60 mcg/kg per hour for 20 hours, and 90 mcg/kg per hour for 28 hours, followed by a taper to 60 mcg/kg per hour for 4 hours and then 30 mcg/kg per hour for 4 hours. Study 1 also evaluated a titration to a target dosage of 60 mcg/kg per hour.¹⁰

In both studies, brexanolone titrated to a target dose of 90 mcg/kg per hour was significantly superior at improving depressive symptoms compared with placebo (Table). Brexanolone titrated to a target dose of 60 mcg/kg per hour (Study 1) was also significantly superior to placebo in symptom improvement.^8,10 Moreover, improvement was observed within 24 hours and was sustained through the end of the 30-day follow-up period.¹⁰

Adverse Events

The most common adverse events (incidence ≥5% and at least twice the rate of placebo) reported with brexanolone at doses of 60 mcg/kg per hour and 90 mcg/kg per hour were sedation or somnolence (21% and 13%, respectively), dry mouth (11% and 3%, respectively), loss of consciousness (5% and 3%, respectively), and flushing or hot flush (5% and 2%, respectively).¹⁰

In pooled, placebo-controlled clinical trials, 7% of patients receiving brexanolone had an interruption or reduction in dose because of any adverse event versus 3% of patients receiving placebo.¹⁰

Brexanolone has no contraindications.¹⁰

Drug Interactions

The concomitant use of brexanolone with central nervous system depressants (eg, benzodiazepines, opioids) may increase the risk for or severity of sedation-­related adverse reactions.¹⁰

Based on placebo-controlled clinical trials, patients receiving brexanolone concomitant with antidepressant therapy are at an increased risk for sedation-related events.¹⁰

Use in Specific Populations

Brexanolone may cause fetal harm, based on studies of other drugs that enhance GABAergic inhibition. Data on the use of brexanolone in pregnant women are insufficient to establish its potential risk for birth defects, miscarriage, or adverse fetal or maternal effects.¹⁰

Brexanolone can be transferred to breast milk in nursing mothers; there were no reports on the effects of brexanolone on milk production. Data are not available on the effects of brexanolone on the breastfed infant. The benefits of breastfeeding should be weighed against the mother’s need for brexanolone and any potential adverse effects of brexanolone on the breastfed child or from the mother’s underlying condition.¹⁰

No dose adjustment of brexanolone is required for patients with hepatic impairment or with mild, moderate, or severe renal impairment; however, brexanolone should not be used in patients with end-stage renal disease.¹⁰

Warnings and Precautions

Brexanolone has a boxed warning about the risk for excessive sedation or sudden loss of consciousness during the administration of the drug. Patients must be monitored for excessive sedation and the sudden loss of consciousness and have continuous pulse oximetry monitoring; in addition, the patient must be accompanied during interactions with their children. Brexanolone is available only through a restricted REMS program.¹⁰

Excessive sedation, somnolence, and loss or altered state of consciousness were reported during the infusion of brexanolone in clinical studies. Patients should be monitored for sedative effects every 2 hours during planned nonsleep periods of brexanolone infusion; the infusion should be stopped immediately if the patient shows signs or symptoms of excessive sedation. Once symptoms resolve, the infusion may be resumed at the same or at a lower dose.¹⁰

If the patient’s pulse oximetry shows hypoxia, the infusion should be stopped immediately and should not be resumed.¹⁰

For patients whose postpartum depression worsens or those who have emergent suicidal thoughts and behaviors, the therapeutic regimen of brexanolone may require adjustment or discontinuation.¹⁰

Conclusion

Brexanolone, a GABAA receptor–positive modulator, became the first treatment to receive FDA approval specifically for women with postpartum depression, a serious complication of childbirth. In 2 pivotal clinical trials, brexanolone demonstrated significant and rapid improvement in the symptoms of postpartum depression. Moreover, the treatment response with brexanolone was sustained through the 30-day follow-up period.

References

1. Ko JY, Rockhill KM, Tong VT, et al. Trends in postpartum depressive symptoms—27 states, 2004, 2008, and 2012. MMWR Morb Mortal Wkly Rep. 2017;66:153-158.
2. Payne JL, Maguire J. Pathophysiological mechanisms implicated in postpartum depression. Front Neuroendocrinol. 2019;52:165-180.
3. Meltzer-Brody S, Howard LM, Bergink V, et al. Postpartum psychiatric disorders. Nat Rev Dis Primers. 2018;4:18022.
4. National Institute of Mental Health. Postpartum depression facts. NIH Publication No. 13-8000. Accessed June 12, 2019.
5. Committee on Obstetric Practice. ACOG Committee Opinion number 757: screening for perinatal depression. Obstet Gynecol. 2018;132:e208-e212.
6. Siu AL; US Preventive Services Task Force. Screening for depression in adults: US Preventive Services Task Force recommendation statement. JAMA. 2016;315:380-387.
7. Fitelson E, Kim S, Baker AS, Leight K. Treatment of postpartum depression: clinical, psychological and pharmacological options. Int J Womens Health. 2011;3:1-14.
8. Meltzer-Brody S, Colquhoun H, Riesenberg R, et al. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-­controlled, phase 3 trials. Lancet. 2018;392:1058-1070. Erratum in: Lancet. 2018;392:1116.
9. US Food and Drug Administration. FDA approves first treatment for post-partum depression. March 19, 2019. www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-post-partum-depression. Accessed June 10, 2019.
10. Zulresso (brexanolone) injection, for intravenous use [controlled substance schedule pending] [prescribing information]. Cambridge, MA: Sage Therapeutics; March 2019.
11. Sage Therapeutics. Sage Therapeutics announces FDA approval of Zulresso (brexanolone) injection, the first and only treatment specifically indicated for postpartum depression. March 19, 2019. https://investor.sagerx.com/news-­releases/news-release-details/sage-therapeutics-announces-fda-approval-zulressotm-­brexanolone. Accessed June 13, 2019.