The Medical Letter on Drugs and Therapeutics
Brexanolone (Zulresso) for Postpartum Depression
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Revised 8/9/19: The article was revised following scheduling of brexanolone as a schedule IV controlled substance by the DEA.
Summary: Brexanolone (Zulresso)
  • A GABAA receptor modulator, structurally identical to the endogenous neuroactive steroid allopregnanolone
  • First drug to be FDA-approved for treatment of PPD
  • Administered as continuous 60-hour IV infusion in a certified healthcare setting
  • Reduced depression symptoms at 60 hours significantly more than placebo in women with moderate to severe PPD
  • Reduced depression symptoms at 30 days significantly more than placebo in women with severe PPD, but not in those with moderate PPD
  • Can cause excessive sedation and sudden loss of consciousness; continuous supervision during administration is required
  • Five vials of brexanolone, the amount needed for a single treatment in women weighing <90 kg, cost $34,000

The FDA has approved the GABAA receptor modulator brexanolone (Zulresso – Sage Therapeutics) for IV treatment of postpartum depression (PPD). Brexanolone is the first drug to be approved by the FDA for this indication.

PPD — Postpartum depression may affect up to 20% of women after childbirth. It has been associated with impaired mother-infant bonding and with adverse effects on the cognitive, behavioral, and emotional development of the child.

Selective serotonin reuptake inhibitors (SSRIs) are generally used for initial treatment of moderate to severe PPD, but data on their efficacy for this indication are mixed and maximal effects are only achieved after several weeks of treatment. Serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants have also been used, but data on their efficacy are limited. Electroconvulsive therapy is rapid-acting and has been reported to be effective for treatment of refractory PPD.1

PHARMACOLOGY — Brexanolone positively modulates neuronal activation of inhibitory GABAA receptors. It is chemically identical to the endogenous neuroactive steroid allopregnanolone, the major metabolite of progesterone. Allopregnanolone levels rise during pregnancy, peak in the third trimester, and then drop sharply after parturition.2

CLINICAL STUDIES — Approval of brexanolone was based on the results of two randomized, double-blind, placebo-controlled trials in a total of 246 adult women who were ≤6 months postpartum and had experienced an onset of major depressive symptoms during the third trimester or ≤4 weeks after delivery. Women in Study 1 had severe PPD (defined as a Hamilton Depression Rating Scale [HAM-D] score ≥26); those in Study 2 had moderate PPD (HAM-D score of 20-25). In both trials, mean HAM-D scores were significantly lower at the end of a 60-hour infusion of brexanolone than after administration of placebo (the primary endpoint). At 30 days, HAM-D scores remained significantly lower in women who had received brexanolone in Study 1, but not in Study 2 (see Table 2).3

ADVERSE EFFECTS — In clinical trials, the most common adverse effects of brexanolone (occurring in ≥5% of patients and more commonly than with placebo) were sedation/somnolence, headache, dizziness, presyncope/vertigo, dry mouth, hot flash/flushing, and loss of consciousness. A boxed warning in the brexanolone label states that women receiving the drug should be monitored for excessive sedation and sudden loss of consciousness, receive continuous pulse oximetry monitoring, and be accompanied during interactions with their children. All patients with depression should be monitored for suicidal ideation and behavior. Brexanolone is classified as a schedule IV controlled substance.

REMS — Because of the risk of harm associated with excessive sedation or sudden loss of consciousness, the FDA has instituted a Risk Evaluation and Mitigation Strategy (REMS) program which requires that pharmacies and healthcare facilities purchasing, dispensing, and/or administering brexanolone be certified to do so, and that only women enrolled in the program receive the drug.

PREGNANCY AND LACTATION — Brexanolone should not be used in pregnant women; developmental toxicities have occurred in the fetuses of animals given brexanolone doses higher than the recommended human dose. Brexanolone has low oral bioavailability and is not expected to adversely affect the breastfed infants of women given the drug.

DRUG INTERACTIONS — Administration of brexanolone with other CNS depressants could result in additive effects. In clinical trials, coadministration of brexanolone and other antidepressants was associated with an increased risk of sedation-related events.

DOSAGE AND ADMINISTRATION — Zulresso is administered in a healthcare setting as a continuous IV infusion over 60 hours at varying rates (see Table 3).

Continuous pulse oximetry equipped with an alarm should be used to monitor women receiving brexanolone; if hypoxemia occurs, treatment should be stopped and not resumed. Women receiving the drug should also be monitored every 2 hours for excessive sedation during planned nonsleep periods. If excessive sedation occurs, the infusion should be stopped until symptoms resolve; treatment may then be resumed at the same or a lower dosage.

Zulresso should not be used in patients with end-stage renal disease (eGFR <15 mL/min/1.73 m2) because its solubilizing agent, betadex sulfobutyl ether sodium, may accumulate.

COST — At least 5 vials of Zulresso are required to complete the 60-hour course of treatment (additional vials are required for women weighing ≥90 kg). Five vials of Zulresso cost $34,000.4

CONCLUSION — Administered as a continuous IV infusion over 60 hours, the GABAA receptor modulator brexanolone (Zulresso) is modestly more effective than placebo in reducing post-infusion depressive symptom scores in women with moderate to severe postpartum depression (PPD). The durability of its antidepressant effect is unclear. Brexanolone can cause excessive sedation and loss of consciousness, and women must be monitored throughout the infusion. How this treatment compares to other antidepressants, which cost much less and do not require a 60-hour IV infusion, remains to be determined.

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