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CE: Brexanolone for the Treatment of Postpartum Depression

21 Jan 2021 5:24 PM | Anonymous

By: Bridgette McCauley, PharmD; PGY-2 Psychiatry Pharmacy Practice Resident

Mentor: O. Greg Deardorff, PharmD, BCPP; Clinical Pharmacy Manager, Fulton State Hospital – Fulton, MO

Program Number: 2021-01-03

Approval Dates: February 3, 2021 to August 1, 2021

Approved Contact Hours: 1 hour

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Learning Objectives

  1. Understand the pathophysiology of postpartum depression.
  2. Review the mechanism of action of brexanolone.
  3. Discuss the rationale for the REMS program required for brexanolone.
  4. Explain the dosing regimen for brexanolone.

Introduction

Postpartum depression (PPD) is classified as a major depressive disorder occurring “during pregnancy or within four weeks following delivery.”1 In the United States, the prevalence of PPD is estimated to be 11.5% and is the leading cause of maternal mortality.2-5 Within the first-year after giving birth, one in seven deaths is a result of suicide.6 Those at highest risk of developing PPD are those with a history of depression, history of or current tobacco use, have experienced domestic violence, fear childbirth, are of lower socioeconomic status, have gestational diabetes, ≥40 years old, adolescents, unintentional pregnancy, or maternal anxiety.7-12 While the etiology is not clear, there are a few theories thought to cause PPD.

Pathophysiology

The exact pathophysiology is unknown, but thought to be related to neurotransmitter abnormalities, genetic predisposition, decreased estrogen, hypothalamic dysfunction, thyroid dysfunction, and alterations of reproductive hormones.13-21 One reproductive hormone in particular, allopregnanolone (a progesterone neurosteroid metabolite), is thought to have a role in PPD.18-21 Allopregnanolone is a positive allosteric modulator of GABAA and in animal models has been linked to anxiety and depression.21,24-26 During pregnancy, progesterone rises and is at its highest plasma concentration during the third trimester.22 The concentrations quickly decrease after childbirth.23 If the GABAA receptors do not adapt to the changes in allopregnanolone at child birth, it may trigger PPD.27

Overview of Brexanolone28

Brexanolone (Zulresso®) is a positive allosteric modulator of GABAA receptors, which was approved in 2019 for the treatment of PPD. This was the first medication approved by the FDA for PPD. This medication is given as a continuous infusion over 60 hours and must be administered in a healthcare facility. It is given as 30 µg/kg/h (0-4h), 60 µg/kg/h (4-24h), 90 µg/kg/h (24-52h), 60 µg/kg/h (52-56h), and 30 µg/kg/h (56-60h). If the patient does not tolerate the 90 µg/kg/h infusion, a dose of 60 µg/kg/h may be used instead. Due to the prolonged infusion, all patients are required to have childcare for the time of the infusion.

Adverse Effects

The most common adverse effects are sedation/somnolence (13-21%), dizziness/presyncope (12-13%), loss of consciousness (3-5%), and flushing/hot flush (2-5%). Due to the loss of consciousness/sedation risk, this medication does have a REMS program. This ensures that patients are monitored with pulse oximetry and physical assessment by staff.

Contraindication/Special Populations

While brexanolone has no contraindications, it should not be used in those with end stage renal disease (ESRD) with an eGFR of <15 mL/min/1.73m2 due to the solubilizing agent, betadex sulfobutyl ether sodium. This agent can accumulate in severe renal impairment. This medication does not require dose adjustments in patients with hepatic impairment.

Lactation

During the administration of brexanolone, breast feeding is not recommended, but was found to be safe at 36 hours post-infusion. At 36 hours, the concentration in the breast milk was <10 ng/mL in at least 95% of women. Exposure to the medication in breast milk is not expected to be high as the oral bioavailability is low. Therefore, breastfeeding 36 hours post-infusion should be acceptable as relative infant dose is low.

Evidence Supporting Brexanolone29

Two phase 3 studies were performed. In the studies, there were two different brexanolone infusion rates compared (Table 1). Study 1 looked at both the brexanolone 60 µg/kg/h and 90 µg/kg/h infusion groups. This study showed that at 60 h, the least squares mean reduction in Hamilton Depression Rating Scale (HAM-D) scores were 19.5 points (SE 1.2) in brexanolone 60 µg/kg/h, 14.0 points (SE 1.2) in brexanolone 90 µg/kg/h, and 14.0 points (SE 1.1) in placebo group. The second study of the phase 3 trials, looked at brexanolone 90 µg/kg/h versus placebo and found the least squares mean reduction in HAM-D scores was 14.6 points (SE 0.9) in brexanolone 90 µg/kg/h vs 12.1 points (SE 0.8) in placebo. The phase 3 trial did show that brexanolone was superior to placebo in treatment of postpartum depression at 60 h and showed responses were sustained up to 30 days. Of those that responded to treatment at 60 h, 94% of patients did not relapse at 30 days post-infusion.


Prior to the approval of brexanolone, the mainstay of treatment for PPD was antidepressants.30-32 Most commonly, selective serotonin reuptake inhibitors (SSRIs) were the treatment of choice for PPD. SSRIs do not have a rapid onset of action and may take up to 6-12 weeks to see the full resolution of symptoms.33 A matching-adjusted indirect comparisons and network meta-analysis of brexanolone with SSRIs by Cooper et al demonstrated that brexanolone 90 µg/kg/h showed a greater change from baseline than SSRIs when looking at both HAM-D and Edinburgh Postnatal Depression Scale.34

Eldar-Lissai et al, estimated the average cost of a course of brexanolone to be $34,000, while SSRIs are relatively cheap.35 They estimated that direct maternal medical costs for brexanolone treated patients was $65,908 vs $73,653 for SSRIs over 11 years. This study showed the incremental cost effectiveness ratio of brexanolone was $106,662 per quality adjusted life years over 11-years versus SSRIs. In addition, women treated with brexanolone averaged 6.230 quality adjusted life years vs 5.979 for SSRIs. This study showed that while brexanolone is expensive, it is cost-effective for the treatment of PPD.

Conclusion

Brexanolone is a novel treatment for PPD and has shown promising results. While the long-term effects are not yet known, it has shown itself to be effective for the treatment of PPD and is a viable option for patients suffering with PPD.

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References

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