How do brexanolone and zuranolone compare in patients with postpartum depression?

Introduction
Recent data suggest that 1 in 8 women experience symptoms of postpartum depression (PPD), defined by most experts as a major depressive disorder (MDD) with an onset of symptoms during pregnancy and up to 12 months postpartum.1,2 Contributors to the development of PPD are multifaceted and include hormonal changes during the peripartum period, history of mental health disorders, psychosocial stressors, and unwanted pregnancy. About a quarter of women with PPD will experience depressive symptoms up to 3 years postpartum if left undiagnosed.2 Given that PPD may lead to impairments in maternal functioning, interfere with breastfeeding and mother-baby bonding, and negatively influence child development, effective treatment of patients affected by this condition is critical.3

Conventionally, PPD is treated similarly to other types of MDD.2,4 A 2023 American College of Obstetrics and Gynecology (ACOG) guideline recommends psychotherapy for first-line treatment of mild-to-moderate PPD.2 If patients fail psychotherapy or prefer pharmacotherapy, selective serotonin reuptake inhibitors (SSRIs) are recommended first-line, with serotonin-norepinephrine reuptake inhibitors (SNRIs) considered to be reasonable alternatives. Pharmacotherapy should be individualized for each patient based on their prior history of antidepressant use and response. For treatment-naïve patients, sertraline and escitalopram are commonly recommended. 2 In women who are or are planning to breastfeed, drug passage through breast milk and infant risk should also be considered.

A significant challenge with conventional antidepressants used in patients with PPD, such as SSRIs and SNRIs, is their slow onset of clinical effects, which are estimated to take up to 4 to 8 weeks.4 The development of GABAkinases for this population has been prompted by the need for rapid-acting therapies that target specific physiological changes during the peripartum period that contribute to the development of PPD.2

GABAkinases for PPD

Allopregnanolone is a metabolite of progesterone, which peaks during pregnancy, especially during the third trimester.5 Levels of allopregnanolone abruptly decline after birth, and these reductions have been shown to have profound effects on the development of anxiety and depression during the postpartum period. Brexanolone and zuranolone are exogenous analogs of allopregnanolone that have been shown to aid with rapidly restoring hormonal balance through positive allosteric modulation of synaptic and extrasynaptic γ-aminobutyric acid type A (GABAA) receptors.5-7

Table 1 compares the pharmacological characteristics of the Food and Drug (FDA)-approved GABAkinases for PPD.5-7 Briefly, brexanolone is administered as a one-time 60-hour infusion and zuranolone is administered orally once daily for 14 days.6,7 Both drugs have similar adverse effect profiles and monitoring parameters. However, brexanolone is only available through the Zulresso Risk Evaluation and Mitigation Strategy (REMS) program due to a boxed warning regarding the risk of severe sedation and loss of consciousness.7

ACOG recommends consideration of brexanolone or zuranolone for PPD occurring in the third trimester or within 4 weeks postpartum.2,8 Both drugs were approved without a severity qualifier; however, the inclusion criteria for the pivotal studies included mostly patients with moderate to severe disease (ie, 17-item Hamilton Depression Rating Scale [HAM-D 17] score ≥17).9-12

Table 1. Pharmacological comparison of brexanolone and zuranolone.6-8
BrexanoloneZuranolone
IndicationPPD in patients 15 years of age and olderPPD in adults
Dosing and administration One-time 60-hour continuous intravenous infusion at a healthcare facilityOrally once daily in the evening with a fatty meal for 14 days
Dose AdjustmentsNone; avoid in patients with ESRD with eGFR <15 mL/min/1.73m2Dose reductions in the following populations:
  • Hepatic impairment (Child-Pugh C)
  • Renal impairment (eGFR <60 mL/min/1.73 m2)
  • Concomitant use of strong CYP3A4 inhibitors
  • CNS AEs or use with other CNS depressants
Adverse EffectsSomnolence, dry mouth, loss of consciousness, and flushingSomnolence, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection
Boxed WarningsOnly available through the Zulresso REMS program because excessive sedation or loss of consciousness can cause serious harmDriving impairment due to CNS depressant effects. Patients should not drive or engage in other potentially hazardous activities until at least 12 hours after administration.
Monitoring Parameters
  • Every 2 hours during infusion for CNS depressant effects
  • Suicidal thoughts and behaviors
  • CNS depressant effects
  • Suicidal thoughts and behaviors
Lactation
  • Available data do not suggest a significant risk of AEs in breastfed infants from exposure to the drug; infant exposure is expected to be low
  • No data regarding the effects of zuranolone on a breastfed infant; the drug is present in low levels in human milk
Additional considerations
  • May cause fetal harm; patients should use effective contraception during the treatment course and for 1 week after the final dose
  • Avoid concomitant use with CYP3A4 inducers
Abbreviations: AE=adverse events; CNS=central nervous system; CYP=cytochrome; eGFR=estimated glomerular filtration rate; ESRD=end stage renal disease; GABAA=γ-aminobutyric acid type A; PPD=postpartum depression; REMS=Risk Evaluation and Mitigation Strategy.

Clinical Efficacy
Brexanolone and zuranolone were evaluated for the management of PPD in 2 phase 3 randomized, double-blind, placebo-controlled trials each (Table 2).9-11 In the trials with zuranolone, patients received either 30 mg or 50 mg of zuranolone orally daily for 14 days.9,10 In trials with brexanolone, infusions were gradually increased to a rate of 60 or 90 µg/kg per hour and then reduced back down to lower rates for a total infusion time of 60 hours.11 The primary outcome in all trials was a change from baseline in HAM-D 17 score, assessed on day 15 for zuranolone and at 60 hours post-infusion for brexanolone.9-11

At baseline, the majority of patients in the zuranolone trials experienced an onset of PPD within 4 weeks postpartum (58% to 68%) and 15% to 21% were using antidepressants at baseline; the mean HAM-D 17 score ranged from 28 to 35.9,10 Similarly, most patients in the brexanolone trials experienced an onset of PPD within 4 weeks postpartum (67% to 78%) and 17% to 26% of patients were using antidepressants at baseline; the mean HAM-D 17 score ranged from 22 to 29.11 All trials met their primary endpoint, showing statistically significant results in favor of the study drug.9-11 The literature defines a clinically meaningful change in the HAM-D 17 score as a 4- to 6-point difference, which was demonstrated with both drugs at certain time points but not consistently across all measures.9-11,13 Significant effects were observed as early as 24 hours following the start of infusion with brexanolone in 1 of the 2 pivotal trials and 3 days after initiating treatment with zuranolone in both pivotal trials. Efficacy persisted after discontinuation of treatment through day 45 of follow-up for zuranolone in both trials and day 30 of follow-up for brexanolone in one trial.

In addition to the pivotal trials, meta-analyses have also investigated pooled efficacy and safety data for brexanolone and zuranolone.14 Notably, a 2023 meta-analysis examined HAM-D 17 response (defined as a reduction of >50% from baseline in the HAM-D 17 score) and HAM-D 17 remission (defined as a HAM-D 17 score of ≤7) rates at different time points with both agents. Results demonstrated that zuranolone significantly increased the likelihood of achieving HAM-D 17 response compared to the placebo group, starting on Day 3 (relative risk [RR], 1.698; 95% CI, 1.170 to 2.465; p=0.005) and continuing through follow-up on Day 45 (RR, 1.240; 95% CI, 1.038 to 1.481; p=0.018). Patients receiving zuranolone were also more likely to achieve HAM-D 17 remission starting on Day 3 (RR, 2.358; 95% CI, 1.105 to 5.033; p=0.027) and continuing through follow-up on Day 45 (RR, 1.619; 95% CI, 1.210 to 2.166; p=0.001). The rates of discontinuation did not differ between zuranolone and placebo, although zuranolone did increase the risk of adverse effects, particularly sedation (RR, 10.082; 95% CI, 1.912 to 53.166; p=0.0006), when compared to placebo.

In the same 2023 meta-analysis, brexanolone also significantly increased the likelihood of achieving HAM-D 17 response compared to the placebo group, starting at 24 hours (RR, 1.331; 95% CI, 1.003 to 1.766; p=0.048) and continuing through 72 hours (RR, 1.342; 95% CI, 1.110 to 1.622; p=0.002).12 Correspondingly, the likelihood of patients achieving HAM-D 17 remission was significantly improved with brexanolone starting at 48 hours (RR, 2.073; 95% CI, 1.355 to 3.174; p=0.001) and continuing through 72 hours (RR, 1.898; 95% CI, 1.326 to 2.717; p<0.001). Results at Days 7 and 30 did not reach statistical significance for either HAM-D 17 response or remission. Lastly, while the rate of discontinuation due to any reason was significantly increased with brexanolone (RR, 2.731; 95% CI, 1.171 to 6.367; p=0.020), the risk of adverse effects and severe adverse effects was similar between brexanolone and placebo.

Table 2: Pivotal trials for brexanolone and zuranolone in the management of PPD.9-11
Citation Design/DurationInterventionsOutcomes
Zuranolone
Deligiannidis et al, 20239MC, RCT, DB, PC

Follow up: 45 days		ZUR 50 mg/day for 2 weeks (n=98)

Placebo (n=98)

Use of other antidepressants was permitted if patients were on a stable dose for ≥30 days prior to the first study treatment
dose		Primary: Day 15 change in HAM-D 17
  • ZUR: -15.6; Placebo: -11.6 (LSM difference: -4.0; 95% CI, -6.3 to -1.7; p=0.001)

Other: change in HAM-D 17
Day 3
  • ZUR: -9.5; Placebo: -6.1 (LSM difference: -3.4; 95% CI, -5.4 to -1.4; p=0.001)
Day 45
  • ZUR: -17.9; Placebo: -14.4 (LSM difference: -3.5, 95% CI, -6.0 to -1.0; p=0.007)
Deligiannidis et al, 202110MC, RCT, DB, PC

Follow up: 45 days		ZUR 30 mg/day for 2 weeks (n=77)

Placebo (n=76)

Use of other antidepressants was permitted if patients were on a stable dose for ≥30 days prior to the first study treatment
dose		Primary: Day 15 change in HAM-D 17
  • ZUR: -17.8; Placebo: -13.6 (LSM difference: -4.2, 95% CI, -6.9 to -1.5; p=0.003)

Other: change in HAM-D 17
Day 3
  • ZUR: -12.5; Placebo: -9.8 (LSM difference: -2.7, 95% CI, -5.1 to -0.3; p=0.025)
Day 45
  • ZUR: -19.2; Placebo: -15.1 (LSM difference: -4.1, 95% CI, -6.7 to -1.4; p=0.003)
Brexanolone
Meltzer-Brody et al, 2018112 MC, RCTs, DB, PC

Follow up: 30 days		BRX 90 µg/kg/h one time infusion (Study 1, n=45; Study 2, n=54)

BRX 60 µg/kg/h one time infusion (study 1 only; n=47)

Placebo (Study 1, n=46; Study 2, n=54)

Use of other antidepressants was permitted if the patient was receiving stable doses ≥14 days before screening		Primary: 60 hours post-infusion change in HAM-D 17
Study 1:
  • BRX60: -19.5; Placebo: -14 (LSM difference: -5.5, 95% CI, -8.8 to -2.2; p=0.0013)
  • BRX90: -17.7; Placebo: -14 (LSM difference: -3.7, 95% CI, -6.9 to -0.5; p=0.0252)

Study 2:
  • BRX90: -14.6; Placebo: -12.1 (LSM difference: -2.5, 95% CI, -4.5 to -0.5; p=0.0160)

Other outcomes: change in HAM-D 17
Study 1:
24 Hours
  • BRX60: -15; Placebo: -10.7 (LSM difference: -4.3, 95% CI, -7.5 to -1.1; p=0.0094)
  • BRX90: -13; Placebo: -10.7 (LSM difference: -2.3, 95% CI, -5.5 to 0.8; p=0.1440)

48 Hours
  • BRX60: -18.0; Placebo: -13.6 (LSM difference: -4.5, 95% CI, -7.9 to -1.1; p=0.0110)
  • BRX90: -16.9; Placebo: -13.6 (LSM difference: -3.3, 95% CI, -6.7 to 0.0; p=0.0511)

Day 30
  • BRX60: -19.5; Placebo: -13.8 (LSM difference: -5.6, 95% CI, -9.5 to -1.8; p=0.0044)
  • BRX90: -17.6; Placebo: -13.8 (LSM difference: -3.8, 95% CI, -7.6 to 0.0; p=0.0481)

Study 2:
24 Hours
  • BRX90: -11.4; Placebo: -9.8 (LSM difference: -1.6, 95% CI, -3.8 to 0.6; p=0.1431)

48 Hours
  • BRX90: -13.0; Placebo: -10.6. (LSM difference: -2.4, 95% CI, -4.7 to -0.1; p=0.0389)

Day 30
  • BRX90: -14.7; Placebo: -15.2 (LSM difference: 0.5, 95% CI, -2.0 to 3.1; p=0.6710)
Abbreviations: BRX=brexanolone; DB=double-blind; HAM-D=17-item Hamilton Depression Rating Scale score; LSM=least square mean; MC=multicenter; PC=placebo controlled; PPD=postpartum depression; RCT=randomized controlled trial; ZUR=zuranolone.

Discussion
Brexanolone and zuranolone showed statistically significant reductions in HAM-D 17 scores; however, some important limitations should be considered when applying this data in clinical practice. First, across all trials, patients were allowed to continue therapy with other antidepressants if they were on stable doses within 1 month before starting the trial. This may have introduced confounding as far as whether the primary driver of the change in HAM-D 17 score was the study drug or background antidepressant therapy. Additionally, there was a high placebo effect across trials, and the point estimate for the difference between treatment and placebo was not always clinically relevant (ie, change in the HAM-D 17 score between 4 to 6 points). Second, the follow-up for brexanolone and zuranolone trials did not exceed 30 and 45 days, respectively, which may not be sufficient to assess long-term safety and efficacy of this novel class of drugs. Third, breastfeeding was not permitted in any of the trials, so the effects of brexanolone and zuranolone on lactation were not assessed. Lastly, all trials included mostly patients who reside in the United States, which may limit generalizability to other parts of the world.

Practical considerations must also be taken into account when selecting therapy.2,8 Patients who cannot take oral medications or who may have trouble adhering to daily oral therapy, or those in need of very rapid onset of symptom relief (ie, within 24 hours), may benefit from brexanolone.7,11,14 However, the benefits of this therapy must be weighed against the requirement for hospitalization for the duration of the infusion (~2.5 days), risk of excessive sedation, potential challenges with access due to the REMS program, and the risk of experiencing infusion site reactions.7 Conversely, zuranolone offers the convenience of outpatient treatment with once-daily oral dosing, however, the potential for excessive sedation should be discussed with the patient, especially if that patient will carry the primary caregiver responsibilities in the household.6,8 Furthermore, adherence issues should be considered as remembering to take the medication daily for 14 days may pose a challenge to postpartum patients as they adjust to new routines.

Conclusion
Zuranolone and brexanolone have both demonstrated clinically meaningful improvements in HAM-D 17 scores in patients with PPD. Practical considerations should be considered when selecting between these novel treatments, including the route of administration, safety profile, access to therapy and cost, and the availability of psychosocial support for the patient.

References

  1. Depression Among Women. Centers for Disease Control and Prevention. Updated May 22, 2023. Accessed March 8, 2024. https://www.cdc.gov/reproductivehealth/depression/index.htm#:~:text=Using%20the%20Pregnancy%20Risk%20Assessment,experience%20symptoms%20of%20postpartum%20depression.
  2. Treatment and management of mental health conditions during pregnancy and postpartum: ACOG Clinical Practice Guideline No. 5. Obstet Gynecol. 2023;141(6):1262-1288. doi:10.1097/AOG.0000000000005202
  3. O’Hara MW, McCabe JE. Postpartum depression: current status and future directions. Annu Rev Clin Psychol. 2013;9:379-407. doi:10.1146/annurev-clinpsy-050212-185612
  4. Practice guideline for the treatment of patients with major depressive disorder (revision). American Psychiatric Association. Am J Psychiatry. 2000;157(4 Suppl):1-45.
  5. Clinical Pharmacology. Elsevier Inc; 2024. Accessed March 11, 2024. https://www.clinicalkey.com/pharmacology/
  6. Zurzuvae. Package Insert. Cambridge, MA: Biogen, Inc; 2023.
  7. Zulresso. Package Insert. Cambridge, MA: Sage Therapeutics, Inc; 2022.
  8. Zuranolone for the Treatment of Postpartum Depression. ACOG. Updated January 30, 2024. Accessed March 11, 2024. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2023/08/zuranolone-for-the-treatment-of-postpartum-depression
  9. 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):951-959. doi:10.1001/jamapsychiatry.2021.1559
  10. Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the Treatment of Postpartum Depression. Am J Psychiatry. 2023;180(9):668-675. doi:10.1176/appi.ajp.20220785
  11. 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(10152):1058-1070. doi:10.1016/S0140-6736(18)31551-4
  12. Zimmerman M, Martinez JH, Young D, Chelminski I, Dalrymple K. Severity classification on the Hamilton Depression Rating Scale. J Affect Disord. 2013;150(2):384-388. doi:10.1016/j.jad.2013.04.028
  13. Rush AJ, South C, Jain S, et al. Clinically Significant Changes in the 17- and 6-Item Hamilton Rating Scales for Depression: A STAR*D Report. Neuropsychiatr Dis Treat. 2021;17:2333-2345.. doi:10.2147/NDT.S305331
  14. Zou J, Yang L, Yang G, Gao J. The efficacy and safety of some new GABAkines for treatment of depression: A systematic review and meta-analysis from randomized controlled trials. Psychiatry Res. 2023;328:115450. doi:10.1016/j.psychres.2023.115450

Prepared by:
Aisha Safi
PharmD Candidate Class of 2024
University of Illinois at Chicago College of Pharmacy

Reviewed by:
Katherine Sarna, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

April 2024

The information presented is current as of February 19, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.