Review of Allopregnanolone Agonist Therapy for the Treatment of Depressive Disorders

Abstract

Objective

This paper reviews the current literature available for the efficacy and safety of allopregnanolone agonists and discusses considerations for their place in therapy.

Literature Search

A literature search was conducted utilizing PubMed, clinicaltrials.gov, and the manufacturer’s website.

Data Synthesis

One phase II trial and two phase III trials evaluating the efficacy and safety of brexanolone were identified. Brexanolone demonstrated efficacy through significantly reduced Hamilton Depression Rating Scale (HAM-D) scores compared to placebo in the treatment of postpartum depression (PPD). Noted adverse effects were somnolence and dizziness, excessive sedation, and loss of consciousness. One published phase II study and the interim results of two phase III trials and one phase II trial on zuranolone were included in this review. Zuranolone, an oral allopregnanolone agonist, is given as a single, 14-day course. A significant reduction in HAM-D scores was demonstrated in patients with major depressive disorder (MDD) at 15 and 28 days compared to placebo. Interim results for zuranolone in PPD and bipolar disorder (BPD) show promising reductions in HAM-D scores. Adverse effects included sedation, dizziness, and headache.

Place in Therapy

Allopregnanolone agonists seem to have a role in PPD when weighing the quick onset of action and potential risks of untreated PPD. The class of medications is limited by the single course for this indication and may fit as a bridge to maintenance therapy with selective serotonin reuptake inhibitors (SSRIs). Brexanolone, specifically, is hindered by the long infusion time, hospitalization associated with administration, and risk evaluation and mitigation strategy program. Zuranolone may also have a role in MDD or BPD, but more data are needed.

Conclusion

Allopregnanolone agonists present a novel mechanism of action in the treatment of depressive disorders. Clinical trials and interim results support significant reductions in depression scores for brexanolone in PPD, and for zuranolone in PPD, MDD, and BPD.

Keywords:

• postpartum
• bipolar
• brexanolone
• zuranolone

Disclosure

Dr. Leader reports consulting for Wolters-Kluwer on medication use in pregnancy and lactation and Pfizer, Inc. on their menopause portfolio. Dr. Cooke reports participation in a Sage Therapeutics, Inc. Site Activation Advisory Board Meeting in November 2019. The authors report no other conflicts of interest in this work.