Ohio society of
health-system pharmacy

Author: Mathew Costello, PharmD Candidate, Northeast Ohio Medical University

Brexanolone (Zulresso™) is the first medication approved for the treatment of postpartum depression in adults. Postpartum depression is defined by the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, as a major depressive episode with the onset of symptoms either during pregnancy or in the first four weeks postpartum.¹ The mechanism of action for postpartum depression is not fully understood.Postpartum depression is thought to occur due to a precipitous decline in hormonal levels, including allopregnanolone levels, and downregulation of gamma-aminobutyric acid- A receptors following childbirth. Chemically identical to endogenous allopregnanolone, brexanolone is a neuroactive steroid that acts as a GABA-A receptor modulator.²

Efficacy for brexanolone in postpartum depression was investigated in three randomized, double-blind, placebo-controlled studies. The primary endpoint in all trials was measured with the Hamilton Depression Rating Scale (HDRS).³ The HDRS is a clinician-rated depression scale that can be used in practice or research and is generally considered the gold standard for clinical research.⁴Patients received a continuous infusion over a 60-hour period or placebo. Baseline antidepressant use was reported in 23% of patients. A target dose of 90 mcg/kg/hour was established. However, 38 patients, who were unable to withstand titration up to 90, were titrated to a tolerable dose of 60 mcg/kg/hour which ultimately demonstrated superiority to placebo. The HDRS score was significantly improved for brexanolone versus placebo in all trials.^{3, 5}

Brexanolone is a schedule IV controlled substance with no contraindications. Despite no contraindications, there is a boxed warning regarding the risk of excessive sedation and sudden loss of consciousness. As a result of this risk, it is available only through a Risk Evaluation and Mitigation Strategies (REMS) program. In addition, it contains a warning for suicidal thoughts and behaviors. Some patients may experience adverse effects including sedation, dry mouth, and flushing and any patient on a central nervous system depressant may experience increased likelihood of sedation related to brexanolone use. Brexanolone does not prolong the QT interval to a relevant clinical extent.³ 

Prior to and during brexanolone therapy, monitor all patients for hypoxia with continuous pulse oximetry with alarm. Additionally, every two-hour monitoring for excessive sedation should be exercised during scheduled wake hours. It is important that patients are not the primary caregiver of their child(ren) while receiving this medication. Monitor for emerging suicidal thoughts and worsening postpartum depression.³

Furthermore, a lactation study examining 12 women who were less than six months postpartum found that brexanolone passes into breastmilk. There was, however, a low relative infant dose (RID) being 1%-2% of the maternal weight-adjusted dosage importantly showing low infant drug exposure. No effects on milk production were noted.³

Brexanolone is available as a single-dose vial with a concentration of 100 mg per 20 mL. While dosage adjustments for renal or hepatic impairment are not necessary, avoid brexanolone in patients with end-stage renal disease.³ 

Brexanolone Dosing3
Time (hours)	Dose (mcg/kg/hour)
0-4	30
4-24	60
24-52*	90
52-56	60
56-60	30

*Consider 60 mcg/kg/hour in hours 24-52 if the patient cannot tolerate the 90 mcg/kg/hour dosage

In summary, brexanolone represents a breakthrough in depression pharmacotherapy. It has a unique mechanism of action and is the first FDA approved medication for postpartum depression. Limitations to its use, including a REMS program, 60-hour infusion time, and boxed warning, may limit its clinical utility but remains an option for patients with postpartum depressed mood. It is important that the pharmacist informs the patient of potential medication treatment for postpartum depression and the risks it may expose to themselves and the child. Nevertheless, it is an important step forward for postpartum depression pharmacotherapy.

References:

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, fifth edition. Arlington, VA: American Psychiatric Association, 2013.
2. Powell JG, Garland S, Preston K, Piszczatoski C. Brexanolone (Zulresso): finally, an FDA-approved treatment for postpartum depression. Ann Pharmacother. 2020;54(2):157-63.
3. Zulresso [package insert]. Cambridge, MA: Sage Therapeutics, Inc.; June 2019.
4. Rush AJ, First MB, Blacker D, eds. Handbook of Psychiatric Measures, 2nd ed. American Psychiatric Publishing, Inc. Arlington, VA. 2008.
5. Leader LD, O’Connell M, VandenBerg A. Brexanolone for postpartum depression: clinical evidence and practice considerations. Pharmacotherapy. 2019;39(11):1105-12.