FDA Approves First Treatment for Postpartum Depression: Brexanolone

In a groundbreaking development for maternal mental health, the U.S. Food and Drug Administration (FDA) has approved the first-ever medication specifically designed to treat postpartum depression (PPD). Brexanolone (marketed as Zulresso) marks a significant advancement in addressing a condition that affects many new mothers, providing a new avenue of hope and recovery.

Understanding Postpartum Depression

Postpartum depression is a severe form of depression that occurs after childbirth, affecting the mother's ability to care for herself and her baby. Symptoms can range from intense sadness, anxiety, and fatigue to severe mood swings and a disconnection from the newborn. Traditional treatments have typically included antidepressants and psychotherapy, but these methods often take weeks to show effectiveness and may not always be sufficient for severe cases.

The Role of Brexanolone

Brexanolone is a synthetic form of allopregnanolone, a neurosteroid that plays a crucial role in mood regulation and is naturally produced in the body. This medication acts as a modulator of the gamma-aminobutyric acid (GABA) system, which is vital for reducing neural excitability and promoting a calming effect on the brain.

Indication

Brexanolone is a drug indicated for the treatment of postpartum depression in adult women. Brexanolone received FDA approval in March 2019. It is the first drug to be specifically approved for postpartum depression. Postpartum depression is a severe condition that affects 10 to 20% of women worldwide.Clinically, it presents as significant depressive symptoms following delivery and often coexists with anxiety. Approximately 5 to 10% of these patients develop severe postpartum depression. Postpartum depression is one of the leading causes of maternal mortality and morbidity, which ultimately affects the mother, infant, and siblings' cognitive, behavioral, emotional, and physical well-being.

Mechanism of Action

The mechanism of action of brexanolone is not fully known. Brexanolone is an aqueous formulation of allopregnanolone. Allopregnanolone is a major metabolite of progesterone. Levels of allopregnanolone continue to rise with progesterone during pregnancy, with the highest in the third trimester. Allopregnanolone is a potent, endogenous neuroactive steroid that modulates neuronal excitability through positive allosteric modulation on the synaptic and extrasynaptic gamma-aminobutyric acid (GABA) type A receptors. The extrasynaptic GABA type A receptors mediate tonic inhibition which makes allopregnanolone’s mechanism unique compared to benzodiazepines which mediate the phasic inhibition at GABA type A receptors.

Administration

Brexanolone is currently available only in U.S.A, through a restricted program called the Risk Evaluation and Mitigation Strategy(REMS) Program. This program requires brexanolone to be administered intravenously at a certified health care facility under the close supervision of a health care provider. Patients are required to enroll in this program before drug administration. Brexanolone is administered as a continuous IV infusion over a period of 60 hours, for approximately 2.5 days.

The prescribed dosing regimen is as follows:

• 0 to 4 hours: Start with a dose of 30 mcg/kg/hour

• 4 to 24 hours: Increase the dose to 60 mcg/kg/hour

• 24 to 52 hours: Increase the dose to 90 mcg/kg/hour

• 52 to 56 hours: Decrease the dose to 60 mcg/kg/hour

• 56 to 60 hours: Decrease the dose to 30 mcg/kg/hour

If the patient does not tolerate the dose of 90 mcg/kg/hour, dose reduction to 60 mcg/kg/hour is the recommendation. Brexanolone is available as 100mg/20ml single-dose vials and requires dilution before administration.

Brexanolone exhibits dose-proportional pharmacokinetics over a dose range of 30 mcg/kg/hour to 270mg/kg/hour. After administration, brexanolone is extensively bound to plasma proteins, approximately 99%, and has an elimination half-life of 9 hours. Brexanolone has a volume of distribution of  3L/kg, suggesting extensive distribution in tissues. Brexanolone is metabolized by extra-hepatic, non-CYP pathways mainly through keto-reduction, glucuronidation, and sulfation; therefore, no dosage adjustment is necessary with hepatic impairment. Excretion is mostly in feces and urine, approximately 47% and 42%, respectively, with the remaining 1% as unchanged brexanolone. The FDA prohibits the usage of brexanolone in patients who have an eGFR of less than 15 mL/minute/1.73 m^2 due to the possible accumulation of solubilizing agent, betadex sulfobutyl ether sodium, in brexanolone. 

Brexanolone transfers to breastmilk; however, the relative infant exposure to the drug is considered low. A concentration of less than 10ng/ml of brexanolone was present in breast milk 36 hours after the completion of infusion, suggesting the maximum relative infant dose for brexanolone during the infusion was 1% to 2%.

Adverse Effects

Clinical trials have demonstrated brexanolone as generally well tolerated. The most common adverse effects associated with brexanolone are dizziness, sedation/somnolence, xerostomia, loss of consciousness, and hot flushes.

In patients whose symptoms of postpartum depression worsen or develop suicidal ideation or behavior, providers should consider changing the therapeutic regimen or stopping brexanolone completely. 

At the highest recommended infusion rate of 90 mcg/kg/hour, brexanolone causes a minimal increase in the QTc interval.

Monitoring

Continuous monitoring is necessary as brexanolone can cause excessive sedation and sudden loss of consciousness. Because of this, brexanolone is only available through the restricted distribution program. During infusion, patients need continuous monitoring with pulse oximetry and must be accompanied at all times by staff or family members while interacting with their children. 

If patients experience hypoxia, infusion needs to be stopped immediately and should not be resumed. The FDA has cautioned providers to monitor patients every 2 hours for sedative effects during non-sleep periods. In the case of excessive sedation or sudden loss of consciousness, dose interruption is recommended. Patients regain consciousness within 15 to 60 minutes of dose interruption.[10] After recovery, infusion may be resumed at the same or lower dose as determined by the health care provider.

Patients are prohibited from driving or operating machinery until the sedative effects of the drug have entirely resolved.

Patients require close monitoring for worsening depression and suicidal thoughts or behaviors. In such cases, it is recommended to change the dosing regimen or discontinue brexanolone altogether. Concomitant use with central nervous system(CNS) depressants such benzodiazepines, alcohol, opioids, and antidepressants also requires close monitoring and/or avoidance of these agents.

Conclusion

Brexanolone's FDA approval as the first treatment for postpartum depression offers new hope for mothers worldwide. Its rapid effectiveness and targeted approach highlight the importance of advancing research and development in maternal mental health care. This landmark approval not only addresses a critical need but also sets the stage for future innovations in treating mood disorders.

References

1. FDA Approves First Treatment for Postpartum Depression

2. Brexanolone in Postpartum Depression: A Modulator Class of Medications