Since the the Food and Drug Administration (FDA) approved brexanolone as an intravenous infusion for the treatment of postpartum depression last week, we have been deluged with questions from patents, providers and the media regarding this new drug.  Sage Therapeutics plans to market the drug under the name ZULRESSO and plans to launch in the United States in June 2019.


What is brexanolone (Zulresso)? How does it work?

Brexanolone (introduced as SAGE-547 by SAGE Therapeutics) is a neurosteroid, an analogue of allopregnanolone. (Allopregnanolone is produced by the human body as a byproduct of progesterone.)  It was originally under investigation for the treatment of refractory seizure disorders; however, it was discovered that SAGE-547 was effective for the treatment of severe postpartum depression (PPD).  We don’t know exactly how brexanolone exerts its antidepressant effects; however, we do know that it is an allosteric modulator of GABA-A receptors. GABA is the primary inhibitory neurotransmitter in the brain and may play an important role in modulating vulnerability to depression and anxiety.  

Brexanolone is a neurosteroid.  Is it a hormone? Or is it an antidepressant?

Brexanolone is a derivative of allopregnanolone.  In the human body, the hormone progesterone is metabolized into a variety of active and inactive compounds, including allopregnanolone.  Because allopregnanolone modulates brain function, it is a hormone with neuroactive properties, a neurosteroid. While brexanolone has antidepressant effects, it seems to work differently from traditional antidepressants which increase levels of neurotransmitters, such as serotonin or norepinephrine.  It is hypothesized that brexanolone may exert its effects on anxiety and depression by modulating the hypothalamic-pituitary-adrenal or HPA axis which mediates the body’s response to stress and is modulated by GABAergic signaling.


Why is everybody so excited about brexanolone?  

It has been a while since we have seen an innovative approach to the treatment of depression.  Brexanolone represents a novel approach. While brexanolone has been advanced as a treatment specifically for postpartum depression, there is indication that other derivatives of allopregnanolone (including the oral compound SAGE-217) may be effective for depression unrelated to pregnancy or the postpartum period and may be of utility in both men and women.  One of the other really exciting things about brexanolone is that it seems to work very quickly.  Given traditional antidepressants typically take 2 to 4 weeks to have a significant effect, it would be phenomenal to have a treatment which may result in remission of depression within a couple of days.  


What about side effects?  It looks as it brexanolone may be more tolerable than conventional antidepressants?

The preliminary data from the company suggests that brexanolone is well tolerated.  The most commonly reported side effects are drowsiness and dizziness. The FDA has raised concerns about  two serious adverse events: suicidal ideation after the infusion in one subject and syncope/altered consciousness in another patient.  Because of these concerns, Zulresso was approved with a Risk Evaluation and Mitigation Strategy (REMS) and “will only be available to patients through a restricted distribution program at certified health care facilities where the health care provider can carefully monitor the patient.” While hospitalization is not necessarily considered a side effect, it must be considered in estimating the risks and benefits of treatment with brexanolone.  Because there are only a handful of mother-baby units in the United States, the hospitalization required to receive the 60-hour infusion of brexanolone may result in disruptions in family life, bonding and breastfeeding.


Can brexanolone be used while breastfeeding?

All of the clinical trials involving brexanolone excluded women who were breastfeeding or asked them to suspend breastfeeding while receiving treatment with the medication.  Therefore, we have no data on the safety of brexanolone while breastfeeding.  The manufacturer give the following advice:ZULRESSO passes into breast milk. Talk to your healthcare provider about the risks and benefits of breastfeeding and about the best way to feed your baby while receiving ZULRESSO.” Because Zulpresso will be administered in a hospital setting, I suspect that breastfeeding will be discouraged and it may take a while to generate data on the safety of breaxanolone to nursing infants.  


Who is the ideal candidate for Zulresso?

While Zulresso is touted as the first and only drug approved by the FDA for the treatment of postpartum depression, there are many options for the treatment of PPD.  Women with mild to moderate PPD symptoms are likely to benefit from psychotherapy and bolstering social supports. For women with more severe illness, conventional antidepressants, including the SSRIs sertraline (Zoloft) and fluoxetine (Prozac), are highly effective for the treatment of depressive symptoms and anxiety.   For women with the most severe illness, we would consider hospitalization and treatment with adjunctive medications ( such as atypical antipsychotics) and electroconvulsive therapy (ECT). Given the high cost of Zulresso (estimated by the company to be 25K – 34K per infusion) and the need for inpatient treatment, it is unlikely that Zulresso will be a first line treatment for women with PPD; however, it may be an attractive option for women with severe illness who have failed other treatments.  


Ruta Nonacs, MD PhD


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