In This article

• Brexanolone is a neuroactive steroid and GABA-A receptor modulator initially approved for severe postpartum depression.
• An open-label pilot study of 10 women with postpartum psychosis tested a 60-hour intravenous brexanolone infusion.
  
• Psychotic, manic, and depressive symptoms (PANSS, YMRS, HAMD) improved during treatment and remained lower at Day 7.
  
• Treatment was generally well tolerated, with only mild to moderate, self-limited adverse events such as dizziness and sedation.
• Despite study limitations and the need for inpatient IV administration, brexanolone may offer a rapid-acting option for postpartum psychosis, though Zulresso is being discontinued commercially.

Brexanolone was first launched in 2019, approved by the FDA as a treatment for severe postpartum depression.  Brexanolone is a derivative of allopregnanolone and the first of a novel class of neuroactive steroids that act as positive allosteric modulators of the GABA-A receptor.  What sets brexanolone and similar neurosteroid derivatives of allopregnanolone from traditional antidepressants is their potent and rapid antidepressant effects.  A new open-label, proof-of-concept study has investigated the efficacy, safety, and tolerability of brexanolone for the treatment of postpartum psychosis.

Brexanolone for Postpartum Psychosis

In this study, ten women with postpartum psychosis received brexanolone as a single, continuous, 60-hour intravenous infusion, titrated to a target dose of 90 ug/kg/hour. Symptoms were measured using the Young Mania Rating Scale (YMRS), the Positive and Negative Syndrome Scale (PANSS), and the Hamilton Depression Rating Scale (HAMD). Assessments were conducted from baseline through Day 7, and patients were followed through Day 90.

The mean age of participants was 27 years (range 21–33); seven patients were primiparous, and on average participants were 1.85 months postpartum (range < 1 month to 5 months). Nine of the ten patients reported a prior psychiatric history, including depressive disorders (n = 8), anxiety disorders (n = 8), trauma-related disorders (n = 4), obsessive-compulsive disorder (OCD; n = 3), bipolar disorder (n = 2), eating disorder (n = 1), and ADHD (n = 1).

At study entry, 3 patients were taking a single antidepressant, 3 were taking an antipsychotic, and 1 patient was taking multiple psychotropic medications; 3 of the 10 patients were not taking any psychotropic medications at baseline. Low doses of lorazepam were prescribed to manage anxiety, and olanzapine was used in some patients to treat agitation.

All ten patients completed the brexanolone infusion without any need for dose reductions and without intolerable adverse side effects. 

• Mean scores for psychotic symptoms (PANSS) and manic symptoms (YMRS) decreased throughout the infusion and remained lower at the Day 7 assessment. 
• Mean scores on the HAMD also decreased during the infusion and remained lower at the Day 7 endpoint. 
• Treatment-related adverse events included dizziness and sedation; all adverse events were of mild or moderate intensity and self-limited. 
• No patients discontinued because of an adverse event, and no dose adjustments were required due to adverse events.

What’s Next?

While this was a small, open-label pilot study, the findings are promising, demonstrating that intravenously administered brexanolone was associated with a clinically meaningful decrease in psychotic and manic symptoms, as well as depressive symptoms, in women with postpartum psychosis. Three of the participants received brexanolone monotherapy, while the remainder received brexanolone as an adjunct to an antidepressant, antipsychotic, or mood stabilizer.

There are important limitations, including the small sample size, lack of randomization, and absence of a control group; nonetheless, this study paves the way for further exploration of brexanolone and related neuroactive steroids for the treatment of postpartum psychosis. Although the requirement for a 60-hour intravenous infusion in an inpatient setting has limited the broader use of brexanolone for postpartum depression, this mode of administration may be less of a deterrent in postpartum psychosis, where patients are typically hospitalized.

Current treatment algorithms for postpartum psychosis are complex and usually consist of a combination of antipsychotics, benzodiazepines, and lithium. While we do not have robust data regarding the time to remission, the stepwise addition and optimization of medications can be time-consuming. Because women with postpartum psychosis are hospitalized and often separated from their infants and unable to fully participate in the care of their child, rapid and effective treatments are urgently needed.

In October 2024, Sage Therapeutics announced that it would discontinue commercial marketing of brexanolone (Zulresso). Similar medications, like zuranolone (Zurzuvae) will continue to be available; however, these other neuroactive steroids have not been examined in patients with postpartum psychosis.  

—Ruta Nonacs, MD PhD