Mass General Hospital

Harvard Medical School

Brexanolone: Related to Allopregnanolone, Effective for the Treatment of Postpartum Depression

In 2015, we first reported on SAGE-547 (SAGE Therapeutics), a new medication for the treatment of severe postpartum depression.  SAGE-547, now called brexanolone, is an allosteric modulator of GABAA receptors.  This drug was initially under investigation for the treatment of refractory seizure disorders but it turned out to be a good antidepressant.  The information we presented in 2015 was from a press release put out by Sage Therapeutics; their findings were recently published in the peer-reviewed journal Human Psychopharmacology.  

In this report, the researchers reported findings from the first open trial.  The four women included in this study had severe depressive symptoms with a mean score of 26.5 on the Hamilton Depression Rating Scale (HAM-D).  All participants had an inadequate response to prior antidepressant therapy.  After treatment with intravenous SAGE-547, the mean HAM-D score declined to 1.8 ± 1.5 at 60 hours and to 5.3 ± 2.9 at 84 hours after infusion.  (A HAM-D score of less than 7 is considered to be depression-free.)  SAGE-547 was well-tolerated with no serious adverse events reported during treatment or during the 30-day follow-up period.  No patients discontinued treatment. The only adverse event reported in more than one patient was sedation, which was noted in two patients.

You might wonder why we are reviewing this study again.  Well, the original press release left out one very important detail.  It turns out that this new medication — brexanolone — is actually an intravenous formulation of allopregnanolone.  The hormone allopregnanolone (ALLO) is produced by the body as a metabolite of progesterone, and animal studies have suggested that allopregnanolone has significant anxiolytic effects.  Although the data has been somewhat mixed, some studies have suggested that progesterone and its metabolites may play a role in perinatal mood and anxiety disorders.

Brexanolone represents a novel approach to the treatment of postpartum mood disorders.  One of the most exciting things about brexanolone is the rapidity of the response — remission of depression within 24 hours!  Because antidepressants typically take 2-4 weeks to kick in, an antidepressant agent with rapid onset of action would be particularly appealing to women with severe PPD, particularly women with suicidality.  

While the published study is very small, Sage Therapeutics has reported similar results in a larger randomized, placebo-controlled trial.  One of the downsides of brexanolone is that it must be given intravenously.  Sage Therapeutics is moving forward with a similar compound (SAGE-217) which is intended for once-daily oral dosing. In an open trial of patients with major (non-postpartum) depression, it appears that SAGE-217 was effective and well-tolerated.  We look forward to hearing more about these novel treatments for PPD.

Ruta Nonacs, MD PhD

 

Kanes SJ, Colquhoun H, Doherty J, Raines S, Hoffmann E, Rubinow DR, Meltzer-Brody S.  Open-label, proof-of-concept study of brexanolone in the treatment of severe postpartum depression.  Hum Psychopharmacol. 2017 Mar;32(2).

 

 

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