Allopregnanolone is all over the place these days.  We have seen several different allopregnanolone derivatives being used to treat postpartum depression (PPD).  Last year, intravenous brexanolone (Zulresso) was approved by the FDA as the first treatment specifically for postpartum depression.  An oral version of allopregnanolone, called zuranolone, is also being pursued as a treatment for PPD.  

In a new study at the MGH Center for Women’s Mental Health, we are using a neurosteroid related to allopregnanolone to treat menopausal depressionAnd there is also sepranolone, which is now in Phase II clinical trials in Europe for the treatment of premenstrual dysphoric disorder (PMDD).   

A Novel Treatment for PMDD?

Various research studies have explored the role that allopregnanolone may play in the etiology of PMDD.  (If you are interested in reading about allopregnanolone and PMDD in greater detail, I would recommend the recent review from Dr. Nell Epper;son.) 

Sepranolone is a new medication which is being developed by Asarina Pharma for the treatment of PMDD.  Sepranolone (study compound UC1010) is isopregnanolone (also known as isoallopregnanolone).  Isopregnanolone is normally produced by the body as a metabolic byproduct of  progesterone, although we do not fully understand the biological effects of isopregnanolone.  

Like brexanololone, isopregnanolone is an allosteric modulator of the GABAA receptor.  Unlike brexanolone, isopregnanolone appears to have no effect on the GABA-A receptor by itself; instead it is a negative allosteric modulator which selectively antagonizes the effects of allopregnanolone.  (Brexanolone is a positive allosteric modulator of the GABAA receptor.)

In a proof of concept study, isoallopregnanolone (UC1010) was tested as a novel treatment  for PMDD. Women with PMDD (n=60) were identified using the Daily Record of Severity of Problems or DRSP scale prior to randomization.  The DRSP scale was also to monitor the effectiveness of treatment.  

The active drug (UC1010) and placebo were administered as subcutaneous injections during the luteal phase of the menstrual cycle.  (From the published report, it is not clear how often the drug was administered.) No severe side effects were reported.)

UC1010 or isopregnanolone was superior to placebo with regard to reduction of negative mood symptoms (70.9% vs. 51.5%, P < .005), as well as total DRSP scores (64.4% vs. 48.1%, P < .01).  The magnitude of the effect size seen with UC1010 in this study was similar to that observed in studies evaluating SSRIs for the treatment of PMDD. Similar to SSRIs, sepranolone did not significantly reduce the physical symptoms of PMDD (such as breast tenderness, headaches, bloating).

The compound UC1010 or isopregnanolone is now called sepranolone and is finishing up Phase II clinical trials in Europe.  The pilot study was fairly large, as far as pilot studies go; however, it will be helpful to have more granular information regarding dosing, side effects, and duration of response.  

At the present time, women with PMDD have only a few treatment options.  Women often try hormonal contraceptives to treat PMDD; however, many women do not experience improvement in their symptoms, and others are not good candidates for hormonal treatments.  SSRIs are highly effective, but many women, especially those who do not have a history of depression, do not like the idea of long-term treatment with an antidepressant. Others cannot tolerate the side effects of SSRIs. 

It would be lovely to have another option to offer women with PMDD.

Ruta Nonacs, MD PhD

Bixo M, Johansson M, Timby E, Michalski L, Bäckström T.  Effects of GABA active steroids in the female brain with a focus on the premenstrual dysphoric disorder.  J Neuroendocrinol. 2018 Feb;30(2).

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