Women with premenstrual dysphoric disorder (PMDD) experience mood symptoms during the late luteal phase of the menstrual cycle, the week preceding the onset of menses. While we do not completely understand what causes PMDD, some experts speculate that these mood changes may be triggered by increasing levels of progesterone and its metabolite, the neuroactive steroid allopregnanolone (ALLO). (If you are interested in reading about allopregnanolone and PMDD in greater detail, I would recommend the recent review from Dr. Nell Epperson.)
Because previous studies have suggested that progesterone and its metabolic byproduct, allopregnanolone, may play a role in the etiology of PMDD, recent treatment approaches for PMDD have focused on modulating the effects of progesterone and allopregnanolone. Sepranolone is a new medication which is being developed by Asarina Pharma for the treatment of PMDD. Sepranolone is isopregnanolone, which is a neuroactive steroid normally produced by the body as a metabolic byproduct of progesterone, although we do not fully understand the biological effects of isopregnanolone.
Sepranolone — like brexanolone, the new treatment of postpartum depression — is an allosteric modulator of the GABA-A receptor. Unlike brexanolone, sepranolone is a negative allosteric modulator; when bound to its site on the GABA-A receptor, sepranolone antagonizes the effects of allopregnanolone. (In contrast, brexanolone is a positive allosteric modulator of the GABA-A receptor and increases GABA activity.)
In a proof of concept study, sepranolone was tested as a novel treatment for PMDD in 60 women. In this placebo-controlled trial, sepranolone outperformed placebo, reducing PMDD mood symptom scores by 75% when administered in the luteal phase in women with PMDD (Bixo et al, 2017).
Phase II Randomized Controlled Trial of Sepranolone
In a Phase II study from Bäckström and colleagues, sepranolone was tested in a larger, double-blind random controlled trial. PMDD was confirmed according to DSM-5 criteria and verified with two menstrual cycles of daily symptom ratings using the Daily Record of Severity of Problems (DRSP) scale in an eDiary. A total of 206 patients with PMDD were recruited from 12 European centers, randomized in a parallel double-blind study and treated with placebo, sepranolone 10 mg or sepranolone 16 mg. Participants self-administered sepranolone subcutaneously every 48 hours during the 14 days prior to the onset of menses for three consecutive menstrual cycles.
When the researchers looked at total symptom scores (Sum21, the score for all 21 symptom questions in the DRSP), they observed improvements in all three groups but did not see a statistically significant difference in response between sepranolone and placebo. However, when they focused on ratings of distress, they did observe that those receiving sepranolone improved more than those receiving placebo (p = 0.037). In addition, there was a trend toward improvement in ratings of impairment.
PMDD studies typically use the five worst days of symptoms to assess PMDD symptoms; however, previous studies have demonstrated that women with PMDD commonly have a longer duration of symptoms, extending beyond the last five days of the luteal phase. In another analysis, the researchers looked at treatment effects over nine premenstrual days in the third treatment cycle. The Sum21 results of this analysis showed that the sepranolone 10 mg was significantly better than placebo (p = 0.008) and was associated with reductions in PMDD symptoms, impairment and distress. A significantly larger number of individuals taking sepranolone 10 mg experienced no or minimal PMDD symptoms (defined as a Sum21 < 42 points) with the 10 mg sepranolone treatment compared to placebo (p = 0.020).
Is Sepranolone a Viable Option for the Treatment of PMDD?
In this phase II study of sepranolone 10 mg and 16 mg administered subcutaneously during the late luteal phase for the treatment of PMDD, sepranolone 10 mg reduced PMDD symptoms significantly more than placebo. (While a dose of 16 mg also resulted in a reduction of symptoms, this was not statistically significant.) Based on DRSP scores, sepranolone at 10 mg resulted in a shift from severe to mild/minimal-absent symptoms. The magnitude of the improvements seen with sepranolone in this study is similar or better than those seen in an earlier study with sepranolone (Bixo et al, 2017) and are similar to improvements observed in PMDD treatment studies with SSRIs.
This study also confirms that sepranolone given subcutaneously is a safe and well tolerated treatment. Very few side effects were observed; injection site reactions were reported with greater frequency. In the 10 mg and the placebo groups injection site pain occurred in 3% and 4%, respectively. However, few participants dropped out due to side effects. What remains to be seen is whether women with PMDD would be willing to use a medication delivered subcutaneously on a monthly basis. Sepranolone injections may not end up being a first-line treatment; however, I suspect that sepranolone may be a viable option for women with more severe PMDD. In this population, the symptoms can be so severe and disabling that women consider oophorectomy (removal of the ovaries) as a possible intervention.
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. There is a clear need for other treatment options to offer to women with PMDD.
Ruta Nonacs, MD PhD
Bäckström T, Ekberg K, Hirschberg AL, Bixo M, Epperson CN, Briggs P, Panay N, O’Brien S. A randomized, double-blind study on efficacy and safety of sepranolone in premenstrual dysphoric disorder. Psychoneuroendocrinology. 2021 Nov;133:105426.