Treatment of premenstrual dysphoric disorder with the GABAAreceptor modulating steroid antagonist Sepranolone (UC1010)-A randomized controlled trial.
BACKGROUND
Allopregnanolone is a metabolite from progesterone and a positive modulator of the GABAAreceptor. This endogenous steroid may induce negative mood in sensitive women when present in serum levels comparable to the premenstrual phase. Its endogenous isomer, isoallopregnanolone, has been shown to antagonize allopregnanolone effects in experimental animal and human models.


OBJECTIVE
The objective was to test whether inhibition of allopregnanolone by treatment with the GABAAmodulating steroid antagonist (GAMSA) Sepranolone (UC1010) during the premenstrual phase could reduce symptoms of the premenstrual dysphoric disorder (PMDD). The pharmacokinetic parameters of UC1010 when given as a subcutaneous injection were measured in healthy women prior to the study in women with PMDD.


METHODS
This was an explorative randomized, double-blind, placebo-controlled study.


METHODS
Swedish multicentre study with 10 centers.


METHODS
Participants were 26 healthy women in a pharmacokinetic phase I study part, and 126 women with PMDD in a phase II study part. Diagnosis followed the criteria for PMDD in DSM-5 using Daily Record of Severity of Problems (DRSP) and Endicott's algorithm.


METHODS
Subjects were randomized to treatment with UC1010 (10 or 16mg) subcutaneously every second day during the luteal phase or placebo during one menstrual cycle.


METHODS
The primary outcome measure was the sum of all 21 items in DRSP (Total DRSP score). Secondary outcomes were Negative mood score i.e. the ratings of the 4 key symptoms in PMDD (anger/irritability, depression, anxiety and lability) and impairment (impact on daily life).


RESULTS
26 healthy women completed the pharmacokinetic phase I study and the dosing in the following trial was adjusted according to the results. 106 of the 126 women completed the phase II study. Within this group, a significant treatment effect with UC1010 compared to placebo was obtained for the Total DRSP score (p=0.041) and borderline significance (p=0.051) for the sum of Negative mood score. Nineteen participants however showed symptoms during the follicular phase that might be signs of an underlying other conditions, and 27 participants had not received the medication as intended during the symptomatic phase. Hence, to secure that the significant result described above was not due to chance, a post hoc sub-group analysis was performed, including only women with pure PMDD who completed the trial as intended (n=60). In this group UC1010 reduced Total DRSP scores by 75% compared with 47% following placebo; the effect size 0.7 (p=0.006), and for sum of Negative mood score (p=0.003) and impairment (p=0.010) with the effect size 0.6. No severe adverse events were reported during the treatment and safety parameters (vital signs and blood chemistry) remained normal during the study.


CONCLUSIONS
This explorative study indicates promising results for UC1010 as a potential treatment for PMDD. The effect size was comparable to that of SSRIs and drospirenone containing oral contraceptives. UC1010 was well tolerated and deemed safe.
Department of Clinical Science, Umeå University, SE-901 85 Umeå, Sweden. Electronic address: marie.bixo@umu.se.
Marie
M
Bixo
Asarina Pharma AB, Fogdevreten 2, SE-171 65 Solna, Sweden.
Karin
K
Ekberg
Department of Women's and Children's Health, Uppsala University, SE-751 85 Uppsala, Sweden.
Inger Sundström
IS
Poromaa
Department of Women's and Children's Health, Karolinska Institutet and Department of Obstetrics and Gynecology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
Angelica Lindén
AL
Hirschberg
Kvinnoforskningsenheten, Karolinska University Hospital, SE-141 46 Huddinge, Sweden.
Aino Fianu
AF
Jonasson
Department of Obstetrics and Gynecology, Sundsvall Hospital, SE-851 86 Sundsvall, Sweden.
Lotta
L
Andréen
Department of Clinical Science, Umeå University, SE-901 85 Umeå, Sweden.
Erika
E
Timby
Slottsstadens Läkarhus Malmö, Fågelbacksgatan 11, SE-217 44 Malmö, Sweden.
Marianne
M
Wulff
Specialistläkarna Kungsbacka (Qvinnolivet), Södra Torggatan 18, SE-434 30 Kungsbacka, Sweden.
Agneta
A
Ehrenborg
Department of Clinical Science, Umeå University, SE-901 85 Umeå, Sweden.
Torbjörn
T
Bäckström
D000328:Adult; D000339:Affect / Q000502:physiology; D000786:Anger; D001007:Anxiety; D003276:Contraceptives, Oral / Q000494:pharmacology; D003863:Depression; D004311:Double-Blind Method; D005260:Female; D005498:Follicular Phase; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D006801:Humans; D008183:Luteal Phase / Q000187:drug effects; D008597:Menstrual Cycle; D008875:Middle Aged; D011280:Pregnanolone / Q000494:pharmacology* / Q000627:therapeutic use*; D065446:Premenstrual Dysphoric Disorder / Q000188:drug therapy*; D011293:Premenstrual Syndrome; D011374:Progesterone / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D003276:Contraceptives, Oral; D058787:GABA-A Receptor Antagonists; D011280:Pregnanolone; D011374:Progesterone; D011963:Receptors, GABA-A; D017367:Selective Serotonin Reuptake Inhibitors
Allopregnanolone; GABA; Isoallopregnanolone; Premenstrual dysphoric disorder; Randomized controlled trial