1 Ulipristal Acetate for Treatment of Premenstrual

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Ulipristal Acetate for Treatment of Premenstrual
Dysphoric Disorder: A Proof-of-Concept Randomized
Controlled Trial
Erika Comasco, Ph.D., Helena Kopp Kallner, M.D., Ph.D., Marie Bixo, M.D., Ph.D., Angelica L. Hirschberg, M.D., Ph.D.,
Sara Nyback, R.N., Haro de Grauw, M.Sc., C. Neill Epperson, M.D., Inger Sundström-Poromaa, M.D., Ph.D.
Objective: Premenstrual dysphoric disorder (PMDD) is a com-
mon mood disorder, characterized by distressing affective,
behavioral, and somatic symptoms in the late luteal phase of
the menstrual cycle. The authors investigated continuous
treatmentwith a selective progesterone receptormodulator,
ulipristal acetate (UPA), as a potential treatment for PMDD.
Methods: The authors conducted an investigator-initiated,
multicenter, double-blind, randomized, parallel-group clinical
trial in which women with PMDD (N=95) were treated with
either 5 mg/day of UPA or placebo during three 28-day
treatment cycles. The primary outcome was the change in
premenstrual total score on the Daily Record of Severity of
Problems (DRSP) from baseline to end of treatment. DRSP
scores were captured by daily ratings using a smartphone
application and were analyzed with linear mixed models for
repeated measures.
Results: The mean improvement in DRSP score after 3
months was 41% (SD=18) in the UPA group, compared with
22% (SD=27) in the placebo group (mean difference 218%;
95% CI=229,28). Treatment effects were also noted for the
DRSPdepressive symptomsubscale (42% [SD=22] compared
with 22% [SD=32]) and the DRSP anger/irritability subscale
(47% [SD=21] compared with 23% [SD=35]), but not for the
DRSP physical symptom subscale. Remission based onDRSP
score was attained by 20 women in the UPA group (50.0%)
and eight women in the placebo group (21.1%) (a statistically
significant difference).
Conclusions: If these results are replicated, UPA could be a
useful treatment for PMDD, particularly for the psychological
symptoms associated with the disorder.
AmJPsychiatry 2021; 178:256–265; doi: 10.1176/appi.ajp.2020.20030286
Premenstrual dysphoric disorder (PMDD) is a common
mood disorder occurring in 3%25% of reproductive-age
women (1). According to DSM-5 (2), PMDD is character-
ized by distressing affective, behavioral, and somatic symp-
toms in the late luteal phase of themenstrual cycle. Hallmark
mood symptoms include mood lability, irritability, anxiety,
and depression (1).
Fluctuations in ovarian steroids, in particular progesterone,
arethought tounderlie thepathophysiologyofPMDD.Research
in support of this include the temporal relationship with pro-
gesterone during the menstrual cycle, symptom relief during
gonadotropin-releasing hormone (GnRH) agonist–induced
anovulatory cycles (3), the reinstatement of symptoms when
add-back progesterone (and estradiol) is administered together
with GnRH agonists (4), and findings of progestin-induced
mood symptoms in postmenopausal women (5–7). The criti-
cal impact of acute variations in progesterone and estradiol on
PMDDsymptoms further supports the pathophysiologic role of
fluctuations in ovarian steroids in PMDD (8).
Progesterone is highly lipophilic andeasily passes through
the blood-brain barrier (9). Animal studies and postmortem
studies in reproductive and postmenopausal women indicate
that progesterone is accumulated in the brain (10–12), with
the highest concentrations found in the amygdala (10).
Preclinical data suggest that progesterone receptors are found
throughout the amygdala, hippocampus, hypothalamus,
thalamus, and frontal cortex (13–17), regions of importance in
emotionprocessing.Although the exactmechanismbywhich
progesterone precipitates the symptoms of PMDD is un-
known, interactions with the serotonin (18, 19) and the
GABAergic systems (20, 21) are plausible (22).
Ulipristal acetate (UPA) is a selective progesterone re-
ceptor modulator that acts as a progesterone antagonist in
progesterone-responsive tissues, including the brain (23).
UPA binds to progesterone receptors A and B with high
affinity (24, 25) and interferes with progesterone receptor–
mediated DNA transcription (26). UPA, in the dose and reg-
imen employed in this study, is used for treatment of uterine
See related features: Editorial by Dr. Rubinow (p. 215), and Video by Dr. Pine (online)
256 ajp.psychiatryonline.org Am J Psychiatry 178:3, March 2021
ARTICLES
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fibroids (27). Low-dose continuous UPA treatment leads to
anovulation in approximately 80% of women with uterine
fibroids (23); this effect and progesterone receptor antago-
nism are the suspected mechanisms for symptom relief in
women with PMDD. Thus, the aim of this proof-of-concept
study was to investigate the usefulness of UPA for treat-
ment of PMDD. We hypothesized that overall premenstrual
PMDD symptoms would improve in the group treated with
UPA compared with the placebo group, with efficacy being
more marked for the mental symptoms of irritability and
depression.
METHODS
Participants
The study was carried out at the Departments of Obstetrics
and Gynecology at Uppsala University Hospital, Karolinska
UniversityHospital, DanderydUniversityHospital, andUmeå
University Hospital between January 15, 2017, and October
19, 2019. Because of the European Medical Agency’s Phar-
macovigilance Risk Assessment Committee review of the
study drug, recruitment was temporarily stopped between
February 9, 2018, and August 13, 2018. We recruited par-
ticipants by advertisements in local newspapers and social
media.
Womenwereeligible if theywere18–46yearsofage,healthy,
had regular menstrual cycles, and met criteria for PMDD. We
excluded women who had ongoing mental health problems as
assessed with the Mini International Neuropsychiatric In-
terview (MINI) (28), ongoing drug or alcohol abuse, past
hospitalization for a psychiatric disorder or attempted suicide,
or treatment with psychotropic medication during the pre-
vious 3months. In addition, we excludedwomenwith severe
medical conditions, including liver disease, women who had
been treated with hormonal contraceptives or any other
steroid hormone treatment during the previous 3 months,
women who were breastfeeding, pregnant, or planned a
pregnancy, and women with abnormal liver function tests.
Women with past depressive and anxiety disorders were
allowed to participate in the study. Past depressive episodes
and past panic disorder were captured by the MINI. Past
anxiety disorders and treatment were assessed with struc-
tured questions in the case report form.
Weused theDailyRecord of Severity of Problems (DRSP),
filled out daily for at least two menstrual cycles using a
smartphone application, for the PMDD diagnosis (29). The
DRSP consists of 21 items that reflect the 11 candidate
symptoms for PMDD, depression, anxiety, mood swings, ir-
ritability, decreased interest in usual activities, difficulties
concentrating, fatigue, sleep disturbances, increased appe-
tite or cravings, sense of being overwhelmed, and physical
symptoms. Each item is scored on a 6-point Likert scale
ranging from 1 (not at all) to 6 (extreme).
According to DSM-5, PMDD is defined as an increase
.50% in at least five of 11 symptoms between the follicular
(days 6–12) and luteal phase (days27 to21). Among the five
symptoms, at least onemust be a core symptom (30). Percent
increase was calculated as (mean luteal phase scores2mean
follicular phase scores / mean follicular phase scores)3 100.
We required that diagnostic symptoms be at leastmild (mean
luteal phase score.3.0) anddisappearedduring the follicular
phase (mean follicular phase score ,2.0). If women did not
meet criteria for PMDDafter 2months of charting, theywere
allowed to score symptoms for an additional cycle. However,
only two women who needed a follow-up cycle were even-
tually included. The majority of women who needed a
follow-up cycle did not meet diagnostic criteria. Additionally,
as part of the daily diary, women were asked to report on
menstrual bleeding.
Thewomenreceivedoral andwritten informationandhadthe opportunity to ask questions before signing informed
consent in the presence of an investigator. They were not
reimbursed. The study procedures were conducted in ac-
cordance with Good Clinical Practice and the Helsinki Dec-
laration’s ethical standards for human experimentation. The
study was approved by the Regional Ethical Review Board
(2016/184), Uppsala, and the Medical Products Agency in
Sweden. The clinical trial identifier is EudraCT 2016-
001719-19.
Study Design and Procedures
The study was an investigator-initiated, multicenter, double-
blind, randomized, parallel-group clinical trial in which par-
ticipantswere treatedwitheither5mg/dayofUPAorplacebo
during three 28-day treatment cycles. Women were ran-
domly assigned to these treatments in a 1:1 ratio.
Screening, study visits, and assessments. Eligible women first
attended a screening visit, during which demographic data
and information on previous, recent, and ongoingmedication
were collected. After two diagnostic cycles, eligible women
made a second visit (baseline/randomization), scheduled in
the late luteal phase. At this visit, they filled out the EuroQoL
visual analogue scale (EQ-VAS) (31) and the Montgomery-
Åsberg Depression Rating Scale, self-rated version (MADRS-S)
(32). After randomization, women started taking the study
drug on the first day of menses. Participants were not in-
formed that UPA could alter their menstrual cycles. The last
and thirdvisitwasmadeduring thepremenstrual phaseof the
third treatment cycle or, for womenwho developed irregular
menses or lost their menses, during the final week of active
treatment. At the last visit, participantsfilled out the EQ-VAS
and MADRS-S once again. A blood sample was collected at
baseline and during the final visit for hormone analyses. In
between the face-to-face meetings, the study nurses were
in contact with the patients by telephone during the first
treatment cycle. Any adverse events or change in concomitant
medicationwerequeried and registeredat eachvisit.The study
nurses followed the daily symptom charts and contacted pa-
tients who failed to chart symptoms for more than 3 consec-
utivedays.AsofFebruary9,2018,allwomenmadeanadditional
visit during each treatment cycle for liver function tests.
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COMASCO ET AL.
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UPA and placebo. UPA and identical-looking placebo tablets
were provided by Gedeon Richter Nordics AB. Apoteksbo-
laget Production and Laboratories (theNational Corporation
of Swedish Pharmacies) prepared the randomization lists,
using a computerized random number generator in blocks of
four, whichwas blinded to the local investigators. Recipharm
AB (Stockholm) did the packaging and labeling of study
drugs.At randomization, participants received thenumbered
containerwith the lowest available number.During the study,
participants and study personnel were not informed about
which treatment the patient received, and randomization
codes were kept at Recipharm AB until the study was com-
pleted. Upon completion of the study, participants brought
backemptycontainersandanyremainingtabletswerecounted
by the study nurses.
Hormone analyses. Venous blood samples were collected
from each participant to determine the levels of estradiol and
progesterone. Steroid hormones were measured in serum at
theCore Facility ofMetabolomics at theUniversity of Bergen
by liquid chromatography–tandem mass spectrometry.
Sample processing was robotized (Hamilton STAR) and in-
cluded protein precipitation with acetonitrile and liquid-
liquid extraction with ethyl acetate-heptane. The samples
were analyzed on an Acquity UPLC system (Waters,Milford,
Mass.) connected to a Xevo TQ-S tandemmass spectrometer
(Waters). The compounds were separated on a C-18 column
(5032.1 mm, 1.7-mm particle size), which is developed by
gradient elution over 14 minutes, using water and methanol
containing ammonium hydroxide as mobile phases. They
were detected in negative (e.g., estradiol) or positive ion
(progesterone)MRMmode. Twoproduct ions aremonitored
for each compound to check for interferences. Themethod is
validated for estradiol (sensitivity, 3.6 pmol/L [lower limit of
quantitation] and 1.2 pmol/L [level of detection] and total
control volume [coefficient of variation] for intermediate
concentrations, 5.0%) and progesterone (10.3%). Because of
theCOVID-19pandemic, only 70 samples at baseline (36 from
the UPA treatment group) and 46 samples at follow-up
(22 from the UPA group) could be analyzed.
Outcomes
Weanticipated thatwomen assigned toUPA treatment could
develop amenorrhea or sparse menstrual cycles (.35 days
between menses). Thus, treatment outcomes are reported in
relation to premenstrual periods rather than treatment cy-
cles. We evaluated treatment outcomes during 5 premen-
strual daysof the two lastmenstrual cycles of eachparticipant
during the study period (here referred to as the penultimate
and last premenstrual periods). Inwomenwhohad nomenses
during the study period, the final 5 days of treatment cycles
2 and 3were used—that is, the approximate days of their luteal
phases had their menses continued to be regular.
The primary outcome measure was the change from
baseline in premenstrual DRSP total score.We generated the
DRSP total score by computing themean of each item during
the final 5 days of the premenstrual phase of the baseline and
treatment cycles, and summed the 21 items.
Secondary outcomes were change from baseline in three
DRSP subscales, in the individual DRSP symptoms, and the
threeDRSP functional items. TheDRSPdepressive symptom
subscale consists of the symptoms felt depressed, felt hopeless,
felt worthless or guilty, slept more, had trouble sleeping, and
felt overwhelmed; the anger/irritability subscale consists of
the symptoms anger and/or irritability and conflicts with
others; and the physical symptom subscale consists of the
symptoms breast tenderness, bloating, headache, and joint or
muscle pain. The subscales and individual symptoms, in-
cluding the functional items, from the DRSP were scored on
the same days as the DRSP total score.
We also evaluated PMDD remission at the final treatment
cycle, basedon themeanpremenstrualDRSPscores fromthis
cycle. In linewith thediagnostic criteria forPMDD, complete
remission was defined as no symptom with a mean pre-
menstrual score.3.0 during thefinal treatment cycle. Partial
remissionwas defined as having one to four symptomswith a
mean lutealphase score.3.0during thefinal treatmentcycle.
Because of many prolonged menstrual cycles, we refrained
from using change from follicular phase in the remission
criteria.
Secondary outcomes also included self-rated depressive
symptoms (MADRS-S) and quality of life (EQ-VAS). The
MADRS-S inquires about nine symptoms of depression, each
rated on a six-point scale (e.g., with regard to inability to
feel: 0=normal interest in surroundings/other people; 2=
reduced ability to enjoy usual interests; 4=loss of interest in
surroundings/loss of feelings for friends; 6=emotionally
paralyzed, unable to feel anger, grief, or pleasure; complete
failure to feel for close relatives and friends), yielding a
maximum score of 54. Compared with other depression rating
scales, the psychometric profile of theMADRS-S is excellent
for detecting change in depressive symptoms (33). We com-
pared the change from baseline in luteal phase MADRS-S
scores between treatment groups.
The EQ-5D is the most widely used generic patient-
reported outcome questionnaire internationally, capturing
information on mobility, self-care, usual activities, pain/
discomfort, and anxiety/depression (34). For this relatively
young population, we used the EQ-VAS, which measures
current health status on a scale from 0 to 100, where 0 is the
worst imaginable health state and 100 is the best. We com-
pared the change frombaseline in luteal phaseEQ-VASratings
between treatments.
Statistical Analysis
The power analysis was based on other strategiesthat are
used to inhibit ovulation inwomenwithPMDD(35).Basedon
a difference of 1.5 of the core DRSP symptoms and a standard
deviation ranging between 1.8 and2.0,wehadmore than 90%
power to detect a difference between treatments after
recruiting 75 subjects. As for treatment response, the study
had sufficient power (.80%) to detect a difference between
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ULIPRISTAL ACETATE FOR TREATMENT OF PREMENSTRUAL DYSPHORIC DISORDER
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treatments, assuming complete or partial response in 75% of
womenrandomized toUPAand40%remission in theplacebo
group. As we assumed a 25% dropout rate, we planned to
recruit 100 women.
Primary outcomes. We used an intention-to-treat concept—
that is, women were retained in the analyses if they had
sufficient data—and primary analyses were performed with
unblinded data. We used linear mixed-model analysis of
variance to evaluate the treatment effect onDRSP total score.
Participants were entered as subjects, with time point
(baseline and the last two premenstrual periods) as a re-
peated variable, and using the first-order autoregressive
repeated covariance type. Treatment (UPA or placebo) was
entered as a fixed factor, and the maximum likelihood es-
timation method was used. The interaction term between
treatment and time was included to assess the effect of
treatment. We calculated mean difference and 95% confi-
dence intervals for the DRSP total score for the last two
premenstrual periods.
Secondary outcomes. We used the same approach for the
DRSP summed subscales and individual symptoms, the
MADRS-S scores, and the ED-VAS scores as we did for the
DRSP total score.
Chi-square tests were used to compare the treatment
response between UPA and placebo. Correction for multiple
testing was applied to the DRSP subscales (three tests), the
DRSP single items (21 tests), and the functional subscales
(three tests).
SPSS (IBM, Armonk, N.Y.) was used for the analyses, and
p values ,0.05 were considered statistically significant.
RESULTS
Study Population
In total, 95 women with PMDD underwent randomized
assignment to either UPA (N=48) or placebo (N=47) (see
Figure S1 in the online supplement). Seventeen women
discontinued (eight in theUPA group and nine in the placebo
group; thedropout ratewas 17.9%),mostoftenduring thefirst
treatment cycle (eight in the UPA group and five in the
placebo group). Sevenwomen in theUPAgroupdiscontinued
because ofmild ormoderate side effects. Themost commonly
reported side effects that led to discontinuation in the UPA
group were headache, fatigue, and nausea, but one woman
discontinued because of worsening of depressive symptoms.
Among women in the placebo group, three discontinued
because of depressive symptoms or anxiety. Two of the
women who dropped out had data that could be included in
the primary outcome analyses. According to hormonal levels
measured at baseline, women were assessed during the late
luteal phase (meanestradiol levels, 416 pmol/L [SD=287], and
mean progesterone level, 17.8 nmol/L [SD=15.0]), with no
significant differences between groups. As expected, the
women in the UPA group had lower progesterone levels
(5.8 nmol/L, SD=9.9) than those in the placebo group
(15.0 nmol/L, SD=16.3) at the last premenstrual period (t=2.3,
df=44, p=0.03), while estradiol levels remained in the mid-
follicular range (488 pmol/L [SD=418] compared with
402 pmol/L [SD=267]; t=20.83, df=44, p=0.41).
Among women who completed the study, 6 days (SD=11)
were missing in the daily diaries, mostly outside the pre-
menstrual phase. Two women with more than 40% missing
days were excluded from the analyses that incorporated the
DRSP ratings. Thus, 41 women in the UPA group and 39 the
placebo group were included in the analyses. Adherence to
treatment was good, with 0–5 remaining tablets at the final
visit among women who completed the trial. Among women
in theUPA groupwho completed the study, 11 (27.5%) had no
menses during the study period, 23 (57.5%) had sparse
menses (i.e., more than 35 days between menses), and six
(15.0%) maintained regular menses.
The demographic and clinical characteristics of the study
population are summarized in Table 1. The mean age of
women in the placebo and UPA groups was 35.0 years
(SD=6.4) and 36.6 years (SD=5.7), respectively. The majority
TABLE 1. Demographic and clinical characteristics of participants
in a study of ulipristal acetate for PMDDa
Placebo Group
(N=47)
UPA Group
(N=48)
Characteristic N % N %
Age group
20–29 years 10 21.3 8 16.7
30–39 years 21 44.7 24 50.0
.40 years 16 34.0 16 33.3
Smoker 7 14.9 2 4.2
Civil status
Married or cohabiting 34 72.3 34 70.8
Single living but in
relationship
4 8.5 6 12.5
Single 9 19.1 8 16.7
Parity
Nulliparous 20 42.6 18 37.5
Parous 27 57.4 30 62.5
Education level
University examination 35 74.5 35 72.9
No university examination 12 25.5 13 27.1
Employment
Working part-time or
full-time
39 83.0 45 93.8
Studying 5 10.6 2 4.2
Other 3 6.4 1 2.1
Previous treatment for PMDD
Any treatment 32 68.1 36 75.0
Antidepressant treatment 25 45.5 30 54.5
Hormonal treatmentb 14 29.8 13 27.1
Psychological treatment 6 12.8 2 4.2
Psychiatric history
Previous depressive episode 28 59.6 33 68.7
Previous anxiety disorder 7 14.9 4 8.3
a PMDD=premenstrual dysphoric disorder; UPA=ulipristal acetate.
b Combined hormonal contraceptives, gonadotropin-releasing hormone
agonists, or progesterone/progestogen treatment.
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of women were married or cohabiting, were working part-
timeor full-time, andhadahigheducation level. Themajority
had a history of depressive episodes or anxiety disorders, and
more than two-thirds hadpreviously been treated forPMDD.
Among women who had previously used antidepressants,
35.7% had stopped because of nonresponse. We found no
significant differences between the two treatment groups in
demographic and clinical variables.
TABLE2. Symptomscores forparticipants inastudyofulipristalacetate forPMDDatbaselineandat thepenultimateand lastpremenstrual
periods of the studya
Baseline
Penultimate Premenstrual Period Last Premenstrual Period
UPA (N=48)
Placebo
(N=47)
UPA
(N=40)
Placebo
(N=38)
Difference in
Change From
Baseline UPA (N=39)
Placebo
(N=37)
Difference in
Change From
Baseline
Variable Mean SD Mean SD Mean SD Mean SD Mean 95% CI Mean SD Mean SD Mean 95% CI pb
Total DRSP score 69.6 18.7 73.8 15.8 38.2 12.5 52.6 20.1 –11.4 –19.5, –3.3 39.2 13.9 57.2 23.0 –11.6 –20.4, –2.8 0.003
Change from
baseline in total
DRSP score (%)
43 17 27 23 –16 –25, –6 41 18 22 27 –18 –29, –8 0.003
DRSP subscale
scores
Depressive
symptoms
20.0 5.6 21.4 4.5 11.1 4.7 15.0 6.1 –2.8 –5.2, –0.3 10.9 4.0 16.4 6.9 –3.4 –6.1, –0.8 0.009
Anger/irritability 7.4 2.3 7.4 1.9 3.5 1.5 5.1 2.6 –1.7 –2.8, –0.7 3.8 1.3 5.6 2.6 –1.8 –2.9, –0.7 0.001
Physical symptoms 10.4 4.2 11.6 3.7 7.4 3.1 8.9 3.6 –0.4 –2.1, 1.3 7.3 3.3 9.7 4.1 –0.9 –2.5, 0.8 0.5
Individual DRSP
scores
Felt depressed 3.7 1.0 3.7 1.0 1.8 0.9 2.6 1.3 –0.8 –1.3, –0.3 1.9 0.7 2.7 1.4 –0.7 –1.2, –0.2 0.001
Felt hopeless 3.4 1.2 3.7 0.9 1.8 1.0 2.3 1.2 –0.2 –0.8, 0.3 1.7 0.7 2.6 1.4 –0.6 –1.1, 0.0 0.1
Felt worthless
or guilty
3.5 1.2 3.7 0.9 1.9 0.9 2.3 1.3 –0.3 –0.8, 0.2 1.9 0.8 2.5 1.2 –0.4 –0.9, 0.1 0.2
Felt anxious 3.7 1.1 3.7 1.0 1.9 1.0 2.7 1.3 –0.7 –1.2, –0.2 2.0 0.8 2.9 1.3 –0.7 –1.3, –0.2 0.004c
Had mood swings 3.9 1.1 4.1 0.9 1.8 0.9 2.8 1.3 –0.8 –1.4, –0.3 1.9 0.9 2.9 1.4 –0.7 –1.2,–0.2 0.003c
Sensitive to rejection 3.7 1.1 4.0 0.9 1.8 0.9 2.6 1.4 –0.5 –1.1, 0.0 2.0 1.0 2.9 1.4 –0.5 –1.0, 0.1 0.2
Angry, irritable 4.0 1.1 4.0 1.0 1.9 0.9 2.8 1.4 –0.9 –1.5, –0.4 2.0 0.7 3.0 1.4 –1.0 –1.6, –0.4 0.001
Had conflicts or
problems
3.4 1.2 3.4 1.0 1.6 0.8 2.4 1.3 –0.8 –1.3, –0.3 1.7 0.7 2.6 1.3 –0.8 –1.4, –0.3 0.001
Decreased interest
in usual activities
3.7 1.2 3.9 0.9 1.8 0.9 2.8 1.4 –0.8 –1.4, –0.2 2.0 0.9 3.0 1.5 –0.8 –1.4,–0.1 0.014c
Difficulties
concentrating
3.6 1.2 3.7 1.1 1.8 0.8 2.6 1.3 –0.8 –1.4, –0.2 1.9 0.9 2.9 1.4 –0.8 –1.4, –0.3 0.002
Lack of energy 4.1 1.1 4.2 0.9 2.1 1.0 3.4 1.4 –1.1 –1.6, –0.6 2.3 1.1 3.5 1.3 –0.9 –1.5, –0.3 0.001
Increased appetite 3.2 1.3 3.3 1.5 1.7 1.0 2.4 1.4 –0.6 –1.1, 0.0 1.8 0.9 2.5 1.6 –0.5 –1.0, 0.1 0.1
Cravings for specific
food
3.1 1.3 3.4 1.4 1.7 0.9 2.4 1.5 –0.4 –1.0, 0.2 1.7 0.9 2.6 1.6 –0.4 –1.0, 0.1 0.2
Slept more 3.4 1.3 3.5 1.2 2.0 1.1 2.6 1.3 –0.5 –1.1, 0.1 1.9 1.0 2.9 1.3 –0.8 –1.4, –0.1 0.013c
Had trouble sleeping 2.7 1.3 3.2 1.2 1.8 1.1 2.5 1.2 –0.3 –0.9, 0.3 1.8 1.0 2.7 1.5 –0.3 –0.9, 0.3 0.5
Felt overwhelmed 3.3 1.2 3.5 1.0 1.7 0.9 2.5 1.2 –0.6 –1.2, –0.1 1.8 0.9 2.9 1.4 –0.7 –1.2, –0.1 0.015c
Felt out of control 2.9 1.3 3.2 0.8 1.5 0.8 2.0 1.1 –0.3 –0.8, 0.3 1.6 0.8 2.4 1.3 –0.3 –0.8, 0.2 0.5
Breast tenderness 2.7 1.4 2.9 1.4 2.0 1.5 2.4 1.5 –0.3 –1.0, 0.4 1.9 1.4 2.4 1.4 –0.3 –1.0, 0.4 0.6
Bloated 3.4 1.5 3.7 1.3 2.3 1.4 2.7 1.5 0.1 –0.7, 0.9 2.2 1.3 2.9 1.4 –0.1 –0.8, 0.7 0.6
Headache 2.1 1.0 2.4 1.1 1.5 0.7 1.8 1.0 0.2 –0.5, 0.4 1.6 0.7 1.9 1.1 0.0 –0.5, 0.5 1.0
Joint or muscle pain 2.3 1.3 2.7 1.2 1.5 0.8 2.0 1.0 –0.1 –0.6, 0.4 1.6 0.9 2.3 1.3 –0.3 –0.7, 0.2 0.4
Functional
impairment
Work function 3.5 1.1 3.9 0.9 1.7 0.9 2.6 1.4 –0.6 –1.2, –0.1 1.8 0.9 2.9 1.4 –0.7 –1.2, –0.1 0.018c
Social function 3.4 1.2 3.8 1.0 1.6 0.8 2.6 1.4 –0.7 –1.4, –0.1 1.7 0.9 2.8 1.5 –0.7 –1.3, –0.1 0.008
Family function 3.5 1.2 3.7 1.0 1.6 0.7 2.5 1.4 –0.6 –1.2, –0.1 1.7 0.8 2.7 1.4 –0.7 –1.2, –0.1 0.012
Secondary
outcomes
MADRS-S score 20.8 10.2 23.0 10.1 7.6 8.2 12.7 10.1 –1.0 –6.5, 4.5 0.7
EQ-VAS score 47 18 42 22 78 15 62 22 10 –3, 24 0.2
a DRSP=DailyRatingof Severity of Problems; EQ-VAS=EuroQoLvisual analogue scale;MADRS-S=MontgomeryÅsbergDepressionRatingScale, self-rated version;
PMDD=premenstrual dysphoric disorder; UPA=ulipristal acetate.
b Treatment-by-time interaction, mixed-model analysis of variance.
c Not significant after correction for multiple testing.
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Primary Outcome
Primary and secondary treatment outcomes are presented in
Table 2.We found significant treatment-by-time interactions
in favor forUPA treatment forDRSP total score (F=6.02, df=2,
134.8, p=0.003). The mean improvement in DRSP total score
at the penultimate premenstrual period was 43% (SD=17) in
the UPA group, compared with 27% (SD=23) in the placebo
group (mean difference, 216%, 95% CI=225, 26). The
corresponding numbers during the last premenstrual period
were 41% (SD=18) and 22% (SD=27) in the UPA and placebo
groups, respectively (mean difference, 218%, 95% CI=
229, 28). Figure 1 illustrates DRSP scores across the pre-
menstrual periods of the study.
Secondary Outcomes
We noted significant treatment-by-time interactions for the
DRSP depressive symptom subscale (F=4.92, df=2, 133.0,
p=0.009) and the DRSP anger/irritability subscale (F=8.53,
df=2, 140.3, p,0.001), butnot for theDRSPphysical symptom
subscale (F=0.72, df=2, 142.6, p=0.5) (Table 2). The treatment
effects were observed by the penultimate premenstrual pe-
riod on the DRSP depressive symptom subscale (mean dif-
ference between treatments in change from baseline, 22.8,
95% CI=25.2, 20.3) and on the DRSP anger/irritability
subscale (mean difference between treatments in change
frombaseline,21.7, 95%CI=22.8,20.7) (Table 2). In the last
premenstrual period, the mean difference in change from
baseline was 23.4 (95% CI=26.1, 20.8) for the DRSP de-
pressive symptomsubscale and21.8 (95%CI=22.9,20.7) for
the DRSP anger/irritability subscale (Table 2).
We found significant treatment effects, favoringUPA, for a
number of individual symptoms on the DRSP scale, although
some items did not remain significant after correction for
multiple testing: felt depressed (F=6.98, df=2, 140.0, p=0.001),
angry/irritable (F=8.38, df=2, 135.5, p,0.001), had conflicts or
problems with others (F=6.92, df=2, 144.8, p=0.001), and lack
of energy (F=9.28, df=2, 126.7, p,0.001) (Table 2). Formost of
these symptoms, treatment effects were noticeable by the
penultimate premenstrual period (Figure 2). The UPA and
placebo groups did not differ in physical symptom severity
from baseline to end of study (all p values .0.05) (Table 2).
We also noted treatment effects, favoring UPA, in the
DRSP functional items, namely, social function (F=4.96, df=2,
129.0, p=0.008) and family function (F=4.60, df=2, 140.9,
p=0.012) (Table 2).
Complete or partial remission during the last pre-
menstrual period was attained by 20 women (50.0%) and
14 women (35.0%), respectively, in the UPA group, whereas
the corresponding numbers in the placebo group were eight
women (21.1%) and 12 women (31.6%), respectively (x2=11.2,
p=0.004).
Women in both treatment groups had lower MADRS-S
and higher EQ-VAS scores at the final visit, but no effect of
UPA treatment was demonstrated (MADRS-S score, F=0.14,
df=1, 74, p=0.7; EQ-VAS score, F=2.09, df=1, 73, p=0.2)
(Table 2).
Side Effects
Side effectswere rare (seeTableS1 in theonline supplement).
The most commonly reported side effects among women in
the UPA group were headache (8.3%), nausea (8.3%), and
fatigue (6.3%). Nausea was significantly more common
among women in the UPA group than in the placebo group
(x2=4.1, p=0.043). No other differences in side effects were
noted. No serious adverse events occurred, and none of the
women had abnormal liver function tests at any point during
the study.
DISCUSSION
The present findings suggest that UPA is an effective treat-
ment for PMDD, and particularly for the mental symptoms
associated with the syndrome. We found significant treat-
ment effects for the DRSP total score and the depressive
symptom and anger/irritability subscales. Complete or par-
tial remission was attained by 85% of women in the UPA
treatment group. Improvements were noted in quality of life
and self-reported depressive symptoms in both groups, al-
though the improvement did not differ significantly between
the treatment groups.
FIGURE 1. Symptom scores across premenstrual periods for
patients with PMDD being treated with ulipristal acetate or
placeboa
Baseline Penultimate Last Baseline Penultimate Last
D
R
S
P
 S
c
o
re
Premenstrual Period
0
80
60
40
20
140
120
100
UPA Placebo
aDRSP=Daily Record of Severity of Problems; PMDD=premenstrual
dysphoric disorder; UPA=ulipristal acetate.
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COMASCO ET AL.
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No previous studies have investigated UPA for use in
PMDD, but the results are not surprising given that con-
tinuousUPA treatment leads to anovulation in themajority of
women (23). Previous attempts to use treatments that induce
anovulation, such as GnRH agonists, have been successful in
alleviating both mental and physical PMDD symptoms (3, 4).
However, the usefulness of GnRH agonists is limited by their
hypoestrogenic side effects, which in the short term are
experienced by the women as vasomotor symptoms, and in
the long term may lead to bone demineralization (3, 4). In
contrast, with UPA treatment, estradiol serum concentra-
tions are maintained at mid-follicular-phase levels (23), and
women onUPA rarely suffer from vasomotor symptoms (36).
This study also confirms the beneficial side effect profile of
the compoundand themaintainedestradiol levels (26, 27, 36).
Two small randomized clinical trials conducted in the
1990s with a progesterone receptor antagonist were likely
compromised by the administration of the drug days after
ovulation, which is too late in themenstrual cycle to have any
effect (37, 38).
While UPAwas effective in treating themental symptoms
of PMDD, we found no beneficial effects on the physical
symptoms. This is in contrast with the GnRH agonists and
certain combined hormonal contraceptives, which are helpful
also for breast tenderness,bloating, and other physical symp-
toms associated with the syndrome (3, 39). Reasons for the
absence of treatment effect on physical symptomsmay reside
in the study population, mainly characterized by high scores
on mental symptoms, or progesterone receptor agonist ef-
fects in certain tissues, or insufficient suppressionof estradiol
levels (23).Moreover, in contrast to the emotional symptoms,
somatic symptoms have also shown limited improvement in
studies of serotonin reuptake inhibitors with various dosing
regimens (40, 41). Physical discomfort may, however, be
better tolerated in the presence of diminished irritability and
dysphoria.
The strengths of the study include its being a multicenter
randomized controlled trial and the use of daily diaries for
capturing bothmenses andmental symptoms throughout the
study. Adherence was excellent, both with treatment and
with daily symptom chartings. Another strength is the three-
cycle duration, which demonstrates the persistence of
response and the viability of the treatment over time. The
use of one primary outcome measure (i.e., change from base-
line in premenstrual DRSP total score) in an adequately
powered sample is another strength. Given that this was a
FIGURE 2. Improvement from baseline in symptoms in patients with PMDD treated with ulipristal acetate, compared with the placebo
group, on the penultimate and last premenstrual cyclesa
Worthless,
guiltyConflicts
 Angry, 
irritable
 Sensitive 
to rejectionMood swings Depressed
Anhedonia Concentration
Energy
loss Appetite
Food
craving Fatigue Sleep Overwhelmed
Control
loss
Hopeless Anxious
Affective Lability Irritability, Anger, or Conflicts Depressed Mood
Anxiety and
Tension
UPAPlacebo
Penultimate premenstrual cycle
Last premenstrual cycle
M
e
a
n
 D
e
c
re
a
se
 i
n
 D
R
S
P
 S
y
m
p
to
m
 S
c
o
re
C
o
m
p
a
re
d
 t
o
 B
a
se
li
n
e
 (
%
)
M
e
a
n
 D
e
c
re
a
se
 i
n
 D
R
S
P
 S
y
m
p
to
m
 S
c
o
re
C
o
m
p
a
re
d
 t
o
 B
a
se
li
n
e
 (
%
)
0
20
10
40
30
60
50
20
10
0
40
30
60
50
aDRSP=Daily Record of Severity of Problems; PMDD=premenstrual dysphoric disorder; UPA=ulipristal acetate.
262 ajp.psychiatryonline.org Am J Psychiatry 178:3, March 2021
ULIPRISTAL ACETATE FOR TREATMENT OF PREMENSTRUAL DYSPHORIC DISORDER
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proof-of-concept study, the findings related to the secondary
outcomes were presented according to an exploratory ap-
proach, although some were not significant after correction
for multiple testing.
Limitations of the study include the likely possibility that
blinding was compromised, as UPA treatment in some pa-
tients led to irregular menses or amenorrhea.While intrinsic
to the pharmacological effects of UPA, this problem is shared
with studies of GnRH agonists and some hormonal contra-
ceptives. Even though women were not informed that UPA
could lead to amenorrhea, theymayhave read aboutUPAand
its side effects. Future studies should include a larger sample
to investigate symptomatic benefit separately among the
women who remain ovulatory.
As this study was not designed to capture ovulation and
progesterone levels during treatment, we cannot ascertain
whether theeffect ofUPA ismediatedbyanovulation, leading
to low progesterone and allopregnanolone levels, or via
specific actions at the progesterone receptor. However, we
note that the proportion of women who developed amen-
orrhea in response to UPA was much lower (27.5%) than in
studies on uterine fibroids, where amenorrhea occurs in
approximately 80%ofwomen (26, 31, 42). For this reason,we
speculate that both factors are likely involved—that is, low-
ered progesterone levels and specific actions at the receptor
in women who maintained menstrual cycles.
Moreover, as estradiol levels are maintained at mid-
follicular-phase levels, the effect of UPA may also comprise
estrogen’s effects on mood. In line with this, menopause-like
pharmacologically induced estrogen levels have been associ-
atedwith depressive symptoms (43).While not discerning the
effect of these hormones separately, after GnRH agonist
treatment, PMDD symptom reinstatement has indeed been
demonstratedwithestradiol andprogesterone add-back (4, 8).
Thus, it is plausible that UPA contributes to PMDD symptom
relief by maintaining low and constant levels of both pro-
gesterone and estradiol. Clearly, further studies are needed to
elucidate the specific actions of UPA in women with PMDD.
Moreover, with one-third of the PMDD patients pre-
viously unsuccessfully treated with an antidepressant, symp-
tom improvement following UPA treatment highlights this
treatment as a valid alternative for patients who do not re-
spond to selective serotonin reuptake inhibitors, but also
calls for further studies to generalize the present findings to
treatment-naive patients.
Regarding the study population, the mild to moderate
baselineDRSP scores are in the range of previous studies (40,
44). MADRS-S scores define the present sample as moder-
ately depressed at baseline (scores were slightly to much
lower than in samples with major depression or treatment-
resistant major depression [45, 46]). At follow-up, the scores
of the UPA group describe women as having no depression
but those in the placebo group as having mild depressive
symptoms (32). Similarly, in the UPA group, EQ-VAS scores
meaningfully improved from indicating poor health-related
quality of life to values defined as normal in population-based
samples, while in the placebo group the improved health
status remained well below these levels (47). Whereas
MADRS-S or EQ-VAS scores improved over time, the lack of
between-group differences may be explained by the fact that
they are one-time-pointmeasurements and thus are sensitive
to the daily mood of the participant. Additionally, the con-
stellation of mood-related impairment addressed by the
MADRS-S may apply only to a subset of women with PMDD
and possibly not be the main target of UPA treatment, as
irritability showed the highest improvement. Additionally, a
greater general health-related quality of life improvement
due to UPA treatment may be seen over a longer period as
the patient becomes familiar with its effects and adjusts her
daily life.
UPA was introduced in 2012, and more than 750,000
women have been treated for uterine fibroids with the drug
(48). Most commonly, women received a 3-month treatment
course, but studies with safety and efficacy data with up to
four 3-month courses have shown that side effects remain
stable or even decrease with an increasing number of
treatment courses (26). During the spring of 2018, the
Pharmacovigilance Risk Assessment Committee (PRAC) of
the European Medicines Agency (EMA) investigated the
potential role of UPA in liver injury and concluded that the
drugmayhave contributed to someof the cases of severe liver
injury that had been reported (26). As a result, the PRAC
proposednewprescription rules inorder tominimize the risk
of livery injury, including repeated liver function tests during
thefirst 3months of treatment (49). At the same time, theU.S.
Food and Drug Administration has requested additional in-
formation tobeable to approveUPAin its current form. In the
spring of 2020, PRAC started a new review of the drug after a
single case of liver injury (50). The results of the new review
are still pending. Studies to determine the effects of UPA on
the liver are ongoing, and somepreliminary results, including
ours, are reassuring (51). As this proof-of-concept study is the
first to evaluateUPA for treatment ofPMDD,wecannotmake
any treatment recommendations at present. Further studies
to validate our findings, and positive outcomes from ongoing
liver safety studies, are needed. Last but not least, other se-
lective progesterone receptor modulators with theoretically
less effects on the liver are on their way into the market,
potentially representing safer alternatives (52).
In conclusion, UPA is a promising drug for treatmentof
PMDD, particularly for the psychological symptoms asso-
ciated with the syndrome and as an alternative pharmaco-
logic treatment to antidepressants for patients who do not
respond or cannot tolerate selective serotonin reuptake in-
hibitors, the current standard of care. Moreover, the unique
mechanism of action of this study, namely, modulation of
progesterone receptors, provides insights into the potential
molecular mechanisms underlying PMDD and its treatment.
Further validating studies, as well as more reassuring in-
formation regarding the effect on liver function, are needed
before this potentially highly effective treatment is made
available to affected women.
Am J Psychiatry 178:3, March 2021 ajp.psychiatryonline.org 263
COMASCO ET AL.
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AUTHOR AND ARTICLE INFORMATION
Department ofNeuroscience, Science for Life Laboratory (Comasco), and
Department of Women’s and Children’s Health, Uppsala University,
Uppsala (Nyback, de Grauw, Sundström-Poromaa); Department of
Clinical Sciences at Danderyd Hospital Karolinska Institutet, and De-
partment of Obstetrics and Gynecology, Danderyd Hospital, Stockholm
(Kopp Kallner); Department of Clinical Sciences, Umeå University, Umeå,
Sweden (Bixo); Department ofWomen’s andChildren’s Health, Karolinska
Institutet, and Department of Gynecology and Reproductive Medicine,
Karolinska University Hospital, Stockholm (Hirschberg); Department of
Psychiatry, University of Colorado School ofMedicine, Aurora (Epperson).
Send correspondence to Dr. Sundström-Poromaa (inger.sundstrom@
kbh.uu.se).
EU Clinical Trials Register (EudraCT) identifier: 2016-001719-19.
Supported by the Swedish Research Council (2016-01439) and the
Swedish Society of Medicine (SLS-573171, SLS-597211, SLS-789101). Dr.
Comasco is a Marie Skłodowska Curie fellow and receives funds from the
Swedish Research Council (2015-00495), EU FP7-People-Cofund (INCA
600398), and SciLifeLab. Gedeon Richter provided study drugs.
The authors thank Prof. Hustad and colleagues, Department of Clinical
Science, University of Bergen, for performing the hormonal analyses.
Dr. Kopp Kallner receives honoraria for lectures from Actavis, Bayer,
Exeltis, Gedeon Richter, Merck, Mithra, Natural Cycles, Nordic Pharma,
and Teva; has provided expert opinion for Bayer, Evolan, Exeltis, Gedeon
Richter, Merck, Natural Cycles, Teva, and TV4; has been an investigator in
trials sponsored by Bayer, Gedeon Richter, Mithra, and MSD; has taught
courses sponsored by Bayer, Merck, and MSD and courses organized by
Karolinska Institutet, SFOG, and Sophiahemmet; has written book
chapters sponsoredbyBayer; and is amemberof theboardof theSwedish
Society of Obstetricians and Gynecologists and serves on the Executive
Committee of the Board of the European Society of Contraception and
Reproductive Health. Dr. Bixo has served as a medical adviser for Asarina
Pharma.Dr. Epperson has served on the advisory board of Asarina Pharma
andSageTherapeutics andhas received research funding fromandserved
as a consultant and advisory board member for Sage Therapeutics. Dr.
Sundström-Poromaa has served on advisory boards or as an invited
speaker at scientific meetings for Asarina Pharma, Bayer Health Care,
Gedeon Richter, Lundbeck, MSD, Peptonic, and Shire/Takeda. The other
authors report no financial relationships with commercial interests.
Received March 11, 2020; revision received June 30, 2020; accepted
September 21, 2020; published online Dec. 10, 2020.
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