Yaz Parallel

Efficacy of a New Low-Dose OralContraceptive With Drospirenone inPremenstrual Dysphoric DisorderKimberly A. Yonkers, MD, Candace Brown, RN, PharmD, Teri B. Pearlstein, MD,Marie Foegh, MD, DSc, Carole Sampson-Landers, MD, and Andrea Rapkin, MD

Objective: To compare the efficacy of a new low-dose oralcontraceptive pill (OCP) formulation with placebo in reduc-ing symptoms of premenstrual dysphoric disorder.

Methods: This multicenter, double-blind, randomizedclinical trial consisted of 2 run-in and 3 treatment cycleswith daily symptom charting; 450 women with symptomsof premenstrual dysphoric disorder were randomized toeither placebo or an OCP formulation containing dro-spirenone 3 mg and ethinyl estradiol 20 g. Hormoneswere administered for 24 days, followed by 4 days ofinactive pills (24/4).

Results: Scores on the total Daily Record of Severity ofProblems decreased by 37.49 in the drospirenone/ethinylestradiol group and by 29.99 in the placebo group (ad-justed mean difference 7.5, 95% confidence interval [CI]11.2 to 3.8; P .001 by rank analysis of covariance).Mood symptom scores were reduced by 19.2 and 15.3 inactive-treatment and placebo groups, respectively (adjustedmean difference 3.9, 95% CI 5.84 to 2.01; P .003);physical symptom scores were reduced by 10.7 and 8.6in active-treatment and placebo groups, respectively (ad-

justed mean difference 2.1, 95% CI 3.3 to 0.95; P .001); and behavioral symptom scores were reduced by7.7 and 6.2 in active-treatment and placebo groups,respectively (adjusted mean difference 1.5, 95% CI 2.251to 0.727; P .001). Response, defined as a 50% decreasein daily symptom scores, occurred in 48% of the active-treatment group and 36% of the placebo group (relative risk1.7, 95% CI 1.1 to 2.6; P .015) and corresponds to anumber-needed-to-treat of 8 patients.

Conclusion: A 24/4 regimen of drospirenone 3 mg andethinyl estradiol 20 g improves symptoms associated withpremenstrual dysphoric disorder.(Obstet Gynecol 2005;106:492501)

Level of Evidence: I

Although many women encounter mildly trouble-some premenstrual symptoms during their repro-ductive years, approximately 35% of women sufferfrom the more debilitating condition, premenstrual dys-phoric disorder. Women with premenstrual dysphoricdisorder experience moderate-to-severe mood, behav-ioral, and physical symptoms that disrupt their lives athome or work.1,2 Given that women with premenstrualdysphoric disorder face symptoms on a monthly basisfrom their early 20s until menopause (age 51), theymay be symptomatic for about 2,800 days, or 78 years,over their lifetime. This extended symptomatic period,in addition to the prevalence of the illness, placespremenstrual dysphoric disorder in a similar burden-of-illness category as dysthymic disorder, major depres-sion, and other common medical disorders.3

The biological processes underlying premen-strual dysphoric disorder are not known. However,symptoms are diminished by suppressing ovarianactivity4,5 and can be provoked in medically ovariec-tomized women by exposing them to exogenous

From the Departments of Psychiatry and Epidemiology and Public Health, YaleUniversity, New Haven, Connecticut; Departments of Pharmacy, Obstetrics andGynecology, and Psychiatry, University of Tennessee Health Science Center,Memphis, Tennessee; Department of Psychiatry and Human Behavior, BrownMedical School, Providence, Rhode Island; Berlex Incorporated, Montville, NewJersey; and Department of Obstetrics and Gynecology, University of CaliforniaLos Angeles, Los Angeles, California.

Corresponding author: Kimberly A. Yonkers, MD, Departments of Psychiatry andEpidemiology and Public Health, Yale University School of Medicine, 142 TempleStreet, Suite 301, New Haven, CT 06510; e-mail: [email protected].

Financial DisclosureSchering AG (Berlin, Germany) provided the financial support for this study,which was conducted by Berlex Incorporated (U.S. affiliate). Drs. Foegh andSampson-Landers are employees of Berlex Incorporated and own stock and holdstock options in Schering AG.

2005 by The American College of Obstetricians and Gynecologists. Publishedby Lippincott Williams & Wilkins.ISSN: 0029-7844/05

492 VOL. 106, NO. 3, SEPTEMBER 2005 OBSTETRICS & GYNECOLOGY

gonadal steroids.6 Combined oral contraceptive pills(OCPs) can prevent ovulation and replace endoge-nous fluctuations of ovarian steroids with stable hor-mone levels. For this reason combined OCPs are usedto treat premenstrual symptoms.7 However, signifi-cant differences between active medication and pla-cebo were not found in the only 2 published random-ized, placebo-controlled trials.8,9

The purpose of this study was to compare post-treatment symptom scores among women sufferingfrom premenstrual dysphoric disorder who were ran-domized to either a new OCP formulation containingdrospirenone 3 mg and ethinyl estradiol 20 g orplacebo. Drospirenone, a novel progestin with anti-mineralocorticoid and antiandrogenic activity, is ananalogue of spironolactone, which has been shown toameliorate symptoms of premenstrual syndrome.10

The active hormones were administered for 24 con-secutive days rather than the conventional 21 days ina 28-day cycle (21/7). This new treatment platform isassociated with greater suppression of follicle devel-opment and a more stable hormonal milieu than isfound with the standard 21/7 regimen.11,12 Given theprior efficacy of spironolactone for premenstrualsymptoms, the follicular suppression found with a24/4 regimen as well as the lower estrogen dose, wehypothesized that women randomized to active treat-ment would experience fewer premenstrual symp-toms than women randomized to placebo.

MATERIALS AND METHODSThis double-blind, randomized, placebo-controlled,parallel-design study consisted of 7 visits: a screeningvisit, 2 single-menstrual-cycle qualification visits, 3single-menstrual-cycle treatment visits in which sub-jects took either drospirenone 3 mg/ethinyl estradiol20 g or placebo, and an end-of-treatment visit.(Participant flow is shown in Fig. 1.) Subjects usedbarrier contraception throughout the study. All pro-tocols were approved by a site or central institutionalreview board, and all subjects provided verbal andwritten informed consent.

Subjects were recruited from 64 centers in theUnited States; recruitment and follow-up occurredfrom January 2001 through September 2003. Eligibil-ity criteria included 1) aged 18 to 40 years; 2) adiagnosis of premenstrual dysphoric disorder accord-ing to the Diagnostic and Statistical Manual of MentalDisorders, 4th edition2; 3) no depressive, anxiety,eating, bipolar, psychotic, somatoform, dysthymic, ordrug/alcohol use disorders during the last 2 years; 4)no OCP use for the 3 months before study entry; 5)no concurrent therapy for premenstrual dysphoricdisorder; 6) regular menstrual cycles (2534 days); 7)no contraindication to OCP treatment; 8) a nonsuspi-

cious Pap test within the prior 6 months; and 9) nocurrent pregnancy.

To meet criteria for randomization, subjects wererequired to have 2 consecutive menstrual cycles ofmoderate-to-severe premenstrual symptoms and min-imal-to-no follicular-phase symptoms immediatelybefore beginning the 3 double-blind placebo or activetreatment cycles. Premenstrual dysphoric disorderseverity criteria included 1) a premenstrual-phase(days 5 to 1 before bleeding) daily average of 3.0 orgreater for 5 distinct items in the Daily Record ofSeverity of Problems13; 2) a premenstrual-phase dailyaverage that was twice as high as the correspondingpostmenstrual-phase average for the 5 distinct items;3) a postmenstrual phase (days 610) daily average of2.5 or less for each of the 11 distinct items in the DailyRecord of Severity of Problems; and 4) a score of 3 orgreater on one Daily Record of Severity of Problemsfunctional impairment item for at least 2 premenstrualdays.

Randomization numbers were generated in fixedblocks of 4 and were allocated in a 1:1 ratio. Thesponsors central coordinating group assigned andsent out the blocks in advance of enrollment. Becausewe anticipated that relatively few patients would beenrolled per site, patients were not stratified by site.

The Daily Record of Severity of Problems scalehas 24 questions that are grouped into 11 distinctsymptom items and 3 functional impairment items,which are self-rated on a 6-point scale from 1 (not atall) to 6 (extreme). The averages of the last 5 daysbefore menses for the 11 distinct symptom items weresummed and constitute the total Daily Record ofSeverity of Problems symptom score. The a prioriprimary efficacy variable was the difference betweenthe average luteal phase Daily Record of Severity ofProblems total scores from the 2 qualification cyclesand the average luteal phase Daily Record of Severityof Problems total scores from the 3 treatment cycles.Responders were defined as subjects who had a reduc-tion from baseline of 50% or greater in their totalDaily Record of Severity of Problems symptom score.

Secondary outcome measures included each ofthe 11 individual items from the Daily Record ofSeverity of Problems, the 3 functional impairmentitems from this scale, the Premenstrual Tension Scalesobserver-rated and self-rated questionnaires,14 the En-dicott Quality of Life Enjoyment and SatisfactionQuestionnaire,15 and the Clinical Global Impression-Improvement scale.16 Scores for both PremenstrualTension Scales range between 0 and 36; a premen-strual score of 1821 is typically found in patientswith premenstrual dysphoric disorder.17 Baseline andtreatment-related quality of life were assessed with thegeneral activities subscale of the Endicott Quality of

VOL. 106, NO. 3, SEPTEMBER 2005 Yonkers et al Drospirenone OCP and Premenstrual Symptoms 493

Life Enjoyment and Satisfaction Questionnaire.15 Thisself-report measure includes 14 items rated on a scaleof 15 (range 1470), with higher scores indicating abetter quality of life. The Clinical Global Impression-Improvement scale is a single-item measure thatobservers and subjects used to rate global improve-ment from baseline on a scale of 1 (very muchimproved) to 7 (very much worse).16

After screening, subjects were administered theStructured Clinical Interview for the Diagnostic andStatistical Manual of Mental Disorders, 4th edition,18 todetermine the presence of exclusionary psychiatric

diagnoses. Daily ratings were kept throughout the study.Clinical Global Impression-Improvement scales werecompleted during each treatment visit in each cycle.The other scales were completed once before random-ization and after the first and third treatment cycles.

Women underwent general physical and pelvicexaminations and had routine blood, urine, and preg-nancy tests performed during the diagnostic period andafter the 3 treatment cycles. Vital signs, weight, andadverse event information were collected at all visits.Randomized subjects started drospirenone/ethinyl es-tradiol or matching placebo on day 1 or 2 of the

Fig. 1. Participant flow. Drospirenone/EE drospirenone 3 mg ethinyl estradiol 20 g. * Other included 3 subjectsmoving away, 1 sponsoring company employee, 1 suspected pregnancy, and 2 subject screens that failed in error. Onewoman discontinued the study before taking any medication; therefore, 449 women were included in the full analysis set,and 231 women started the active drug. Other included 1 patient out of her study visit window for a study visit, 1 withnoncompliance, 1 with loss of the diary and month 3 of medication, and 1 moving out of state.Yonkers. Drospirenone OCP and Premenstrual Symptoms. Obstet Gynecol 2005.

494 Yonkers et al Drospirenone OCP and Premenstrual Symptoms OBSTETRICS & GYNECOLOGY

menstrual cycle and continued until day 24. The last 4days of the pill pack consisted of inert placebo pills forboth groups. Subjects took pills for 3 menstrual cycles.

Data were analyzed from the intent-to-treat co-hort that included all randomized subjects who tookat least 1 dose of study pills. Study centers werepooled from largest to smallest until the pooled centerhad more than 5 subjects with postbaseline data ineach treatment group. No pooled center had morethan 15% of the total number of subjects. Analysis ofvariance (ANOVA) was used to compare differencesin baseline scores between the active-treatment andplacebo groups. The ANOVA model included termsfor treatment assignment and pooled center. Compar-isons of categorical measures were made using ageneralized Cochran Mantel Haenszel test stratifiedby pooled center.

Daily Record of Severity of Problems scores fromthe final 5 days of the menstrual cycle were averagedto obtain mean pretreatment (qualifying cycles 1 and2) or posttreatment (treatment cycles 13) individual-item and total values. Missing data points were im-puted by averaging days bordering the missing value.There were fewer than 0.25% missing data points,which were distributed equally in both groups. Theindividual-item and summary scores were carriedforward for noncompleters. Differences between dailyratings for the 2 treatment groups were estimatedinitially using an analysis of covariance (ANCOVA)model containing terms for treatment and pooledcenter, with the baseline value as a covariate. Normal-ity of the residuals was assessed with the Shapiro-Wilkstatistic. Because the data violated the normalityassumption in many instances, analyses were re-peated using a rank ANCOVA with the same terms.In these instances, the rank ANCOVA was reported.The Fisher exact test was used for analyses where cellsincluded fewer than 10 observations.

Rates of response ( 50% decrease in dailyratings after treatment) in both groups were comparedusing logistic regression, with additional terms fortreatment and pooled center. The addition of bodymass index and age to the logistic model did not addexplanatory power (P value for regression coefficients 0.5) and therefore were not included in the finalmodel.

A similar statistical approach was used for addi-tional secondary measures. For subjects who droppedout of the trial, scores were carried forward to the endof the double-blind treatment phase. Differencesamong continuous measures were estimated usingANCOVA models that included terms for treatmentassignment, pooled center, and baseline score as acovariate. If the assumption of homogeneity of slopeswas violated at the 0.05 level, a supportive rank

ANCOVA was performed and was reported. Weestimated that by recruiting 408 subjects, we wouldhave 90% power to show a significant (P .05)difference between groups of at least 6.5 (standarddeviation 18) points on the total Daily Record ofSeverity of Problems, if a difference truly exists. For arepeated measures design, we assumed that 80% ofthe randomized subjects would have at least oneresponse during the treatment period. Data wereanalyzed with SAS 8.12 (SAS Institute, Cary, NC).

RESULTSWomen were recruited by advertisement and referral.Of the 3,496 women who requested participation, 449subjects were included in the intent-to-treat analysis.Screening flow is shown in Figure 1. Eligibility amongwomen interested in participation was similar to thatfound in other clinical trials of premenstrual dyspho-ric disorder.13,17,19,20 The only statistically significantdifferences in baseline characteristics between thedrospirenone/ethinyl estradiol and placebo groupswere in mean age (31.0 versus 32.0 years, respectively, P .048) and body mass index (26.1 versus 25.1 kg/m2,respectively, P .015) (Table 1). Of the subjects ran-domized, 161 (69.4%) in the drospirenone/ethinyl estra-diol group and 167 (76.6%) in the placebo group com-pleted the study. There were no statistically significantdifferences (P .473 by ANOVA) in the main outcomemeasure between treatment and placebo groups forthose women who failed to complete the study. Therewas no significant difference in the number of womenwho completed active treatment and those who re-ceived placebo (P .09 by Fisher exact test).

The on-treatment differences in cycle lengths forpatients receiving active treatment and placebo weresmall and nonsignificant (27.3 days for drospirenone/

Table 1. Demographic and Baseline Characteristics

Treatment Group

CharacteristicsDrospirenone/EthinylEstradiol (n 231*)

Placebo(n 218)

Age (y) 31.0 5.6 32.0 5.5Race/ethnicityWhite 176 (76.2) 170 (78.0)Black 25 (10.8) 20 (9.2)Hispanic 22 (9.5) 21 (9.6)Asian 2 (0.9) 3 (1.4)Other 6 (2.6) 4 (1.8)Weight (kg) 70.6 13.2 68.4 12.9Height (cm) 166.0 6.2 166.4 7.0Body mass index 26.1 4.6 25.1 4.3Cycle length (d) 28.7 2.0 28.8 1.7

Data are expressed as mean standard deviation or n (%).* One subject randomized to active treatment who discontinued

before taking anymedication is not included in the full analysis set. P .05.


ethinyl estradiol and 27.6 days for placebo; P .23).Bleeding began an average of 3 days after cessation ofactive pills when subjects took drospirenone/ethinylestradiol; therefore, approximately 3 days of thehormone-free interval were included in the premen-strual phase.

The total Daily Record of Severity of Problemssymptom score in subjects receiving drospirenone/ethinyl estradiol decreased by 47%, from a mean (standard deviation [SD]) of 77.40 ( 16.7) during thequalification cycles to an average of 41.2 ( 17.3) forthe 3 treatment cycles; the corresponding reduction inthe placebo group was 38%, from 78.1 ( 17.8) to48.1 ( 21.1). The estimated adjusted mean changefrom baseline over 3 cycles in the total Daily Recordof Severity of Problems symptom score was 37.49for the drospirenone/ethinyl group and 29.99 forthe placebo group, for an adjusted mean difference of7.50 (95% confidence interval [CI] 11.2 to 3.8; P.001 by rank ANCOVA). The estimated improve-ment was significantly greater for subjects assigned todrospirenone/ethinyl estradiol than for those receiv-ing placebo for all 11 distinct items in the DailyRecord of Severity of Problems (Table 2). When theestimated difference was corrected for multiple testing(n 11, P .005), differences between groups foritems tired/fatigued and slept more were nolonger statistically significant.

Symptoms from the Daily Record of Severitywere summed into clinically derived subscales re-ported by others.13,17,20 Active treatment reducedphysical symptoms by 10.7 points, compared with8.6 points in the placebo group (adjusted meandifference 2.1, 95% CI 3.3 to 0.95; P .001 byrank ANCOVA). Similarly, mood symptoms weredecreased by 19.2 and 15.3 points in active-treat-ment and placebo groups, respectively (adjustedmean difference 3.9, 95% CI 5.84 to 2.010; P .003 by rank ANCOVA), and behavioral symptomsimproved by 7.7 and 6.2, in active-treatment andplacebo groups, respectively (adjusted mean differ-ence 1.5, 95% CI 2.25 to 0.73; P .001).

To determine whether subjects experienced hor-mone withdrawal symptoms or a shift in their symp-tomatic period, we compared the total Daily Recordof Severity of Problems score from days 2124 (activehormone administration) with that from days 2528(placebo administration) for women assigned to dro-spirenone/ethinyl estradiol. Terms in the ANOVAmodel included subject, pill pack, pill-packdays, and the interaction of pill-pack days with pillpack. There was no significant difference in model-estimated mean total Daily Record of Severity ofProblems scores between these 2 intervals (38.4 17.6 for days 2124 versus 39.6 18.8 for days

2528, 95% CI 3.19 to 0.12, P .069). This lack ofdifference is particularly notable because, aside fromwithdrawal, there is a tendency for women to experi-ence more symptoms as menses approach.

Overall improvement according to the ClinicalGlobal Impression-Improvement observer-rated scalewas greater for subjects receiving active treatmentthan for those in the placebo group (2.2 versus 2.5,adjusted mean difference 0.30, 95% CI 0.55 to0.05; P .004 by rank ANCOVA). Similarly,self-rated improvement was greater in the active-treatment than in the placebo group (2.3 versus 2.5,adjusted mean difference 0.26, 95% CI 0.53 to0.008; P .014 by rank ANCOVA). Active treatmentwas significantly more effective than placebo in ob-server-rated (adjusted mean difference 1.9, 95% CI3.8 to .05; P .023 by rank ANCOVA) andself-rated (3.5, 95% CI 5.7 to 1.3, P .004 by rankANCOVA) Premenstrual Tension Scales scores. Themedian pretreatment and on-treatment values and theadjusted mean differences between groups for thePremenstrual Tension Scales are shown in Table 3.

Functional-impairment and quality-of-life do-mains were included as secondary outcome measures(Table 3). Compared with the placebo group, thesubjects randomized to drospirenone/ethinyl estra-diol experienced significant improvement in the func-tional items from the Daily Record of Severity ofProblems: productivity (adjusted mean difference0.33, 95% CI 0.55 to 0.12; P .003 by rankANCOVA); enhanced enjoyment in social activities(adjusted mean difference 0.34, 95% CI 0.55 to0.12; P .003 by rank ANCOVA); and betterquality of relationships (adjusted mean difference0.42, 95% CI 0.64 to 0.20; P .001 by rankANCOVA). Subjects using drospirenone/ethinyl es-tradiol reported statistically greater improvement initems 114 of the Endicott Quality of Life Enjoymentand Satisfaction Questionnaire (P .047 by rankANCOVA) compared with those subjects random-ized to placebo, although statistical significance wasnot achieved for medication satisfaction (item 15) andoverall life satisfaction (item 16). By cycle 3, 48.4%(95% CI 41.1% to 55.8%) of actively treated and36.1% (95% CI 29.3% to 43.3%) of placebo-treatedsubjects met the criteria for response (odds ratio 1.7,95% CI 1.1 to 2.6; P .015). The number-needed-to-treat was 8 patients.

Adverse events considered by investigators to bepossibly related to the study drug occurred in 118(51.1%) subjects in the drospirenone/ethinyl estradiolgroup and 66 (30.3%) subjects in the placebo group.Adverse events that occurred in 5% or more of eithertreatment assignment are shown in Table 4. There


Table2.

Changes

inIndividu

alDailyRatingItem

s*in

theDailyRecordof

Severityof

Prob

lemsWith

Drospire

none

/EthinylEstradiolV

ersusPlaceb

o

Med

ianBaselineScore

Med

ianTreatmen

tScore

Individu

alSymptom

Item

sDrospirenon

e/Ethinyl

Estradiol

Placeb

oDrospirenon

e/Ethinyl

Estradiol

Placeb

oAdjustedMean

Difference

95%CI

P

1a.D

epressed,b

.hop

eless,c.worthless/guilty

9.7

9.7

4.0

4.6

0.8

1.38to

0.30

.005

2.Anx

ious/tense

4.2

4.2

1.9

2.4

0.4

0.66to

0.23

.001

3a.M

oodsw

ings,b

.feelsensitiv

e8.3

8.5

3.3

4.5

1.0

1.43to

0.57

.001

4a.A

ngry/irritable,b.

conflicts

8.2

8.4

3.7

4.7

0.9

1.36to

0.49

.001

5.Dim

inishedinterest

4.0

3.9

1.7

1.8

0.3

0.52to

0.10

.003

6.Difficulty

concentrating

3.9

3.8

1.5

1.9

0.4

0.58to

0.15

.001

7.Tired/fatigued

4.4

4.2

2.1

2.5

0.3

0.51to

0.07

.010

8a.Increased

appetite,b.

food

cravings

7.7

7.6

3.3

3.8

0.8

1.32to

0.35

.010

9a.S

lept

more,b.

trou

blesleeping

6.9

6.8

3.5

3.9

0.4

0.79to

0.12

.033

10.O

verw

helm

ed/lackof

control

6.8

7.3

2.8

3.3

0.7

1.15to

0.35

.001

11a.Breasttend

erness,b

.breastsw

ellin

g,c.bloated

sensation,

d.headache,e.m

usclepain

13.4

13.3

7.4

8.6

1.4

2.11to

0.77

.001

CI,confidence

interval.

*Low

erscoreindicatesim

provem

ent.

Num

ber

231;

onesubjectrand

omized

toactiv

etreatm

entwho

discon

tinuedbefore

taking

anymedicationisno

tinclud

edin

thefullanalysisset.

Num

ber

218.

Unlessotherw

iseno

ted,

allP

values

arefrom

rank

analysisof

covariance

with

term

sfortreatm

ent,po

oled

center,and

baselin

escorefortheon

-treatm

entcomparisons.

Analysisof

variance

with

term

sfortreatm

entandcenter;no

violationof

norm

ality

.


was one severe adverse event (dysplasia) consideredby the investigator to be possibly related to study drugin the active-treatment group. Thirty-five subjectsreceiving drospirenone/ethinyl estradiol and 9 subjectsin the placebo group discontinued due to adverseevents. The reasons most commonly given by subjectsin the active treatment group for discontinuing the studyincluded nausea (11 subjects, 31.4%), intermenstrualbleeding (8 subjects, 22.9%), and asthenia (7 subjects,20.0%). No deaths were reported in the study.

There were no significant differences in serumpotassium levels between active and placebo groupsduring the treatment period (4.3 mEq/L for bothgroups). Four subjects receiving active treatment andone subject in the placebo group had serum potas-sium levels above the normal range ( 5.5 mEq/L).One of the 4 subjects receiving drospirenone/ethinylestradiol had a serum potassium level of 6.0 mEq/L orgreater, but a repeat serum potassium value 4 dayslater was 4.6 mEq/L. None of the subjects withelevated potassium levels reported arrhythmias, diz-ziness, palpitations, bradycardia, tachycardia, or syn-cope at any point in the study.

DISCUSSIONThis placebo-controlled, double-blind study showsthat the new drospirenone-containing OCP formula-tion administered for 24 of 28 days in a cycle amelio-rates symptoms associated with premenstrual dyspho-ric disorder. Active treatment was associated with a47% reduction in the total Daily Record of Severity ofProblems scale, while the median reductions in dis-tinct items ranged from 45% to 62%. The palliativeeffect of OCPs, particularly for physical premenstrualsymptoms, has been suggested by previous epidemi-ological and nonplacebo-controlled research.7,2123

However, before this trial, it was far less certain thatan OCP formulation would be therapeutic for womensuffering from the more severe condition, premen-strual dysphoric disorder. Moreover, women withpremenstrual dysphoric disorder experience severemood symptoms, and OCPs have been thought bysome to worsen or cause symptoms of depression.24,25

Therefore, it is notable that in the current study, activetreatment was associated with a 49% reduction inpremenstrual depression. Our finding showing effi-cacy for a hormonal contraceptive intervention con-trasts with the only 2 published placebo-controlledstudies to evaluate OCP treatment for premenstrualsymptoms. The first study enrolled 82 women withpremenstrual syndrome, and the active treatment wasa triphasic OCP (ethinyl estradiol 35 g plus noreth-indrone 0.5 mg days 17 and 1721 and 1.0 mg days816).8 Differences between the OCP and placebowere minimal, although mood worsened in the active-Ta

ble3.

Cha

nges

inSe

cond

aryOutco

meMeasuresWithDrospiren

one

/Ethinyl

Estrad

iolVersusPlaceb

o

Med

ianBaselineScore

Med

ianTreatmen

tScore

OutcomeMeasure

Drospiren

one/Ethinyl

Estradiol

*Placeb

oDrospiren

one/Ethinyl

Estradiol

*Placeb

oAdjustedMean

Difference

95%CI

P

DRSP

Functio

nalimpairmentitems

Moreprod

uctiv

e3.8

4.0

1.7

2.0

0.3

0.55to

0.12

.002

Enh

ancedsocial

activ

ities

3.7

3.9

1.6

1.9

0.3

0.55to

0.12

.002

Betterrelatio

nships

3.9

4.2

1.7

2.2

0.4

0.64to

0.20

.001

Q-LES-Q

Item

s114

57.1

57.9

77.1

74.3

2.9

0.02to

5.77

.047

Overalllifesatisfaction

3.0

3.0

4.0

4.0

0.1

0.08to

0.31

.243

PMTS

Observerrated

27.0

27.0

13.0

17.0

1.9

3.79to

0.05

.045

Selfrated

28.0

29.0

9.0

15.5

3.5

5.71to

1.26

.002

CI,confidence

interval;DRSP

,Daily

Recordof

Severity

ofProb

lems;Q-LES-Q,E

ndicottQualityof

Life

EnjoymentandSatisfactionQuestionn

aire;PM

TS,

Prem

enstrual

Tension

Scales.

*Num

ber

231;

onesubjectrand

omized

toactiv

etreatm

entwho

discon

tinuedbefore

taking

anymedicationisno

tinclud

edin

thefullanalysisset.

Num

ber

218.

Unlessotherw

iseno

ted,

allP

values

arefrom

analysisof

variance

with

term

sfortreatm

entandcenter,b

aselinescoreas

covariate;

noviolationof

norm

ality

.Pvalues

from

rank

analysisof

covariance

with

term

sfortreatm

ent,po

oled

center,and

baselin

escoreas

acovariate;

norm

ality

was

violated.


treatment group during the hormone-free, postmen-strual period. In the second trial, either placebo or anOCP with drospirenone 3 mg and ethinyl estradiol 30g was administered in a 21/7 platform to 82 womenwho met premenstrual dysphoric disorder criteria.9

Although active treatment was associated with greaterpositive change than with placebo, the between-groupdifferences did not reach statistical significance, pos-sibly due to the modest sample size in the setting of aconsiderable placebo response rate (43%). The cur-rent study also used a formulation composed ofdrospirenone and ethinyl estradiol, but the dose ofethinyl estradiol was lower (ie, 20 g rather than 30g), and the active drug was given for 24 rather than21 days in a 28-day cycle. These differences inestrogen dose and shortened drug-free interval maycontribute to the significant differences between ac-tive treatment (48.4%) and placebo (36.1%) found inthis study. This finding corresponds to a number-needed-to-treat of 8 to achieve at least a 50% reduc-tion in symptom severity (ie, response) in one patient.

U.S. Food and Drug Administration (FDA)-ap-proved treatments for premenstrual dysphoric disor-der are limited to selective serotonin reuptake inhib-itors (SSRIs).13,20,26 In the current study, the overalleffect size estimating the general therapeutic benefit isroughly similar to that found for SSRIs as reported ina recent meta-analysis.26 In addition, physical symp-toms (eg, those found in item 11 of the Daily Recordof Severity of Problems) responded well to treatmentwith drospirenone and ethinyl estradiol. These symp-toms are less likely to respond to SSRIs,13 or theyrequire higher doses for response.27,28

In the current study, as in many studies usingSSRIs,17,20,27,28 the placebo group had high responserates. Although this could simply be due to subjectspositive expectations, study methods, such as closecontact with study staff and completing daily ratings

of mood, may have contributed to this nonspecificresponse. The latter is particularly important becausemood monitoring is a time-honored therapeuticintervention in behavioral medicine and contributesto improvement in emotional symptoms for a numberof mood and anxiety disorders.

Attrition associated with adverse events occurredin 15% of subjects randomized to active treatmentcompared with 4% taking placebo. The most com-mon adverse event in the active treatment group wasintermenstrual bleeding (25.1% versus 4.6% for pla-cebo). Intracyclic bleeding is a frequent occurrenceduring the initial cycles of treatment with OCPscontaining low doses of estrogen, an effect that typi-cally decreases and then remains stable after the firstfew cycles.2931 Nausea was more common with activetreatment compared with placebo, but the incidenceof nausea (18.6%) is similar to that found with otherlow-dose OCP formulations.32 Relevant to this trial,complaints of nausea and breast tenderness decreaseafter the first few cycles of low-dose OCP use. Therewas no difference between the groups with respect topostbaseline serum potassium levels.

There are several possible limitations to the cur-rent study. First, OCPs potentially change the char-acteristics of the menstrual cycle, which could unblindstudy personnel as well as participants. This is ofgreater concern for the second and third cycles be-cause subjects and clinicians are more likely to beunblinded by menstrual characteristics. In this study,the first set of premenstrual ratings were done beforethe first menstrual period. The active treatment-pla-cebo difference occurring in the first study cycle wasat least as large as, if not larger than, that for subse-quent study cycles (data available upon request).Therefore, if unblinding occurred, it either workedagainst active treatment or was not of substantialmagnitude. Second, it is possible that drospirenone/

Table 4. Most Common Adverse Events*

No. of Patients (%)

Adverse Event

Drospirenone/EthinylEstradiol(n 231)

Placebo(n 218)

Between-GroupP

Intermenstrual bleeding 58 (25.1) 10 (4.6) .001Headache 45 (19.5) 44 (20.2) .946Nausea 43 (18.6) 11 (5.0) .001Breast pain 31 (13.4) 11 (5.0) .004Upper respiratory infection 23 (10.0) 24 (11.0) .834Asthenia 19 (8.2) 8 (3.7) .067Abdominal pain 12 (5.2) 6 (2.8) .281Sinusitis 9 (3.9) 11 (5.0) .718

* Occurring in at Least 5% of either treatment group. One subject randomized to active treatment, who discontinued before taking any medication, is not included in the full analysis set. P values from continuity-corrected Pearson 2 test.


ethinyl estradiol shifted the symptomatic period to thehormone-free interval, as in a prior OCP study.8

However, our analyses of subjects assigned to dro-spirenone/ethinyl estradiol failed to show differencesbetween premenstrual medication and premenstrualplacebo days.

In summary, the OCP formulation with dro-spirenone 3 mg and ethinyl estradiol 20 g adminis-tered in a 24/4 regimen was more effective thanplacebo at ameliorating premenstrual symptoms inwomen with premenstrual dysphoric disorder. ThisOCP formulation may have a unique role in womenwho both desire contraception and suffer from symp-toms of premenstrual dysphoric disorder.

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