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ORIGINAL RESEARCH |
From the Perinatal Psychiatry Clinical Research Program, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania; and Department of Psychiatry, State University of New York at Buffalo, Buffalo, New York.
Address reprint requests to: Lee S. Cohen, MD, Harvard Medical School, Perinatal Psychiatry Clinical Research Program, Massachusetts General Hospital, WAC 815, Boston, MA 02114; E-mail: lcohen2{at}partners.org.
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ABSTRACT |
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METHODS: After a two-cycle screening and one-cycle single-blind placebo period, 260 women were randomized to fluoxetine 10 mg, fluoxetine 20 mg, or placebo (dosed daily from 14 days before next expected menses through the first full day of bleeding) for three cycles. Women recorded premenstrual dysphoric disorder symptoms daily using a computerized version of the Daily Record of Severity of Problems.
RESULTS: Premenstrual daily fluoxetine 20 mg demonstrated significant improvement in mean Daily Record of Severity of Problems luteal scores compared with placebo (P = .005); premenstrual daily fluoxetine 10 mg did not (P = .100). Daily Record of Severity of Problems total scores were statistically significantly improved by the first treatment cycle for both active treatment groups. However, only fluoxetine 20 mg remained statistically significantly superior to placebo throughout the active treatment phase of the trial. Both fluoxetine groups showed significant treatment advantage over placebo for mood-related symptoms (P < .05). Only premenstrual daily fluoxetine 20 mg showed significant treatment advantage over placebo for physical symptoms of breast tenderness (P < .001), bloating (P = .001), and joint/muscle pain (P = .037). Treatment was well tolerated; discontinuations due to adverse events did not differ among the three groups (P = .316).
CONCLUSION: Premenstrual daily dosing with fluoxetine effectively treats mood, physical, and social functioning symptoms associated with premenstrual dysphoric disorder. Fluoxetine 20 mg appears to have comparable tolerability with, and better efficacy than, fluoxetine 10 mg.
Premenstrual dysphoric disorder affects 3–8% of women in their reproductive years.1,2 Premenstrual dysphoric disorder is a significant mood disturbance that appears during the week before the onset of menstrual bleeding (the late luteal phase) and remits after the onset of menses. This mood disturbance may manifest with symptoms of tension, irritability, depressed mood, or affective lability. Women who suffer from premenstrual dysphoric disorder may also experience decreased interest in usual activities, difficulty concentrating, lack of energy, appetite changes, sleep changes, and/or a sense of being overwhelmed.
According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, specific physical symptoms, such as breast tenderness, bloating, headache, and joint and muscle pain, may also contribute to the clinical picture of premenstrual dysphoric disorder.3 Premenstrual dysphoric disorder symptoms must be severe enough to impair functioning in occupational or social domains or both.3,4
Premenstrual dysphoric disorder symptoms typically resolve within a few days of onset of the follicular phase of the menstrual cycle.5 In contrast, symptoms of major depressive disorder or other significant mood disorders may be exacerbated during the premenstruum, but are present throughout the menstrual cycle. For this reason, diagnosis of premenstrual dysphoric disorder can be only provisional until premenstrual pathology is confirmed by two consecutive cycles of prospective symptom monitoring.
Efficacy of the serotonin reuptake inhibitors for the treatment of premenstrual dysphoric disorder has been demonstrated in multiple double-blind, randomized studies.6–9 Currently, daily dosing with fluoxetine throughout the whole menstrual cycle is the only Food and Drug Administration-approved treatment for premenstrual dysphoric disorder. This treatment is safe and effective; however, premenstrual daily dosing might result in even fewer adverse events than continuous daily dosing and might be more convenient and thus more acceptable for some patients.
An open-label study with fluoxetine,10 as well as several double-blind studies with other serotonin reuptake inhibitors,9,11–15 suggest that premenstrual daily dosing with fluoxetine might be efficacious and safe for the treatment of women with premenstrual dysphoric disorder. This large scale, double-blind clinical trial was designed to examine the efficacy and safety of premenstrual daily dosing with fluoxetine for the treatment of premenstrual dysphoric disorder.
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MATERIALS AND METHODS |
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). Women were seen once during each follicular phase and each luteal phase of their cycles.
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Menstruating women, aged 18–45 years, with regular menstrual cycles 23–35 days in length, were eligible to enter the screening phase of the study. The Structured Clinical Interview according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I Disorders was used to exclude women who met diagnostic criteria for an Axis I psychiatric disorder other than premenstrual dysphoric disorder. Women were also excluded if they had a history of Axis I pathology occurring within the past 6 months (with the exception of specific phobias). Women using hormonal contraceptives were also excluded. Women were randomized into the double-blind, randomized, treatment portion of the study only if, for two consecutive menstrual cycles, their scores averaged 3.0 or more each for five of the 11 Daily Record of Severity of Problems items (at least one a mood symptom) during the luteal phase, and their scores averaged 2.5 or less for each of the same items during the follicular week; and if they showed a 50% or more increase from follicular to luteal scores for these items; and if at least twice during the defined luteal period, they had scores of 4 or more on any of the three functional items. Patients were randomized to drug via a computer-generated randomization code that was stratified by investigative site.
The primary efficacy measure was the Daily Record of Severity of Problems total score. Diary data were used to calculate average luteal score (using scores from the five most symptomatic days occurring from 6 days before menses to the first day of menses) and average follicular score (using scores from days 5–11 of the menstrual cycle) for each woman.
In addition, as hypothesized a priori, three subtotals were analyzed. These were a mood subtotal (sum of questions regarding depressed mood/hopeless/worthless, anxiety, mood swings, and irritability/had conflicts), the physical symptoms subtotal (sum of questions regarding breast tenderness, breast swelling or bloating, headache, and joint/muscle pain), and the sum of the three functional impairment questions (impairment noticed at work/home/daily routine, symptoms interfered with hobbies/social activities, symptoms interfered with relationships with others). Additional exploratory analysis was performed on those individual items that made up the subtotals.
The three treatment groups were compared using an analysis of variance on the change from baseline luteal scores (average of the two screening cycles and the placebo lead-in cycle) to treatment luteal average scores (average of the three treatment cycles). The placebo lead-in cycle was included in the calculation of the baseline value along with the screening cycles to gain a more stable assessment of women’s baseline condition. Treatment group, investigator, and treatment group by investigator interactions were included in the model. If the interaction was not significant at the .10 level, then it was dropped from the final model. Pairwise comparisons between the treatment groups were based on the least-squares means from the analysis of variance model without adjustment for multiple comparison.
An additional secondary measure that collected the clinicians’ assessment of premenstrual dysphoric disorder symptomology via the Rating Scale for Premenstrual Tension17 was performed during each office visit. Change from baseline (visit 2, luteal visit before randomization) to treatment luteal average scores were compared among the three treatment groups using an analysis of variance model similar to that of the Daily Record of Severity of Problems analysis.
In addition, change from baseline to each subsequent cycle was assessed using a repeated measures analysis of variance for the Daily Record of Severity of Problems total score. The model included treatment, investigator, treatment-by-investigator interaction (which was dropped if it was not significant at level .10), cycle, and cycle-by-treatment interaction. The dependent variable included the baseline value along with the three treatment cycles and the final placebo washout cycle. The change from baseline to each visit was compared between treatment groups by estimating the single degree of freedom contrasts of the treatment-by-visit interaction. Inference from the repeated measures analysis was based on the restricted maximum likelihood solution and from the approximate F tests from SAS PROC MIXED (SAS Institute Inc., Cary, NC). An unstructured variance-covariance matrix was used.
Safety of premenstrual daily dosing was evaluated based on assessing vital signs, laboratory analytes, and change in cycle length. The incidence of treatment-emergent adverse events during placebo or fluoxetine therapy was compared using Fisher exact test. Baseline for treatment emergent adverse events was visits 1 and 2, during the placebo lead-in cycle.
The patient-rated Arizona Sexual Experience Scale18 was used to evaluate the effect of premenstrual daily fluoxetine treatment on sexual functioning. This scale consists of five gender-customized items relating to sexual functioning, interest, and satisfaction, rated from 1 (enhanced) to 6 (markedly impaired). The Arizona Sexual Experience Scale was administered at a baseline follicular visit before randomization as well as at the follicular visit immediately after the last cycle of treatment when symptoms of sexual dysfunction could not be ascribed to premenstrual dysphoric disorder symptomology. Change from baseline to end point in total score and individual questions were compared among the treatment groups using an analysis of variance with treatment, investigator, and treatment-by-investigator interaction (which was dropped if not significant). In addition, each item of the Arizona Sexual Experience Scale was analyzed among the treatment groups by comparing the percent of patients who claimed a greater sexual impairment (by a change of two or more points) at end point compared with baseline. This analysis was carried out using the Cochran-Mantel-Haenszel general association statistic, stratified by investigator.
All analyses were based upon the intent-to-treat principle and were performed using SAS 6 (SAS Institute). Tests of treatment effects were conducted at a two-sided 
level of 0.05. Results from investigators who did have patients randomized to all three treatment groups were pooled for statistical analysis purposes.
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RESULTS |
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). Of the 469 women who did not meet study entrance criteria, the majority (420) did not meet the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for premenstrual dysphoric disorder. Thirty-five women were not randomized because they were not compliant with the requirements for electronic diary entries during the screening phase.
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); this difference was not considered clinically relevant. The majority of patients (83.5%) did not have a prior history of depression. Baseline measures confirmed the cyclic nature of premenstrual dysphoric disorder, as evidenced by the clear worsening of symptoms during the luteal phase compared with the follicular phase (Table 1).
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). Analyses were also done using the average of the two screening cycles as baseline, and results were similar to those originally obtained.
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). Fluoxetine 20 mg showed a significant improvement over placebo in the analysis of the individual mood-related symptom items of depressed/hopeless/worthless (P = .005), anxious/tense (P = .019), mood swings/more sensitive (P < .001), and irritable/conflicts (P = .002). Fluoxetine 10 mg showed a significant improvement over placebo for depressed/hopeless/worthless (P = .014), mood swings/ more sensitive (P = .003), and irritable/conflicts (P = .004).
Analysis of the physical symptom subtotal showed that fluoxetine 20 mg had a significant treatment advantage over placebo and fluoxetine 10 mg (P = .002 for both). Of the four individual symptoms comprising the physical symptom subtotal, fluoxetine 20 mg had significant treatment advantage over placebo for breast tenderness (P < .001), bloating (P = .001), and joint/muscle pain (P = .037) but not for headache (P = .155). Fluoxetine 10 mg was not statistically significantly different from placebo for any physical symptom (P > .60 for all comparisons) (Figure 3).
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).
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).
The clinician rated Premenstrual Tension Scale was used as a secondary measure of efficacy. Mean change from baseline to treatment luteal phase average was statistically significantly greater for fluoxetine 20 mg and for fluoxetine 10 mg compared with placebo (P = .043 and .003, respectively) (Table 2).
Seven patients discontinued the study because of non-serious adverse events (placebo: dyspepsia; fluoxetine 10 mg: dysphagia, metrorrhagia; fluoxetine 20 mg: agitation, headache, insomnia, nausea). No statistically significant differences between treatment groups were observed in adverse events leading to discontinuation (P = .316).
The adverse event profile was comparable between the 10-mg and 20-mg treatment groups, with no event occurring at a significantly higher rate in either group. There were no statistically significant differences between treatment groups for any adverse events reported by 5% or more of patients in either fluoxetine treatment group (Table 4). There were statistically significant differences between the three treatment groups for only two adverse events, "libido decreased" (P = .007) and "accidental injury" (P = .019). Significantly more placebo-treated than fluoxetine-treated patients experienced accidental injury during this trial.
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). With specific reference to libido, when question #1 from the Arizona Sexual Experience Scale ("How strong is your sex drive?") was analyzed in a categoric fashion, 13% of the placebo patients, and 16% of both the fluoxetine groups experienced an increase of 2 or more points at end point compared with baseline (P = .902). No statistically significant differences were found between treatment groups for the other four Arizona Sexual Experience Scale questions either. This implies that fluoxetine-treated patients did not experience statistically significant impairment in sexual functioning compared with placebo-treated patients.
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There was no significant difference among treatment groups in patient compliance to medication, which was measured both by investigator assessment and by electronic diary. During the first active treatment cycle, mean numbers of days taking drug were: placebo = 13.2, fluoxetine 10 mg = 13.7, fluoxetine 20 mg = 13.1. Second cycle on drug: placebo = 13.6, fluoxetine 10 mg = 13.9, fluoxetine 20 mg = 12.7. Third cycle on drug: placebo = 12.7, fluoxetine 10 mg = 13.3, fluoxetine 20 mg = 13.2.
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DISCUSSION |
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The primary efficacy measure, the mean treatment Daily Record of Severity of Problems total score, was statistically significant in favor of fluoxetine 20 mg treatment versus placebo treatment, although no statistically significant difference was detected between the fluoxetine 10-mg and the placebo treatment group. Overall, mean percentage decrease from luteal baseline means were 38% for fluoxetine 20 mg, 35% for fluoxetine 10 mg, and 20% for placebo. Notably, these improvements were diminished after active treatment with fluoxetine was replaced with placebo; total scores of patients who discontinued fluoxetine became comparable with those of the placebo-treated patients. Analyses of two symptom clusters (mood and social functioning) provide evidence for the efficacy of fluoxetine 10 mg and fluoxetine 20 mg across these premenstrual dysphoric disorder-associated symptoms. Efficacy for physical symptoms, however, was only seen in the fluoxetine 20-mg treatment group. Interestingly, this difference suggests that the apparent benefits for physical symptoms are not a direct result of improvement in mood symptoms.
The overall safety and tolerability profile of premenstrual daily fluoxetine dosing in this population of women suffering from premenstrual dysphoric disorder is consistent with that observed in continuous daily treatment studies. The adverse event profile was comparable between the 10-mg and 20-mg treatment groups, with no event occurring at a significantly higher rate in either group.
The only spontaneously reported treatment-emergent adverse event observed with statistically significantly greater frequency among fluoxetine-treated patients was decrease in libido. Decrease in libido has also been reported as an adverse event for the active treatment arm in studies of continuous daily fluoxetine treatment (30% of patients)7 and continuous, semicontinuous, and intermittent citalopram treatment (up to 41%, 35%, and 39% of patients).12 In a naturalistic study of paroxetine, anorgasmia was reported by up to 50% of patients during each treatment cycle.11
Anticipating the potential barriers to accurate assessment of sexual functioning by spontaneous report (eg, hesitancy of patient or interviewer to discuss this personal subject),19 we used a systematically administered scale specific to sexual functioning. This allowed us to determine whether fluoxetine adversely affected sexual functioning by directly assessing change in sexual functioning from baseline. Analysis was conducted during the follicular phase when premenstrual dysphoric disorder symptoms, which can include sexual dysfunction, would not interfere. Because of the long half-life of fluoxetine and its metabolite norfluoxetine, near peak levels of these compounds should be present shortly after the start of the follicular phase. We would expect sexual dysfunction occurring solely as an effect of fluoxetine treatment (not affected by premenstrual dysphoric disorder symptomology) to be most prevalent at this time.
Studies that have systematically inquired about sexual functioning have generally revealed higher estimates of dysfunction than those relying on spontaneous reports.20 In this study, the percentage of women reporting dysfunction with libido was higher on systematic assessment (Arizona Sexual Experience Scale) compared with spontaneous report for all treatment groups. However, analysis of Arizona Sexual Experience Scale data did not show statistically significant differences in sexual functioning between fluoxetine- and placebo-treated patients, indicating that fluoxetine caused no more sexual dysfunction than did placebo. This finding was inconsistent with spontaneous reports. Longer-term studies, using specific measures of sexual functioning, are necessary to determine which factors (ie, dosing schedule or specific features of the study population) may influence the incidence of treatment-emergent sexual dysfunction.
In this study, as in previous studies of fluoxetine in patients with premenstrual dysphoric disorder, statistically significant symptom improvement occurred as early as the first cycle of treatment and was sustained across the treatment cycles for fluoxetine 20 mg. Given this finding, it seems likely that the mechanism underlying response to fluoxetine in patients with premenstrual dysphoric disorder21,22 is distinct from that postulated for major depression, which involves postsynaptic downregulation of serotonergic receptors over a period of weeks.23 Unlike in major depressive disorder, symptoms of premenstrual dysphoric disorder may result from a mechanism involving dysregulation of serotonergic neuromodulation, which is triggered by exposure to normal ovarian function. Thus, it can be hypothesized that the rapid response to treatment with fluoxetine seen in premenstrual dysphoric disorder derives not from duration of therapy or plasma concentration of antide-pressant but by an alternative mechanism which potentially modulates altered sensitivity to gonadal steroid both in the brain and peripherally.21,22
Although there are no data suggesting superior efficacy of premenstrual daily dosing of fluoxetine 20 mg compared with continuous daily dosing, one might speculate that premenstrual treatment will be more useful for patients reluctant to take continuous therapy for a cyclic disorder. In addition, given the burden of illness and impairment of function seen in patients with premenstrual dysphoric disorder,24 identification of tolerable, efficacious, and acceptable treatments for this disorder becomes that much more imperative. A further finding in the current study, also with significant clinical relevance, is the observation of recurrence of premenstrual dysphoric disorder within a 4-week period after substitution of placebo for fluoxetine, although symptoms did not revert to baseline severity.
The findings of this study support the efficacy and safety of premenstrual daily dosing with daily fluoxetine 20 mg in the treatment of premenstrual dysphoric disorder. Because some patients may be reluctant to take continuous daily fluoxetine for a cyclic condition, premenstrual daily dosing offers an attractive treatment option. Further study is needed to address the appropriate length of fluoxetine treatment in this chronic disorder, as well as to directly compare luteal phase dosing with daily dosing of fluoxetine.
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Footnotes |
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This study was supported by a grant from Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. C. Miner, E. Brown, K. Sundell, and S. McCray are employees of Eli Lilly and Company and own stock in the company. U. Halbreich received a research grant from Eli Lilly and Company. L. Cohen received grant and research support, works as a consultant, and is a member of the speaker’s bureau for Eli Lilly and Company. E. Freeman received a research grant from Eli Lilly and Company.
Received October 26, 2001. Received in revised form February 20, 2002. Accepted March 21, 2002.
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REFERENCES |
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24. Hylan T, Sundell KL, Judge R. The impact of premenstrual symptomatology on functioning and treatment-seeking behavior: Experience from the United States, United Kingdom and France. J Womens’ Health & Gender-Based Med 1999;8:1043–52.
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