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Paroxetine Controlled Release for Premenstrual Dysphoric Disorder: A Double-Blind, Placebo-Controlled Trial

From the Perinatal and Reproductive Psychiatry Program (L.S.C., C.N.S.), Massachusetts General Hospital, Boston, MA; Department of Psychiatry (K.A.Y.), Yale University School of Medicine, New Haven, CT; GlaxoSmithKline Clinical Development and Medical Affairs (K.M.B.), Psychiatry, King of Prussia, PA; GlaxoSmithKline Biostatistics and Data Sciences (I.M.B.), Harlow, UK; and Women’s Health Concerns Clinic (M.S.), St. Joseph’s Hospital, Hamilton, Ontario, Canada.

Address correspondence and reprint requests to Lee S. Cohen, MD, Perinatal & Reproductive Psychiatry, Clinical Research Program, Massachusetts General Hospital, 15 Parkman Street, WACC 812, Boston, MA 02114. E-mail: Lcohen2{at}partners.org

	ABSTRACT

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BACKGROUND: Better characterization of safety and efficacy of multiple doses of selective serotonin reuptake inhibitors for the treatment of a wider range of symptoms of premenstrual dysphoric disorder (PMDD) will provide clinicians with flexibility to provide symptom relief along with acceptable tolerability. This study was designed to assess the efficacy and tolerability of multiple doses of paroxetine controlled release (CR) in PMDD.

METHODS: In a multicenter (43 outpatient U.S. sites), placebo-controlled trial, 327 females aged 18 to 45 years, with regular menstrual cycles, meeting DSM-IV criteria for PMDD, were randomly assigned to receive paroxetine CR 12.5 mg; paroxetine CR 25 mg; or placebo, once daily, for up to three treatment cycles. The primary efficacy outcome was change from baseline to end point in mean luteal phase Visual Analogue Scale-Mood (irritability, tension, affective lability, depressed mood) score.

RESULTS: At end point, subjects treated with paroxetine CR (12.5 mg and 25 mg) demonstrated significant improvement in VAS-Mood scores compared with those who received placebo (paroxetine CR 12.5 mg mean treatment difference vs. placebo, –8.7 mm; 95% CI, –15.7, –1.7; p = .015; paroxetine CR 25 mg mean treatment difference vs. placebo, –12.1 mm; 95% CI, –18.9, –5.3; p < .001). Results were also significant across measures of physical symptoms and social functioning. Paroxetine CR was well tolerated; 9.5% of subjects treated with 12.5 mg and 13.5% of subjects treated with 25 mg withdrew from the trial due to adverse events, compared with 6.5% of subjects in the placebo group.

CONCLUSIONS: Both doses of paroxetine CR 12.5 mg and 25 mg daily are effective and well tolerated in patients who suffer from PMDD. Efficacy with both doses affords greater flexibility to the prescribing physician.

Key Words: premenstrual dysphoric disorder, • premenstrual syndrome, • selective serotonin reuptake inhibitors, • controlled release, • Clinical Global Impression severity, • last-observation-carried-forward, • visual analog scale.

Abbreviations: PMDD = premenstrual dysphoric disorder;; PMS = premenstrual syndrome;; SSRIs = selective serotonin reuptake inhibitors;; CR = controlled release;; CGI-S = Clinical Global Impression severity;; LOCF = last observation carried forward;; VAS = visual analog scale.

	INTRODUCTION

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Premenstrualdysphoric disorder (PMDD) is the most severe form of premenstrual syndrome (PMS). It is estimated that 3% to 9% of women suffer from PMDD (1–4). PMDD is characterized by psychiatric and somatic symptoms that appear during the 3 to 10 days before menstrual bleeding (luteal phase) and remit after the onset of menstruation (follicular phase). Essential features of PMDD include markedly depressed mood, anxiety, tension, irritability, affective lability, and decreased interest in activities (5). Physical symptoms may include breast tenderness, headaches, joint/muscle pain, weight gain, and bloating. These symptoms are present in most menstrual cycles and often associated with reduction in quality of life (6,7).

Data accumulated over the last decade support the efficacy of selective serotonin reuptake inhibitors (SSRIs) for the treatment of PMDD (8–14). Results from recent clinical trials evaluating efficacy of SSRIs for PMDD suggest variability of response across different dosages (15). Better characterization of safety and efficacy of multiple doses for a wider range of symptoms will provide clinicians with flexibility to promote symptom relief along with acceptable tolerability.

This report describes findings from a large randomized placebo-controlled clinical trial in patients diagnosed with PMDD in which two fixed-dosages of paroxetine controlled release (CR) were evaluated with respect to efficacy and safety.

	METHODS

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Subject Selection
This was a multicenter, randomized, double-blind, placebo-controlled, fixed-dose study to assess the efficacy and safety of paroxetine CR in women with PMDD. Eligible patients included females aged 18 to 45 years with regular menstrual cycles (duration between 22–35 days) who met diagnostic criteria for PMDD according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) (5). Symptoms of PMDD must have been present in at least 9 of 12 menstrual cycles over the previous year. Subjects prospectively rated their PMDD symptoms using daily diaries for two consecutive "reference" cycles before randomization. Subjects were eligible for randomization if the onset of severe premenstrual symptoms during the luteal phase was followed by symptom subsidence during the follicular phase on the four core symptoms of PMDD (irritability, tension, affective lability, and depressed mood). Patients were required to demonstrate a 200% worsening on one core symptom or a 100% worsening on two or more core symptoms during the luteal phase relative to their follicular phase score. A baseline Clinical Global Impression severity of illness (CGI-S) score of 3 (16) was also required.

Exclusion criteria included other primary psychiatric disorders (Axis I, DSM-IV criteria, assessed by the Mini International Neuropsychiatric Interview (MINI)) (17), except specific phobias, in the previous 6 months; gynecologic or other clinically significant diseases; significant depressive symptoms (defined as MADRS score 10 at screening) during the follicular phase; and current use of medication for PMDD symptoms.

Signed informed consent was obtained before participation. The study protocol was reviewed and approved by local regulatory authorities and ethics committees and conducted in accordance with the Declaration of Helsinki (1996 revision) and principles of good clinical practice (International Conference on Harmonization document Good Clinical Practice Consolidated Guideline).

All the participants in the study, including those administering the study visits and those assessing the outcomes, were blinded to the study assignment. There was no systematic evaluation of the study blind. However, the primary outcome measure was patient-rated and therefore limited any potential investigator bias of efficacy assessment.

Clinical Trial Methodology
Subjects were evaluated based on entry criteria at an initial screening visit (Figure 1). Eligible patients rated their daily PMDD symptoms in daily diaries using a visual analog scale (VAS). The use and validity of visual analog scales for assessment of mood symptoms are well documented (18). The VAS consists of a 100-mm horizontal line with descriptors that range from "not at all" (0 mm) to "extreme" (100 mm). The following symptoms were recorded: irritability, tension, affective lability, depressed mood, decreased interest, difficulty concentrating, lack of energy, change in appetite, change in sleep pattern, feeling out of control, and physical symptoms. The primary efficacy variable, the VAS-Mood score, is a mean score of the four core PMDD symptoms (irritability, tension, depressed mood, and affective lability), and is considered a valid, reliable, and sensitive instrument to measure changes in premenstrual mood symptoms (19). No medication was administered during the first reference cycle. Single blind placebo was administered once daily during the second reference cycle. An additional reference cycle was available to patients who met all entry criteria before the first reference cycle but failed to achieve the predefined severity of core PMDD symptoms after a first period of symptom tracking. Eligible patients were randomly assigned by a computer-generated randomization code to once daily paroxetine CR 25 mg, paroxetine CR 12.5 mg, or similar appearing placebo (1:1:1 ratio).

View larger version (41K): [in this window] [in a new window]   Figure 1. Study flow.

Study Objectives
The primary objective was to compare the efficacy of daily treatment throughout the menstrual cycle with paroxetine CR (12.5 mg/day or 25 mg/day) versus placebo. The secondary objective was to assess the safety of treatment with paroxetine CR. The primary efficacy variable was the change in the mean luteal phase VAS-Mood scores from baseline to end of treatment cycle 3. Secondary outcome measures included change from baseline to treatment cycle 3 in the sum of the 11 VAS symptoms (VAS-Total), physical symptoms, social impairment, the proportion of responders (defined as a 50% reduction from baseline VAS-Mood scores), and the proportion of responders defined as a CGI-I item score of 1 (very much improved) or 2 (much improved).

Statistical Methods
A sample of 86 patients in each of the three study arms provides 90% power to detect a difference of 16.3 mm (common SD of 33.5) between either dose of paroxetine CR, and placebo, for the primary efficacy variable. Allowing for a 20% attrition rate, this resulted in a target of 108 patients randomized to each treatment group. To adjust for multiple comparisons, a two-sided alpha level of 0.025 was used.

A normal, linear regression model was used to analyze the primary variable, adjusting for the following prespecified covariates: treatment group, center grouping, baseline VAS-Mood score, and age (in years) at entry to the study, regardless of their significance. The same model was fitted to each continuous secondary variable with the remaining responder end points analyzed using logistic regression (adjusting for the same covariates, except CGI-I where a baseline value does not exist). All models were fitted using the SAS computer package (21).

For all efficacy measures, the primary conclusions were based on the TC3 study end point using the last observation carried forward (LOCF) approach to handle missing data. All hypothesis testing was two-sided. For the primary end point alone, an adjustment for two treatment comparisons was made using Hochberg’s modification to the Bonferroni inequality (22).

	RESULTS

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Patients
A total of 1,751 women were screened at 43 outpatient centers across the United States (Figure 1), from November 1999 to October, 2001. Of these, 327 patients successfully completed the reference phase and were randomized to double-blinded study medication. Fourteen randomized patients were excluded from all efficacy and safety analyses (Figure 1). Of the remaining 313 patients, 111 were randomized to 25 mg paroxetine CR, 95 to 12.5 mg paroxetine CR, and 107 to placebo. Subjects completed the treatment phase by February 2002.

Baseline Data
Baseline demographic characteristics were well balanced across treatment groups. There were no marked differences across treatment groups with respect to baseline severity of the efficacy parameters. Global assessments of disease severity at baseline revealed the presence of moderate to marked illness that was accompanied by substantial impairment in areas of social functioning (work life, social life, and family life). Mean baseline VAS-Mood scores ranged from 54 to 60 mm and were similar to baseline scores observed in previous PMDD studies (9,11,23).

Efficacy Endpoints
At study end point (treatment cycle 3 LOCF), statistically significant differences were observed in favor of paroxetine CR 25 mg versus placebo [adjusted mean difference = –12.10 mm, 95% CI (–18.91, –5.29), p = .001] and paroxetine CR 12.5 mg vs. placebo [adjusted mean difference = –8.72 mm, 95% CI (–15.72, –1.71), p = .015] on the VAS-Mood (Table 1). No significant differences were found between paroxetine CR 12.5 mg and 25 mg with respect to changes observed in VAS-Mood, irritability, tension, affective lability, and depressed mood (Table 1).

View larger version (11K): [in this window] [in a new window]   Figure 2. VAS-total scores at baseline and at each treatment cycle for subjects randomized to receive placebo, paroxetine CR 12.5 mg, or paroxetine CR 25 mg.

A total of 71% of patients randomized to 25 mg of paroxetine CR and 67% of patients randomized to 12.5 mg paroxetine CR had a significant response to treatment (defined as 50% reduction from baseline VAS-Mood) at end point compared with 49% of subjects on placebo. The estimated odds of responding on paroxetine CR was between 2 to 3 times higher compared with placebo and statistically significant for both doses of paroxetine CR. The estimated odds of responding on a higher dosing (25 mg) was not significantly different than that observed on a lower dosing (12.5 mg) (Table 2). A response analysis based on CGI improvement scores (defined as CGI-I 2) demonstrated superior efficacy of paroxetine CR 25 mg and 12.5 mg (71% and 66%, respectively), compared with placebo (49%). The odds ratios for both paroxetine CR groups vs. placebo comparisons were statistically significant, without significant differences between the two treatment groups (Table 2). Secondary analysis suggests that the odds of responding to treatment with paroxetine decreases as duration of illness increases [odds ratio = 0.96, 95% CI (0.93, 1.00); p = .039].

View this table: [in this window] [in a new window]   TABLE 4. Number (%) of Subjects With the Most Frequently Reported (5% in Any Treatment Group) Treatment Phase-Emergent Adverse Events (ITT Population)

	DISCUSSION

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Additional corroborative evidence supporting the efficacy of 25 mg and 12.5 mg of paroxetine CR was provided by a responder analysis based on clinically relevant reductions in symptoms of PMDD. A significant percentage of patients treated with paroxetine CR 25 mg (71%) and paroxetine CR 12.5 mg (67%) had a 50% reduction from baseline VAS-Mood scores. Similar results were observed when using the CGI-I, which was scored independently of the primary outcome measure. Response rates are comparable to those seen with other SSRIs in PMDD such as fluoxetine (52%) (9) and sertraline (62%) (10).

Paroxetine CR was also effective in treating the physical symptoms associated with PMDD, as demonstrated by a superior efficacy of paroxetine CR 25 mg compared with placebo. Although the 12.5 mg dose failed to reach statistical significance for the improvement of physical symptoms in this study, subsequent analyses of pooled data, using data from 933 patients enrolled in 3 clinical trials evaluating the efficacy of paroxetine CR for the treatment of PMDD, demonstrated a benefit for the 12.5 mg dose in treating physical symptoms (24). Furthermore, a statistically significant benefit for both 25 mg and 12.5 mg was observed on all end points, including physical symptoms, following an analysis of 6-month treatment data with paroxetine CR (25). This finding suggests that response to lower dose of paroxetine CR may be progressive over time.

To the best of our knowledge, this study is the first to demonstrate both efficacy and tolerability of more than one dosage of a daily-administered SSRI, allowing more flexibility for the treatment of PMDD. Although various comparisons failed to show statistically significant differences between paroxetine CR 25 mg and paroxetine 12.5 mg treatment groups, the results overall suggest a trend toward an improved response with paroxetine CR 25 mg. However, data also suggest increased tolerability for the lower dose (only 9% dropouts due to adverse events, compared with 13.5% with paroxetine CR 25 mg/day). Previously, higher doses of fluoxetine (60 mg/day) have shown no additional benefit in treating PMDD compared with a lower dose (20 mg/day) and caused increased adverse events (9).

The strict entry criteria assured that the appropriate population of PMDD subjects was studied. The number of subjects randomized in relation to the number of patients screened (327 of 1,751; 19%) demonstrates the stringent requirements for a diagnosis of PMDD, which includes meticulous prospective assessments of the cyclical nature of the patient’s symptoms.

Consistent with previous studies, this sample of PMDD subjects demonstrated a substantial level of functional impairment at baseline. Average baseline SDS scores were among the highest documented levels of impairment associated with a mental disorder (6,26). This was particularly apparent for the family life domain that measures impairment in the patient’s ability to relate to family members, and conduct routine daily activities such as managing the home, shopping and cleaning. Paroxetine CR was able to reduce functional impairment as a result of direct improvements in PMDD symptoms.

It is noteworthy that duration of illness appeared to adversely impact response to treatment; subjects who reported suffering from PMDD for a longer period of time were less likely to respond to medication. Most subjects enrolled in the study, however, reported that their PMDD symptoms had persisted since their initial onset (on average, for 11 years). If confirmed by other studies, this finding may indicate the accumulative impairment caused by a more chronic exposure to PMDD symptoms and would justify greater efforts to early detection and treatment of this condition.

In conclusion, paroxetine CR at doses of 12.5 mg or 25 mg is effective in treating symptoms of PMDD, and in improving social functioning. Response to treatment can be expected within the first treatment cycle, with associated significant improvement in the core symptoms of irritability, tension, affective lability and depressed mood. Future studies with longer periods of treatment follow up are needed to support the current findings of efficacy, favorable tolerability, and lack of significant weight gain observed with treatment with paroxetine CR.

Paroxetine CR Study Investigators
David Adson, MD, Richard Beyerlein, MD, James Grimm, MD, Robert Bielski, MD, Geoffrey Bowman, MD, Hillary Brown, MD, Lisa Johnson, MD, Thomas Chiambretti, DO, Lee Cohen, MD, Clinton Corder, PhD, MD, Lydia Corn, MD, Joseph David, MD, John Debus MD, David Dozer, MD, Stephen Gordon, MD, Stephen England, MD, Robert Feldman, MD, James Cook, MD, Marilynn Frederiksen, MD, Ellen Freeman, PhD, Steven Sondheimer, MD, Kenneth Grant, MD, David Harari, MD, Burton Lazar, MD, Frederick Lewis, DO, Candace Brown, Pharm D, Frank Ling, MD, Robert Lipetz, DO, Peter Londborg, MD, Majorie Merod, MD, Michael Solloway, MD, Kenneth Palmer, MD, Teri Pearlstein, MD, Mary Lake Polan, MD, PhD, Andrea Rapkin, MD, Gerald Shockey, MD, Kenneth Sokolski, MD, Margaret Spinelli, MD, Ronald Tachibana, MD, Christopher Thoming, MD, Warren Ricks, PhD, Kimberly Yonkers, MD, Francoise Adan, MD, Anne Macek, MD, Murray Rosenthal, DO, Louis Fabre, MD, PhD, Leslie Taylor, MD.

Received for publication November 2, 2003.

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