| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
ORIGINAL RESEARCH |
From the State University of New York at Buffalo School of Medicine, Buffalo, New York; Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Yale University School of Medicine, New Haven, Connecticut; University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; Duke University School of Medicine, Durham, North Carolina; and Harvard Medical School, Cambridge, Massachusetts.
Address reprint requests to: Uriel Halbreich, MD, State University of New York at Buffalo, SUNY Clinical Center, 462 Grider Street, Buffalo, NY 14215; E-mail: urielh{at}acsu.buffalo.edu.
 |
ABSTRACT |
|---|
TOP
 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
METHODS: Two hundred eighty-one women who met Diagnostic and Statistical Manual of Mental Disorders (4th edition) criteria for premenstrual dysphoric disorder and who completed two prospective screening cycles and one single-blind placebo cycle were randomized to three cycles of double-blind, luteal phase treatment with either a placebo or sertraline in a flexible daily dose of 50–100 mg. Outcome measures included the Daily Record of Severity of Problems and the Clinical Global Impression Severity and Improvement scales.
RESULTS: Luteal phase treatment with sertraline was significantly superior to the placebo, as demonstrated by endpoint analysis of Clinical Global Impression Improvement scale scores (sertraline, 2.3 ± 1.1, versus placebo, 2.7 ± 1.1; P < .001), and cycle 3 Daily Record of Severity of Problems change scores (sertraline, 27.6 ± 26.8, versus placebo, 17.6 ± 23.3; P < .002). A significant difference was also noted in responder rates in favor of sertraline (50%) versus placebo (26%, P < .001) by cycle 1 (with responder defined as a Clinical Global Impression Improvement scale score of 1 or 2). Quality of life and functioning outcomes were also significantly improved. Intermittent luteal administration of sertraline was well tolerated, with only approximately 8% of patients on sertraline and less than 1% on placebo discontinuing because of adverse events.
CONCLUSION: Sertraline was significantly more effective than a placebo and was well tolerated as a treatment for premenstrual dysphoric disorder when administered intermittently during the luteal phase of the menstrual cycle.
Premenstrual dysphoric disorder is a severe subtype of premenstrual syndrome (PMS) that occurs in 2–9% of women of reproductive age.1,2 It is characterized by a diverse array of symptoms including depressed mood, irritability, anxiety, mood swings, anger dyscontrol, impaired concentration and energy, and physical symptoms such as bloating and breast tenderness. Symptoms are intermittent, occurring during the luteal phase of the menstrual cycle, and remit shortly after the beginning of menses. Premenstrual dysphoric disorder has fairly high symptom stability from cycle to cycle.3 The age of onset typically is in the early to midtwenties, though it may begin at any time after menarche.1,4 Premenstrual dysphoric disorder tends to persist for many years, usually until menopause. Severe premenstrual symptoms meeting premenstrual dysphoric disorder criteria often are associated with significant impairment in a woman’s individual, familial, social, and occupational activities.5,6 Most women with PMS or premenstrual dysphoric disorder do not seek treatment, and if they do, they are most likely to consult their general practitioner or gynecologist.6
The pathophysiology of premenstrual dysphoric disorder is still not certain. Twin studies examining genetic determinants have provided heritability estimates that range from 35% to above 50%, with a suggestion of substantial environmental impact.7,8 Though premenstrual dysphoric disorder and major depressive disorder clearly exhibit shared risk, almost two thirds of the genetic risk factors for premenstrual dysphoric disorder were independent of risk factors for depression, suggesting the validity of premenstrual dysphoric disorder as a separate diagnosis. Nonetheless, premenstrual dysphoric disorder appears to share with major depressive disorder and with anxiety disorders an association with abnormal serotonergic dysfunction.9–13 The abnormal neurotransmitter function is probably modulated by menstrually related fluctuation in gonadal hormones, sensitivity to which might be amended in women with PMS.11,14,15 Given the apparent link to serotonergic dysfunction, it is not surprising that agents blocking the serotonin transporter, including selective serotonin re-uptake inhibitors, have become a focus of treatment research.16,17
For decades the management of premenstrual disturbances included the use of numerous, mostly unproven treatment modalities. The interventions that have been shown to be effective include hormonal interventions, mostly gonadotropin-releasing hormone analogues but also danazole and some oral contraceptives; serotonergic but not noradrenergic agonist antidepressants18; and many others, most of them still not unanimously proven. They include diuretics; various anxiolytics; prostaglandin inhibitors and precursors; nonsteroidal anti-inflammatory drugs; various vitamins, amino acids, and mineral supplements (eg, B6, A, E, phenylalanine, L-tryptophan, calcium, magnesium); and herbal remedies, especially chasteberry extract. Among the treatment modalities that have not been shown to be effective in well-controlled studies are progesterone, thyroid hormones, lithium, and evening primrose oil (for reviews, see Altshuler et al19 and Mitwally et al20).
Two main treatment approaches have demonstrated consistent efficacy: suppression of ovulation14 and treatment with antidepressants, mainly selective serotonin reuptake inhibitors.16 Several large, well-designed, placebo-controlled studies have been reported that demonstrate the efficacy of the selective serotonin reuptake inhibitor antidepressants fluoxetine17 and sertraline4,18 as well as other selective serotonin reuptake inhibitors for the treatment of premenstrual dysphoric disorder.
The rapid improvement in premenstrual dysphoric disorder symptoms observed in selective serotonin re-uptake inhibitor studies using continuous dosing (up to 75% of maximal improvement already by cycle 1)4 and the serotonergic abnormalities during the symptomatic period11,13 suggest that an intermittent, luteal phase treatment strategy for this intermittent disorder might be feasible. Such a dosing strategy has several potential advantages over continuous treatment. It should be more convenient and acceptable to the patient, thus enhancing compliance. It might also reduce adverse effects and show better tolerability for a long-term treatment. Because the impact of a chronic continuous long-term stimulation of the serotonergic system over many years is still unknown, intermittent intervention, though repeated, might be safer than a continuous one. Pilot studies testing an intermittent treatment strategy have been promising.21–26 The purpose of the current study is to provide a large, multicenter, double-blind, placebo-controlled evaluation of the efficacy of intermittent luteal phase treatment, using sertraline in doses of 50 or 100 mg daily.
|
MATERIALS AND METHODS |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Study entry criteria required women to be between the ages of 24 and 45 years inclusive, with regular menstrual cycles lasting 24–36 days, and to have had at least a 2-year self-reported history of premenstrual dysphoric disorder. Patients were required to meet specific Diagnostic and Statistical Manual of Mental Disorders (4th edition)27 luteal phase symptom criteria for premenstrual dysphoric disorder, based on two cycles of prospective daily ratings with the quantitative Daily Record of Severity of Problems.28 The symptom criteria used in the study required above-threshold symptom severity (moderate or greater) and also that the mean luteal phase score during the 5 most symptomatic days in the week before the onset of menses be at least 75% higher than the mean midfollicular phase score for days 6–10 of that cycle. In addition, a marked level of functional impairment was required on the Daily Record of Severity of Problems for a minimum of 2 premenstrual days.
Women were excluded for the following reasons: 1) follicular phase Hamilton Rating Scale for Depression score greater than 10; 2) use of oral contraceptives or other hormonal preparations within 2 months before screening; 3) current or lifetime diagnosis of bipolar or psychotic disorder, schizophrenia, obsessive-compulsive disorder, or antisocial/borderline/schizotypal personality disorder; 4) current (or past 6 months) diagnosis of major depression, dysthymic disorder, or depression not otherwise specified (other than premenstrual dysphoric disorder); panic disorder; generalized anxiety disorder; posttraumatic stress disorder; or eating disorder; 5) older than 38 years and having luteinizing hormone (LH) levels of more than 38 U/L or follicle-stimulating hormone levels of more than 20 U/L; 6) hysterectomy, or a failure to demonstrate ovulation in two of the cycles leading up to randomization; 7) failure to respond to two or more adequate trials of antidepressants to treat their premenstrual dysphoric disorder; or 8) current use of any psychotropic medication.
The study was conducted in accordance with the Helsinki Declaration of 1975, as revised in 1983. Study procedures were explained to patients, and written informed consent was obtained. The study and the consent form were approved by the institutional review board at each study site.
The study design consisted of retrospective screening for inclusion and exclusion criteria, followed by prospective screening that included daily self-monitoring of symptoms as well as both midfollicular and late luteal phase evaluations at office appointments with an investigator. Patients were then given one cycle of a single-blind placebo, beginning 14 days before the anticipated onset of menses. If patients continued to meet study entry criteria, they were randomized, double blind, to three cycles of luteal phase treatment with either sertraline or the placebo. Patients were medication-free during the follicular phase of the cycle. Compliance was assessed by pill counts at each visit. Patients were instructed not to self-medicate during the course of the study with any drugs that might influence their premenstrual symptomatology (eg, hormones, diuretics, vitamins, or other psychotropic medication).
Treatment consisted of flexible dosing in the range of 50–100 mg per day of sertraline or matching placebo tablets during the luteal phase. Active medication and the placebo were manufactured and supplied by Pfizer Inc. (New York, NY). Medications were dispensed in blister cards. The randomization list was created using a computer-based random number generation program, and blinding was achieved by blister-packed, double-blind treatment cards containing either 50 mg of sertraline or an identical placebo. Cards were returned at the end of each treatment cycle and the number of consumed tablets and compliance were noted.
Time of initiation of study treatment was determined by an algorithm based on prospective assessment of an individual’s average cycle length: For women with a cycle length of 28 days or longer, study medication was begun 14 days before the anticipated onset of bleeding; for women with a cycle length up to and including 27 days, study medication was begun 12 days before the anticipated onset of bleeding.
The starting dose for sertraline was 50 mg. If, in the investigator’s opinion, an adequate response had not been observed at the end of the first or second treatment cycle, then, in the absence of dose-limiting side effects, subjects were titrated up to 100 mg per day (or matching placebo). The dose of sertraline (or placebo) could also be decreased between visits if intolerable adverse events occurred.
At study entry, each patient underwent a medical evaluation that included a physical examination, laboratory tests (chemistry profile, thyroid panel, follicle-stimulating hormone, urinalysis, and red and white blood cell counts), and a serum ß–human chorionic gonadotropin pregnancy test. Preovulatory LH surge was confirmed by a urine test that was completed and documented at each cycle throughout the study.
Lifetime psychiatric diagnoses were established by means of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (4th edition), patient version.29 The 21-item Hamilton Rating Scale for Depression30 was used to assess the severity of premenstrual mood disturbance. The 7-point clinician-rated Clinical Global Impression Severity and Improvement scales31 were used to provide global assessment of outcome. Patients rated their improvement on a similar 7-point global scale, the Patient Global Evaluation, which uses the same anchors as the Clinical Global Impression Improvement scale.
Functional impairment affecting interpersonal relationships and role function was also evaluated by means of the patient-rated 56-item Social Adjustment Scale.32 This scale evaluates the status of a patient’s relationships with his or her spouse, children, and other family members. It also includes questions about efficiency and functioning at work and home. Quality of life was evaluated using the Quality of Life Enjoyment and Satisfaction Questionnaire (short version).33
Throughout the trial participants completed the Daily Record of Severity of Problems28 on a daily basis. The Daily Record of Severity of Problems is a widely used and validated 24-item, patient-rated scale that incorporates all Diagnostic and Statistical Manual of Mental Disorders (4th edition) symptoms of premenstrual dysphoric disorder. The first 21 items rate the psychologic and physical symptoms of premenstrual dysphoric disorder, and the final three items measure three domains of functioning: 1) productivity at work, home, or school; 2) interference with hobbies or social activities; and 3) interference with relationships. The severity of each item is recorded on a 6-point scale that ranges from 1 (absent) to 4 (moderate) to 6 (extreme).
Clinicians’ ratings, self-report questionnaires, and efficacy and safety evaluations were performed during the late luteal phase of the single-blind, placebo lead-in period, and at each double-blind treatment cycle.
On daily ratings during the two pretreatment cycles, all patients were required to have at least one of the following symptoms rated as moderate or greater in severity for at least 2 days during the late luteal phase: depression, irritability, anxiety/tension, or mood lability, as well as at least four additional Diagnostic and Statistical Manual of Mental Disorders (4th edition) criterion symptoms of premenstrual dysphoric disorder. The average pretreatment score on a minimum of five symptoms should have worsened by at least 75% during the 5 days preceding menses relative to the average midfollicular phase score (days 6–10). As required by the Diagnostic and Statistical Manual of Mental Disorders (4th edition), each woman had premenstrual functional impairment and a postmenstrual symptom–free week. Because Diagnostic and Statistical Manual of Mental Disorders (4th edition) diagnostic criteria for premenstrual dysphoric disorder were used, the presence of physical symptoms alone was not sufficient for eligibility.
The primary efficacy parameters include 1) the 7-point Clinical Global Impression Severity score,31 2) the 7-point Clinical Global Impression Improvement score,31 and 3) the total score from the Daily Record of Severity of Problems.28
The secondary efficacy parameters include 1) responder status, defined as a Clinical Global Impression Improvement score of 1 or 2 (very much improved or much improved); 2) four factor totals from the Daily Record of Severity of Problems, consisting of the Daily Record of Severity of Problems depressive symptoms factor (felt depressed, felt hopeless, felt worthless or guilty, decreased interest in usual activities [eg, work, school, friends, hobbies], increased appetite, slept more, trouble sleeping, and felt overwhelmed; range of scores 8–48); the Daily Record of Severity of Problems anxiety/somatization symptoms factor, the Daily Record of Severity of Problems physical symptoms factor (breast tenderness, bloating, headache, joint or muscle pain; range 4–24); and the Daily Record of Severity of Problems anger/irritability factor (anger or irritability and conflicts with people; range 2–12); 3) individual Daily Record of Severity of Problems items; 4) the Hamilton Rating Scale for Depression total score, as well as factor scores (eg, cognitive disturbance, anxiety/somatization); 5) the total score from the Quality of Life Enjoyment and Satisfaction Questionnaire (short version); and 6) the total score and seven factor scores from the Social Adjustment Scale (self-rated version).
Daily Daily Record of Severity of Problems total scores during the late luteal phase (5 days preceding onset of menses) were averaged together in all analyses. Only Daily Record of Severity of Problems scores from within the defined late luteal phase of each menstrual cycle were used. Midfollicular and late luteal phases were defined as days 6 through 10 after the onset of menstrual flow and the 5 days before menses, respectively. Statistical analyses were conducted for the late luteal phase ratings of each treatment cycle and at "end point," being the final visit for each patient. In cases where more than 20% of the constituent items were missing, a score was not calculated. When less than 20% of time points were missing, a mean of the nonmissing items was determined, and then prorated to be consistent with the number of items in the scale. An intention-to-treat with last observation carried forward perspective was adopted, so that data from all study patients were included, regardless of patient compliance with the protocol. The intention-to-treat sample was defined to include all patients who were randomized to study medication and completed at least one postrandomization efficacy measure. Both observed cases of intention to treat–last observation carried forward end point data are considered and presented.
Baseline comparability of the treatment groups was assessed by means of analyses of variance or Cochran-Mantel-Haenszel (
2) tests. For Daily Record of Severity of Problems and 21-item Hamilton Rating Scale for Depression scores, analysis of variance models were used to compare sertraline and placebo groups at the luteal phase of each double-blind cycle and at end point. Cochran-Mantel-Haenszel tests were used to compare responder rates at the same time points—as well as for comparison of center effect. Additionally, for the primary efficacy outcomes of Daily Record of Severity of Problems, Clinical Global Impression Severity scale, and Clinical Global Impression Improvement scale, repeated-measures analysis of variance models were implemented, which augmented the by-cycle analyses of variance with effects for cycle and treatment-by-cycle interaction. All hypotheses were two sided, and significance was declared at the 5% level. Analysis of the various Daily Record of Severity of Problems factors was a priori hypothesized and stipulated, and no adjustments for multiplicity were planned.
Because no large-scale placebo-controlled trials using intermittent dosing with selective serotonin reuptake inhibitors were available, the required sample size was estimated based on results of a placebo-controlled trial in which sertraline was administered continuously throughout the month. The mean ± standard deviation (SD) difference in Daily Record of Severity of Problems scores at end point for sertraline versus placebo in this trial was 10.2 ± 21.6. It was assumed, based on clinical judgment, that the end point Daily Record of Severity of Problems difference score would be smaller than 10.2 because of the intermittent dosing strategy. Consequently, the sample size requirement was calculated to be able to detect a 7-point end point difference between sertraline and placebo as being statistically significant, assuming a proportionately smaller SD of 19.0.
Ninety-eight patients per treatment group who completed the study were needed to provide 80% power, to detect such a difference in Daily Record of Severity of Problems. A 20% dropout rate was assumed, so that 240 randomized patients were needed to ensure adequate power for patients completing the trial. All analyses were conducted with the Statistical Analysis System 6.08 or 6.10 (SAS Institute Inc., Cary, NC). Data are given as means ± SDs.
|
RESULTS |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
). The typical study patient was white (91%), well educated, employed, and married with either one or two children. At screening, 16% of patients reported that they had missed work because of premenstrual dysphoric disorder symptoms in the preceding month, and 77% reported reduced work productivity during the previous month. A relatively high proportion of patients reported a history of oral contraceptive use, with 13% of the total reporting that premenstrual dysphoric disorder symptoms worsened while on contraceptives, and 15% reporting improvement in symptoms. Finally, the histories of postpartum depression (14.9% for the sertraline group and 12.7% for the placebo group) and major depression (19.7% and 17.3%, respectively) were lower than has previously been reported in some studies, which may be partly due to carefully structured diagnostic assessment.
|
A flow diagram (Figure 1) summarizes the patient numbers and patient disposition throughout the course of study treatment. Of the 907 patients who met entry criteria and consented to participate in the study, a total of 626 discontinued during the two cycles of screening and the single-blind placebo run-in cycle, 208 (33.2%) withdrew consent (because of change of mind, inavailability of time, treatment sought with their clinician, etc), 125 (20.0%) were lost to follow-up, 202 (32.3%) no longer met study entry criteria, 19 (3.0%) discontinued for miscellaneous reasons, and 72 (11.5%) discontinued for reasons unknown. Two hundred eighty-one patients were randomized to sertraline (n = 142) or a placebo (n = 139), and 221 patients completed the trial (115 sertraline and 106 placebo).
|
Sertraline showed statistically significant superiority on all three a priori primary outcome parameters throughout all three cycles of double-blind treatment. The efficacy was achieved rapidly, and was evident by the end of the first cycle of double-blind treatment (Table 2).
|
reflect the mean total score for the 5 luteal days immediately preceding the onset of menses. Daily Record of Severity of Problems results for the mean of the 5 most severe symptomatic luteal days closely paralleled these results—for example, at intention-to-treat end point, the mean Daily Record of Severity of Problems total scores for the worst 5 days were 49.8 ± 19.6 for sertraline and 59.2 ± 25.6 for the placebo (P < .001). The cycle 3 Daily Record of Severity of Problems change score for patients on sertraline was 27.6 ± 26.8, whereas for patients on placebo it was 17.6 ± 23.3 (P < .002). Repeated-measures analyses of variance results were consistent with the analyses at each cycle: Treatment differences were significant (Daily Record of Severity of Problems: F1,206 = 14.34, P < .001; Clinical Global Impression Severity: F1,216 = 21.39, P < .001; Clinical Global Impression Improvement: F1,215 = 23.25, P < .001). Treatment-by-cycle interaction effects were not significant for any primary outcome.
Table 3 summarizes the effects of study treatment on the key outcome dimensions that contribute to the clinical presentation of premenstrual dysphoric disorder. Sertraline had significantly greater efficacy in improving depression across all measures, including the self-reported Daily Record of Severity of Problems depressive mood and depression symptom factors (the latter includes such Daily Record of Severity of Problems items as loss of interest, appetite and sleep disturbance, etc). The investigator-rated Hamilton Rating Scale for Depression, which was explicitly limited to late luteal phase symptomatology, also showed greater improvement on sertraline. Sertraline also showed significantly greater efficacy in improving anxiety, as measured by both the Daily Record of Severity of Problems anxious/tension item and the Hamilton Rating Scale for Depression anxiety/somatization factor.
|
). These included both the Daily Record of Severity of Problems irritability/conflict/anger factor and the Daily Record of Severity of Problems rejection factor, which measures the degree of interpersonal sensitivity.
Because the Daily Record of Severity of Problems items were highly correlated with each other, no adjustment for multiplicity was applied. The significance levels of Daily Record of Severity of Problems reported in Table 3 (mostly P < .001) are highly significant. Use of a conservative Bonferroni correction for multiplicity would affect significance (.05 > P < .06) of three Daily Record of Severity of Problems factors or items: depressive symptoms factor, reduction in productivity item, and difficulty concentrating item.
Sertraline did not have a significant advantage over the placebo in improving physical symptoms commonly associated with PMS and premenstrual dysphoric disorder (eg, breast tenderness, headache, feeling bloated). In contrast, sertraline was significantly more effective than the placebo in reducing the premenstrual cognitive disturbance, as well as such vegetative symptoms as increased appetite, increased sleep/napping, and lethargy (Table 3).
Reflecting the broad improvement across all symptom domains, sertraline treatment resulted in a significantly higher rate of treatment response, defined as a Clinical Global Impression Improvement score of 1 or 2 ("much" or "very much" improved) (Figure 2). This advantage in responder rate was evident already from the start of treatment in cycle 1. Similarly, patients rated themselves as significantly more improved on sertraline. Intention-to-treat end point scores for sertraline on the 7-point global evaluation scale (the patient-rated equivalent to the Clinical Global Impression Improvement scale) were 2.3 ± 0.1, compared with 2.9 ± 0.1 on placebo (P < .001).
|
). At the end point, there was a statistically significant difference between the sertraline and placebo groups in the adjusted mean change from baseline to end point for four of the seven Social Adjustment Scale factor averages: social/leisure (P = .001), parental (P = .001), extended family (P = .01), and family unit (P = .045). The three Social Adjustment Scale factor scores that were not statistically significant between the sertraline and placebo groups were the work factor, the housework factor, and the marital or dating factor. By cycle 3, 63% of patients treated with sertraline versus 46% of patients treated with placebo had achieved scores within 10% of the community norm of 83 on the Quality of Life Enjoyment and Satisfaction Questionnaire. Treatment was well tolerated. Treatment-emergent adverse event rates (for sertraline and the placebo, respectively) were as follows: headache (15.4% versus 7.9%, P = .084), nausea (12.5% versus 3.1%, P = .006), insomnia (11.8% versus 10.2%, P = 0.844), diarrhea (10.3% versus 6.3%, P = .272), and dry mouth (10.3% versus 3.1%, P = .027). Six patients on sertraline reported decreased libido during luteal treatment, and one patient reported sexual dysfunction. (These numbers may be low because of reliance on spontaneous self-report.) In addition, 16.9% of patients on sertraline reported adverse events that were severe, compared with 7.1% on the placebo (P = .022). Despite or, perhaps, because of intermittent dosing, adverse event rates were notably lower during cycle 3. An analysis of study completers found that, after cycle 1, 56 of 115 (48.7%) reported no adverse events, whereas, after cycle 3, 89 of 115 (77.4%) reported no adverse events.
Mean change in weight was -0.8 + 4.4 lb on sertraline and + 0.5 + 4.4 lb on the placebo (P = .005). There were no significant differences between sertraline and the placebo in the incidence of clinically significant laboratory test results or vital signs.
|
DISCUSSION |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The current study also demonstrates that sertraline treatment results in significant and rapid improvement in premenstrual dysphoric disorder symptoms using a lower dose range (50–100 mg) than was employed in the previous continuous dosing studies, which permitted titration up to 150 mg of sertraline. The current dose range is at the lower end of the therapeutic range that has demonstrated efficacy in other severe affective disorders.
The efficacy of brief, targeted treatment differs from several decades of widespread conventional wisdom regarding the efficacy of antidepressants in episodic affective and anxiety disorders. The results of the current study, together with consistently positive results from previous pilot studies,21–25 confirm that premenstrual dysphoric disorder is an intermittent, cyclic illness in which treatment may prove efficacious even if it is limited to the length of the presumed underlying pathophysiologic processes.13–15
Future research should explore whether the treatment period can be further shortened while retaining efficacy, perhaps with initiation of treatment at the onset of actual premenstrual dysphoric disorder symptoms.
It is of heuristic as well as practical clinical importance to elucidate whether intermittent and continuous treatment intervention would induce different long-term adverse effects as well as different adaptational responses.
The long-term comparison of short half-life selective serotonin reuptake inhibitors with long-life selective serotonin reuptake inhibitors is a necessary and intriguing subject of further investigation. Intermittent dosing when the half-life of a drug is longer than the off-drug period may provide convenience to the patient, but exposure to pharmacologically active blood levels is continuous though variable.
The efficacy of intermittent treatment with a relatively low dose of the serotonergic agent sertraline underscores the involvement of serotonin in the pathophysiology of premenstrual symptoms as well as the difference between PMS and premenstrual dysphoric disorder and other depressive and anxiety disorders. The main components of the processes leading to premenstrual dysphoric disorder are suggested to be dynamically evolving vulnerability influenced by genetics and environmental inputs (predilection to serotonergic dysregulation may be part of that vulnerability) and an interaction between fluctuations of gonadal hormones and neurotransmitters. Some women may be more sensitive to the hormonal fluctuations and develop symptoms.
The serotonergic abnormalities may be trait-vulnerability related and state related. It is still unclear if the fast response to treatment with relatively low doses indicates a uniquely abnormal serotonergic system in women with premenstrual dysphoric disorder, which would lend itself to brief intermittent interventions, as opposed to the lengthy continuous treatment required in other dysphoric disorders.
A potentially important method for studying and optimizing an intermittent luteal phase treatment approach would be a pattern analysis of the consistency of onset and offset of premenstrual dysphoric disorder symptoms and their relationship to hormonal and serotonergic changes, as well as the onset of menses.
The efficacy of intermittent sertraline was consistent across all primary outcome measures and at all time points (Tables 2 and 3). A distinctive feature of premenstrual dysphoric disorder is the multidimensional diversified nature of the disorder, which includes mood, anxiety, cognitive, interpersonal, physical, and neurovegetative symptoms. Sertraline had significantly greater efficacy than a placebo in reducing the severity of symptoms in all of these dimensions with one exception: physical symptoms (Table 3). This latter result differs from the findings of several published controlled studies of selective serotonin reuptake inhibitors including sertraline.16 One study showed sertraline to have significant efficacy versus placebo on the physical symptom cluster,4 and the other showed a trend significant effect.22 Of note is that in the current study the mean Daily Record of Severity of Problems physical symptom factor score was much lower at baseline than in the previously published study of sertraline,4 perhaps making it more difficult to demonstrate a treatment effect.
Consistent with the overall improvement in premenstrual dysphoric disorder symptoms observed in the current study, quality of life, functional, and social adjustment measures also showed significant improvement by study end point (Table 3). Among patients who met Clinical Global Impression Improvement responder criteria, 51% were within 10% of community norms on the Quality of Life Enjoyment and Satisfaction Questionnaire by treatment end point.
Patients tolerated intermittent treatment with sertraline very well, with few patients (7.7%) dropping out because of adverse events. Most side effects were mild, with only 16.9% of patients on sertraline reporting severe adverse events (versus 7.1% on placebo). The incidence of adverse events was notably less in the third cycle than in the first cycle, with 77.4% of patients reporting no adverse events at all on sertraline. This is unlikely to be due to the traditional mechanism of tolerance, which generally requires continuous exposure to a drug to trigger adaptive receptor or neurochemical changes.
The current study has several strengths, including the use of a large sample size, use of rigorous eligibility criteria, diagnosis based on structured interview and prospective confirmation, and hypotheses that were clearly stated a priori. However, several potential study limitations should be mentioned. First, consistent with all regulatory studies, study exclusion criteria limited entry of patients with comorbidity of other affective and anxiety disorders. This may reduce the generalizability of the study results because affective and/or anxiety disorder comorbidity is common in women with premenstrual dysphoric disorder34 (though sertraline has demonstrated broad spectrum efficacy across a wide range of affective and anxiety disorders). A second limit to generalizability relates to the educational level of the study sample, their self-treatment seeking, and their high level of motivation and compliance, which required many months of daily ratings and repeated office visits. Women were included in the study if their Hamilton Rating Scale for Depression scores during the midfollicular phase were less than 10, meaning that they might have very mild depressive symptoms. In such patients, placebos have been shown to be quite effective. The presence of such limiting variables may have the potential for contributing to the high nonspecific placebo response. The demonstration of significant efficacy for sertraline despite the high degree of nonspecific effects provides further evidence of the robustness of the result.
Intermittent luteal phase treatment with sertraline, in doses of 50–100 mg daily, is a highly effective treatment strategy for managing patients suffering from premenstrual dysphoric disorder of moderate or greater severity. It effectively improved not only premenstrual dysphoric disorder symptoms, but also quality of life, functional, and social adjustment measures. Intermittent dosing with sertraline was well tolerated. It appears to provide an appealing treatment option for a disorder that is both intermittent-episodic and chronic.
|
Footnotes |
|---|
Received January 30, 2002. Received in revised form April 8, 2002. Accepted June 6, 2002.
|
REFERENCES |
|---|
|
TOP
ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
2. Wittchen HU, Becker E, Lieb R, Krause P. Prevalence, incidence and stability of premenstrual dysphoric disorder in the community. Psychol Med 2002;32:119–32.[Medline]
3. Bloch M, Schmidt PJ, Rubinow DR. Premenstrual syndrome: Evidence for symptom stability across cycles. Am J Psychiatry 1997;154:1741–6.
4. Yonkers KA, Halbriech U, Freeman E, Brown C, Endicott J, Frank E, et al. The Sertraline Premenstrual Dysphoric Collaborative Study Group. Symptomatic improvement of premenstrual dysphoric disorder with sertraline treatment. JAMA 1997;278:983–8.[Abstract]
5. Pearlstein TB, Halbreich U, Batzar ED, Brown CS, Endicott J, Frank E, et al. Psychosocial functioning in women with premenstrual dysphoric disorder before and after treatment with sertraline or placebo. J Clin Psychiatry 2000;61:101–9.[Medline]
6. Hylan TR, Sundell K, 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 Gend Based Med 1999;8:1043–52.[Medline]
7. Kendler KS, Karkowski LM, Corey LA, Neale MC. Longitudinal population-based twin study of retrospectively reported premenstrual symptoms and lifetime major depression. Am J Psychiatry 1998;155:1234–40.
8. Condon JT. The premenstrual syndrome: A twin study. Br J Psychiatry 1993;162:481–6.
9. Rojansky N, Halbreich U, Zander K, Barkai A, Goldstein S. Imipramine receptor binding and serotonin uptake in platelets of women with premenstrual changes. Gynecol Obstet Invest 1991;31:146–52.[Medline]
10. Bancroft J, Cook A, Davidson D, Bennie J, Goodwin G. Blunting of neuroendocrine responses to infusion of L-tryptophan in women with perimenstrual mood change. Psychol Med 1991;21:305–12.[Medline]
11. Ashby CR, Carr LA, Cook CL, Steptoe MM, Franks DD. Alteration of platelet serotonergic mechanism and monoamine oxidase activity in premenstrual syndrome. Biol Psychiatry 1988;24:225–33.[Medline]
12. Steiner M, Yatham LN, Coote M, Wilkins A, Lepage P. Serotonergic dysfunction in women with pure premenstrual dysphoric disorder: Is the fenfluramine challenge test still relevant? Psychiatry Res 1999;87:107–15.[Medline]
13. Kouri EM, Halbreich U. State and trait serotonergic abnormalities in women with dysphoric premenstrual syndromes. Psychopharmacol Bull 1997;33:767–70.[Medline]
14. Schmidt PJ, Nieman LK, Danaceau MA, Adams LF, Rubinow DR. Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. N Engl J Med 1998;338:209–16.
15. Halbreich U, Endicott J, Goldstein S, Nee J. Premenstrual changes and changes in gonadal hormones. Acta Psychiatr Scand 1986;74:576–86.[Medline]
16. Dimmock PW, Wyatt KM, Jones PW, O’Brien PM. Efficacy of selective serotonin reuptake inhibitors in premenstrual syndrome: A systematic review. Lancet 2000;356: 1131–6.[Medline]
17. Steiner M, Steinberg S, Stewart D, Carter D, Berger C, Reid R, et al. Fluoxetine in the treatment of premenstrual dysphoria. Canadian Fluoxetine/Premenstrual Dysphoria Collaborative Study Group. N Engl J Med 1995;332: 1529–34.
18. Freeman EW, Rickels K, Sondheimer SJ, Polansky M. Differential response to antidepressants in women with premenstrual syndrome/premenstrual dysphoric disorder: A randomized controlled trial. Arch Gen Psychiatry 1999; 56:932–9.
19. Altshuler LL, Cohen LS, Moline ML, Kahn DA, Carpenter D, Docherty JP. Treatment of depression in women [review]. Postgrad Med 2001;1–107.
20. Mitwally MF, Kahn L, Halbreich U. Pharmacological management of premenstrual syndrome and dysphoric premenstrual syndrome. Expert Opin Pharmacother. In press.
21. Sundblad C, Hedberg MA, Eriksson E. Clomipramine administered during the luteal phase reduces the symptoms of premenstrual syndrome: A placebo-controlled trial. Neuropsychopharmacology 1993;9:133–45.[Medline]
22. Freeman EW, Rickels K, Arredondo F, Kao LC, Pollack SE, Sondheimer SJ. Full- or half-cycle treatment of severe premenstrual syndrome with a serotonergic antidepressant. J Clin Psychopharmacol 1999;19:3–8.[Medline]
23. Halbreich U, Smoller JW. Intermittent luteal phase sertraline treatment of dysphoric premenstrual syndrome. J Clin Psychiatry 1997;58:399–402.[Medline]
24. Young SA, Hurt PH, Benedek DM, Howard RS. Treatment of premenstrual dysphoric disorder with sertraline during the luteal phase: A randomized, double-blind, placebo-controlled crossover trial. J Clin Psychiatry 1998;59: 76–80.[Medline]
25. Jermain DM, Preece CK, Sykes RL, Kuehl TJ, Sulak PJ. Luteal phase sertraline treatment for premenstrual dysphoric disorder. Results of a double-blind, placebo-controlled, crossover study. Arch Fam Med 1999;8:328–32.
26. Wikander I, Sundblad C, Andersch B, Dagnell I, Zylberstein D, Bengtsson F, et al. Citalopram in premenstrual dysphoria: Is intermittent treatment during luteal phases more effective than continuous medication throughout the menstrual cycle? J Clin Psychopharmacol 1998;18:390–8.[Medline]
27. First MB, Frances A, Pincus HA, eds. DSM-IV handbook of differential diagnosis. Washington: American Psychiatric Press, 1995.
28. Endicott J, Harrison W. Daily Rating of Severity of Problems form. New York: New York State Psychiatric Institute, Department of Research Assessment and Training, 1990.
29. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV Axis I Disorders, clinician version (SCID-CV). Washington: American Psychiatric Press, 1996.
30. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56–62.
31. Guy W. ECDEU assessment manual for psychopharmacology. Department of Health, Education and Welfare publication no. (ADM) 76-338. Washington: U.S. Government Printing Office, 1976.
32. Weissman MM, Bothwell S. Assessment of social adjustment by patient self-report. Arch Gen Psychiatry 1976;33: 1111–5.[Medline]
33. Endicott J, Nee J, Harrison W, Blumenthal R. Quality of Life Enjoyment and Satisfaction Questionnaire: A new measure. Psychopharmacol Bull 1993;29:321–6.[Medline]
34. Pearlstein TB, Frank E, Rivera-Tovar A, Thoft JS, Jacobs E, Mieczkowski TA. Prevalence of axis I and axis II disorders in women with late luteal phase dysphoric disorder. J Affect Disord 1990;20:129–34.[Medline]
This article has been cited by other articles:
|
|
 |
|
  C. I Jarvis, A. M Lynch, and A. K Morin Management Strategies for Premenstrual Syndrome/Premenstrual Dysphoric Disorder Ann. Pharmacother., July 1, 2008; 42(7): 967 - 978. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. R. Shah, J. B. Jones, J. Aperi, R. Shemtov, A. Karne, and J. Borenstein Selective Serotonin Reuptake Inhibitors for Premenstrual Syndrome and Premenstrual Dysphoric Disorder: A Meta-Analysis Obstet. Gynecol., May 1, 2008; 111(5): 1175 - 1182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Yonkers, C. Brown, T. B. Pearlstein, M. Foegh, C. Sampson-Landers, and A. Rapkin Efficacy of a New Low-Dose Oral Contraceptive With Drospirenone in Premenstrual Dysphoric Disorder Obstet. Gynecol., September 1, 2005; 106(3): 492 - 501. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. H. Rapaport, C. Clary, R. Fayyad, and J. Endicott Quality-of-Life Impairment in Depressive and Anxiety Disorders Am J Psychiatry, June 1, 2005; 162(6): 1171 - 1178. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Johnson Premenstrual Syndrome, Premenstrual Dysphoric Disorder, and Beyond: A Clinical Primer for Practitioners Obstet. Gynecol., October 1, 2004; 104(4): 845 - 859. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Hartlage, D. L. Brandenburg, and H. M. Kravitz Premenstrual Exacerbation of Depressive Disorders In a Community-Based Sample in the United States Psychosom Med, September 1, 2004; 66(5): 698 - 706. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. W. Freeman, K. Rickels, S. J. Sondheimer, M. Polansky, and S. Xiao Continuous or Intermittent Dosing With Sertraline for Patients With Severe Premenstrual Syndrome or Premenstrual Dysphoric Disorder Am J Psychiatry, February 1, 2004; 161(2): 343 - 351. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
