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Original Article
Volume 332:1529-1534 June 8, 1995 Number 23
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Fluoxetine in the Treatment of Premenstrual Dysphoria
Meir Steiner, M.D., Ph.D., Susanne Steinberg, M.D., Donna Stewart, M.D., Diana Carter, M.D., Charlene Berger, Ph.D., Robert Reid, M.D., Douglas Grover, M.D., David Streiner, Ph.D., for The Canadian Fluoxetine/Premenstrual Dysphoria Collaborative Study Group

 

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ABSTRACT

Background Premenstrual dysphoria shares certain features with depression and anxiety states, which have been linked to serotonergic dysregulation. We evaluated the efficacy and safety of fluoxetine (which selectively inhibits the reuptake of serotonin) in the treatment of premenstrual dysphoria.

Methods The trial consisted of a single-blind, placebo washout period lasting two menstrual cycles, followed by a randomized, double-blind, placebo-controlled trial of fluoxetine at a dose of either 20 mg or 60 mg per day or placebo for six menstrual cycles. Healthy women meeting criteria for what was then called late-luteal-phase dysphoric disorder were recruited at seven university-affiliated women's health clinics in Canada. The primary outcome measure consisted of visual-analogue scales for tension, irritability, and dysphoria during the late luteal phase of each cycle.

Results Of 405 women enrolled in the placebo washout period, 313 subsequently entered the randomized phase of the study, which lasted six menstrual cycles, and 180 completed it. Fluoxetine at a dose of 20 or 60 mg per day was significantly superior to placebo in reducing symptoms of tension, irritability, and dysphoria, as measured by the visual-analogue scales (P<0.001). The women who received 60 mg of fluoxetine per day reported significantly more side effects than those who received 20 mg per day or placebo (P<0.001).

Conclusions Fluoxetine is useful in the treatment of premenstrual dysphoria. Treatment with fluoxetine at a dose of 20 mg per day reduces the potential for side effects while maximizing therapeutic efficacy.

Late-luteal-phase dysphoric disorder,1 currently referred to as premenstrual dysphoric disorder2 (and commonly called the premenstrual syndrome), is characterized by a cluster of symptoms appearing regularly during the week before and disappearing within a few days after the onset of menstrual bleeding. Tension, irritability, and dysphoria are among the most prominent symptoms.3,4,5 Surveys indicate that it affects up to 3 to 8 percent of North American women in their reproductive years,6,7,8 with a substantial negative impact on health. The cause of this disorder is unknown, and it is therefore not surprising that over the years at least 50 treatment options have been suggested to be effective, many of them based on the popular hypothesis of the moment.9,10,11,12 To date, however, although some treatments, such as medical or surgical ovariectomy13,14,15,16 and some anxiolytic drugs, have been found to be superior to placebo in some studies,17,18 no treatments have proved consistently effective.19

Premenstrual dysphoria shares many of the features of depression and anxiety states20,21,22 that have been linked to serotonergic dysregulation, and there is increasing evidence that serotonin may also be important in the pathogenesis of premenstrual dysphoria.23,24,25,26,27 Clomipramine and fluoxetine (Prozac), which selectively inhibit the reuptake of serotonin, have therefore been proposed for the treatment of premenstrual dysphoria, and preliminary results of single-dose or small double-blind, placebo-controlled trials were encouraging28,29,30 but not unanimous.31 We therefore undertook a multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of fluoxetine in women with premenstrual dysphoria.

Methods

Selection of Patients

Women between 18 and 45 years of age who met the diagnostic criteria for premenstrual dysphoria were enrolled in the trial after providing oral and written informed consent. The study was carried out at seven university-affiliated women's health clinics in Canada. The protocol was approved by the institutional ethics review committees of all the clinics. All subjects were either self-referred or referred by their physicians.

The entry requirements were a diagnosis of late-luteal-phase dysphoric disorder, as it was then called, with at least a one-year history of five (or more) symptoms attributable to the disorder (with at least one symptom being marked affective lability, irritability, tension, or depressed mood) that were present premenstrually and began to remit within a few days postmenstrually. The condition must also have been severe enough to impair activities of daily living. These criteria were confirmed prospectively by the subjects, who rated the severity of their symptoms during at least two consecutive symptomatic cycles.1

Women were excluded if they were pregnant or lactating or were taking an oral contraceptive, or if they had irregular menstrual cycles, an unstable medical illness, a history of a seizure disorder with a seizure occurring within the past year, a record of multiple adverse drug reactions, known allergies to inhibitors of the reuptake of serotonin, or a history of fluoxetine use. To minimize the inclusion of women with anovulatory cycles, the women were required to have menstrual cycles between 24 and 35 days in length.

Women were also excluded if they met diagnostic criteria for a major psychiatric syndrome other than late-luteal-phase dysphoric disorder, expressed suicidal ideation or intent, had used psychoactive medications or investigational drugs within two months before the study, or were taking any other medication to treat premenstrual symptoms.

Study Design

The two-phase study design consisted of a single-blind washout period, during which the women received placebo for two menstrual cycles, followed by a randomized, double-blind, placebo-controlled trial lasting six menstrual cycles. Women who remained eligible after the placebo washout phase were randomly assigned to receive placebo, fluoxetine at a dose of 20 mg per day, or fluoxetine at a dose of 60 mg per day beginning on the first day of cycle 3. The study drugs were to be taken each morning. No other psychoactive medications were permitted.

The women were required to visit the clinics twice during each menstrual cycle throughout the study. Visits and assessments coincided with the follicular and late luteal phases of each cycle. The study involved a total of 18 visits: 1 prescreening visit, 4 visits during the two-cycle placebo washout phase, 12 visits during the six cycles in the randomized controlled trial, and 1 follow-up visit after the trial ended.

Measurements

The primary outcome was defined as the reduction in the raw luteal-phase score (reported as the percent change from the base-line score) for premenstrual symptoms, as measured by the mean score on three visual-analogue scales — one each for tension, irritability, and dysphoria. Visual-analogue scales have been found to be an effective tool in measuring changes over time in response to treatment for the symptoms of mood disturbance, and their reliability and validity have been well documented.32,33,34 The participants were prompted to rate how they were feeling each day using 100-mm scales in which the descriptors ranged from "no symptoms" (0 mm) to "severe or extreme symptoms" (100 mm). The mean of these three scales was calculated to determine the total psychological-symptom score. Secondary outcome measures included the premenstrual tension syndrome scales, which consist of a 36-item scale completed by the patient and a 10-item scale completed by the therapist.3,35 Both scales rate premenstrual symptoms for a particular day; the total score can range from 0, indicating no symptoms, to 36, indicating all symptoms present and severe. Tertiary outcome measures included visual-analogue scales for physical symptoms of headache, bloating, and breast tenderness, as well as a modified Prospective Record of the Impact and Severity of Menstrual Symptomatology calendar, which was completed daily.36 A standardized questionnaire was used at each visit to determine whether the subjects had had any side effects. All these data were collected at each visit.

Compliance was monitored through monthly pill counts, by the subjects' own assessments, and, for 15 percent of the study population, by measuring serum concentrations of fluoxetine and norfluoxetine (the principal active metabolite of fluoxetine). Blood was drawn after a minimum of two cycles of the study medication and assayed after the completion of the study.37 Subjects who missed more than six consecutive doses of study medication during any cycle were withdrawn from the trial.38 On completion of six cycles of treatment, the subjects stopped taking the study medication and were allowed to pursue independent treatment with their own physicians.

Statistical Analysis

Analysis of efficacy for all study participants who completed at least one cycle of the randomized trial was conducted with BMDP5V unbalanced repeated-measures models with structured covariance matrixes. Akaike's Information Criterion was used to select the most appropriate covariance structure.39 In order to perform this analysis, changes in the raw scores of the visual-analogue scales within subjects were recalculated to obtain the percent change from base-line scores within subjects according to the following formula: (base-line luteal-phase score - treatment luteal-phase score)/base-line luteal-phase score x 100. These values ranged from -100 percent (worsening) to +100 percent (improvement). Parametric base-line characteristics were analyzed by one-way analysis of variance. All continuous efficacy variables for those who completed all six cycles of the protocol were analyzed with repeated-measures multivariate analysis of variance.40,41 The frequency of side effects and other nonparametric data were analyzed with Fisher's exact test or the chi-square test for association where appropriate. Pearson's correlation coefficients were used to ensure the validity of the primary outcome data as compared with the secondary and tertiary outcome measures. P values of 0.01 or less were considered to indicate statistical significance; all tests were two-tailed.

The safety analysis included all subjects who underwent randomization. Side effects were classified according to their frequency and their occurrence in combination with other events.

Results

Of the 405 women screened for entry during the placebo washout period, 92 did not enter the second phase of the trial for the reasons listed in Table 1. Thus, 313 eligible women were randomly assigned to the treatment groups. The study participants were between 20 and 45 years of age (mean [±SD], 36±5); all were high-school graduates; 55 percent were married; and 70 percent had at least one child. At base line the mean (±SD) follicular-phase score for the visual-analogue scales was 14.9±13.4 mm, and the mean luteal-phase score was 56.1±18.2 mm. Base-line demographic and clinical characteristics were comparable in the three treatment groups.

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  		Table 1. Classification of the Study Subjects According to How Much of the Trial They Completed.

 
Of the 313 women who underwent randomization, 277 completed cycle 1 of phase 2 and were included in the efficacy analysis (Table 2). The raw follicular-phase scores for primary and secondary outcome measures throughout the trial were stable, with minimal variation between groups or over time (P = 0.57). Scores on the visual-analogue scales for tension, irritability, and dysphoria were similar within subjects (P = 0.42), allowing the use of the mean scores of the three visual-analogue scales to represent the total premenstrual-symptom score at each visit for the primary efficacy analysis.

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  		Table 2. Scores on Primary and Secondary Outcome Measures for the 277 Women Who Completed Cycle 1 of the Randomized Trial.

 
Fluoxetine at a daily dose of either 20 mg or 60 mg proved to be superior to placebo in reducing psychological symptoms within the first cycle of treatment, as demonstrated by both the primary and secondary outcome measures (Table 2). Despite a high dropout rate in the placebo group and the group that received 60 mg of fluoxetine per day, regression analysis identified a statistically significant effect of the group (P<0.001) and of the change from base line (P<0.001). The mean percent improvement in the luteal-phase score from base line was four to six times greater in the fluoxetine groups than in the placebo group, as measured by the total visual-analogue scale and by the subject-rated premenstrual tension syndrome scale, and two to three times greater as measured by the observer-rated premenstrual tension syndrome scale. In the first cycle alone, the raw scores on the luteal-phase visual-analogue scale were reduced to one half the base-line score in 46 of the 96 women receiving 20 mg of fluoxetine per day and 49 of the 86 women receiving 60 mg of fluoxetine per day, as compared with 21 of the 95 women receiving placebo (P<0.001). The significant difference in the scores on the visual-analogue scale between women receiving fluoxetine and women receiving placebo was maintained during the six cycles of the trial in the 180 women who completed the protocol (P<0.001) (Figure 1). This improvement over time was corroborated by an analysis of the secondary outcome measures (P<0.001).


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  		Figure 1. Percent Improvement in the Total Luteal-Phase Scores of the Visual-Analogue Scale for the 180 Women Who Completed the Protocol (P<0.001).

The degree of improvement recorded during the placebo washout period did not differ between groups (mean improvement, 11.2 percent).

 
To define clinically relevant changes throughout this trial, we considered 50 percent improvement from base line to represent moderate improvement and 75 percent to represent marked improvement. With the use of these criteria, 52 percent of the women receiving fluoxetine at either dose had at least moderate improvement in their symptoms within the first cycle of active treatment, as compared with 22 percent of the women receiving placebo (P<0.001). These proportions remained consistent throughout the trial: 53 percent of all cycles involving fluoxetine therapy (437 of 832) were associated with at least moderate improvement, as compared with 28 percent of the cycles involving placebo (113 of 410, P<0.001). The proportion of cycles in which there was marked improvement was also significantly different between groups (266 of 832 cycles involving fluoxetine therapy vs. 56 of 410 cycles involving placebo, P<0.001). The results were combined because the rates of response were very similar in the two groups of women who received fluoxetine (20 mg per day or 60 mg per day).

Of the 313 women included in the safety analysis, the study medication was discontinued in 133 (Table 1). The rate of withdrawal was similar in the three groups for the first three cycles of the randomized trial but became significantly different by cycle 6 (P<0.028) as a result of the high rate of withdrawal of women from the group receiving 60 mg of fluoxetine per day (35 of 106) and from the placebo group (27 of 105), the former because of side effects and the latter because of lack of efficacy. It is important to note that 97 percent of the withdrawals due to side effects in the group given 60 mg of fluoxetine per day occurred during the first three cycles of the trial.

The side effects reported during the trial were dose-related, with significantly fewer events occurring in the placebo group and the group receiving 20 mg of fluoxetine per day than in the group given 60 mg of fluoxetine per day (P<0.001). In addition, statistically significant differences were found across the three groups for the 12 most frequently identified types of events, as listed in Table 3. These events were reported alone or in various combinations, and they occurred more frequently in the group given 60 mg of fluoxetine per day than in the other two groups. No serious or life-threatening events were reported during the trial.

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  		Table 3. Most Frequently Reported Side Effects.

 
Discussion

We compared two doses of fluoxetine with placebo in women with severe premenstrual dysphoria. Fluoxetine at doses of 20 mg or 60 mg per day proved significantly superior to placebo in reducing symptoms associated with this disorder, as measured by visual-analogue scales for tension, irritability, and dysphoria. These results were corroborated by an analysis of secondary outcome data.

The primary outcome measure was the percent improvement from base line in luteal-phase symptom scores. This approach is similar to that taken in other clinical trials and allows some comparisons between studies regardless of differences in the primary outcome measure used. An analysis of the clinical relevance of our study showed that moderate and marked improvement was twice as common in cycles involving fluoxetine as in cycles involving placebo. This rate of improvement was similar to that found in studies that defined outcome according to the percent change from base line in luteal-phase symptom scores.16,42,43,44

Reports of the occurrence of a preoccupation with suicide during fluoxetine treatment45 garnered much media attention and affected our ability to recruit and retain subjects, since many potential candidates refused to participate. Fortunately, this association has since been refuted.46 None of the women we studied had any suicidal or homicidal tendencies during the trial. Our study as well as other large-scale studies, in which fluoxetine was prescribed for psychiatric disorders other than depression, seem to offer further support for the notion that there is no direct link between this medication and the risk of suicide.38,47,48

The dropout rate for this trial was substantial: 42 percent of the women who underwent randomization did not complete the protocol. Reported side effects were an important contributor to this high rate of withdrawal. There is a clear delineation in the event profiles between women receiving 60 mg of fluoxetine per day and those receiving 20 mg of fluoxetine per day or placebo. Thirty-three percent of the women who received 60 mg of fluoxetine per day dropped out of the study because of side effects, and of those who remained in the study, 86 percent reported one or more side effects attributable to the drug. Although the use of a 60-mg daily dose of fluoxetine may be appropriate and efficacious in other psychiatric disorders, there seems to be no indication to use such a high dose in patients with this disorder. The use of a daily dose of 20 mg resulted in rates of side effects that were more similar to those of the placebo group. Side effects attributable to the drug that were reported most frequently were typical of those reported in other clinical trials of fluoxetine.38,44,49,50 The high dropout rate in the placebo group due to a lack of efficacy (26 percent) indicates the perceived severity of symptoms associated with this diagnosis. Since most of the women were referred by their family physicians and had not responded to more conservative treatments for premenstrual dysphoria, this dropout rate may be taken as an indication of the appropriateness of and necessity for the use of selective inhibitors of serotonin reuptake to treat the mood-disturbance symptoms associated with this disorder.

The mechanism of action of fluoxetine in premenstrual dysphoria remains uncertain, but it probably differs from the mechanisms by which the inhibitors of serotonin reuptake alleviate symptoms of depression. There is some question whether by blocking reuptake, fluoxetine augments the action of serotonin only at brain synapses where it is already being released (the synaptic information-transmission mechanism)51 or whether the primary mechanism of action is of the nonsynaptic diffusion-neurotransmission type.52 The clinical observation that a lag of three to six weeks is required before the inhibitors of serotonin reuptake (as well as most other antidepressant drugs) become effective in depression further suggests that the synaptic model may not be as relevant in premenstrual dysphoria, where the response seems to be more immediate. In our study, active medication was given for approximately three weeks before the first luteal phase of the randomized trial, and the improvement at that time was already significantly better for fluoxetine at both doses than for placebo.

When this study was begun there were only three reports in the literature of the use of inhibitors of serotonin reuptake in premenstrual dysphoria.28,29,30 The results of several additional drug trials have since been published,43,44,50,53,54 further establishing a role for specific serotonin-reuptake inhibitors in the treatment of this disorder.

Our study did not address whether fluoxetine is required on a daily basis throughout the menstrual cycle to treat premenstrual dysphoria. At the time the study was initiated, the use of doses of 20 mg or 60 mg per day was the accepted practice (without gradual or flexible dosing), and no problems had been reported with the use of a similar schedule in other trials in North America.55 A recent case study suggests that a single dose of fluoxetine during the early luteal phase may be as effective as daily doses.56 At the end of one study, once the medications were discontinued, the improvement realized during the trial was not maintained, and most women opted to resume taking medication.57 We are in the process of analyzing data from an open study in which women who met the criteria for premenstrual dysphoria responded to treatment with fluoxetine given during the late luteal phase alone.58

It thus appears that fluoxetine in doses of 20 mg per day or lower may be effective in decreasing the psychological symptoms of tension, irritability, and dysphoria in women who have premenstrual dysphoric disorder.

Supported by Eli Lilly Canada.

We are indebted to the study subjects; to Dr. P. Lepage, Dr. W. Tam, Mrs. M. Coote, Mrs. M. Fairman, Mrs. G. Huxley, Mrs. K. Scordino, Miss R. Steiner, Miss J. Taylor, and Ms. W. Trojan (St. Joseph's Hospital, McMaster University, Hamilton, Ont.); to Ms. S. Mainville and Ms. F. Houle (St. Mary's Hospital, McGill University, Montreal); to Ms. P. Zownir and Ms. A. Gaughan (St. Michael's Hospital, Toronto); to Ms. A. Kuan and Mr. D. Keller (University Hospital, University of British Columbia, Vancouver); to Ms. D. Coffin, Ms. G. McIvor, and Ms. C. Sergeant (PMS Clinic, Montreal General Hospital, Montreal); to Ms. L. Merriott (University of Montreal, Montreal); to Ms. C. Ferguson and Ms. J. Reid (Queen's University, Kingston, Ont.); to Ms. A. Wilkins for assistance in statistical analysis, data management, and the preparation of the manuscript; and to Mrs. M. Jaszek for assistance in the preparation of the manuscript.

* The following are additional members of the Canadian Fluoxetine/Premenstrual Dysphoria Collaborative Study Group: M. Korzekwa and J. Lamont, St. Joseph's Hospital, McMaster University, Hamilton, Ont.; G. DeMarchi, L. Paquette, S. Reed-Walkiewicz, J. Aldridge, and G. Robinson, St. Michael's Hospital, University of Toronto, Toronto; S. Misri, University Hospital, University of British Columbia, Vancouver; B. Presser, Royal Victoria Hospital, Montreal; and D. Cumming and C. Cumming, University of Alberta Hospital, Edmonton.


Source Information

From the Departments of Psychiatry and Biomedical Sciences, St. Joseph's Hospital, McMaster University, Hamilton, Ont. (M.S.); the Department of Psychiatry, St. Mary's Hospital, McGill University, Montreal (S.S.); the Department of Psychiatry, St. Michael's Hospital, University of Toronto, Toronto (D. Stewart); the Department of Psychiatry, University Hospital, University of British Columbia, Vancouver (D.C.); the Department of Psychiatry, Montreal General Hospital, Concordia University, Montreal (C.B.); the Department of Obstetrics and Gynecology, Queen's University, Kingston, Ont. (R.R.); the Department of Psychiatry, University of Alberta Hospital, Edmonton (D.G.); and the Departments of Psychiatry and Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ont. (D. Streiner) — all in Canada.

Address reprint requests to Dr. Steiner at the Department of Psychiatry, St. Joseph's Hospital, 50 Charlton Ave. E., Hamilton, ON L8N 4A6, Canada.

References

  1. Diagnostic and statistical manual of mental disorders. 3rd ed. rev. Washington, D.C.: American Psychiatric Association, 1987:367-9. 
  2. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, D.C.: American Psychiatric Association, 1994:717-8.
  3. Steiner M, Haskett RF, Carroll BJ. Premenstrual tension syndrome: the development of research diagnostic criteria and new rating scales. Acta Psychiatr Scand 1980;62:177-190. [Medline]
  4. Haskett RF, Steiner M, Osmun JN, Carroll BJ. Severe premenstrual tension: delineation of the syndrome. Biol Psychiatry 1980;15:121-139. [Medline]
  5. Hurt SW, Schnurr PP, Severino SK, et al. Late luteal phase dysphoric disorder in 670 women evaluated for premenstrual complaints. Am J Psychiatry 1992;149:525-530. [Free Full Text]
  6. Haskett RF, De Longis A, Kessler RC. Premenstrual dysphoria: a community survey. Presented at the 140th Annual Meeting of the American Psychiatric Association, Chicago, May 9–15, 1987. abstract.
  7. Johnson SR, McChesney C, Bean JA. Epidemiology of premenstrual symptoms in a nonclinical sample. I. Prevalence, natural history and help-seeking behavior. J Reprod Med 1988;33:340-346. [Medline]
  8. Rivera-Tovar AD, Frank E. Late luteal phase dysphoric disorder in young women. Am J Psychiatry 1990;147:1634-1636. [Free Full Text]
  9. Treatment options. In: Severino SK, Moline ML. Premenstrual syndrome: a clinician's guide. New York: Guilford Press, 1989:162-246.
  10. Robinson GE, Garfinkel PE. Problems in the treatment of premenstrual syndrome. Can J Psychiatry 1990;35:199-206. [Medline]
  11. Steinberg S. The treatment of late luteal phase dysphoric disorder. Life Sci 1991;49:767-802. [Medline]
  12. Reid RL. Premenstrual syndrome. N Engl J Med 1991;324:1208-1210. [Medline]
  13. Muse KN, Cetel NS, Futterman LA, Yen SSC. The premenstrual syndrome: effects of "medical oophorectomy." N Engl J Med 1984;311:1345-1349. [Abstract]
  14. Casper RF, Hearn MT. The effect of hysterectomy and bilateral oophorectomy in women with severe premenstrual syndrome. Am J Obstet Gynecol 1990;162:105-109. [Medline]
  15. Casson P, Hahn PM, Van Vugt DA, Reid RL. Lasting response to ovariectomy in severe intractable premenstrual syndrome. Am J Obstet Gynecol 1990;162:99-105. [Medline]
  16. Mortola JF, Girton L, Fischer U. Successful treatment of severe premenstrual syndrome by combined use of gonadotropin-releasing hormone agonist and estrogen/progestin. J Clin Endocrinol Metab 1991;72:252A-252F. [Medline]
  17. Harrison WM, Endicott J, Nee J. Treatment of premenstrual dysphoria with alprazolam: a controlled study. Arch Gen Psychiatry 1990;47:270-275. [Abstract]
  18. Berger CP, Presser B. Alprazolam in the treatment of two subsamples of patients with late luteal phase dysphoric disorder: a double-blind, placebo-controlled crossover study. Obstet Gynecol 1994;84:379-385. [Free Full Text]
  19. Schmidt PJ, Grover GN, Rubinow DR. Alprazolam in the treatment of premenstrual syndrome: a double-blind, placebo-controlled trial. Arch Gen Psychiatry 1993;50:467-473. [Abstract]
  20. Pearlstein TB, Frank E, Rivera-Tovar A, Thoft JS, Jacob E, Mieczkowski TA. Prevalence of axis I and axis II disorders in women with late luteal phase dysphoric disorder. J Affect Disord 1990;20:129-134. [CrossRef][Medline]
  21. Wurtman JJ. Depression and weight gain: the serotonin connection. J Affect Disord 1993;29:183-192. [CrossRef][Medline]
  22. Endicott J. The menstrual cycle and mood disorders. J Affect Disord 1993;29:193-200. [CrossRef][Medline]
  23. Lepage P, Steiner M. Gender and serotonergic dysregulation: implications for late luteal phase dysphoric disorder. In: Cassano GB, Akiskal HS, eds. Serotonin-related psychiatric syndromes: clinical and therapeutic links. London: Royal Society of Medicine Services, 1991:131-43.
  24. 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;31:146-152. [Medline]
  25. Rapkin AJ. The role of serotonin in premenstrual syndrome. Clin Obstet Gynecol 1992;35:629-636. [CrossRef][Medline]
  26. Steiner M. Female-specific mood disorders. Clin Obstet Gynecol 1992;35:599-611. [CrossRef][Medline]
  27. Yatham LN. Is 5HT1A receptor subsensitivity a trait marker for late luteal phase dysphoric disorder? A pilot study. Can J Psychiatry 1993;38:662-664. [Medline]
  28. Eriksson E, Lisjo P, Sundblad C, Andersson K, Andersch B, Modigh K. Effect of clomipramine on premenstrual syndrome. Acta Psychiatr Scand 1990;81:87-88. [Medline]
  29. Stone AB, Pearlstein TB, Brown WA. Fluoxetine in the treatment of premenstrual syndrome. Psychopharmacol Bull 1990;26:331-335. [Medline]
  30. Rickels K, Freeman EW, Sondheimer S, Albert J. Fluoxetine in the treatment of premenstrual syndrome. Curr Ther Res 1990;48:161-6.
  31. Veeninga AT, Westenberg HGM, Weusten JTN. Fluvoxamine in the treatment of menstrually related mood disorders. Psychopharmacology 1990;102:414-6.
  32. Rubinow DR, Roy-Byrne P, Hoban MC, Gold PW, Post RM. Prospective assessment of menstrually related mood disorders. Am J Psychiatry 1984;141:684-686. [Free Full Text]
  33. Casper RF, Powell A-M. Premenstrual syndrome: documentation by a linear analog scale compared with two descriptive scales. Am J Obstet Gynecol 1986;155:862-867. [Medline]
  34. McCormack HM, Horne DJ, Sheather S. Clinical applications of visual analogue scales: a critical review. Psychol Med 1988;18:1007-1019. [Medline]
  35. Condon JT. The premenstrual syndrome: a twin study. Br J Psychiatry 1993;162:481-486. [Free Full Text]
  36. Reid RL. Premenstrual syndrome. Curr Probl Obstet Gynecol Fertil 1985;8:1-57.
  37. Stewart DE, Fairman M, Barbadoro S, Zownir P, Steiner M. Follicular and late luteal phase serum fluoxetine levels in women suffering from late luteal phase dysphoric disorder. Biol Psychiatry 1994;36:201-202. [Medline]
  38. Levine LR. Fluoxetine in the treatment of bulimia nervosa: a multicenter, placebo-controlled, double-blind trial. Arch Gen Psychiatry 1992;49:139-147. [Abstract]
  39. Dixon WJ, ed. BMDP statistical software manual. Vol. 2. Berkeley: University of California Press, 1992.
  40. Streiner DL. An introduction to multivariate statistics. Can J Psychiatry 1993;38:9-13. [Medline]
  41. Gibbons RD, Hedeker D, Elkin I, et al. Some conceptual and statistical issues in analysis of longitudinal psychiatric data: application to the NIMH treatment of Depression Collaborative Research Program dataset. Arch Gen Psychiatry 1993;50:739-750. [Abstract]
  42. Brzezinski AA, Wurtman JJ, Wurtman RJ, Gleason R, Greenfield J, Nader T. d-Fenfluramine suppresses the increased calorie and carbohydrate intakes and improves the mood of women with premenstrual depression. Obstet Gynecol 1990;76:296-301. [Free Full Text]
  43. Sundblad C, Modigh K, Andersch B, Eriksson E. Clomipramine effectively reduces premenstrual irritability and dysphoria: a placebo-controlled trial. Acta Psychiatr Scand 1992;85:39-47. [Medline]
  44. Wood SH, Mortola JF, Chan YF, Moossazadeh F, Yen SSC. Treatment of premenstrual syndrome with fluoxetine: a double-blind, placebo-controlled, crossover study. Obstet Gynecol 1992;80:339-344. [Medline]
  45. Teicher MH, Glod C, Cole JO. Emergence of intense suicidal preoccupation during fluoxetine treatment. Am J Psychiatry 1990;147:207-210. [Free Full Text]
  46. Mann JJ, Kapur S. The emergence of suicidal ideation and behaviour during antidepressant pharmacotherapy. Arch Gen Psychiatry 1991;48:1027-1033. [Medline]
  47. Kapur S, Mieczkowski T, Mann JJ. Antidepressant medications and the relative risk of suicide attempt and suicide. JAMA 1992;268:3441-3445. [Abstract]
  48. Suicidal behavior and psychotropic medication: accepted as consensus statement by the ACNP Council, March 2, 1992. Neuropsychopharmacology 1993;8:177-183. [Medline]
  49. Wernicke JF. The side effect profile and safety of fluoxetine. J Clin Psychiatry 1985;46:59-67. [Medline]
  50. Stone AB, Pearlstein TB, Brown WA. Fluoxetine in the treatment of late luteal phase dysphoric disorder. J Clin Psychiatry 1991;52:290-293. [Medline]
  51. Barondes SH. Thinking about Prozac. Science 1994;263:1102-1103. [Free Full Text]
  52. Bach-y-Rita P. Psychopharmacologic drugs: mechanisms of action. Science 1994;264:642-644. [Free Full Text]
  53. Menkes DB, Taghavi E, Mason PA, Spears GFS, Howard RC. Fluoxetine treatment of severe premenstrual syndrome. BMJ 1992;305:346-347.
  54. Menkes DB, Taghavi E, Mason PA, Howard RC. Fluoxetine's spectrum of action in premenstrual syndrome. Int Clin Psychopharmacol 1993;8:95-102. [Medline]
  55. Benfield P, Heel RC, Lewis SP. Fluoxetine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness. Drugs 1986;32:481-508. [Medline]
  56. Daamen MJ, Brown WA. Single-dose fluoxetine in management of premenstrual syndrome. J Clin Psychiatry 1992;53:210-211. 
  57. Freeman EW, Rickels K, Sondheimer SJ. Course of premenstrual syndrome symptom severity after treatment. Am J Psychiatry 1992;149:531-533. [Free Full Text]
  58. Steiner M. Fluoxetine in the treatment of LLPDD: a multicentre, placebo-controlled, double-blind trial. Int J Gynaecol Obstet 1994;46:Suppl 2:122-122. 

 

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Fluoxetine for Premenstrual Dysphoria
Prior J. C., Gill K., Vigna Y. M., Edbril S. D., Steiner M.
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N Engl J Med 1995; 333:1152-1153, Oct 26, 1995. Correspondence

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