Correspondence

Fluoxetine for Premenstrual Dysphoria

N Engl J Med 1995; 333:1152-1153October 26, 1995

Article

To the Editor:

The multicenter clinical trial of fluoxetine for the treatment of premenstrual mood symptoms reported by Steiner et al. (June 8 issue)1 is good science but bad medicine. Cyclic changes in breast tenderness, fluid retention, nutrition, and emotional experiences are normal, are modulated by lifestyle, and are related to the emotional and social environment and culture. What evidence, other than help-seeking behavior, is there that the women in the study had pathologic depression requiring pharmacologic treatment?

Was an inhibitor of serotonin reuptake tested because disturbances of serotonin are caused by normal hormonal changes during the menstrual cycle or because a pharmaceutical company paid clinical investigators to develop a new indication for their designer drug?

We question the use of a medication with short-term and unknown long-term adverse effects when effective approaches to depression, such as aerobic exercise, are well documented.2 Premenstrual fluid retention and breast tenderness improved after three months of a program of mildly increasing exercise, and after six months of minimal, regular physical activity, mood symptoms also decreased.3 Why test an expensive drug when an inexpensive change in lifestyle, free of side effects and with positive effects on cardiovascular disease and the risk of osteoporosis, can be expected to provide benefit?

The high rate of attrition among the women in this study is remarkable. Is it good medicine to treat women with a medication and dosage that one third of a highly motivated, symptomatic group of patients feel they must discontinue because of side effects? Is it good medicine to give continuous therapy for an intermittent symptom?

This study provides further evidence that science thinks it must rescue women from their bodies. And it gives more evidence of the negative view this culture holds of women and their physiology.

Jerilynn C. Prior, M.D.
Kuldip Gill, Ph.D.
Yvette M. Vigna, R.N.
University of British Columbia, Vancouver, BC V5Z 1M9, Canada

3 References

1. 1

   Steiner M, Steinberg S, Stewart D, et al. Fluoxetine in the treatment of premenstrual dysphoria. N Engl J Med 1995;332:1529-1534
   Full Text | Web of Science | Medline

2. 2

   McCann L, Holmes DS. Influence of aerobic exercise on depression. J Pers Soc Psychol 1984;46:1142-1147
   CrossRef | Web of Science | Medline

3. 3

   Prior JC, Vigna Y, Sciarretta D, Alojado N, Schulzer M. Conditioning exercise decreases premenstrual symptoms: a prospective, controlled 6-month trial. Fertil Steril 1987;47:402-408
   Web of Science | Medline

To the Editor:

Although Steiner et al. demonstrated the benefit of fluoxetine in the treatment of premenstrual syndrome, they did not address its effect on individual symptoms that characterize late-luteal-phase dysphoria. Prominent among these is irritability. Although the general mechanism of action of fluoxetine in premenstrual dysphoria remains unclear, the evidence suggests that it has a specific role in altering the clinical presentation and neurohormonal process of the premenstrual irritable state.

Patients report that the interpersonal effects of the premenstrual irritable state are the primary reason for seeking treatment for mood changes in the late luteal phase. During this time, affected women feel exquisitely sensitive to areas of conflict in their relationships. The expression of premenstrual irritability appears to provide only temporary relief and lacks the cathartic effect that may accompany justified outbursts of anger.1 Frequently such women report a substantial diminution in the intensity of their premenstrual irritability after treatment with fluoxetine.

The presence of increased levels of testosterone during the late luteal phase may help explain the irritative and impulsive quality that characterizes the premenstrual irritable state. Levels of testosterone, specifically free testosterone, have been positively correlated with premenstrual irritability.2 Inhibitors of serotonin reuptake may play an important part in mitigating late-luteal-phase irritability by altering levels of free testosterone.

Susan D. Edbril, Ph.D.
Beth Israel Hospital, Boston, MA 02215

2 References

1. 1

   Snaith RP, Taylor CM. Irritability: definition, assessment and associated factors. Br J Psychiatry 1985;147:127-136
   CrossRef | Web of Science | Medline

2. 2

   Eriksson E, Sunblad C, Lisjo P, Modigh K, Andersch B. Serum levels of androgens are higher in women with premenstrual irritability and dysphoria than in controls. Psychoneuroendocrinology 1992;17:195-204
   CrossRef | Web of Science | Medline

Author/Editor Response

Dr. Steiner replies:

To the Editor: We certainly agree with Dr. Edbril's comments about the prominence of irritability among the symptoms characterizing premenstrual dysphoria. Because of space requirements, and since there was no difference between the scores on the visual-analogue scales for tension, irritability, and dysphoria (for a given subject), we presented only mean total scores on the three scales as our primary outcome measure. It is tempting, however, to speculate that the principal effect of the selective inhibitors of serotonin reuptake is on irritability and that the diminution in tension and dysphoria is somewhat secondary.

We did not measure testosterone levels in our study. However, there is recent evidence that reduced central serotonin turnover is associated with impulsivity and high testosterone concentrations in male offenders.1 Further studies of the interaction between the serotonergic cascade and the hypothalamic–pituitary–gonadal axis in women with premenstrual dysphoria who respond to treatment with serotonin-reuptake inhibitors are clearly indicated.

The letter by Prior et al., on the other hand, is mainly a political polemic with scientific flaws. One cannot establish a diagnosis on the basis of the response to treatment. Women with severe premenstrual dysphoria do not have “pathologic depression” simply because they respond to an antidepressant, in this case a serotonin-reuptake inhibitor. We initiated this study because there was mounting evidence that serotonin had a role in premenstrual dysphoria2,3 and because sufficient pilot data suggested that reuptake inhibitors might be effective in these women, not because a pharmaceutical company paid us to develop a new indication for their “designer” drug. The participants in this study were seeking help because their symptoms were so severe that they affected the women's functioning substantially. The evidence was not based solely on the presence of help-seeking behavior; instead, there were rigorous criteria for inclusion and exclusion from the study, as well as daily prospective ratings. All the women had conditions resistant to prior treatment and had tried more conservative approaches, such as dietary changes, regular exercise programs, and lifestyle management. Exercise is clearly not a panacea for mood disorders,4 as Prior and her colleagues are obviously aware. In their own study (which they cite), they were only able to demonstrate in a small sample (15 subjects) that conditioning exercise carried out to the extent of marathon training decreased symptoms of molimina, such as breast tenderness and fluid retention, but neither anxiety nor depression.

Severe premenstrual dysphoria affects 3 to 5 percent of women of reproductive age. To deny these women effective treatment merely because our culture has negative views of female physiology is bad medicine.

Meir Steiner, M.D., Ph.D.
St. Joseph's Hospital, Hamilton, ON L8N 4A6, Canada

4 References

1. 1

   Virkkunen M, Rawlings R, Tokola R, et al. CSF biochemistries, glucose metabolism, and diurnal activity rhythms in alcoholic, violent offenders, fire setters, and healthy volunteers. Arch Gen Psychiatry 1994;51:20-27
   Web of Science | Medline

2. 2

   Rapkin AJ. The role of serotonin in premenstrual syndrome. Clin Obstet Gynecol 1992;35:629-636
   CrossRef | Web of Science | Medline

3. 3

   Rubinow DR, Schmidt PJ. The treatment of premenstrual syndrome -- forward into the past. N Engl J Med 1995;332:1574-1575
   Full Text | Web of Science | Medline

4. 4

   Byrne A, Byrne DG. The effect of exercise on depression, anxiety and other mood states: a review. J Psychosom Res 1993;37:565-574
   CrossRef | Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   Nathan Greenslit. (2005) DEP®ESSION AND CONSUM♀TION: PSYCHOPHARMACEUTICALS, BRANDING, AND NEW IDENTITY PRACTICES. Culture, Medicine and Psychiatry 29:4, 477-502
   CrossRef

2. 2

   Carmen Poulin, Lynne Gouliquer. (2003) Part-Time Disabled Lesbian Passing on Roller Blades, or PMS, Prozac, and Essentializing Women's Ailments. Women & Therapy 26:1-2, 95-108
   CrossRef