Through the development of both DSM-III-R and DSM-IV, the validity of premenstrual dysphoric disorder (PMDD) as a distinct, diagnosable condition has been intensely debated. Now the U.S. Food and Drug Administration has weighed in with its own position. Last month the agency accepted PMDD as a valid indication for pharmacologic therapy and approved fluoxetine for its treatment.

The decision nearly 15 years ago by the DSM-III-R Task Force to include PMDD, then referred to as "late luteal phase dysphoric disorder," in Appendix A, "Proposed Diagnostic Categories Needing Further Study," rather than as an officially approved diagnostic category, was one of intense discussion and controversy.

Those who favored the recognition of PMDD as a bona fide diagnosis claimed they were well supported by a large body of research and clinical literature. They argued that if the diagnosis was left out of the officially approved nomenclature, it could lead to underdiagnosis, misdiagnosis, and failure to give patients appropriate care.

Critics cited several difficulties with the proposed disorder. They argued that it was vague, that the research was marred by numerous methodological problems, and that the inclusion would lead to widespread stigmatization of women.

The highly charged debate continued during the development of DSM-IV, resulting in the formation of an unusually large work group—consisting of five members, one consultant, and 36 advisors.

The group conducted an exhaustive literature review, which encompassed more than 500 articles, and attempted to come to consensus regarding whether PMDD should stay in the appendix, be moved to the body of the text as a recognized diagnostic category, be omitted altogether, or be classified elsewhere, for example, as a genitourinary, rather than psychiatric, disorder.

At this point, members of the task force agreed that there were a number of problems with methodology within the PMDD literature. The problems included unclear definitions, small sample sizes, lack of control groups, lack of prospective daily ratings of symptoms, no documentation of the timing and duration of symptoms, and failure to collect appropriate hormonal samples.

Researchers no longer doubt the basic validity of the diagnosis; however, opponents of the diagnosis argued that diagnosis and assessment of the disorder were inconsistent at best.

Critics also argued that formal recognition of PMDD would stigmatize women on the whole. But proponents said that the stigmatization went both ways—not including the diagnosis might lead to women with the disorder being ignored or blamed for simply being "temperamental."

The PMDD Work Group recommended that the DSM-IV Task Force keep the disorder in Appendix A.

The federal government now says it’s convinced of what the DSM experts had determined in 1993 needed further study.

The FDA’s regulations for the labeling of a drug for a specific indication require that the condition be recognized and accepted in the clinical setting and identified and defined unambiguously, that appropriate methods be used in assessment and measurement of the condition, and that clinical trials show efficacy and safety for the proposed pharmacotherapy.

Both researchers and clinicians see the FDA’s approval of PMDD as a message to patients and clinicians that PMDD is a distinct clinical entity and that accepted, proven treatments exist. As work on DSM-V gets under way, the relevant work groups and task force will undoubtedly have to address the question again.

Jean Endicott, Ph.D., a professor of clinical psychology in the department of psychiatry at Columbia University and chief of the department of research, assessment, and training at the New York State Psychiatric Institute, believes that the task force’s debate will be easier to resolve because of the FDA decision. Endicott testified before the FDA Advisory Panel that recommended approval of the new indication.

In fall 1998 Endicott convened a round-table discussion of many of the experts on PMDD, about half of whom, including Endicott, had also served on the DSM-IV PMDD Work Group. The round table, funded by the Society for Women’s Health Research, was charged with summarizing the evidence as to whether PMDD is a distinct clinical entity. While generally endorsing the diagnostic category, the round-table panel did cite significant difficulties with PMDD.

For one, most of the body of research on PMDD has been done on Northern American or European subjects.

Sally Severino, M.D., a professor of psychiatry at the University of New Mexico, noted during the round-table discussions, "If affective premenstrual distress cannot be identified consistently in non-United States or non-European populations, consideration will have to be given to the criticism that PMDD is a culturally bound syndrome or an unnecessary pathologizing of cyclical changes in women."

In addition, the round-table panel noted that researchers are well aware that applying different methods to rate severity of symptoms has resulted in differing study populations and differing results.

"PMDD is an operationally defined construct," said Severino, "that is method dependent for diagnosis." The panel concluded that although "the application of an objective rating scale. . . , administered by interview, could improve reliability," PMDD is a distinct clinical entity.

The conclusions of the round-table discussion appeared in the June 1999 issue of the Journal of Women’s Health and Gender-Based Medicine.

"We [the round-table panelists] wanted to make it clear that we thought there was considerable evidence from multiple sources that the pathophysiology of the condition was different from the other mood and anxiety disorders, that the course of the illness was certainly quite different, and that treatment response was even different," said Endicott.

The FDA’s Psychopharmacologic Drugs Advisory Committee, chaired by Carol A. Tamminga, M.D., a professor of psychiatry at the University of Maryland and a member of APA’s Council on Research, heard extensive testimony and reviewed nearly 400 pages of documentation prior to voting to recommend approval of the new PMDD indication for fluoxetine.

Considerable discussion was focused on the fact that PMDD was not listed in DSM, the standard nomenclature that is accepted by the clinical community. The FDA panel also considered methodological problems with the assessment of PMDD patients. In the end, however, the group was satisfied of the treatment community’s acceptance of the disorder, voting unanimously in favor of the new indication.

With Endicott’s testimony, the round-table panel’s paper played a prominent role in the FDA’s decision to adopt the new indication and will likely be reviewed when the diagnosis is considered for inclusion in DSM-V. It remains to be seen how influential it proves to be with the DSM-V work group, however.

Darrel A. Regier, M.D., M.P.H, director of APA’s Office of Research and executive director of the American Psychiatric Institute for Research and Education, commented on the FDA’s recognition of the PMDD diagnosis.

"Given the disability associated with the condition, and the responsiveness to new treatments demonstrated by controlled clinical trials, the FDA has been willing to provide an indication for a diagnostic entity that appears to their consultants to meet validity criteria, prior to full consideration by DSM committees."

The Office of Research will be responsible for the development of DSM-V, whose completion is seven to 10 years away, said Regier.

When asked about the significance of the FDA’s approval of the new indication, Regier commented, "As intervals between DSM and the International Classification of Diseases (ICD) revisions continue to expand, there will be additional pressure on the scientific community to address diagnostic and therapeutic issues of the type represented by the PMDD decision by the FDA."

Although significant questions remain regarding PMDD, the DSM placement of the disorder in the appendix seems to have served its intended purpose—to spur additional research into diagnosis and treatment.

Ellen Freeman, Ph.D., research professor in the departments of psychiatry and obstetrics and gynecology at the University of Pennsylvania Medical School, served as a consultant to the DSM-IV PMDD Work Group and participated in Endicott’s round-table discussion.

"DSM’s treatment of PMDD in the appendix has been very useful in promoting new research," Freeman told Psychiatric News. "There has certainly been pressure, which researchers have responded to, to use the criteria. It has enabled reports of samples to have a greater replicability than they did before."

Endicott added, "More and more evidence will continue to accumulate by the time the Mood Disorders Work Group starts working on DSM-V."

The FDA’s approval of fluoxetine for PMDD, under the new trade name Sarafem, was requested by Eli Lilly and Co.

Lilly’s best-selling fluoxetine product, sold since 1987 under the trade name Prozac, will lose patent protection in 2003. Both U.S. and global sales of Prozac have been declining recently. Lilly claims the cause is stiff competition in the SSRI market, but the drop also may be due to unfavorable press accounts of potential adverse drug reactions linked to Prozac (Psychiatric News, August 4.) The company is currently overseeing clinical trials of fluoxetine-R, a chemical isomer that it hopes will have an improved safety profile.

Lilly says that the renaming of fluoxetine as Sarafem will "help with educational efforts for this largely underrecognized disorder while reducing confusion about the differences between depression and PMDD."

PMDD, estimated to affect 3 percent to 5 percent of menstruating women in the United States, could provide a significant new market to boost sales. And the global treatment market is also expanding. According to Endicott, the diagnosis of PMDD is now an accepted indication for treatment in at least 16 countries, including the United Kingdom (which should lead to approval for the entire European Union), New Zealand, and Australia.

Lilly has many critics over its decision to change the Prozac name. "It erodes the trusting relationship between the doctor and the patient," said Nada Stotland, M.D., chair of psychiatry at Illinois Masonic Medical Center, a professor of psychiatry and obstetrics and gynecology at Rush Medical College, and speaker-elect of the APA Assembly.

"Why change the name?" asked Stotland, who also served on the PMDD Work Group, in an interview with Psychiatric News. "People shouldn’t be ashamed of taking Prozac; this simply feeds into the prejudice against psychiatry and against psychoactive drugs. Is an internist or gynecologist—who is most likely to see these patients—going to have time to explain to women that this is the same thing as Prozac?"

Stotland, an expert on women’s issues in psychiatry, has been critical of PMDD as a formal diagnosis because of her concerns for the methodological problems, as well as the lack of research concerning the social aspects of the disorder.

"So far, biomedicine has ignored the social medicine aspects of PMDD," Stotland told Psychiatric News. "Psychiatry is supposed to be both."

Stotland also is concerned that with a new medication approved to treat women with PMDD, some clinicians may be quick to prescribe without going through the rigorous workup, including prospective daily ratings, necessary to diagnose the disorder accurately and appropriately.

Regardless of whether PMDD gains widespread acceptance and is included as a recognized diagnostic category in DSM-V, it is clear that many factors will play a part in the complex decision: the growing body of research spurred by DSM-IV’s research criteria, approval by the FDA as well as many foreign governments, and the increasing global acceptance of the disorder by clinicians and their willingness to treat it.

"Physicians who adhere more closely to what the FDA does or does not approve will be more comfortable with diagnosing and treating PMDD," Freeman told Psychiatric News. However, she noted, the change is likely to affect only primary care.

Endicott agreed. "Gynecologists and psychiatrists have been successfully treating PMDD with SSRIs for years."

Donna Stewart, M.D., a professor of psychiatry at the University of Toronto and chair of APA’s Committee on Women, is optimistic. "Any progress that is made in helping women to manage their symptoms better is to be applauded," she told Psychiatric News. Stewart, who was also an advisor to the DSM-IV PMDD Work Group and a member of Endicott’s panel, agreed with Stotland, however, in that it is important that appropriate distinction be made between PMDD and other disorders, such as depression, the more common and less severe "PMS," or the unrelated dysmenorrhea.

"In general," Stewart said, "I applaud the FDA’s approval and hope it will lead to better women’s health care."