Institute for the Study of
Healthcare Organizations & Transactions

Premenstrual Dysphoric Disorder

Introduction  An article in the Wall Street Journal (July 7, 2000) reports that the antidepressant, fluoxetine, marketed as an antidepressant by Eli Lilly under the trade name "Prozac", will also be marketed under the new trade name "Sarafem" for treatment of premenstrual dysphoric disorder (PMDD), a severe form of premenstrual syndrome (PMS), a cluster of emotional, motivational, cognitive, and behavioral changes which occur in regular association with elevated estrogen levels immediately prior to, or during the early phases, of menstruation.  For a discussion of the distinction between PMDD and PMS, click on

 http://www.wdxcyber.com/nmood06.htm.

 

For related press releases from Eli Lilly and the Food and Drug Administration, click on
www.pharmacology.about.com/health/pharmacology/library/0daily/00news/blnews000706_sarafem.htm.

 

What is Premenstrual Dysphoric Disorder?  Considerable controversy exists over the status of PMDD and PMS as valid diagnostic categories.  For extensive discussions of the debate, see Paula J. Caplan, They Say you’re Crazy: How the World’s Most Powerful Psychiatrists Decide Who’s Normal (Addison Wesley, 1995); Anne E. Figert, Women and the Ownership of PMS: The Structuring of a Psychiatric Disorder (Aldine De Gruyter, 1996); Herb Kutchins & Stuart A. Kirk, Making Us Crazy: DSM: The Psychiatric Bible and the Creation of Mental Disorders (Free Press, 1997); and Carol Tavris, The Mismeasure of Woman (Simon & Schuster, 1992). 

Even when there was agreement about the diagnostic entity, there was disagreement about its name. In preparing the 1987 revision of the American Psychiatric Association’s Diagnostic and Statistical Manual for Mental Disorders (DSM-IIIR), the syndrome was variously referred to as "Premenstrual Dysphoric Disorder" (PMDD) and "Periluteal Phase Dysphoric Disorder" (PPDD), before the responsible committee settled on "Late Luteal Phase Dysphoric Disorder" (LLPDD ). In the most recent edition of DSM (DSM-IV, 1994), the label reverted to PMDD.

It should be noted that "Periluteal Phase Dysphoric Disorder" greatly expanded the scope of the diagnostic category – a problem that frequently crops up in psychiatric diagnosis. PMDD was originally intended to cover women who experienced severe mental and behavioral symptoms during a particular phase of the menstrual cycle. But the adjective "periluteal" would permit a psychiatric diagnosis to be made in the case of a woman who experienced particular symptoms at any phase of her cycle. Not only would this designation have freed PMDD from its tie to periodic changes in the woman’s hormonal endowment, thus undermining the implicit theory of the etiology of PMDD; it would also have extended the number of women for whom Serafem/Prozac would be the treatment of choice. (See the discussion of Prozac and Serafem below.) To the extent that economic considerations play a role in psychiatric practice, we may anticipate the rediscovery of PPDD, with Serafem/Prozac as the treatment of choice, sometime in the not-too-distant future.

To return to the history of PMDD, some feminist professionals, including the APA’s Committee on Women and the National Coalition for Women’s Mental Health, objected to the inclusion of such a syndrome under any label. From their point of view, menstruation is a normal bodily function, and any psychological changes associated with this function should be seen as normal as well. Classifying PMS or PMDD as a mental disorder stigmatizes women, and may have other undesirable social consequences by laying additional foundations for disability claims and the insanity defense. Setting ideology and politics aside, PMDD raises fundamental questions about the nature of psychiatric diagnosis. What are the standards for distinguishing between "normal" PMS and "pathological" PMDD? Even if there were solid criteria for distinguishing between normal and abnormal changes in estrogen levels, why should the mental and behavioral consequences of these physiological changes be construed as symptoms of a mental disorder? What is the difference between a "physical" disorder and a "mental" one?

As with the APA’s debate over homosexuality in the 1970s, the debate over PMDD raises questions about the social construction of mental illness. A 1992 review by Paula J. Caplan, Joan McCurdy-Myers, and Maureen Gans concluded that there no compelling empirical justification for identifying any particular cluster of symptoms as PMDD, nor for considering PMDD a form of mental disorder (Feminism & Psychology, 2:27-44, 109). There was no link between the symptoms ascribed to PMDD and premenstrual changes in hormonal levels. And there was no evidence that any pharmacological adjustment of hormonal levels had any effect on PMDD. 

Not surprisingly, the APA committee assigned to review the literature on PMDD reached an impasse, and a new committee was assigned to decide whether the category would be included in DSM as a fully proven, legitimate diagnosis. Ultimately, as with homosexuality, the fate of PMDD was put up to a vote of the Legislative Assembly of the APA – an essentially political process. It is hard to imagine other groups of physicians voting on the legitimacy of such diagnoses as coronary heart disease or kidney failure. But given the "legislative history" of the diagnosis, as summarized by Caplan, it appears clear that the inclusion of PMDD, or something like it, in DSM was a foregone conclusion. But there is no parallel diagnosis for men (e.g., "Testosterone-Based Dysphoric Disorder"), and there are no gender-neutral categories for dysphoria attributed to hormonal imbalances. There seems to be something special about women, and about menstruation.

In the absence of objective criteria for diagnosing mental illness, framing the psychiatric nosology is inherently political, and making a psychiatric diagnosis is inherently subjective. Patients are brought, or bring themselves, to the attention of mental-health professionals because they "seem different" from others. Would PMDD have been placed in DSM if there had been more women on the committee? If women had more political power within the APA? If there were no cultural stereotypes about women and "that time of the month"? If there were objective criteria for identifying psychiatric disorders, and for making diagnoses?
 

What is Prozac?   Prozac (generic name: fluoxetine hydrochloride), one of a class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs), is a "designer drug" engineered in the laboratory to have specific properties; other popular SSRIs are Paxil and Zoloft. In theory, some forms of depression are related to deficiencies in the production and flow of serotonin, an important neurotransmitter in the brain; some theories also implicate norepinephrine, another important neurotransmitter. 

In view of the evidence for a biological cause of some forms of depression, it seems reasonable to search for a treatment that would correct the underlying biochemical disorder. Previous antidepressants, including monoamine oxidase inhibitors (MAOIs) such as Nardil and tricyclic antidepressants such as Tofranil, act by increasing the flow of both norepinephrine and serotonin in the brain. Prozac, as an SSRI, exerts most of its effect on serotonin, and has relatively little effect on norepinephrine. It is claimed that Prozac is at least as effective, but produces fewer side effects and may be taken with greater safety, compared to the older, alternative drugs. 

The virtues of Prozac in the treatment of depression were famously touted in Peter Kramer’s book, Listening to Prozac (Viking, 1993); for a brief history of Prozac, see D.T. Wong et al., "Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: Twenty years since its first publication" [Life Sciences 57(5):411-441, 1995].
 

prescription pad.jpg (23856 bytes)Why Call Prozac "Sarafem"?   If this new drug is just the old, familiar Prozac, then why call it "Sarafem"? In its press release, Eli Lilly expressed the hope that the new trade name would "[reduce] confusion about the differences between depression and PMDD". However, Prozac has also been approved for treating obsessive-compulsive disorder and bulimia, and these additional indications were not accompanied by the introduction of a new trade name. By calling the drug "Sarafem" instead of "Prozac", perhaps Lilly hopes to increase the market for the drug by avoiding the stigma and other negative connotations of mental illness. 

According to the Wall Street Journal, however, industry analysts do not expect Sarafem to have a significant impact on Prozac sales. If Sarafem were prescribed only for those 3%-5% of women who qualify for the diagnosis of PMDD, this might be the case. At present, Prozac is so widely prescribed, for even minor cases of depression, that in 1990, just three years after the drug came onto the market, the New York Times (December 3, 1993) referred to the rise of a "legal drug culture". Just as the anti-anxiety drug Valium (diazepam) attained wide popularity in the 1960s and 1970s, in 1994 Newsweek wrote that ‘Prozac has attained the familiarity of Kleenex and the social status of spring water" (February 7). Against this background, the substantial number of women who experience minor symptoms of PMS, even if they do not suffer from full-blown PMDD, promises to greatly enlarge market for a drug that is already the #2 best-selling drug in the world (#1 is the ulcer drug Zantac).

In addition, the patent protections on Prozac, which began in 1987 are about to run out. Marketing essentially the same drug (fluoxetine hydrochloride) under a new trade name effectively extends patent protections for another 14 years.
 

How Does Serafem/Prozac Work Against PMDD?  Setting aside the controversy over the diagnosis itself, the effectiveness of Serafem (or Prozac) in the treatment of PMDD raises additional questions. This new use of the drug is based on the results of two double-blind clinical trials which showed that the drug was significantly more effective than placebo in relieving the symptoms of PMDD. However, the precise mechanism by which Serafem/Prozac achieved its effect remains unknown. In theory, PMDD is caused by changes in estrogen levels occurring in the transition between the luteal phase and the follicular phase of the menstrual cycle. But, as noted earlier, Serafem/Prozac acts selectively on serotonin, a neurotransmitter found in the brain, and has no apparent effect on estrogen, a hormone secreted by the ovaries. On the other hand, depression is one of the primary symptoms of PMDD, and the well-known effects of Prozac on depression may mediate its effects on PMDD. In other words, Serafem may not be a specific treatment for PMDD at all.

However, two psychologists at the University of Connecticut, have argued that the effects of Prozac and other antidepressants are largely attributable to the placebo response [see Irving Kirsch & Guy Saperstein, "Listening to Prozac by hearing placebo: A meta-analysis of antidepressant medications" in I. Kirsch (Ed.), How Expectancies Shape Experience (American Psychological Association, 1999)]. These investigators concluded that approximately 75% of the outcome of drug treatment for depression may be attributable to the placebo effects associated with providers’ and consumers’ expectations, and only about 25% is specifically attributable to their active pharmacological effect. 

Kirsch and Sapirstein’s conclusion is controversial, and has been discussed in a set of articles published in the electronic journal Prevention & Treatment, posted June 1, 1998.  Readers with personal or institutional subscriptions may access these papers by clicking on http://journals.apa.org/prevention/volume1. If Kirsch and Sapirstein are right, the same conclusion might apply to the outcome of Serafem on PMDD as well -- that it largely represents a placebo effect. In the final analysis, if PMDD reflects cultural stereotypes of women, and the effects of Prozac are strongly mediated by interpersonal expectations, then the treatment of PMDD by Serafem represents an interesting instance in which one social construction is treated by another.

 

Acknowledgement

The illustration is from "Carter's Little Nerve Pills," 19th century, trade card.  Bella C. Landauer Collection of Business and Advertsing Art, The New York Historical Society

 

 

John F. Kihlstrom

Copyright © 2000 Institute for the Study of Healthcare Organizations & Transactions

Last modified:  04.08.2010 02:58 PM