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Spotlight on PMDD -- Symptom-Based Treatment: An Expert Interview With Dr. Uriel Halbreich

Posted 02/13/2008
Uriel Halbreich, MD

Editor's Note:
Currently, there are a number of pharmacologic agents used to treat the symptoms of premenstrual dysphoric disorder (PMDD), the most severe form of premenstrual syndrome (PMS). Uriel Halbreich, MD, Professor, Department of Psychiatry, Department of Gynecology and Obstetrics, School of Medicine and Biomedical Sciences, and Director of Biobehavioral Research, the State University of New York at Buffalo, has conducted research in the area of PMS/PMDD for over 25 years. In this interview, Peggy Keen, PhD, FNP, Editorial Director of Medscape Ob/Gyn & Women's Health, talks with Dr. Halbreich about how patient symptoms or subgroups could help with identifying initial pharmacologic treatment for PMDD.

Dr. Keen: I'd like to start the interview today by reading from your 2006 publication titled "Are There Differential Symptom Profiles That Improve in Response to Different Pharmacological Treatments of Premenstrual Syndrome/Premenstrual Dysphoric Disorder?"[1] "Current evidence suggests that the accepted treatments for PMDD have similar overall efficacy. While these treatments are more effective than placebo, the response rates are far from satisfactory (less than 60%), such that irrespective of treatment modality, there remains a significant number of women who are unresponsive. The overall treatment response rates may improve if treatments are targeted at well defined subgroups of women."

What I would like to talk with you about is how clinicians can use patient symptoms or subgroups to help identify optimal, initial pharmacologic treatment for PMDD.

Dr. Halbreich: Well, this first is an issue involving whether or not there is a single entity -- PMS -- or a diversified range of premenstrual syndromes, including PMDD, or even other different conditions that reflect mood and behavioral syndromes. Almost any symptom that might appear premenstrually can be considered PMS. If this is the case, the clinician can determine whether she or he wants to treat PMS or PMDD symptomatically or wants to treat the patient using a broader approach. This broader treatment approach might cover symptoms not necessarily specific to the symptoms that a particular woman has.

So, evaluation here is very important, mainly to see what the target symptoms are and, of course, to determine whether these symptoms appear only premenstrually or are more generalized. For example, the symptom of depression might be general depression and might be present throughout the menstrual cycle, with or without exacerbation or worsening premenstrually. Or it might also occur only premenstrually. Only when it occurs exclusively premenstrually would it be considered a symptom of PMDD.

Dr. Keen: Once the diagnosis has been made, how would certain symptom profiles be matched with a treatment approach?

Dr. Halbreich: Basically, there are 2 main pharmacologic approaches to treatment. One is a general approach; suppression of ovulation. The other is treating with antidepressants, primarily selective serotonin reuptake inhibitors (SSRIs).

If the clinician is not sure about the reliability of symptoms as a guide for choice of treatment, suppressing ovulation is playing it safe. Suppression of ovulation can ameliorate a broad range of behavioral as well as physical symptoms.

This is usually done by treating with an oral contraceptive (OC) because there are very few adverse effects. This is not the case with other suppression agents -- gonadotropin-releasing hormone (GnRH) agonists such as leuprolide, goserelin, and nafarelin. Treatment with these agents can create a situation that might be equal to menopause unless the patient is also prescribed a high enough dosage of replacement estrogen and progestin to counter the related effects.

Dr. Keen: What about the newest agent approved by the US Food and Drug Administration (FDA) for treatment of PMDD -- the OC containing the progestin drospirenone (DRSP) and low-dose ethinyl estradiol -- would this agent fall into the suppression-of-ovulation category or would it be considered a hormonal agent?

Dr. Halbreich: With OCs, there are 2 considerations. Although all OC [formulations] suppress ovulation, the potential adverse effects depend very much on the type of progestin the OC contains. This is especially true for progestin-only OCs.

Progestins are associated with quite a number of adverse effects and, in many ways, can make certain symptoms of PMDD more severe. Some of these adverse effects are anxiety and depression, which could be exactly the symptoms that you want to treat. So, the choice of an OC is according to the needs of each individual woman.

The main advantage of the DRSP/ethinyl estradiol product, besides being an OC (which, of course, is a big advantage for women who want to avoid pregnancy) is that DRSP is similar to [naturally occurring] progesterone. However, though it was effective in about 60% of participants in clinical trials, there were still 40% of women who did not respond well. And there was a very small number of women whose PMDD symptoms actually became worse. That's because of the similarity between the progestin and the natural progesterone. So that's not necessarily a positive effect for some women.

The other main pharmacologic approach is treating with antidepressants, mostly SSRIs. For the main affective symptoms of PMDD -- irritability, tension, anxiety, and impulsivity -- SSRIs work better than other categories of antidepressants. It has been recognized that some of the older tricyclic antidepressant agents don't work as well as the SSRIs.

Deciding what SSRI to prescribe is basically up to the clinician. Three SSRIs have been approved for treatment of PMDD by the FDA. And, as far as I know, there aren't too many differences between these agents. It should also be noted that efficacy associated with treatment of PMDD with SSRIs is also around 60%.

There might be an advantage to prescribing a compound that is both a serotonin and a norepinephrine reuptake inhibitor (SNRI). There are 2 SNRIs currently on the market. Concurrent use increases the possibility that the amount of coverage is higher.

Dr. Keen: In your 2006 article, you suggested that reanalyses of the available data from randomized clinical trials could shed more light on the approach that women with specific symptom profiles could be targeted for specific treatment -- and that doing so would improve response rates. To your knowledge, have any reanalyses of this type been done?

Dr. Halbreich: To my knowledge, the only time that such an analysis was published was a long time ago -- actually in the very early '80s -- by Dr. Jean Endicott and me, in which we demonstrated the diversity of PMS symptoms.[2] At that time, PMDD had not been recognized as a entity yet. But we demonstrated that there were women with completely different symptom profiles within the spectrum of this condition.

I'll give an example of what we found. Some women have what is called atypical depression. That means they have symptoms of increased sleep, decreased energy, increased reactivity to external stimuli, and so on. Other women are just the opposite. They have impaired sleep, increased impulsivity, increased energy, and decreased appetite as opposed to an increased appetite.

This diversification of symptoms is similar to what can be seen with major depressive disorder. In this disorder, there is evidence that women, or people in general, with atypical depression respond far better to treatment with monoamine oxidase inhibitors than do those with endogenous-like depression. It might be the same with PMDD, but this is something that is not clear yet.

One of the issues [with treatment approaches] is that the FDA doesn't have a PMS definition at this time. However, there was a consensus meeting about a year ago that came up with quite well-defined definitions.[3] Participants at this meeting were not only from the United States, but from European countries as well -- Italy, Germany, France, the United Kingdom, Sweden, Australia. Some of these experts unofficially reported that, when they choose medication, they consider subtypes.

For medications that are going to be applying for specific FDA indications -- that's more complicated. Considering the investment in the development of a medication by a pharmaceutical company -- as far as I know, they are not that interested in showing subtypes, though there is a Swedish group that showed that the efficacy of SSRIs is higher if treatment is focused on women with symptoms of irritability, anxiety, and impulsivity, as compared with women who have more endogenous depression, where the main symptom is decreased energy.[4]

Dr. Keen: Are there any investigative findings related more to the physical symptoms of PMDD?

Dr. Halbreich: There is a publication that claimed that fluoxetine is also effective for physical symptoms -- not only for emotional/behavioral symptoms. Probably, to some degree that's the case, but not necessarily so. To my knowledge, it has not really been proven yet beyond any doubt that there is a difference between treating women with PMDD who have physical symptoms and women with PMDD without physical symptoms.

However, this is when the suppression of ovulation comes into play. When you are treating a very broad gamut of symptoms, you are better off using an agent that suppresses ovulation. Then, any symptom that might appear premenstrually is influenced by suppression of ovulation.
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