Premenstrual Exacerbation May Increase Severity of Bipolar Disorder

Deborah Brauser

March 09, 2011

March 9, 2011 — Premenstrual exacerbation (PME) may be a clinical predictor of increased bipolar disorder (BD) severity, new research suggests.

In a study of nearly 300 women with BD, investigators found that those with PME had more symptoms of depression and mood elevation, more illness episodes, and a more rapid rate of relapse compared with those without PME.

In addition, although the women with PME were more likely to report rapid cycling retrospectively, they were not more likely to meet the criteria for a diagnosis of that condition.

"I would say premenstrual worsening in mental disorders is a common complaint but not much studied," lead study author Rodrigo S. Dias, MD, PhD, from the Bipolar Clinic and Research Program at Massachusetts General Hospital in Boston during this study, now at the Institute of Psychiatry at the University of São Paulo Medical School, Brazil, told Medscape Medical News.

Dr. Rodrigo S. Dias

Dr. Dias reported that he was "not surprised" at the high prevalence of study participants who had PME (65.2%) or that there were a higher number of depressive episodes observed in these women during the 1-year follow-up period.

"But the shorter time to relapse, which was half that of women without premenstrual worsening, was a surprise," he said. This group also "spent more time with residual symptoms, which have been associated with poor functioning and a higher rate of relapse."

The investigators note that this is the first large study to prospectively investigate the impact of PME on the course of BD.

"It would be great if every clinician would follow their patient's menstrual cycle at every appointment and look at any complaint related to a reproductive event, such as PMDD [premenstrual dysphoric disorder], postpartum disorders, etc. Those women could be seen as a special population of patients," said Dr. Dias.

The study was published online February 15 in the American Journal of Psychiatry.

Clinical Implications Unknown

Approximately 80% of women experience mild premenstrual symptoms, but only 6% are diagnosed as having PMDD. However, about 19% of women have subsyndromal PMDD — having many of the symptoms but not quite enough to qualify for a full PMDD diagnosis.

"Despite evidence that [PME] occurs in a substantial proportion of women with bipolar disorder, little is known about the clinical implications of this association," they add.

"I've been involved in studying mood disorders and women's mental health, especially focused on the impact of menstrual cycle because this is a common complaint in our daily practice," said Dr. Dias.

I always believed the link between hormones and mood regulation could be a marker/modulator, a trigger for new mood episodes, in a special population of women who are sensitive to hormonal changes.

"I always believed the link between hormones and mood regulation could be a marker/modulator, a trigger for new mood episodes, in a special population of women who are sensitive to hormonal changes," he added.

The investigators evaluated data on 293 premenopausal participants in the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study.

For this analysis, the women with PME (n = 191) were compared with those without (n = 102) for frequency of mood episodes and symptoms of depression and mood elevation.

In addition, time to relapse was assessed in the 129 women (51.2% with PME) who were considered recovered from BD at baseline.

Marker for Course of Illness

Results showed that the women with PME had significantly more premenstrual mood symptoms than the women without PME (P < .001) and these symptoms were more likely to interfere with work or school (P < .001). They also had higher total depressive symptom and mood elevation scores.

In addition, the PME group experienced more mood episodes overall (P = .02) and more depressive episodes (P < .001) specifically but not more manic or hypomanic episodes.

They were also more likely to have 1 to 3 mood episodes per year compared with those without PME (73.8% vs 55.9%).

When including "subsyndromal episodes as part of a broader definition of relapse," the researchers found that the PME group had a median time to relapse of 4.5 months vs 8.5 months for the non-PME group.

These women were also at greater risk for relapse (hazard ratio, 1.7; P = .04). However, "this association was not significant after adjustment for retrospectively reported rapid cycling.

"Taken together, these findings suggest that [PME] may be a marker for a more recurrent and symptomatic course of illness among premenopausal women with BD. The results...reinforce the importance of characterizing the fluctuations of mood symptoms across the menstrual cycle," write the study authors.

"Maybe the point is to pay more attention to what we call subthreshold mood episodes; it is not about just having symptoms in the luteal phase," added Dr. Dias.

He reported that "the next challenge" is to conduct new research that follows up women with BD prospectively to observe their mood changes, as well as treatment impact.

"We still don't have answers about how to treat these changes. Although some studies have pointed out that women who are good responders to mood stabilizers have less mood fluctuations at the luteal phase, the exact impact of these findings is unknown," said Dr. Dias.

Exciting First Step

Dr. Jennifer L. Payne

"I think the main gist of the study is that it supports the idea that the best prevention against future illness is to get fully well. And [PME] is 1 example among many of how people with bipolar disorder do not always get fully well," Jennifer L. Payne, MD, assistant professor of psychiatry at Johns Hopkins School of Medicine in Baltimore, Maryland, and director of the Johns Hopkins Women's Mood Disorders Center, told Medscape Medical News.

"We know that in major depression, people with residual symptoms are more likely to relapse even if they have a response to medication. And I think we can look at this study from that perspective," added Dr. Payne.

She noted that "one thing that complicates interpretation" of the results is that the investigators did not prospectively confirm PME in the participants.

"It's been shown in multiple studies that women who report premenstrual mood symptoms don't always demonstrate these symptoms if you follow them prospectively. A period is something that women relate things to and that may or may not always be accurate."

She also pointed out that whether the worse course of illness was directly related to hormonal fluctuations triggering exacerbation of the mood disorder or not remains unclear.

"That said, from a clinician's perspective, if you have a woman who is reporting PME, you may need to work a little harder to get her fully well."

Although it's been talked about some over the years, it's high time that we look at the differences between men and women with bipolar disorder. This study is starting to do that and displays some of the complexities of treating women with mood disorders.

Dr. Payne, who wrote an editorial that will accompany this study when it is published in the journal's print edition, said she would like to see the investigators continue to follow up these women prospectively, confirm whether or not they actually have PME, and then look at whether those with PME are more treatment resistant.

"It is unclear if these women are just partially treated and that's why they're reporting exacerbation or if they're resistant to treatment. For example, the PME could be a marker for not being able to fully respond to the medications that we have available right now. But we simply don't know that at this point."

She went on to call the study both "exciting" and "a good first step."

"Although it's been talked about some over the years, it's high time that we look at the differences between men and women with bipolar disorder. This study is starting to do that and displays some of the complexities of treating women with mood disorders," concluded Dr. Payne.

The STEP-BD project is funded by the National Institute of Mental Health. The study authors have disclosed several financial relationships; the full list can be found in the original article. Dr. Payne has disclosed no relevant financial relationships.

Am J Psychiatry. Published online February 15, 2011.

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