Update on Premenstrual Dysphoric Disorder (PMDD)

THE MONTHLY CYCLES associated with women’s reproductive systems have been a source of scientific curiosity for millennia. As far back as 3,800 years ago, the Kahun Gynaecological Papyrus described the experiences associated with menstruation — including back pain, migraines and heavy bleeding.1 And about 2,000 years after that, Hippocrates further described these symptoms.

In 1931, Robert T. Frank, MD, proposed that when these monthly symptoms are so severe as to intrude into a patient’s day-to-day life, it should be recognized as a condition he termed premenstrual tension. In 1953, the current term of premenstrual syndrome (PMS) was adopted.

While 90 percent of women will have at least some discomfort associated with their menstrual cycle — typically cramping, headaches and/or bloating2 — about three-quarters of all women will endure PMS at some point in their life, according to the Mayo Clinic.³

And while PMS is itself disruptive enough that there are numerous treatments available, for a smaller subset of women, their mental health symptoms surrounding their menstrual cycle are so severe that they make meeting the demands of daily life extremely challenging. This condition is known as premenstrual dysphoric disorder (PMDD). While first included in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) in 1994,⁴ the condition remains poorly understood, is likely underdiagnosed and is almost certainly poorly treated in too many cases.⁵

What Is PMDD?

PMDD, alongside PMS, is grouped as a premenstrual disorder. It is considered a more severe form of PMS and affects between three and eight percent of women.⁶

In the current fifth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-V), published in 2013, PMDD is categorized as a depressive disorder. The World Health Association’s International Statistical Classification of Diseases (11th edition) lists PMDD with other genitourinary diseases, although it is also cross-listed with depressive conditions.

While premenstrual disorders have been known to medical science for many centuries, even with advances in scientific rigor in the field during the 20th century, they were not afforded the same attention as other conditions. Diagnostic standards were haphazard and treatment uneven. Too often, patients were told it was “all in their head” or it was dismissed as female emotionalism.1 In response, in 2008, the International Society for Premenstrual Disorders was founded to bring consistency to the treatment of these conditions, including PMDD.⁵

One of the recurring debates regarding premenstrual disorders revolves around whether it makes sense to view these symptoms as a disorder, when many researchers and clinicians believe it is simply a natural variation in how women experience their menstrual cycles.⁵ This view holds that the pharmaceutical companies have a vested (and outsized) interest in expanding the definitions of “disorder” to increase diagnoses and, thus, prescribing of their products. (This roughly mirrors similar debates regarding both autism spectrum and attention deficit/hyperactivity disorder in which a significant number of clinicians feel normal, healthy individuals are being unnecessarily classified as having a disorder.)

Countering this view is the fact that women with PMDD are statistically more prone to suicide, making prompt diagnosis and treatment all the more important.⁷

What Causes PMDD?

As with PMS, the specific causes of the symptoms of PMDD are not yet well understood. Researchers have noted that many patients with PMDD have lower than normal levels of serotonin, which may be tied to how an individual’s body reacts to the natural hormonal changes associated with the menstrual cycle.⁸ This ties in with studies that have found women with PMS and PMDD have normal hormone levels — it is their body’s reaction to the hormones that causes the symptoms, not maladjusted hormone levels.⁹

In 2007, researchers at the National Institute of Mental Health performed genetic testing and analyses on women with PMDD and healthy control subjects and found variants in the estrogen receptor alpha gene are associated with PMDD. They discovered that this association is seen only in women with a variant form of another gene, catechol–o– methyltransferase, which is involved in regulating the function of the prefrontal cortex.10 (See the Physician Profile for more information about research findings surrounding genetics and PMDD.)

Diagnosing PMDD

If a patient presents with symptoms consistent with PMDD, referral to a mental health clinician may be warranted. The clinician will likely have the patient fill out the Premenstrual Symptoms Screening Tool, a 19-question form that allows the patient to quickly record how severe her symptoms are.¹¹ Other similar tools include the Calendar of Premenstrual Experiences,¹² the Daily Record of Severity of Problems13 and the Patient Reported Outcomes Measurement Information System.¹⁴

Making a diagnosis of PMDD is a four-step process under DSM-V:

1) Patient experiences five of the following 11 criteria:

• Feelings of depression or hopelessness
• Feeling tense or anxious
• Significant mood swings
• Persistent anger or irritability
• Lowered interest in normal activities
• Difficulty concentrating
• Fatigue or lethargy
• Change in appetite
• Change in sleep patterns
• Feeling overwhelmed or out of control
• Physical symptoms consistent with PMS: sensitive breasts, bloating, weight gain, joint pain, etc.

2) The symptoms are severe enough to interfere with school, work or personal life.

3) The symptoms are directly tied to the menstrual cycle — i.e., beginning around ovulation, and easing after menstruation begins.

4) This pattern is consistent for at least two consecutive menstrual cycles (if there is an inconsistency, then include a third cycle).

In addition, other possible explanations for the symptoms, including major depressive disorder, should be ruled out before making a diagnosis of PMDD. And even if symptoms are shown to be tied to the menstrual cycle, a separate diagnosis of depression can co-exist with PMDD.⁶

Treating PMDD

Because PMDD is tied to normal, natural cycles, the only cure for PMDD is menopause. And as the specific triggers that cause some women to have PMDD remain unknown, there is also no prevention for the condition.

Treatment of PMDD is aimed at reducing the severity of symptoms. Because PMDD is a chronic condition, treatment will likely last until the patient reaches menopause. And because PMDD involves both physical and psychological elements, primary care physicians should work with psychiatrists or psychologists in a team approach.

Treatment typically consists of a combination of lifestyle changes, medications and counseling.

The most effective lifestyle changes involve diet and exercise. Eating better, and perhaps increasing intake of complex carbs between ovulation and menstruation, is thought to play a role in increasing levels of serotonin.5 While the mainstream press has numerous articles touting various vitamin and mineral supplements as effective at treating PMDD, the scientific literature indicates the evidence is actually not clear on their effectiveness.

Moderate aerobic exercise has been shown to help improve mood, and helps increase overall health as well.15 However, these lifestyle changes take time to show results.

The typical first-line treatment for PMDD is anti-depressants. The class of anti-depressants used to treat PMDD are known as selective serotonin reuptake inhibitors (SSRIs), which can increase levels of serotonin in the brain. They include:

• Fluoxetine (Prozac, Sarafem)
• Paroxetine (Paxil, Pexeva, Aropax, Seroxat, Brisdelle)
• Sertraline (Zoloft)
• Escitalopram (Lexapro)
• Citalopram (Celexa)

The U.S. Food and Drug Administration (FDA) has approved the first three specifically to treat PMDD; the other two are widely used off-label. Other types of anti-depressants have not shown to be as effective as SSRIs.¹⁶

While some studies had indicated SSRIs could be effective if taken at the onset of symptoms, subsequent research indicates they are most effective for most patients when taken continuously, although dosages can be lower than for treating other conditions.¹⁷ Side effects can be intense (nausea, insomnia, fatigue, loss of sexual desire), and only half of patients prescribed SSRIs continue with them for more than six months.⁵

Other types of drugs used to relieve symptoms of PMDD are those that suppress ovulation. Both hormonal therapies and birth control pills will prevent monthly ovulation by altering the hormonal cycles, and they can be effective in preventing onset of PMDD. However, there is growing evidence that newer synthetic hormonal treatments are not as effective as earlier formulae.⁵

Since PMDD is classified as a form of depression, lifestyle changes, antidepressants and ovulation prevention will often be combined with ongoing therapy — particularly cognitive behavioral therapy (CBT). With this form of psychotherapy, a therapist leads the patient through a series of exercises to help her better control negative thoughts and worries.

While relatively few studies specifically look at CBT’s success in relieving PMDD symptoms, its well-documented success in treating other forms of depression and anxiety suggests further study is warranted and that patients are likely to benefit from it.¹⁸ And of the studies that have been conducted, results show an efficacy about equal to that of anti-depressants.¹⁹

Further, for those patients who find the side effects of the pharmacological treatments unbearable, CBT offers another option that can help them better deal with symptoms, including irritability, depression and anxiety. While CBT is known to provide relief for insomnia in other cases, its effectiveness for treating PMDD-related insomnia is less clear.²⁰

Finally, for patients with severe PMDD that does not respond to any of the above treatments, and if future children are not desired, surgical intervention to remove the ovaries may be considered. Before proceeding, it is generally recommended that drugs that suppress ovarian function be tried first to ensure it helps with the PMDD. While removal of the ovaries will bring about immediate menopause, hormone replacement therapy is often required after surgery to alleviate potential side effects.⁵

Looking Ahead

As with the entirety of the animal kingdom — all of life, in fact — the human body was designed to reproduce the species. PMDD is likely an accidental byproduct of natural selection, and thus physicians will likely be treating it for the foreseeable future.

However, our understanding of PMDD has increased dramatically over the past few decades. It is now known to be a real condition some women experience — not something imagined. That alone is a huge step forward that is allowing researchers to focus on more effective treatments to better balance symptom relief against potentially unpleasant side effects.

FDA’s clinicaltrials.gov database lists only a few dozen research projects into PMDD. But there are some novel approaches being explored. One study at the Tübingen University Hospital in Germany will compare inflammation and brain imaging in women with major depressive disorder and PMDD patients to see what differences (and commonalities) there are.²¹ Another is investigating the effect of acceptance and commitment therapy on PMDD.²² And a third, in Sweden, is exploring whether Internet-based online CBT can be effective at helping women gain effective control of emotional symptoms of PMDD.²³

As these and other studies come to fruition, physicians and therapists should have more effective treatments to help their patients tackle the symptoms of PMDD in years to come.