Premenstrual Dysphoric Disorder

DEFINITION AND ETIOLOGY

Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome (PMS) that causes marked social impairment in approximately 5 of 100 women. Women present with multiple physical and behavioral symptoms including fatigue, irritability, bloating, anxiety, breast tenderness, and mood lability which occur exclusively in the 10 to 14 days before menses. The exact cause of PMDD is unknown, but it is believed that the normal cyclic fluctuation of hormone levels in the menstrual cycle leads to symptoms.

PREVALENCE AND RISK FACTORS

PMS is a common condition that affects as many as 75% of menstruating women. It is characterized by a myriad of physical and behavioral symptoms that occur repetitively in the luteal phase of the menstrual cycle. Women with PMS often describe feelings of anger, fatigue, abdominal bloating, irritability, anxiety, breast tenderness, changes in appetite and sleep, and headaches. These symptoms usually do not preclude a woman from performing her day-to-day activities.

On the other hand, a very small subgroup of women (3%-8%)¹ in their late 20s to mid-30s suffer from a severe form of PMS that is serious enough to interfere with their daily functioning and personal relationships. These women suffer from PMDD, a condition first defined in 1987 in the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) and subsequently modified in 2000 in the manual’s fourth revised text edition (DSM IV-TR).

Some women are more prone to PMDD, including women in their 20s to mid-30s,² women with a prior history of mood disorders³ and women with low parity (fewer pregnancies lead to additional hormone exposure from more menstrual cycles).⁴ Genetic and psychosocial factors may also cause increased risk to develop PMDD.³

PATHOPHYSIOLOGY

A number of theories have been suggested to explain PMDD, but the most current theory suggests that cyclic changes in ovarian steroids interact with central neurotransmitters to create symptoms of PMDD.³ In other words, normal ovarian function rather than hormone imbalance is the inciting factor for PMDD-related biochemical events in the central nervous system.^3,⁵ Serotonin is the neurotransmitter most studied in PMDD, although there is likely a role for gamma-aminobutyric acid (GABA) and β-endorphin. Deficiencies of trace elements may also be implicated.

Ovarian Steroids

In 1984, Muse and associates ⁶ studied the effects of medical ovariectomy using the gonadotropin-releasing hormone (GnRH) agonist leuprolide, which led to resolution of symptoms by eliminating the fluctuation of ovarian hormones. In the 6-month study of eight patients, symptoms resolved with GnRH treatment, but recurred when the medication was withdrawn.⁶ However, cyclic changes in ovarian steroids may not be the sole explanation for symptoms in PMDD. Estrogen and progesterone levels of control subjects and women with premenstrual symptoms have been shown to be the same, suggesting that affected women may have an abnormal response to normal hormone levels.⁶

Neurotransmitters

The three main neurotransmitters implicated in PMDD are serotonin, GABA, and β-endorphin. Evidence currently suggests a leading role for altered serotonin levels in the etiology of PMDD. Central serotonin levels are typically low in women with PMDD, and symptoms worsen with depletion of the serotonin precursor tryptophan.^7,⁸ Notably, many women report benefiting from selective serotonin reuptake inhibitors (SSRIs). The role of GABA has not been clearly defined, but some women improve with the GABA agonist alprazolam. Differences in β-endorphin levels between the periovulatory and premenstrual phases remain unconfirmed.

Vitamins and Minerals

Several attempts to link vitamin and mineral deficiencies with PMDD have been inconclusive. No observable differences have been found in levels of vitamin A, vitamin E, or vitamin B₆ in affected or unaffected women. Treatment with vitamin B₆ supplements has shown inconsistent results. Additionally, initial studies suggested that women with PMDD may have lower levels of magnesium,⁹ although subsequent studies have not confirmed this finding.¹⁰ Calcium levels may also be low in the premenstrual phase.¹¹

DIAGNOSIS

PMDD is accurately diagnosed with a thorough history and physical examination and by excluding other causes for the patient’s symptoms. The history must review psychiatric disorders in the patient and her family. The clinician should distinguish PMDD from other psychiatric disorders with premenstrual exacerbation. Symptoms should be limited to the luteal phase (second half) of the menstrual cycle, and the patient must be symptom free in the follicular phase (first half). Symptoms also must be of such magnitude that they markedly impair the woman’s day-to-day functioning. Women must also not be on hormones, including oral contraceptives.

DSM-IV Criteria

The DSM-IV criteria published in 2000 by the American Psychiatric Association are most commonly used for the diagnosis of PMDD. The presence of five or more of the following symptoms, which must be documented by the patient in most menstrual cycles during the past 12 months, is required to make the diagnosis of PMDD. These symptoms must be present most of the time in the week before menses and resolve in the first few days after menses begins. Also, one of the five symptoms must be one of the first four listed.¹²

• Marked depression with feelings of hopelessness

• Marked anxiety or tension (patient feels wound up or on edge)

• Marked affective lability (patient gets tearful suddenly or becomes more sensitive)

• Irritability, anger, and increased interpersonal conflicts

• Decreased interest in activities of daily living, which may include social withdrawal (work, school, friends, or family)

• Fatigue and decreased energy level

• Appetite changes (overeating or cravings)

• Hypersomnia or insomnia

• Feeling out of control or overwhelmed

• Difficulty with concentration

• Somatic symptoms such as abdominal bloating, breast tenderness, headaches, or joint pain

Additionally, symptoms must be severe enough to interfere with one’s usual activities and relationships and should be confirmed by prospective daily charting for at least two to three menstrual cycles. The clinician should also be aware that symptoms may be superimposed on an underlying psychiatric disorder, although the symptoms may not be an exacerbation of another disorder (Box 1).¹²

Box 1 Criteria for the Diagnosis of Premenstrual Dysphoric Disorder

Modified with permission from Diagnostic and Statistical Manual of Mental Disorders: DSM IV-TR, 4th ed. Washington, DC, American Psychiatric Association, 2000.

Symptoms begin 1 wk before menses and resolve in the first few days after menses begins (must occur during most menstrual cycles in the past 1 year).