Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome (PMS) that causes marked social impairment in approximately 5 of 100 women. Women can present with multiple symptoms, such as fatigue, headache, feelings of hopelessness, irritability, and bloating. These occur exclusively in the 10 to 14 days before menses.

PMS is a common condition that affects as many as 75% of 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, headaches, and mood lability. These symptoms usually do not preclude a woman from performing her day-to-day activities.

A small subgroup of women (3% to 8%)¹ in their late 20s to mid-30s, however, 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 1994 in the manual's fourth edition (DSM-IV).

Table1:
Differences Between PMS and PMDD
	PMS	PMDD
Prevalence	75%	3-8%
Number of symptoms required	1	5 of 11
Diagnosis	ICD-10*	DSM-IV
Social impairment	Not required	Required
Prospective charting	Not required	Required
*International Statistical Classification of Diseases and Related Health Problems, 10th revision.

The exact cause of PMDD is unknown. The most current theory suggests that cyclic changes in ovarian steroids interact with central neurotransmitters to create symptoms of PMDD.² In other words, normal ovarian function rather than hormone imbalance is the inciting factor for PMDD-related biochemical events in the central nervous system.^2,3 Serotonin is the neurotransmitter most studied in PMDD, although there is likely a role for gamma-aminobutyric acid (GABA) and beta-endorphin. Deficiencies of trace elements also may be implicated.

Ovarian Steroids
In 1984, Muse et al⁴ studied the effects of medical ovariectomy using the gonadotropin-releasing hormone (GnRH) agonist leuprolide, which led to resolution of symptoms by eliminating fluctuation of ovarian hormones. 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.

Neurotransmitters
The three main neurotransmitters implicated in PMDD are serotonin, GABA, and beta-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 tend to be aggravated by depletion of the serotonin precursor tryptophan. Notably, many women report benefitting 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 beta-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 versus 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,^5,6 although subsequent studies have not confirmed this finding.^7,8

Accurate diagnosis of PMDD is based on a thorough history and physical examination and on exclusion of other potential causes for the patient's symptoms. The history must review psychiatric disorders in the patient and her family. The clinician should be aware that PMDD differs from major depression 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 1994 by the American Psychiatric Association are most commonly used for 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 occur 1 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:⁹

• Marked depression with feelings of hopelessness
• Marked anxiety or tension (patient feels "wound up" or "on edge")
• Marked affective lability
• Irritability, anger, and increased interpersonal conflicts
• Decreased interest in activities of daily living, which may include social withdrawal
• 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 usual activities and relationships and should be confirmed by prospective daily charting for at least two menstrual cycles. The clinician also should be aware that symptoms may be superimposed on an underlying psychiatric disorder, although they may not be an exacerbation of another disorder.^{9 See Table 2.}

Symptom Inventory
Several questionnaires can be used to record symptoms of PMDD, such as the Calendar of Premenstrual Experiences (COPE), the Moos Menstrual Distress Questionnaire (MDQ), the Premenstrual Assessment Form (PAF), and the Prospective Record of the Impact and Severity of Menstruation (PRISM). These forms are similar and are all cited in the literature. The patient should be advised to record her symptoms for at least 2 months using one of the symptom inventory forms to observe fluctuation of symptoms during the menstrual cycle. Recently, it has been suggested that there must be at least a 30% worsening of symptoms between the follicular and luteal phases within each cycle to diagnose PMDD, regardless of which assessment tool is used. The percentage of worsening is calculated by the formula:²

Referring a patient to a women's health psychiatrist may be indicated to evaluate for a mood or anxiety disorder if there is no symptom-free period.

Differential Diagnosis
Because PMDD is a diagnosis of exclusion, the clinician should rule out other conditions that may manifest similar signs or symptoms. Important differential diagnoses include:

• thyroid disorders
• migraine
• chronic fatigue syndrome
• irritable bowel syndrome
• seizures
• anemia
• endometriosis
• psychiatric disorders
• drug or alcohol abuse

Laboratory Testing
Initial laboratory testing should include a complete blood count, chemistry profile, and thyroid-stimulating hormone to evaluate for anemia, electrolyte abnormalities, and thyroid problems.

Multiple treatment options are available for PMDD; however, no single intervention is effective for all women. Initial treatment should begin with lifestyle changes and proceed to medications such as SSRIs; anxiolytics such as alprazolam and buspirone; ovulation suppressants such as GnRH agonists, danazol, and oral contraceptives (OCPs); and diuretics. Radical treatment, such as ovariectomy, may be indicated in PMDD cases refractory to medical treatment. Two studies have demonstrated complete resolution of symptoms in PMDD-affected patients after ovariectomy.^10,11 When considering ovariectomy in women of childbearing age, the clinician needs to remember that this drastic measure can increase the risk of cardiovascular disease and osteoporosis in the absence of adequate estrogen replacement therapy.

Lifestyle Modifications
Treatment should begin with a 2-month to 3-month trial of lifestyle changes while the patient charts her symptoms. Dietary changes, such as reducing salt, sugar, caffeine, dairy products, and alcohol, often aid in decreasing fluid retention, irritability, and bloating. Eating frequent and small portions of foods high in carbohydrates may improve symptoms; this is believed to occur by increasing relative tryptophan levels (a precursor in the serotonin pathway). Exercise, relaxation, and stress management also are recommended for a general state of well-being. Some women may benefit from yoga, which improves muscle flexibility and alleviates stress. If possible, women also can try to schedule their more challenging and stressful events during the follicular phase (as opposed to the luteal phase).

Selective Serotonin Reuptake Inhibitors
SSRIs are considered first-line pharmacologic treatment for PMDD. Studies have shown that intermittent luteal-phase dosing has fewer adverse effects and is just as effective as full-cycle dosing.^12-14 SSRIs have proved to be effective in more than 60% of treated patients.¹⁵

FDA-approved options for daily luteal-phase dosing include fluoxetine 10 mg/day to 20 mg/day and sertraline 50 mg/day to 150 mg/day. A recent study showed that fluoxetine may be efficacious when given at a dose of 90 mg once weekly for 2 weeks in the luteal phase.¹⁶ Paroxetine 10 mg/day to 30 mg/day and citalopram 5 mg/day to 20 mg/day also are used to treat PMDD.

Side effects of SSRIs include sexual dysfunction, insomnia, fatigue, nervousness, headache, and nausea. These agents have a fast onset of action-1 to 2 days-in the treatment of PMDD compared with their treatment of depression.

Alprazolam
Alprazolam, a GABA agonist, is a benzodiazepine anxiolytic that is effective for symptoms such as tension, anxiety, irritability, and hostility. Treatment can be initiated at 0.25 mg three to four times daily in the luteal phase and tapered one to two times daily at the onset of menses, finally stopping 1 to 2 days after menses begins. Due to the addictive potential of alprazolam, it is considered a second-line treatment.

Buspirone
Buspirone, a partial 5-H_T1 receptor agonist, has also been shown to be effective due to its anxiolytic properties. Unlike alprazolam, it is nonaddictive. Dosing may be given as 5 mg to 10 mg three times daily during the luteal phase.

GnRH Agonists
GnRH agonists also are effective in reducing PMDD symptoms. They downregulate GnRH receptors, causing a decrease in luteinizing hormone and follicle-stimulating hormone. This subsequently inhibits ovulation, which decreases estrogen and progesterone levels, thereby creating pharmacologic menopause. Treatment-limiting side effects include hot flashes, headaches, muscle aches, vaginal dryness, and irritability; therefore, this class of medication is reserved for patients with severe symptoms unresponsive to other medical treatment measures. GnRH agonists are expensive; they also have hypoestrogenic side effects, which causes concern for the development of osteoporosis. For this reason, they are not recommended for use longer than 6 months. If a GnRH agonist needs to be used for longer than 6 months, continued symptom relief can be provided by using add-back therapy with estrogen and progesterone.¹⁷

Danazol
Danazol is a weak synthetic androgen that suppresses ovarian steroid production by inhibiting luteinizing hormone and follicle-stimulating hormone secretion. It is given as 600 mg/day to 800 mg/day in divided doses. Danazol's use is limited due to multiple androgenic and antiestrogenic side effects, including amenorrhea, weight gain, acne, fluid retention, hirsutism, hot flushes, vaginal dryness, and emotional lability.

Oral Contraceptives
The efficacy of OCPs for the treatment of PMDD has not been established due to conflicting data, and more studies are indicated. Freeman et al¹⁸ showed that a unique OCP consisting of 30 µg ethinyl estradiol and 3 mg drospirenone (Yasmin) was beneficial for a number of symptoms, including bloating, breast tenderness, and swelling. The combination agent also has antiandrogenic properties that may relieve acne and hirsutism.

Bromocriptine
Bromocriptine, a dopamine agonist, is useful in decreasing mastalgia by lowering prolactin levels. It is dosed as 2.5 mg once daily just before ovulation until the onset of menses. Side effects may include dizziness and nausea.

Diuretics
Spironolactone is the diuretic most studied due to its antimineralocorticoid and antiandrogenic properties. Symptoms most likely to improve with spironolactone treatment include bloating, swelling, breast tenderness, and acne. It may be tried in dosages of 50 mg/day to 100 mg/day for 7 to 10 days during the luteal phase. Side effects, including lethargy, headache, and irregular menses, are more common during continuous dosing. Serum potassium levels should be monitored because spironolactone can cause hyperkalemia.

Other Medications
Nonsteroidal anti-inflammatory drugs (NSAIDs) are available over the counter and are effective for dysmenorrhea. Generic names include ibuprofen and naproxen. Meclofenamate (Meclomen), an NSAID available by prescription, can reduce menstrual cramps and flow. The typical dose is 100 mg twice daily. Acetaminophen may also be beneficial for pain.

Alternative Therapies
In today's modern era, women are likely to seek out other integrative therapies for PMDD. One large trial has shown that 1,200 mg of elemental calcium daily is effective in alleviating tension, anxiety, fluid retention, and food cravings.¹⁹ Physicians are often asked about vitamin supplementation; controlled studies with vitamin A, vitamin E, and vitamin B₆ have failed to consistently show a benefit. Although popular, herbal products are not FDA approved, and some have caused significant toxicities as well as drug-herb interactions. Other innovative therapies include acupuncture, biofeedback, homeopathy, massage, and light therapy.²⁰

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20. Kaur G, Gonsalves L, Thacker HL. Premenstrual dysphoric disorder: a review for the treating practitioner. Cleve Clin J Med. (Submitted 2003).

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