Hal Elliott, MD

Premenstrual dysphoric disorder (PMDD) is a distinct cyclical disorder in which women experience distressed mood and behavioral symptoms in the late luteal or premenstrual phase of their menstrual cycle. PMDD is the most extreme or severe form of premenstrual syndrome (PMS).

Women with PMDD experience marked dysphoria, irritability, mood lability, anxiety, fatigue, change in appetite, and the subjective sense of feeling overwhelmed; the most common complaint is irritability. While up to 75% of women will experience physical and emotional symptoms before their menses and 12.6% to 31% will experience symptoms significant enough to describe as moderate to severe PMS, only 3% to 8% will experience symptoms severe enough to qualify for a diagnosis of PMDD.

Although there has been some debate as to the unique nature of PMDD, there now appears to be a consensus that PMDD is a separate and distinct psychiatric and medical syndrome and not merely an exacerbation of an underlying psychiatric disorder.

 The biological basis of PMDD is supported by twin studies indicating that PMDD is inherited

 and by studies indicating that medical or surgical suppression of ovulation will eliminate premenstrual symptoms.

 In addition, the predictable cyclical recurrence and remission of symptoms is further evidence of PMDD as a biologically driven syndrome.

Diagnosis of PMDD is based on having at least 5 of the following symptoms present in the postovulatory period before menses: depressed mood, anxiety, affective lability, irritability, decreased interest in usual activities, decreased concentration, lack of energy, change in appetite (increased or decreased), change in sleep pattern (increased or decreased), sense of feeling overwhelmed, and physical symptoms (breast tenderness, bloating, headache, joint or muscle pain). Essential to diagnosis is the presence or absence of symptoms in different phases of the menstrual cycle and that the symptoms are severe enough to interfere with social or occupational functioning. Women with PMDD typically will have onset of symptoms in the last 1 to 2 weeks of their menstrual cycle and then remission of symptoms by the end of menstrual flow. Occasionally, there will be an increase in PMDD symptoms at ovulation; however, symptoms generally will begin in a fairly predictable pattern linked to the luteal, or postovulatory, phase of the cycle and remit after menses begins or ends.

Because patients can misinterpret or overemphasize symptoms as relating to their menstrual cycle, it can be useful to have them chart their symptoms throughout the month. There are multiple instruments used to chart symptoms, including the Daily Rating Form, the Menstrual Distress Questionnaire, the Premenstrual Assessment Form, the Calendar of Premenstrual Experiences, the Premenstrual Symptoms Screening Tool, and the Prospective Record of the Impact and Severity of Menstrual Symptoms calendar. All of these instruments aid in identifying and quantifying the timing and impact of symptoms during the menstrual cycle. Charting allows the clinician to differentiate PMDD from other psychiatric or medical disorders and to establish a cyclical basis for symptoms.

Many women report an exacerbation of other psychiatric disorders in the late luteal phase of their menstrual cycle. Depression, bipolar disorder, panic disorder, generalized anxiety disorder, and attention deficit disorder all can worsen in the premenstrual period; however, patients with a pure PMDD diagno- sis generally will have a remission of symptoms when they are not in the postovulatory period of their cycle. In addition to exacerbation of psychiatric disorders, premenstrual changes in hormone levels can exacerbate underlying medical conditions, such as migraine headache, irritable bowel syndrome, asthma, seizure disorders, and various endocrine disorders (eg, diabetes).

Other medical causes of dysphoria or PMS/PMDD should not be overlooked. A complete history should be obtained and a physical examination and routine laboratory tests should be performed to rule out other etiologies of premenstrual complaints. The differential could include hypothyroidism, autoimmune disorders, diabetes, anemia, parathyroid disorders, and endometriosis.

PMDD is closely linked to the hypothalamic-pituitary-gonadal (HPG) axis. However, there is no demonstrable gonadal hormone level abnormality in women with PMDD.

 Rather, it is more likely that women with PMDD have heightened CNS sensitivity to normal ovarian cycling of gonadal steroids.

Serotonin (5-HT) function has a reciprocal relationship with the HPG axis. As women with PMDD cycle through the late luteal phase of their menstrual cycle, availability of 5-HT is reduced. This reduction may trigger symptoms known to be associated with 5-HT depletion, such as irritability, dysphoria, impulsivity, and carbohydrate craving.

Several studies have implicated altered 5-HT function in women with PMDD. Blood 5-HT levels

 are reduced in patients with PMDD; in addition, acute depletion of tryptophan, a precursor of 5-HT, aggravates symptoms of PMS and PMDD.

Although dysregulation of 5-HT mediated through the HPG axis could be one cause of PMDD symptoms, there also is evidence that other neurotransmitters might play a significant role. Reduced g-aminobutyric acid (GABA) levels have been noted in patients with PMDD and PMS.

 Studies using naltrexone and naloxone have suggested a possible acute endogenous opioid withdrawal in the late luteal phase of the menstrual cycle, thus causing irritability and mood lability characteristic of such withdrawal.

Finally, the unusually rapid action of the SSRIs in PMDD has led to the theory that these agents perhaps work by a different mechanism in patients with PMDD than in patients with symptoms of depression or anxiety. Typically, SSRIs take 2 to 4 weeks to begin working in depressed patients. Allopregne- nolone, a metabolite of progesterone, decreases anxiety by binding to central GABA receptors. Women with PMDD have lower levels of allopregnenolone in the luteal phase of their menstrual cycle. In patients with PMDD, SSRIs may work by indirectly increasing allopregnenolone synthesis from progesterone. This may account for the rapid onset of action of the SSRIs in PMDD.

Regardless, it appears that most likely, PMDD is mediated by a complex interplay in the HPG axis and that the cause of symptoms is a central sensitivity to normal fluctuations of gonadal steroids as opposed to any peripheral gonadal hormonal level abnormality. Decreased availability of 5-HT and allopregnenolone centrally may cause heightened symptoms of dysphoria, irritability, and anxiety.

Therefore, treatment should focus on correcting or compensating for central sensitivity, or on stopping the cycle altogether as opposed to modifying the monthly hormonal cycle.

Currently, the SSRIs have the best evidence of effectiveness; they appear to be effective in up to 70% of patients with PMDD. Sertraline, fluoxetine, paroxetine, and citalopram all have controlled trial evidence of efficacy in the treatment of PMS and PMDD symptoms.

As noted above, the SSRIs work rapidly in the treatment of PMS/PMDD symptoms-much more quickly than they do for treatment of depression, panic disorder, or obsessive-compulsive disorder. Because women often see improvement in the first day or two after beginning treatment with an SSRI, there have been several studies investigating whether SSRIs work for PMDD when taken only in the late luteal phase. Indeed, it appears that SSRIs are effective for PMDD when taken only in the week or so before menses. In fact, a 1998 study by Wikander and colleagues

 suggested that intermittent dosing of citalopram might be better than continuous dosing for the treatment of PMDD symptoms. Intermittent/postovulatory dosing can also decrease the impact of adverse effects of SSRIs, including ongoing sexual dysfunction or weight gain.

Of note is that it does not appear that non-serotonin-enhancing antidepressants, such as bupropion or the standard tricyclics, are effective in the treatment of PMS/PMDD symptoms.

While SSRIs target central sensitivity to menstrual cycling, ovulation suppression strategies focus on halting the menstrual cycling. Gonadotropin- releasing hormone (GnRH) agonists act centrally on the hypothalamus, causing anovulation by decreasing follicle-stimulating and luteinizing hormone levels, which, in turn, decreases estrogen and progesterone synthesis. While there is evidence of some efficacy of GnRH agonists in women with PMDD, they do not work as well in women with severe dysphoria in the late luteal phase or who have exacerbation of preexisting major depression in the late luteal phase.

Danazol has also been studied in the treatment of PMDD/PMS. Results for use of danazol have been mixed, but a positive response appears to be linked to suppression of ovulation.

 However, use of danazol has been linked to adverse effects such as acne, facial hair, weight gain, and depression. In addition, long-term reduction of estrogen is linked to decreased bone density.

Other proposed treatments for PMS/ PMDD have included oral contraceptives and the addition of progesterone in the luteal phase. Despite widespread use of standard oral contraceptives as treatment of PMS/PMDD symptoms, there is no real evidence of efficacy. In fact, there is at least 1 study indicating a worsening of PMDD symptoms with the continuous use of 21- to 28-day oral contraceptives.

 Because of the anxiolytic properties of allopregnenolone, there has been interest in the addition of its precursor, progesterone, in the luteal phase; however, several controlled trials have not shown addition of progesterone in the postovulatory phase to be more effective than placebo.

A relatively new oral contraceptive containing low-dose estrogen and dro- spirenone apparently reduces water retention and some symptoms of PMDD.

 In addition, new longer-duration oral contraceptive pills (levonor- gestrel/ethinyl) can decrease the number of menstrual periods to between 1 and 4 times per year. While there might not be a decrease in intensity of symptoms, a decrease in frequency may be a useful option.

Because of their action on GABA, benzodiazepines have been studied in the treatment of PMS/PMDD symptoms. The results have been mixed, with some studies showing mild efficacy and other studies not showing any superiority of alprazolam over placebo. Several studies showed mild improvement in severe PMS symptoms with the addition of low-dose alprazolam, but the improvement rate appears to be significantly less than it was for the SSRIs. Furthermore, alprazolam should be used with caution in patients with a history of substance abuse. Because benzodiazepines may cause disinhibition in some patients, they should be used with caution in patients with a history of impulse control difficulties.

Results of studies with vitamin and mineral supplements have also been mixed, with the best evidence of efficacy having been demonstrated with calcium supplementation. A large 1998 study using calcium carbonate showed a 48% improvement rate compared with 30% with placebo.

 While this rate of response is less than that for SSRIs, calcium carbonate is an inexpensive and nonintrusive option for treatment of PMS/PMDD symptoms.

 has received attention for treatment of PMS. Again, the results of controlled trials have been mixed, showing perhaps a very mild benefit at daily doses of 50 to 100 mg. Doses of B

 should be kept in the 50- to 100-mg range to minimize the risk for the neurotoxicity that can occur at higher daily doses.

There has been at least 1 study indicating improvement in PMDD symptoms with magnesium supplementation, but a more recent study indicated improvement only in fluid retention.

There has been significant interest in herbal treatments of PMDD, such as oil of primrose or St. John's wort. Despite this interest, there has not been significant proof of efficacy for herbal treatments in randomized clinical trials.

 However, the results of a prospective, randomized, placebo-controlled study of 170 women indicated some efficacy for treating PMDD with 

Nonmedication interventions, including dietary recommendations, exercise, and cognitive and relaxation therapy, can also be of significant benefit. An increase in complex carbohydrates, a decrease in caffeine and tobacco, and more frequent meals in the premenstrual phase can be helpful. Carbohydrate craving in the premenstrual period may be an attempt to increase tryptophan, a precursor of serotonin. Exercise may also increase endogenous endorphin levels, alleviating anxiety and dysphoria. Finally, both relaxation techniques and cognitive-behavioral therapy have been reported as effective in relieving PMS/PMDD and in improving coping mechanisms for the core symptoms.

 suggests steps for a reasonable approach to a patient reporting severe PMS or PMDD.

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Hal Elliott, MD

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