Introduction

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

It is common for women to experience changes in mood and to have physical symptoms such as pain and bloating in the one to two weeks leading to their menstrual period. However, although up to 75% of women will experience physical and emotional symptoms before their menses and 12.6%–31% will experience symptoms significant enough to describe as moderate to severe PMS, only 3%–8% will experience symptoms severe enough to qualify for a diagnosis of PMDD.[1]

Scope of the problem

Although there had 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 disorder.[2] PMS/PMDD is more likely to occur in women who have histories of abuse, who have histories of mood disorders, or who have a histories of anxiety disorders. The biological basis of PMDD, however, is supported by twin studies indicating that PMDD is inherited[3] and by studies indicating that medical or surgical suppression of ovulation will eliminate premenstrual symptoms.[4, 5] Menstrual mood disorders are associated with blunted sympathetic reactivity to stress but to a heightened autonomic reactivity to auditory stimuli. In addition, the predictable cyclical recurrence in relation to the menstrual cycle and the remission of symptoms during that cycle is further evidence of PMDD as a distinct and biologically driven syndrome.[6]

Diagnosis

The diagnosis of PMS/PMDD is based on the presence of at least five of the following symptoms during the postovulatory period prior to 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 PMS/PMDD typically will have onset of their symptoms in the last one to two weeks of their menstrual cycle with remission of their symptoms by the end of the menstrual flow. Occasionally, there will be an increase in PMS/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, underemphasize, or overemphasize symptoms as relating to their menstrual cycles, it can be quite useful to have them chart their symptoms throughout the month. Multiple instruments can be 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 establish a cyclical basis for symptoms. Alternatively, the clinician can direct patients to rate their symptoms on a simple scale of one to five or one to ten in terms of pain or mood symptoms. The key is to have a scale of symptoms related to a patient’s menstrual cycle in order to correlate symptoms with that cycle.

In addition to PMS/PMDD, 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 symptoms all can worsen in the premenstrual period. The difference is that patients with a pure PMDD diagnosis generally will have a full remission or nearly full remission of their symptoms when 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 such as diabetes.[7, 8]

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

Etiology

PMS and PMDD are closely linked to the hypothalamic-pituitary-gonadal (HPG) axis. Although women might ask for their “hormone levels” to be checked, there is no demonstrable gonadal hormone level abnormality in women with PMS and PMDD.[9] Rather, it is more likely that women with PMS and PMDD have heightened central nervous system (CNS) sensitivity to normal ovarian cycling of gonadal steroids. Sensitivity exists to the change in hormone levels throughout the menstrual cycle as opposed to any measurable ongoing abnormality in any specific gonadal hormone.

Serotonin (5-HT) functions in a reciprocal relationship with the HPG axis. As women with PMS and PMDD cycle through the late luteal phase of their menstrual cycle and progesterone levels drop, availability of 5-HT is reduced. This abrupt reduction in serotonin could trigger symptoms known to be associated with 5-HT depletion. Symptoms of serotonin depletion include irritability, dysphoria, impulsivity, and carbohydrate craving.[10]

Several studies have implicated altered 5-HT function in women with PMDD. Blood 5-HT levels and platelet uptake of 5-HT are reduced in patients with PMDD.[9, 11] In addition, acute depletion of tryptophan, a precursor of serotonin, aggravates and precipitates symptoms of PMS/PMDD in women who have had PMS/PMDD symptoms in the late luteal phase.[12]

Although dysregulation of serotonin mediated through the HPG axis could be one cause of PMS and PMDD symptoms, there also is evidence that other neurotransmitters could play a significant role. Reduced gamma-aminobutyric acid (GABA) levels have been noted in patients with PMDD and PMS.[13] 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.[14, 15] Women with PMDD given the opiate antagonists naltrexone and naloxone during the nonluteal phase of their cycle experience irritability and mood lability similar to premenstrual symptoms experienced in the late luteal phase.

Finally, the unusually rapid action of the selective serotonin reuptake inhibitors (SSRIs) in PMS/PMDD has led to the theory that these agents perhaps work by a different mechanism in patients with PMS/PMDD than in patients with symptoms of depression or anxiety. Typically, SSRIs take two to four weeks to begin working in depressed patients and up to four to six weeks to show full effect. Patients with PMS/PMDD can see improvement in symptoms within days of beginning or increasing their prescribed SSRI.

Allopregnenolone, a metabolite of progesterone, decreases anxiety by binding to central GABA receptors. Women with PMDD have lower levels of progesterone and alloprognenolone in the luteal phase of their menstrual cycle. In PMDD patients, SSRIs might work by indirectly increasing allopregnenolone synthesis from progesterone. This may account for the rapid onset of action of the SSRIs in patients with PMS/PMDD.[16, 17]

Regardless, it appears that most likely PMDD is mediated by a complex interplay within 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 serotonin and allopregnenolone centrally may cause heightened symptoms of dysphoria, irritability, and anxiety.

Therefore, treatment should focus on the correction or compensation for central sensitivity or on stopping the fluctuations in gonadal hormones altogether instead of just modifying the existing monthly hormonal cycle.

Treatment

Currently, the SSRIs have the best evidence of efficacy and appear to be effective in up to 70% of patients with PMDD. Sertraline, fluoxetine, paroxetine, citalopram, and escitalopram all have controlled trial evidence of efficacy in and are approved by the FDA for the treatment of PMS and PMDD symptoms.

As noted earlier, SSRIs work rapidly in the treatment of PMS/PMDD symptoms and much more quickly than for treatment of depression, panic disorder, or obsessive-compulsive disorder. Because women often see improvement in the first day or two after initiating therapy with an SSRI, several studies have investigated 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 one to two weeks before menses. In fact, a 1998 study by Wikander and colleagues suggested that intermittent dosing of citalopram might be better than continuous dosing for PMDD symptoms.[18]

Side effects for the SSRIs include weight gain and sexual dysfunction. Intermittent/postovulatory dosing can decrease the intensity and frequency of these side effects.

Other antidepressant medications that also have serotonin reuptake effects, such as venlafaxine and duloxetine and clomipramine, might be useful in treating PMS and PMDD symptoms. Note that nonserotonin enhancing antidepressants, such as bupropion or the standard tricyclics, do not appear to have efficacy in the treatment of PMS/PMDD symptoms. Lithium also is ineffective.

In May of 2007, the FDA proposed that all antidepressants carry a warning for a possible increase in suicidal thinking and behavior in patients between 18 and 24 years of age. The risk of suicidality is most likely greatest in the first several months of treatment, but clinicians should be aware of this risk and screen patients, especially in the 18–24 age range, while treating them for PMS/PMDD with antidepressant medication.

Although 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 (FSH) and luteinizing hormone (LH) levels, which, in turn, decreases estrogen and progesterone synthesis. Despite there being evidence of some efficacy in women with PMDD, GnRH agonists 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.[19]

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.[20] However, use of danazol has been linked to 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 luteal phase addition of progesterone. Despite widespread use of standard 21–28-day oral contraceptives as treatment of PMS/PMDD symptoms, there is no real evidence of efficacy. In fact, there is at least one study indicating a worsening of PMDD symptoms with the continuous use of 21–28-day oral contraceptives.[21] 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 the addition of progesterone in the postovulatory phase to be more effective than placebo.[22]

The addition of androgen hormones has been associated with worsening of PMS/PMDD symptoms.

A relatively new oral contraceptive containing low-dose estrogen and drospirenone apparently reduces water retention and some symptoms of PMDD.[23] In addition, newer, longer duration oral contraceptive pills (levonorgestrel/ethinol) can decrease the number of menstrual periods to between one and four times per year by continuing the hormone medication pills and decreasing the intervals of placebo pills. These newer preparations of oral contraceptives will deliver low-dose oral contraceptives more continuously and thereby suppress menstruation and late luteal phase symptoms. Although there might not be a decrease in intensity of symptoms when the late luteal phase does occur, a decrease in frequency might be a useful option and a welcome relief for patients suffering from significant PMS or PMDD.

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 failing to show 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 significantly less than the improvement rate for 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.

Buspirone, a novel anxiolytic with serotonergic properties, has shown some efficacy in decreasing or mitigating PMS-associated irritability and anxiety. Buspirone has the advantage of not causing disinhibition or dependency. However, it should be taken ongoing and not on an as needed basis.

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 with vitamin D showed a 48% improvement rate compared with 30% placebo.[24] The rate of response is less than that for SSRIs, but calcium carbonate with vitamin D is an inexpensive and nonintrusive option for treatment of PMS/PMDD symptoms.

Vitamin B₆ has received attention for treatment of PMS. Again, the results of controlled trials have been mixed, showing perhaps a very mild benefit at doses of 50 mg–100 mg daily. Doses of B₆ should be kept in the 50 mg–100 mg range to minimize the risk for the neurotoxicity that can occur at higher doses. There has been at least one study indicating improvement in PMDD symptoms with magnesium supplementation, but a more recent study indicated only improvement in fluid retention.[25]

Significant interest has been found with herbal treatments of PMDD, such as oil of primrose or St. John’s wort. Despite this interest, no significant proof of efficacy for herbal treatments in randomized clinical trials has been documented.[26] However, the results of a prospective randomized placebo-controlled study of 17 women indicated some efficacy for treating PMDD with Vites agnus castus (chaste tree).[27]

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.[28]