Premenstrual Dysphoric Disorder

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Practice Essentials

Premenstrual dysphoric disorder (PMDD) is a diagnosis used to indicate serious premenstrual distress with associated deterioration in functioning.

Essential update: Premenstrual dysphoric disorder and amygdala reactivity

Several studies indicate that progesterone levels and proneness to anxiety may influence amygdala reactivity to emotional stimulation in women with PMDD.

Researchers found that women with PMDD exhibit increased amygdala activity early in their cycles when progesterone levels are low. This data suggest that heightened emotional responses may be a vulnerability factor in PMDD.

In one study, 15 women with PMDD and 14 without the disorder underwent functional MRI scans and completed an emotional processing task. The women with PMDD had higher amygdala activations during the follicular phase of their menstrual cycles compared to women without PMDD but did not show higher activation in the luteal phase of their cycles.[1, 2]

Signs and symptoms

PMDD is characterized by depressed or labile mood, anxiety, irritability, anger, and other symptoms occurring exclusively during the 2 weeks preceding menses. Other symptoms may include the following:

The symptoms must be severe enough to interfere with occupational and social functioning, in contrast with the more common PMS. PMDD is a severely distressing and disabling condition that requires treatment.

See Clinical Presentation for more detail.

Diagnosis

The initial steps in evaluating a patient for premenstrual dysphoric disorder (PMDD) are aimed at excluding organic syndromes with manifestations similar to those of PMDD, such as thyroid disorders, anemia, perimenopause, and menopause. The role of laboratory studies is limited to screening for medical conditions considered in the differential diagnosis. Although some tests may be needed to reassure the patient, excessive testing can be counterproductive by making the patient more anxious.

Laboratory studies should include the following:

See Workup for more detail.

Management

Treatment of PMDD includes both nonpharmacologic and pharmacologic therapies.

Nonpharmacologic therapy

Options for nonpharmacologic therapy for PMDD include the following:

Pharmacologic therapy

Options for pharmacologic therapy for PMDD include the following:

The combination of drospirenone and ethinyl estradiol is approved by the United States Food and Drug Administration (FDA) for the treatment of PMDD symptoms in women who choose to use an oral contraceptive as their method of contraception.

Buspirone has been shown to be efficacious in the treatment of both premenstrual syndrome (PMS) and PMDD.[3, 4]

See Treatment and Medication for more detail.

Background

Premenstrual dysphoric disorder (PMDD) is a diagnosis used to indicate serious premenstrual distress with associated deterioration in functioning. Clinically significant premenstrual problems with mood and behavior have been recognized since ancient times.[5] Although Frank first described premenstrual syndrome (PMS) in the early 20th century,[6] PMDD is a relatively new concept.

PMDD is characterized by depressed or labile mood, anxiety, irritability, anger, and other symptoms occurring exclusively during the 2 weeks preceding menses. The symptoms must be severe enough to interfere with occupational and social functioning, in contrast with the more common PMS. PMDD is a severely distressing and disabling condition that requires treatment.

In October 1998, a panel of experts evaluated the evidence then available, and a consensus was reached that PMDD was a distinct clinical entity. Subsequently, in November 1999, the US Food and Drug Administration (FDA) Neuropharmacology Advisory Committee supported this concept. Since then, several treatment options for PMDD have been investigated and developed.

Pathophysiology and Etiology

Major theories developed to explain the pathophysiology of PMDD include the following[7] :

The ovarian hormone hypothesis suggests that PMDD is caused by an imbalance in the estrogen-to-progesterone ratio, with a relative progesterone deficiency. Accordingly, in the 1960s, PMS patients were treated with progesterone suppositories. However, later studies of estrogen and progesterone levels in women with PMS were inconclusive because of methodologic difficulties. The current consensus seems to be that normal hormonal fluctuations trigger central biochemical events related to PMDD symptoms in some predisposed women.

The serotonin theory hypothesizes that normal ovarian hormone function (rather than hormone imbalance) is the cyclical trigger for PMDD-related biochemical events within the central nervous system (CNS) and other target tissues.[8]

PMDD shares many of the phenomenologic features of depression and anxiety states that have been linked to serotonergic dysregulation. A growing body of evidence suggests that serotonin (5-hydroxytryptamine [5-HT]) also may be important in the etiology of PMDD. Decreased serotonergic activity in women with PMDD has also been implied by the observation of reduced platelet uptake of serotonin and serotonin levels in peripheral blood.

In women with PMDD, sensitivity to perturbations of the central serotonin system is altered premenstrually. The administration of the serotonin agonist m -chlorophenylpiperazine may induce mood elevation.[9] Agents that transiently diminish serotonin activity have been associated with behavioral changes, including irritability and social withdrawal.

The psychosocial theory hypothesizes that PMDD or PMS is a conscious manifestation of a woman’s unconscious conflict about femininity and motherhood. Psychoanalysts proposed that premenstrual physical changes reminded the woman that she was not pregnant and therefore was not fulfilling her traditional feminine role. Obviously, proving this theory through scientific evidence is quite difficult.

The cognitive and social learning theory hypothesizes that the onset of menses is an aversive psychological event for women susceptible to PMDD. Moreover, these women might have had negative and extreme thoughts that further reinforce the aversiveness of premenstrual symptoms.

Consequently, these women develop maladaptive coping strategies (eg, lability of mood, absence from school or work, and overeating) in an attempt to reduce the immediate stress. The immediate reduction of stress acts as a reinforcement, leading to the regular recurrence of symptoms during the premenstrual period.

Finally, the sociocultural theory hypothesizes that PMDD is a manifestation of the conflict between the dual roles society expects women to fill simultaneously—namely, productive workers and child-rearing mothers. PMDD is postulated to be a cultural expression of women’s discontent with the traditional role of women in the society.

Of these 5 theories, the serotonin theory is perhaps the most popular at present. Although genetic predisposition and societal expectations may play a role, the strongest scientific data implicate serotonin as the primary neurotransmitter whose levels are affected by ovarian steroid levels. Other neurotransmitter systems that have been implicated include the opioid, adrenergic, and gamma-aminobutyric acid (GABA) systems.[10]

Risk factors for PMDD include the following:

Epidemiology

United States statistics

Epidemiologic studies indicate that as many as 80% of women in the United States experience emotional, behavioral, or physical premenstrual symptoms.[11] Between 3% and 8% of women meet the diagnostic criteria for PMDD.

International statistics

Worldwide, PMDD affects 3-8% of women in their reproductive years,[12] imposing an enormous burden on women, their families, and the health care system. A study from India reported a frequency of 6%.[13] A population-based sample of Swiss women from the entire reproductive age range found that 3% of the sample population fulfilled criteria for PMDD.[14] A cross-sectional study of female Nigerian medical students showed that 36% of the respondents met the criteria for the diagnosis of PMDD.[15]

Age- and race-related demographics

Apparently, women in the late third to middle fourth decades of life are most vulnerable to experiencing PMDD. Although premenstrual clinics are reported to be almost exclusively attended by white women, community-based studies found no difference between black women and white women with respect to the prevalence or severity of premenstrual symptoms.

Some isolated reports indicate variations in individual symptoms—though not in the overall prevalence of premenstrual symptoms—among different racial groups. Black women tend to have a higher prevalence of food cravings than white women.[16] White women are more likely than black women to report premenstrual mood changes[17] and weight gain. Pain featured most highly in a sample of Chinese women in Hong Kong.[18]

Prognosis

PMDD is a multifactorial syndrome that occurs with varying degrees of severity and thus may have a range of potential adverse effects on work, social activities, and interpersonal relationships.

Upon treatment, symptoms tend to improve rapidly. After cessation of treatment, symptoms recur rapidly, and their reemergence is more predictable than that with major depressive disorder or dysthymia. After oophorectomy, however, symptoms usually do not recur.

Patient Education

Educate women to seek help for PMDD. Emphasize the following reasons why they should do so:

For patient education resources, see the Women’s Health Center, as well as Premenstrual Syndrome (PMS).

It is important to educate not only the patient but also the partner and family; this disorder has an impact on the entire family context. Useful Web sites for patients and their families include the following:

History

The most common primary symptom of premenstrual dysphoric disorder (PMDD) is irritability. The common symptoms of breast pain and bloating differ from those of women with a major depressive disorder.

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), established 4 research criteria (A through D) for the diagnosis of PMDD.[19]

Criterion A is that in most menstrual cycles during the past year, at least 5 of the following 11 symptoms (including at least 1 of the first 4 listed) were present:

The symptoms must have been present for most of the time during the last week of the luteal phase, must have begun to remit within a few days of the onset of menstrual flow, and must be absent in the week after menses.

Criterion B is that the symptoms must be severe enough to interfere significantly with social, occupational, sexual, or scholastic functioning. For example, the patient may avoid social activities or exhibit decreased productivity and efficiency at work or school.

Criterion C is that the symptoms must be discretely related to the menstrual cycle and must not merely represent an exacerbation of the symptoms of another disorder, such as major depressive disorder, panic disorder, dysthymic disorder, or a personality disorder (although the symptoms may be superimposed on those of any of these disorders).[20]

Criterion D is that criteria A, B, and C must be confirmed by prospective daily ratings during at least 2 consecutive symptomatic menstrual cycles. The diagnosis may be made provisionally before this confirmation.

Of the 11 symptoms listed in DSM-5, 10 are emotional and behavioral in nature; only 1 includes multiple common physical symptoms. Thus, PMDD defines a narrow group of women with the most severe premenstrual emotional symptoms, with functional impairment, and without a concurrent Axis I or Axis II disorder that is exacerbated premenstrually.

Women who meet the PMDD criteria are coded on Axis I as depressive disorder not otherwise specified. Obviously, this classification excludes many women presenting with predominantly physical premenstrual symptoms or with premenstrual exacerbation of underlying Axis I or II disorders. The DSM-5 criteria do state that PMDD may be superimposed on Axis I or II disorders; however, it is not clear how to differentiate between exacerbation of an Axis I or II disorder and superimposition on the symptoms of such a disorder.

Because depression is a common symptom of PMDD, suicide is a risk. A case-control study of fertile females with regular menstrual cycles who attempted suicide (with blood donors used as controls) showed that attempts during the luteal phase were no more frequent in females with PMDD than in those without.[21] However, PMDD was more prevalent in those who attempted suicide than in those who did not. This suggests that PMDD may not be associated with suicidal acts during the luteal phase, when premenstrual symptoms are present.

Several scoring systems are available for symptom quantification. It has been suggested that a within-cycle increase from follicular to luteal phase score (demonstrating “on-offness”) of at least 50% is necessary to confirm the diagnosis of PMDD and to warrant psychopharmacologic intervention. The within-cycle percentage change is calculated by subtracting the follicular score from the luteal score divided by the luteal score and multiplying the result by 100, as follows:

[Luteal score – (follicular score/luteal score)] × 100

More than 60 instruments have been used for symptom recording. Visual analog scales have been used in some studies. It is also common to score symptoms on a Likert scale ranging from “not present” to “severe.” A 24-item form called the Daily Record of Severity of Problems incorporates all of the DSM-5 symptoms of PMDD. As might have been expected from the large number of scoring instruments in use, a review of the scoring methods used in most studies did not find any of them to offer unique advantages.

Physical Examination

The findings from the physical examination are usually unremarkable. Mild swelling of the ankles, feet, and fingers may occur secondary to fluid retention. Breast tenderness may be present.

A Mental Status Examination (MSE) may be abnormal only during the latter part of the luteal phase as described below. The following findings usually are not apparent during other phases of the menstrual cycle

Laboratory Studies

The initial steps in evaluating a patient for premenstrual dysphoric disorder (PMDD) are aimed at excluding organic syndromes with manifestations similar to those of PMDD, such as thyroid disorders, anemia, perimenopause, and menopause. The role of laboratory studies is limited to screening for medical conditions considered in the differential diagnosis. Although some tests may be needed to reassure the patient, excessive testing can be counterproductive by making the patient more anxious.

Laboratory studies should include the following:

Approach Considerations

Treatment of premenstrual dysphoric disorder (PMDD) includes both nonpharmacologic and pharmacologic therapies. Nonpharmacologic therapy includes aerobic exercise, consumption of complex carbohydrates and frequent meals, relaxation training, light therapy, sleep deprivation, and cognitive-behavioral therapy (CBT). The efficacy of lifestyle interventions (eg, diet, exercise, and vitamin supplementation) and psychotherapeutic interventions for PMDD remains unclear.[12]

Nonpharmacologic Therapy

Acupuncture

In a systematic review of 10 trials with methodologic limitations comparing acupuncture versus sham acupuncture, medication, or no treatment for premenstrual syndrome, acupuncture was associated with improved symptoms compared with any control in an analysis of 8 trials with 429 patients. However, important methodological limitations in the included trials weakened the evidence.[22]

Relaxation techniques

The relaxation response is a physiologic response that results in decreased metabolism, a lower heart rate, reduced blood pressure, a lower rate of breathing, and slower brain waves. The repetition of a word, sound, prayer, phrase, or muscular activity is required to elicit the relaxation response.

Most studies of relaxation techniques have used them as adjuncts to other modalities of therapy. Available trials of relaxation treatment showed conflicting results. In one study, twice-daily relaxation therapy yielded greater improvement in physical symptoms of PMDD than keeping a daily symptoms chart and leisure reading.[23] In another study, relaxation therapy was less effective than coping skills training.

Light therapy

The light emitted by conventional fluorescent lamps is deficient in many of the colors and wavelengths of natural sunlight. The basis of light therapy is replacing such lamps with full-spectrum fluorescent lamps whose light (referred to as bright light) is more similar to sunlight. The effect of bright light was postulated to be mediated through the serotonin system.

A randomized, double-blind, counter-balanced, crossover study of dim red light therapy versus bright white light therapy in women who met Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) criteria for late luteal phase dysphoric disorder (LLPDD) showed that the bright light condition significantly reduced depression and premenstrual tension scores during the symptomatic luteal phase in comparison with baseline values, whereas the dim light condition did not.[24]

A systematic review summarized the evidence from 4 randomized clinical trials of bright light therapy for treatment of PMDD in 55 subjects.[25] All 4 trials reported that bright light therapy was effective in reducing depressive symptoms. However, these conclusions were based on the differences between baseline and posttreatment scores within the treatment phase rather than the differences between end-of-treatment and end-of–control phase results, which would have been a more appropriate comparison.

One fully unblinded trial showed a much larger effect than the other 3.[25] The pooled effect size from the random-effects model of the 3 higher-quality trials was –0.20, which did not reach the level of statistical significance.

It was concluded that the small sizes, the correspondingly wide confidence limits, and the methodologic limitations of the trials did not permit definitive conclusions regarding the impact of bright light therapy on premenstrual depressive symptoms.

Sleep deprivation

Most patients with major depressive disorder respond to a night of total sleep deprivation. Because of the relation of this disorder to PMDD, treatments for major depressive disorder may also be effective for PMDD.

A randomized crossover trial comparing early-night sleep deprivation with late-night sleep deprivation in research subjects with PMDD found that both early and late sleep deprivation significantly reduced depressive symptoms after a night of recovery sleep but not after a night of sleep deprivation.[26] The healthy comparison subjects showed no clinically important mood changes. The efficacy of sleep deprivation in reducing depressive symptoms in PMDD parallels its efficacy in major depressive disorder.

Cognitive-behavioral therapy

Cognitive therapy is based on the view that behavioral disorders are influenced by negative or extreme thought patterns, which are so habitual that they become automatic and are unnoticed by the individual. Cognitive treatment teaches patients ways of examining these negative patterns and replacing them with more adaptive ways of viewing life events. CBT for PMDD includes anger control, thought stopping, and reduction of negative emotions through cognitive restructuring.

Although randomized controlled trials have shown CBT to be effective,[27] the results are not consistent across the trials. One systematic review and meta-analysis showed that CBT significantly reduces both anxiety and depression and suggested a possible beneficial effect on behavioral changes and interference of symptoms with daily living.[28] However, the risk of bias is high because of weaknesses in trial design and implementation and possible reporting bias.

Another systematic review also revealed a dearth of evidence supporting the view that CBT exerts statistically significant interventional effects.[29]

Pharmacologic Therapy

Hormones

The combination of drospirenone and ethinyl estradiol is approved by the United States Food and Drug Administration (FDA) for the treatment of PMDD symptoms in women who choose to use an oral contraceptive as their method of contraception.

The effectiveness of drospirenone and ethinyl estradiol for treating PMDD when used for more than 3 menstrual cycles has not been evaluated. Drospirenone with ethinyl estradiol has not been evaluated for the treatment of premenstrual syndrome (PMS). Two multicenter, double-blind, randomized, placebo-controlled studies showed that women with PMDD who received drospirenone and ethinyl estradiol had statistically significantly greater improvements in their Daily Record of Severity of Problems scores.[30]

A systematic review of 14 randomized controlled trials found no improvement in premenstrual symptoms with progesterone as compared with placebo.[3] Of the 14 trials, 3 used oral progesterone and 11 used progesterone suppositories. Adverse effects included abdominal pain, nausea, headache, pruritus vulvae, dizziness, drowsiness, excessive vaginal bleeding, and dysmenorrhea.

The data from randomized controlled trials of synthetic progesteronelike drugs (medroxyprogesterone acetate and dihydrogesterone) for premenstrual symptoms are conflicting.[3] Adverse effects include nausea, breast discomfort, headache, and irregular uterine bleeding. Progestogens may induce premenstrual symptoms during hormone replacement therapy.

A limited number of studies found that estrogenic ovarian suppression with an estradiol transdermal patch or a subcutaneous implant may eliminate premenstrual symptoms. Adverse effects include breast discomfort, nausea, weight gain, headache, and skin pigmentation. Prolonged unopposed estrogen use may lead to endometrial hyperplasia and carcinoma. A 12-day course of local progesterone may be administered to avoid these complications.

Use of the levonorgestrel intrauterine device has been suggested by some to prevent the induction of premenstrual symptoms by systemic progestogens. Currently, there are no data to support the efficacy of this approach.

Danazol suppresses the ovarian cycle in most women. Many randomized, controlled trials found danazol to have beneficial effects on premenstrual symptoms.[3] However, it is important to keep in mind the risk of weight gain, hot flashes, vaginal dryness, emotional lability, and masculinization associated with danazol use; these adverse effects limit the use of this agent.

Randomized, controlled trials have shown the beneficial effect of gonadotropin-releasing hormone (GnRH) analogues on premenstrual symptoms.[31] However, use of GnRH analogues for more than 6 consecutive months carries a significant risk of osteoporosis secondary to the hypoestrogenic hormonal milieu. This phenomenon limits its usefulness on a long-term basis.

Limited data are available on the beneficial effect of bromocriptine in relieving breast tenderness.[32, 33, 34] Rare reports exist of stroke and death after bromocriptine treatment to suppress lactation.

Diuretics

Diuretics are used widely, under the assumption that many symptoms of PMS are secondary to fluid retention. Five randomized control trials that used spironolactone reported an improvement in premenstrual symptoms compared with placebo.[3] In 1976, Werch and Kane reported the beneficial effect of metolazone.[35] Adverse effects include nausea, dizziness, palpitations, excess diuresis, and weakness.

Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used. In 5 randomized, controlled trials, mefenamic acid yielded greater improvement of premenstrual symptoms (except breast pain) than placebo.[3] In a placebo-controlled trial, naproxen sodium was more effective than placebo for physical symptoms. Another trial reported significant improvement in mood changes and headache with naproxen sodium as compared with placebo.[3] Adverse effects include nausea, vomiting, epigastric pain, gastrointestinal (GI) bleeding, and rash.

Beta-blockers

Two trials of beta-blockers (atenolol and propranolol) found favorable effects.[3]

Anxiolytics, antidepressants, and mood stabilizers

Buspirone has been shown to be efficacious in the treatment of both premenstrual syndrome4 (PMS) and PMDD.[3, 4] Adverse effects include nausea, headache, nervousness, and dizziness. Buspirone may be administered throughout the cycle or during the late luteal phase.

Alprazolam was tested in a few clinical trials for its effectiveness in PMDD, but the results are inconsistent.[36, 37] Tolerance and dependence are potential adverse effects.

Nonserotonergic antidepressants, such as maprotiline and bupropion, appear to be ineffective for PMDD symptoms.[38] Two trials of lithium reported no significant difference in symptoms compared with placebo.[3]

The serotonergic system has a close relationship with the gonadal hormones and thus has been identified as the most plausible target for intervention. Selective serotonin reuptake inhibitors (SSRIs) are emerging as the most effective treatment option for PMDD. Of these agents, fluoxetine, sertraline, and controlled-release paroxetine have been approved by the US Food and Drug Administration (FDA) for treatment of PMDD.[39]

Several randomized controlled trials in women with PMDD have clearly demonstrated that SSRIs have excellent efficacy and minimal adverse effects.[40] Several studies indicate that intermittent SSRI therapy limited to the premenstrual phase is equally effective. A Cochrane review demonstrated that all SSRIs (fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, and clomipramine) were effective in reducing premenstrual symptoms.[41] Withdrawals due to side effects were twice as likely to occur in the treatment group.

Fluoxetine was the first SSRI approved for the treatment of PMDD. A large, randomized, controlled study reported that fluoxetine is superior to placebo in reducing symptoms of tension, irritability, and dysphoria.[42] Fluoxetine at 20 or 60 mg/day through 6 menstrual cycles improved mood symptoms in 53% of the cycles, whereas placebo yielded improvement in 28% of the cycles. The women who received fluoxetine 60 mg/day reported significantly more side effects than those who received fluoxetine 20 mg/day or placebo.

Fluoxetine appears to be less effective in controlling physical symptoms of PMDD. Commonly observed adverse effects include nausea, headache, weight gain, rash, fatigue, insomnia, anxiety, nervousness, and somnolence.[43] A long-term study reported sexual dysfunction, including decreased libido and anorgasmia, as the most common adverse effect encountered in 17% of the patients treated.

The Sertraline Premenstrual Dysphoric Collaborative Study Group reported that daily sertraline was significantly better than placebo for treatment of premenstrual dysphoria, as reflected by symptomatic improvement and change in reported functional impairment.[44] Young et al reported that sertraline administered intermittently during the luteal phase only was significantly more effective than placebo in reducing both behavioral and physical symptoms, as assessed by the Calendar of Premenstrual Experiences.[45]

A multicenter, randomized, double-blind, placebo-controlled, 3-arm, fixed-dose study of luteal phase dosing with controlled-release paroxetine in the treatment of PMDD showed that luteal-phase dosing with either 12.5 or 25 mg is effective and generally well tolerated.[46]

In a multicenter, randomized controlled trial involving female outpatients with PMDD from 4 Canadian health centers, luteal-phase-only administration of paroxetine 20 mg significantly reduced irritability symptoms in patients with PMDD. These results also suggest that PMDD may be treated effectively by luteal-phase-only administration of an SSRI.[47]

Dual-action antidepressants have also been used successfully in patients with PMDD. In an open trial from 1994, Freeman et al reported symptomatic improvement with nefazodone.[48] Improvement in symptoms occurred by the end of the first cycle of treatment and was maintained for the entire course of treatment.

In 2001, Freeman et al demonstrated that venlafaxine was more effective than placebo for women with PMDD. Patients’ response to treatment was relatively rapid, sometimes occurring in the first treatment cycle.[49]

A preliminary study using escitalopram showed that PMDD improved significantly with either luteal phase or symptom-onset dosing.[50]

A meta-analysis including approximately 3000 women demonstrated that SSRIs are effective for treating PMS and PMDD. Intermittent dosing regimens were found to be less effective than continuous dosing regimens. No SSRI was demonstrably better than any other.[51]

Special concerns

The studies that demonstrated the beneficial effect of SSRIs in PMDD did not include women who were on oral contraceptives or women younger than 18 years. Many adult women and adolescents take SSRIs, oral contraceptives, or both for other reasons. No major adverse reactions have been reported with this combination; however, it would be sensible to await further studies before prescribing SSRIs for PMDD in younger girls. Relatively low-risk agents (eg, calcium supplements or NSAIDs) may be reasonable options.

On March 22, 2004, an FDA Public Health Advisory was issued on cautions for the use of antidepressants in adults and children. Adults and pediatric patients treated with certain SSRIs listed in the advisory should be closely observed for worsening depression or the development of suicidal ideation. On August 20, 2004, an FDA Talk Paper was issued that updated the FDA’s review on antidepressant drugs in children.

Anticonvulsants

Kindling and impaired electroencephalophysiology have been suggested to play a role in the pathophysiology of PMDD. Levetiracetam is a novel antiepileptic drug that has shown strong antikindling activity in animal models of epilepsy. In a pilot open-label study, 6 of 7 patients experienced a considerable decrease in their Daily Record of Severity of Problems scores with levetiracetam, starting from the first treatment cycle. This suggests that anticonvulsant medications, specifically levetiracetam, could be effective in the treatment of PMDD.[52]

Nutritional Supplementation and Herbal Formulations

Women with premenstrual symptoms often explore alternative therapies that have not been proven effective (eg, nutritional supplements and herbal formulations). Physicians treating this disorder should be acquainted with and inquire about patients’ use of such remedies to identify potential adverse effects or drug interactions.

Nutritional supplements often used by women in self-treatment of PMS symptoms include the following:

The use of pyridoxine (vitamin B-6) has had varying degrees of success, according to the literature. One systematic review reported that no high-quality randomized, controlled trials comparing pyridoxine and placebo were found.[53] Results from low-quality trials suggested that vitamin B-6 dosages as high as 100 mg/day are likely to be beneficial in treating premenstrual symptoms and premenstrual depression.

Calcium supplementation during the luteal phase has proven beneficial with regard to bloating, pain, mood, and food cravings. In a randomized, double-blind, placebo-controlled multicenter trial that enrolled more than 400 women with documented PMS, subjects were randomly assigned to receive either placebo or elemental calcium 1200 mg/day (given as 2 tablets, each including 750 mg of calcium carbonate containing 300 mg of elemental calcium, twice daily), starting 7-10 days after the onset of menses and continuing for 3 complete cycles.[54]

In this study, more than 50% of women in the calcium group had significant decreases in depression, water retention, pain, food cravings, fatigue, and insomnia.[54] Although the possibility of urolithiasis has been a concern with calcium supplementation, in this study, only 1 patient in each group developed a stone.

One study reported that luteal-phase administration of magnesium was helpful for premenstrual emotional and physical symptoms.[55] However, another study reported that daily administration of magnesium was helpful only for reducing premenstrual fluid retention and was not helpful for emotional symptoms.[56] It should be noted that the magnesium dosage was 200 mg/day in the latter study, whereas it was 360 mg/day in the former.

Evening primrose oil contains the essential fatty acid gamma-linolenic acid and is sold widely as a nutritional supplement. Use of the oil is based on the premise that women with PMS have a deficit of gamma-linolenic acid. Although clinicians believe the oil is of little value in treating PMS, it is used widely as a nonprescription remedy for breast tenderness.

With the intention of performing a meta-analysis, Budeiri et al performed a systematic literature search of clinical trials of evening primrose oil for the treatment of PMS.[57] Randomization was clearly indicated in only 5 of the 7 placebo-controlled trials found. A rigorous meta-analysis could not be done, because of inconsistent scoring and response criteria. The 2 best-controlled studies failed to show any beneficial effects for evening primrose oil; however, small effects could not be excluded, because the trials were relatively small.

Overall, data on the effects of dietary supplements on improving premenstrual symptoms are insufficient.

Herbal formulations often used by women in self-treatment of PMS symptoms include the following:

Hysterectomy and Oophorectomy

Randomized controlled trials demonstrated that hysterectomy plus bilateral oophorectomy was curative for patients with PMDD. Hysterectomy alone also resulted in a reduction of symptoms, but the validity of these trials is questionable, because conducting blinded studies was logistically difficult.

Limited data are available on the use of laparoscopic bilateral oophorectomy and endometrial ablation in the treatment of PMDD.

Diet

Dietary advice constitutes an important aspect of nonpharmacologic treatment of PMDD.

Reducing caffeine intake may minimize the potential adverse effects of excess caffeine consumption (eg, nervousness, jitteriness). Restricting sodium intake may reduce bloating.

Some patients are able to avoid symptoms resembling hypoglycemia by reducing intake of highly refined carbohydrates and by having 5 or 6 smaller meals during the day instead of 3 large meals. One study reported that a commercially available carbohydrate-rich beverage improves mood, appetite, and cognitive function when taken in the late luteal phase.

Overall, consumption of complex carbohydrates and restriction or moderation of caffeine and alcohol intake have not been consistently beneficial in alleviating the symptoms of PMDD.

One nonrandomized trial found that a low-fat vegetarian diet reduced premenstrual symptoms.[3]

Activity

Three randomized controlled trials reported that moderate aerobic exercise improved premenstrual symptoms; however, no controlled studies of exercise as a single treatment have been conducted in women with confirmed PMS or PMDD. In addition, aerobic exercise has not been consistently beneficial in alleviating the symptoms of PMDD.

Traditionally, aerobic exercise is recommended, particularly if depressive or fluid retention symptoms predominate. From the available scientific data, it is unclear whether aerobic exercise is more effective than nonaerobic exercise.

The efficacy of exercise could be the result of raised endorphin levels, physiologic changes, psychological changes, or combinations thereof.

Long-Term Monitoring

Individuals with PMDD typically can be treated in an outpatient setting; hospitalization is not necessary in most circumstances. Hospitalization is indicated on those rare occasions when the symptoms are so severe that the individual cannot care for herself at home or when there is a risk of harm to herself and to others, including suicidal or homicidal intent or plan.

Patients treated for PMDD should be assessed every 2 weeks (ie, during the follicular and luteal phases) after commencing therapy and should continue to chart symptoms daily. If no change in symptoms occurs, an alternate therapy should be considered within 2-3 menstrual cycles.

Medication Summary

The goal of pharmacotherapy is to relieve symptoms. Agents used in the management of premenstrual dysphoric disorder (PMDD) include vitamins and minerals, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), antidepressants, beta-blockers, anxiolytics, and contraceptives.

Pyridoxine; vitamin B-6 (Aminoxin, Pyri-500)

Clinical Context:  Pyridoxine is involved in the synthesis of gamma-aminobutyric acid (GABA) within the central nervous system (CNS).

Calcium carbonate (Caltrate 600, TUMS, Oysco 500, Rolaids Extra Strength)

Clinical Context:  Calcium supplementation during the luteal phase has proven beneficial with regard to bloating, pain, mood, and food cravings.

Class Summary

Vitamins and minerals have been used for PMDD with varying success rates, as described in the literature.

Danazol

Clinical Context:  Danazol is a synthetic steroid analogue with strong antigonadotropic activity (ie, inhibition of LH and FSH) and weak androgenic action.

Class Summary

The ability of the androgens to inhibit luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release may have a positive effect in the treatment of PMDD.

Spironolactone (Aldactone)

Clinical Context:  Spironolactone competes with aldosterone for receptor sites in distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions.

Metolazone (Zaroxolyn)

Clinical Context:  Metolazone is a thiazide diuretic with a reported beneficial effect in PMDD. It increases excretion of sodium, water, potassium, and hydrogen ions by inhibiting reabsorption of sodium in distal tubules.

Class Summary

Diuretics are widely used for PMDD, on the assumption that many symptoms are secondary to fluid retention.

Naproxen (Aleve, Naprelan, Naprosyn)

Clinical Context:  Naproxen is reported to improve mood changes and headache in PMDD.

Mefenamic acid (Ponstel)

Clinical Context:  Mefenamic acid is reported to improve premenstrual symptoms, except breast pain.

Class Summary

NSAIDs are reported to improve some physical and mental symptoms in PMDD.

Bupropion (Wellbutrin, Aplenzin)

Clinical Context:  Bupropion inhibits neuronal dopamine reuptake, in addition to being a weak blocker of serotonin and norepinephrine reuptake.

Clomipramine (Anafranil)

Clinical Context:  Clomipramine affects serotonin uptake. When converted into its metabolite, desmethyl clomipramine, it affects norepinephrine uptake.

Nortriptyline (Pamelor)

Clinical Context:  Nortriptyline inhibits reuptake of serotonin, norepinephrine, or both by the presynaptic neuronal membrane.

Fluoxetine (Sarafem, Prozac)

Clinical Context:  Fluoxetine selectively inhibits presynaptic serotonin reuptake, with minimal or no effect on reuptake of norepinephrine or dopamine.

Sertraline (Zoloft)

Clinical Context:  Sertraline selectively inhibits presynaptic serotonin reuptake.

Paroxetine (Paxil, Pexeva)

Clinical Context:  Paroxetine selectively inhibits presynaptic serotonin reuptake. It is reported to have positive effects on 1 or more symptoms of PMDD as compared with placebo.

Class Summary

Antidepressants are reported to have positive effects on 1 or more symptoms of PMDD as compared with placebo. Antidepressant therapy is indicated if PMDD symptoms of depression are moderate to severe.

Atenolol (Tenormin)

Clinical Context:  Atenolol selectively blocks beta1 receptors, with little or no effect on beta2 types.

Class Summary

A double-blinded study found the beta-adrenergic blocking agent atenolol to improve irritability. However, a placebo-controlled study of prospectively diagnosed patients found no improvement with atenolol.

Alprazolam (Xanax, Niravam)

Clinical Context:  Alprazolam reduces depression, irritability, and anxiety in PMDD.

Buspirone

Clinical Context:  Buspirone is a serotonin agonist with serotonergic neurotransmission and some dopaminergic effects in the CNS.

Class Summary

Anxiolytics are reported to have positive effects on 1 or more symptoms of PMDD as compared with placebo. They should be used in the management of PMDD if anxiety is the prominent symptom, with dysphoria occurring secondarily.

Ethinyl estradiol and drospirenone (YAZ, Zarah, Ocella, Loryna, Gianvi)

Clinical Context:  This formulation is an oral contraceptive containing ethinyl estradiol 20 µg and drospirenone 3 mg. It is indicated for PMDD in women who choose to use an oral contraceptive as their method of contraception.

Norethindrone acetate/ethinyl estradiol (Ortho-Novum, Nortrel, Cyclafem)

Clinical Context:  Norethindrone acetate and ethinyl estradiol are used as an oral contraceptive. The formula is used in women who choose to use an oral contraceptive as their method of contraception.

Class Summary

Contraceptives reduce secretion of LH and FSH from the pituitary by decreasing the amount of gonadotropin-releasing hormone (GnRH).

Author

Thwe T Htay, MD, Associate Professor, Department of Medicine, University of Texas Health Science Center at San Antonio

Disclosure: Nothing to disclose.

Coauthor(s)

KoKo Aung, MD, MPH, FACP, Associate Professor, Department of Medicine, University of Texas Health Science Center at San Antonio; Adjunct Associate Professor of Public Health, University of Texas School of Public Health

Disclosure: Nothing to disclose.

Chief Editor

Iqbal Ahmed, MBBS, FRCPsych (UK), Faculty, Department of Psychiatry, Tripler Army Medical Center; Clinical Professor of Psychiatry, Uniformed Services University of the Health Sciences; Clinical Professor of Psychiatry, Clinical Professor of Geriatric Medicine, University of Hawaii, John A Burns School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Ronald C Albucher, MD Chief Medical Officer, Westside Community Services; Consulting Staff, California Pacific Medical Center

Ronald C Albucher, MD is a member of the following medical societies: American Psychiatric Association

Disclosure: Nothing to disclose.

John Carrick, MD Consulting Staff, Department of Psychiatry, Flagstaff Medical Center

John Carrick, MD is a member of the following medical societies: American Association for Geriatric Psychiatry

Disclosure: Nothing to disclose.

Romeo Papica II MD Staff Physician, Premier Physicians

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

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