Premenstrual Dysphoric Disorder Treatment & Management

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. ^[10]

 

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. ^[20]

Another systematic review of 19 studies (8 in acupuncture) found limited evidence supporting the efficacy of alternative medicinal interventions such as acupuncture and herbal medicine in controlling premenstrual syndrome and premenstrual dysphoric disorder. Acupuncture and herbal medicine treatments for premenstrual syndrome and premenstrual dysphoric disorder showed a 50% or better reduction of symptoms compared to the initial state. ^[21]

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. ^[22] 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. ^[23]

A systematic review summarized the evidence from 4 randomized clinical trials of bright light therapy for treatment of PMDD in 55 subjects. ^[24] 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. ^[24] 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. ^[25] 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, ^[26] 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. ^[27] 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. ^[28]

Selective serotonin reuptake inhibitors (SSRIs) are the most effective treatment option for premenstrual dysphoric disorder (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. ^[38]

Several randomized controlled trials in women with PMDD have clearly demonstrated that SSRIs have excellent efficacy and minimal adverse effects. ^[39]  Several studies indicate that intermittent SSRI therapy limited to the premenstrual phase is equally effective. The premenstrual tension syndrome scales (PMTS) symptoms improved as early as 48 hours after starting treatment with fluoxetine during luteal phase. ^[61]  

A Cochrane review demonstrated that all SSRIs (fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, and clomipramine) were effctive in reducing premenstrual symptoms. ^[40]  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. ^[41]  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. ^[42]  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. ^[43]  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. ^[44] . Yonkers et al showed that sertraline 50–100mg taken daily during the premenstrual period of 6 days effectively and efficiency reduced symptoms of anger and irritability compared to placebo in women with PMDD. ^[62]

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. ^[45]

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. ^[46]

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. ^[47]  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. ^[48]

A preliminary study using escitalopram showed that PMDD improved significantly with either luteal phase or symptom-onset dosing. ^[49]

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. ^[50]

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.

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. ^[29]

A systematic review of 14 randomized controlled trials found no improvement in premenstrual symptoms with progesterone as compared with placebo. ^[1] 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. ^[1] 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. ^[1] 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. ^[30] 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. Therefore, in addition to its high cost, GnRH agonists are reserved as third-line medication for severe cases only, behind SSRIs and oral contraceptives.

Limited data are available on the beneficial effect of bromocriptine in relieving breast tenderness. ^{[31, 32, 33]} 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. ^[1] In 1976, Werch and Kane reported the beneficial effect of metolazone. ^[34] 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. ^[1] 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. ^[1] 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. ^[1]

Anxiolytics and mood stabilizers

Buspirone has been shown to be efficacious in the treatment of both premenstrual syndrome4 (PMS) and PMDD. ^{[1, 2]} 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. ^{[35, 36]} . Due to the risk of drug tolerance and dependence, routine use of alprazolam for PMDD is not recommended. ^[67]

Nonserotonergic antidepressants, such as maprotiline and bupropion, appear to be ineffective for PMDD symptoms. ^[37] Two trials of lithium reported no significant difference in symptoms compared with placebo. ^[1]

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. ^[51]

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:

• Vitamin B complex

• Calcium with magnesium chloride

• Evening primrose oil

• Kelp

• L -tyrosine

• Multivitamin-mineral complex with manganese

• Vitamin C with bioflavonoids

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. ^[52] 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. They caution the use of higher than 200 mg/day because peripheral neuropathy can ensue.

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. ^[53]

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. ^[53] 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. ^[54] However, another study reported that daily administration of magnesium was helpful only for reducing premenstrual fluid retention and was not helpful for emotional symptoms. ^[55] 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. ^[56] 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.

Vitex agnus castus or chasteberry extract can be used to treat PMDD at a dosage of 20–40mg/day. The chasteberry extract binds to dopamine-2 receptor, opioid receptor, and B-estrogen receptor, and effectively reduced symptoms over placebo in 17 trials in a meta-analysis of low-quality studies. ^[64]

A double-blinded, placebo-controlled, randomized clinical trial of 36 women reported that St. John's wort may alleviate symptoms of bloating, food craving, headache, and fatigue but does not alleviate pain or mood symptoms. ^[65]

A randomized controlled trial of 85 women reported that Ginkgo biloba 3 times per day through the luteal phase significantly reduced physical and psychological symptoms of PMDD than placebo. More research is necessary to identify the safety and efficacy of its optimal dose, active ingredients, and the duration of the treatment. ^[63]

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

• Cayenne

• Dong quai

• Siberian ginseng

• Pulsatilla

• Raspberry leaves

• Sepia

• Blessed thistle

• American valerian

• Wild yam

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

Surgical intervention (bilateral oophorectomy/bilateral salpingoophorectomy) should be considered as a last option for women who have completed childbearing or women with severe symptoms not responding to medical treatment. Randomized controlled trials demonstrated that hysterectomy plus bilateral oophorectomy with hormone replacement therapy was curative for patients with premenstrual dysphoric disorder (PMDD). ^[66]  Hysterectomy alone also resulted in a reduction of symptoms, but the validity of these trials is questionable, because conducting blinded studies was logistically difficult. Before such definitive surgical intervention, however, a trial of GnRH should be used to produce similar effects to assess the effectiveness of this treatment. ^[60]

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

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. ^[1]

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.

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.