brand logo

From 2 to 10 percent of women of reproductive age have severe distress and dysfunction caused by premenstrual dysphoric disorder, a severe form of premenstrual syndrome. Current research implicates mechanisms of serotonin as relevant to etiology and treatment. Patients with mild to moderate symptoms of premenstrual syndrome may benefit from nonpharmacologic interventions such as education about the disorder, lifestyle changes, and nutritional adjustments. However, patients with premenstrual dysphoric disorder and those who fail to respond to more conservative measures may also require pharmacologic management, typically beginning with a selective serotonin reuptake inhibitor. This drug class seems to reduce emotional, cognitive-behavioral, and physical symptoms, and improve psychosocial functioning. Serotoninergic antidepressants such as fluoxetine, citalopram, sertraline, and clomipramine are effective when used intermittently during the luteal phase of the menstrual cycle. Treatment strategies specific to the luteal phase may reduce cost, long-term side effects, and risk of discontinuation syndrome. Patients who do not respond to a serotoninergic antidepressant may be treated with another selective serotonin reuptake inhibitor. Low-dose alprazolam, administered intermittently during the luteal phase, may be considered as a second-line treatment. A therapeutic trial with a gonadotropin-releasing hormone agonist or danazol may be considered when other treatments are ineffective. However, the risk of serious side effects and the cost of these medications limit their use to short periods.

Millions of women of reproductive age have recurrent emotional, cognitive, and physical symptoms related to their menstrual cycles. These symptoms often recur discretely during the luteal phase of the menstrual cycle and may significantly interfere with social, occupational, and sexual functioning.

Premenstrual dysphoric disorder (PMDD), a severe form of premenstrual syndrome (PMS), is diagnosed by the pattern of symptoms. According to a report by the Committee on Gynecologic Practice of the American College of Obstetricians and Gynecologists,1 up to 80 percent of women of reproductive age have physical changes with menstruation; 20 to 40 percent of them experience symptoms of PMS, while 2 to 10 percent report severe disruption of their daily activities. Menstruation-related physical discomfort, such as dysmenorrhea, may begin with menarche. Often this condition is superseded by PMS in late adolescence or the early 20s. These syndromes generally remain stable over time.

Diagnosis

In the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV), PMDD is classified as “depressive disorder not otherwise specified” and emphasizes emotional and cognitive-behavioral symptoms.2 At least five of the 11 specified symptoms must be present for a diagnosis of PMDD (Table 1).2 These symptoms should be limited to the luteal phase and should not represent amplification of preexisting depression, anxiety, or personality disorder. In addition, they must be confirmed prospectively by daily rating for at least two consecutive menstrual cycles. A symptom-free period during the follicular phase of the menstrual cycle is essential in differentiating PMDD from preexisting anxiety and mood disorders.

The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.

Researchers have developed a reliable and valid self-reporting scale called the Daily Symptom Report (see patient information handout).3 The report consists of 17 common PMS symptoms, including 11 symptoms from the DSM-IV PMDD diagnostic criteria. Patients rate each symptom on a five-point scale, from zero (none) to 4 (severe). The scale provides guidance for scoring the severity of each symptom and may be used in the office setting by primary care physicians for diagnosis and assessment of PMDD.

Etiology

Currently, there is no consensus on the cause of PMDD. Biologic, psychologic, environmental and social factors all seem to play a part. Genetic factors are also pertinent: 70 percent of women whose mothers have been affected by PMS have PMS themselves, compared with 37 percent of women whose mothers have not been affected.4 There is a 93 percent concordance rate in monozygotic twins, compared with a rate of 44 percent in dizygotic twins.4 Genetic influences mediated phenotypically through neurotransmitters and neuroreceptors seem to play a significant role in the etiology.

Features of PMDD and depressive disorders—specifically atypical depression—overlap considerably. Symptoms of atypical depression (i.e., depressed mood, interpersonal rejection hypersensitivity, carbohydrate craving, and hypersomnia) are similar to those of PMDD. Thirty to 76 percent of women diagnosed with PMDD have a lifetime history of depression,5 compared with 15 percent of women of a similar age without PMDD. A family history of depression is common in women diagnosed with moderate to severe PMS.6 There is significant comorbidity between depression and PMDD. Despite this relationship, many patients with PMDD do not have depressive symptoms; therefore, PMDD should not be considered as simply a variant of depressive disorder.7

The effectiveness of selective serotonin reuptake inhibitors (SSRIs), administered only during the luteal phase of the menstrual cycle,814 highlights the difference between PMDD and depressive disorder. Acute treatment with SSRIs increases synaptic serotonin without the down-regulation of serotonin receptors needed for improvement in overt depression. This finding suggests that PMDD is possibly caused by altered sensitivity in the serotoninergic system in response to phasic fluctuations in female gonadal hormone. Other studies also favor the serotonin theory as a cause of PMDD. In particular, the efficacy of l-tryptophan,15 a precursor of serotonin, and of pyridoxine,16 which serves as a cofactor in the conversion of tryptophan into serotonin, also favors serotonin deficiency as a cause of PMDD. Carbohydrate craving, often a symptom of PMDD, is also mediated through serotonin deficiency.

Because PMDD only affects women of reproductive age, it is reasonable to assume that female gonadal hormones play a causative role, possibly mediated through alteration of serotoninergic activity in the brain. Estrogen and progesterone seem to modulate levels of monoamines, including serotonin. Eliminating the effect of ovarian gonadal hormones through the use of a gonadotropin-releasing hormone (GnRH) agonist relieves PMDD symptoms.17 Subsequent administration of estrogen and progesterone causes symptoms to return in women with PMS but not in those without PMS symptoms.18

Treatment

The goals of treatment in patients with PMDD are (1) symptom reduction and (2) improvement in social and occupational functioning, leading to an enhanced quality of life. Available treatment options are summarized in Tables 2 through 6.

LIFESTYLE CHANGES

Lifestyle changes may be valuable in patients with mildly severe symptoms and benefit their overall health. Aerobic exercise and dietary changes often reduce premenstrual symptoms.19,20 Decreasing caffeine intake can abate anxiety and irritability, and reducing sodium decreases edema and bloating. Many patients prefer to try lifestyle changes and/or nutritional supplements as a first step in the treatment of PMDD.

NUTRITIONAL SUPPLEMENTS

Many of the nutritional supplements described in Table 24,15,16,1922 have proven efficacy. A meta-analysis16 of nine randomized, placebo-controlled trials was conducted to ascertain the effectiveness of vitamin B6 in PMS management. The researchers concluded that vitamin B6, in dosages of up to 100 mg per day, is likely to benefit patients with premenstrual symptoms and premenstrual depression. In another study,21 research literature (from January 1967 to September 1999) was reviewed to evaluate the effectiveness of calcium carbonate in patients with PMS. The reviewers concluded that calcium supplementation in a dosage of 1,200 to 1,600 mg per day is a treatment option in women with PMS. Calcium supplementation (using Tums E-X) was found to reduce core premenstrual symptoms by 48 percent in 466 patients.22 Vitamin E, an antioxidant, seems to reduce the affective and physical symptoms of PMS.20 Tryptophan,15 a substrate for serotonin, may also benefit some patients.15

Lifestyle changes
Regular, frequent, small balanced meals rich in complex carbohydrates and low in salt, fat, and caffeine19,20
Regular exercise19,20
Smoking cessation20
Alcohol restriction20
Regular sleep20
Nutritional supplements
Vitamin B6, up to 100 mg per day16
Vitamin E, up to 600 IU per day20
Calcium carbonate, 1,200 to 1,600 mg per day21,22
Magnesium, up to 500 mg per day20
Tryptophan, up to 6 g per day15
Nonpharmacologic treatments
Stress reduction and management20
Anger management4
Self-help support group20
Individual and couples therapy20
Cognitive-behavioral therapy23
Patient education20 about the cause, diagnosis, and treatment of PMS/PMDD
Light therapy20 with 10,000 Lx cool-white fluorescent light

NONPHARMACOLOGIC TREATMENTS

Almost invariably, psychosocial stressors should be addressed, either as a cause or a result of PMDD. Psychosocial stressors are known to alter brain neurochemistry and stress-related hormonal activity. Stress reduction, assertiveness training, and anger management can reduce symptoms and interpersonal conflicts. Women with negative views of themselves and the future caused or exacerbated by PMDD may benefit from cognitive-behavioral therapy.23 This kind of therapy can enhance self-esteem and interpersonal effectiveness, as well as reduce other symptoms.23 Educating patients and their families about the disorder can promote understanding of it and reduce conflict, stress, and symptoms.20

HERBAL THERAPIES

A recent study24 reviewed efficacy and safety data on herbal supplements marketed for women. The author concluded that two herbal products, evening primrose oil and chaste tree berry, have been effective in treating PMS (Table 3).2426 Other researchers25 have arrived at variable conclusions about the efficacy of evening primrose oil. It is thought to provide the gamma-linolenic acid required for synthesis of prostaglandin E1,24 one of the anti-inflammatory prostaglandins. Chaste tree berry may reduce prolactin levels,24,25 thereby reducing symptoms of breast engorgement. These herbal therapies have not been approved by the U.S. Food and Drug Administration (FDA) for use in PMDD, and their safety in pregnancy and lactation has not been established. Moreover, manufacturing standards for herbal products are not uniform.

Herbal productDosageUse recommendationComments
Evening primrose oil24,25 500 mg per day to 1,000 mg three times per dayDays 17 through 28 of menstrual cycleMost-studied of all herbs used in treatment of PMS
May provide a precursor for prostaglandin synthesis
Benefits breast tenderness
Safety data in pregnancy and lactation lacking
Not approved for this use by the FDA
Chaste tree berry2426 30 to 40 mg per dayDays 17 through 28 of menstrual cycleMay benefit breast symptoms
Inhibits prolactin production
Safety data lacking
Not approved for this use by the FDA

PHARMACOLOGIC INTERVENTIONS

Antidepressant and Anxiolytic Medications

The serotoninergic antidepressants are the first-line treatment of choice for severe PMDD (Table 4).814,2737 Fluoxetine, in a dosage of 20 mg per day, has been shown to be superior to placebo, whether used only during the luteal phase12 or throughout the full menstrual cycle.2729 In a review29 of seven controlled and four open-label clinical trials of fluoxetine, symptoms were significantly reduced in patients with PMDD.

AgentsDosageUse recommendationComments
SSRIs
Citalopram13,35 10 to 30 mgper dayFull cycle or luteal phase onlyBenefits physical, cognitive, and emotional symptoms
Administration during luteal phase
Luteal-phase use is superior to continuous treatment
Not approved by FDA for this use
Fluoxetine12,27,29,35 20 mg per dayFull cycle or luteal phase onlySignificant reduction of all symptoms
Decreased libido or delayed orgasm is most common side effect in long-term, continuous use
Approved by FDA for this use
Paroxetine30,35 10 to 30 mgper dayFull cycleBenefits all symptoms
Transient GI and sexual side effects
Superior to maprotiline
Not approved by FDA for this use
Sertraline810,14,3133,35 50 to 150 mg per dayFull cycle or luteal phase onlyBenefits all symptoms
Transient GI and sexual side effects
Approved by FDA for this use
Other serotoninergic antidepressants
Clomipramine11,34 25 to 75 mgper dayFull cycle or luteal phase onlyBenefits all symptoms
Anticholinergic and sexual side effects
Not approved by FDA for this use
Anxiolytics
Alprazolam28,36,37 0.375 to 1.5 mg per dayLuteal phaseInterrupted use during the luteal phase can reduce the risk of drug dependence
Use only if SSRIs are ineffective
Not approved by FDA for this use

In one placebo-controlled study,30 paroxetine in a dosage of 10 to 30 mg per day improved mood and physical symptoms in patients with PMDD. Paroxetine was more effective than the noradrenaline reuptake inhibitor maprotiline.30 Sertraline in a dosage of 50 to 150 mg per day was superior to placebo whether used during the full menstrual cycle3133 or only during the luteal phase.810,14 Citalopram in a dosage of 10 to 30 mg per day was effective in one randomized, placebo-controlled trial.13 Interestingly, intermittent administration of citalopram during the luteal phase was found to be superior to continuous treatment. Clomipramine, a serotoninergic tricyclic antidepressant that affects the noradrenergic system, in a dosage of 25 to 75 mg per day used during the full cycle34 or intermittently during the luteal phase,11 significantly reduced the total symptom complex of PMDD.

In a recent meta-analysis35 of 15 randomized, placebo-controlled studies of the efficacy of SSRIs in PMDD, it was concluded that SSRIs are an effective and safe first-line therapy and that there is no significant difference in symptom reduction between continuous and intermittent dosing. Because fluoxetine, citalopram, clomipramine, and sertraline were effective if administered during the luteal phase only, these drugs may be used as first-line therapy and taken intermittently only during the luteal phase. Such an approach can reduce the risk of long-term side effects (e.g., weight gain), minimize discontinuation syndrome, and reduce the cost of care. SSRIs benefit the total symptom complex of PMDD, not only the mood-related symptoms. It should also be noted that fluoxetine and sertraline are the only two SSRIs with FDA approval for use in the treatment of PMDD.

Alprazolam, a high-potency benzodiazepine with mood-enhancing and anxiolytic effects, has been shown to be somewhat effective in patients with PMS.28,36,37 Because of the potential for drug dependence, alprazolam should be considered a second-line drug and used only if SSRIs fail to achieve an optimal response. Therapy should be limited to the luteal phase, and the agent should be given in low dosages—0.375 to 1.5 mg per day. The risk of drug dependence with alprazolam can be minimized by administering it only during the luteal phase of the menstrual cycle in patients without a history of substance abuse.

Hormonal Therapies

It has been shown that by inducing anovulation and amenorrhea, GnRH agonists, leuprolide, histrelin, and goserelin provide significant relief of symptoms in patients without comorbid depression.3840 However, these medications can induce menopausal symptoms such as hot flushes, vaginal dryness, fatigue, irritability, cardiac problems, and osteopenia. In women with a history of PMDD, treatment of induced menopause with estrogen39 or estrogen plus progestational agents18 can induce recurrent symptoms of PMDD. This finding supports the theory of an etiologic role for female gonadal hormones in PMDD.

Danazol (Danocrine), a weak androgen prescribed for patients with endometriosis, fibrocystic breast disease, and hereditary angioneurotic edema, is sometimes used to treat PMDD. The typical dosage is 100 mg twice a day. Such treatment can reduce symptoms but may result in anovulation and masculinization, either of which may limit regular use.41 Because of the potential for serious side effects and significant costs, GnRH agonists and danazol should be tried as a last resort. These medications must be initiated during menstruation to prevent teratogenicity if there is an unintended pregnancy.

Although oral contraceptive pills (OCPs) suppress ovulation, they are not reported to be consistently effective in the treatment of PMDD (perhaps because the studies had variable samples). OCPs may not suffice if mood symptoms are prominent and, in some patients, these drugs may worsen dysphoria (a known side effect of some birth control pills) in many women without PMDD.

Efficacy studies of progesterone have shown limited benefits. One study42 found progesterone to be superior to placebo; however, another study43 reported efficacy equal to or less than that of placebo. Currently, ovarian gonadal hormones are thought to be of limited usefulness in the treatment of PMDD, and none of the drugs has FDA approval for this indication (Table 5).18,20,3843

DrugDosageUse recommendationComments
Leuprolide depot38,40 3.75 mg IM per monthUp to six cyclesPregnancy category X
Significant relief from symptoms but can induce menopausal syndrome
Leuprolide depot with ovarian hormone supplements18 3.75 mg IM per month with estrogen and progesteroneCan exceed six cyclesLess likely to induce menopause; PMDD symptoms may return, making this combination less effective
Goserelin with estrogen supplementation39 3.6 mg SC every 28 days with estrogenCan exceed six cyclesLess likely to induce menopause; PMDD symptoms may return, making this combination less effective
Pregnancy category X
Use nonhormonal contraception during therapy and for 12 weeks after discontinuation of drug or until menses resume
Danazol41 100 mg twice a dayUp to six cyclesMay cause masculinization from weak androgenic properties
Pregnancy category X
OCPs20 OCPs with varying amounts of estrogen and progesterone, once a dayFull cycleVariable response; may not benefit patients with significant mood symptoms; in some patients, may make mood symptoms worse
Progesterone42,43 Vaginal suppositories, 200 to 400 mg per dayNot recommended for this useQuestionable efficacy

Miscellaneous Pharmacologic Interventions

In a double-blind, placebo-controlled, crossover study,44 spironolactone in a dosage of 100 mg per day was more effective than placebo in reducing irritability, depression, somatic symptoms, feelings of swelling, breast tenderness, and craving for sweets. Bromocriptine in a dosage of up to 2.5 mg three times per day may be beneficial in patients with cyclic mastalgia,4,20 although in one study45 it was not found to be effective. Ibuprofen, in a dosage of up to 1,000 mg per day, can reduce breast pain, headaches, back pain, and other pain symptoms,20 but seems to have limited effect on mood symptoms (Table 6).4,20,44,45

AgentsDosageUse recommendationComments
Diuretics
Spironolactone44 100 mg per dayLuteal phaseAldosterone antagonist
Potassium-sparing diuretic
Could improve physical and psychologic symptoms
Dopamine agonist
Bromocriptine4,20,45 Up to 2.5 mg three times per dayDays 10 through 26 of menstrual cycleMay relieve cyclic mastalgia; evaluate hepatic and renal functions before initiation
NSAIDs
Ibuprofen20 500 to 1,000 mg per dayDays 17 through 28 of menstrual cycleTake with food May relieve mastalgia

Other Medical Interventions

Historically, surgical and radiation oophorectomies have been used to treat severe PMS, but these modalities have no role in the current management of PMDD.

Evidenced-based efficacy ratings of currently available treatments for PMS and PMDD are described in Table 7,816,1925,2839,4145 while an algorithm for the management of these conditions is outlined in Figure 1.

Recommended treatmentEfficacy in PMS/PMDDEfficacy rating*Comments/evidence
Lifestyle changes19,20 PMS or PMDDGHealth benefits without risks
Vitamin B616 PMS or PMDDBDosage > 100 mg per day may cause peripheral neuropathy
Vitamin E20 PMS or PMDDEAntioxidant without significant risk
Calcium carbonate21,22 PMS or PMDDBPlacebo-controlled study supports benefits in moderate to severe PMS
Tryptophan15 PMS or PMDDBSupported by a placebo-controlled study
Cognitive-behavioral therapy23 PMSABenefits documented; not many studies
PMDDB
Herbal therapies24,25 PMS or PMDDESafety in pregnancy and lactation not documented; not FDA-approved
Selective serotonin reuptake inhibitors810,1214,2933,35 Nonresponsive PMS or PMDDAWell-designed, randomized, placebo-controlled studies and metaanalyses
Clomipramine11,34 PMDDBAnticholinergic side effects
Alprazolam28,3637 PMDDBLow-dose, luteal phase treatment; long-term use may cause tolerance
GnRH agonists or danazol18,38,39,41,42 PMDDCMenopausal syndrome/masculinization/cost limit its use
Spironolactone, bromocriptine, or ibuprofen41,44,45 PMS or PMDDDSymptom-focused efficacy; spironolactone efficacy supported by double-blind study
Oral contraceptives or progesterone42,43 PMDDEAnecdotal efficacy or not consistently effective
Surgical or radiation oophorectomyPMDDFNot recommended

Continue Reading


More in AFP

Copyright © 2002 by the American Academy of Family Physicians.

This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP.  See https://www.aafp.org/about/this-site/permissions.html for copyright questions and/or permission requests.