AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Premenstrual dysphoric disorder (PMDD) is a diagnosis used to indicate serious premenstrual distress with associated deterioration in functioning. PMDD is characterized by depressed or labile mood, anxiety, irritability, anger, and other symptoms occurring exclusively during the 2 weeks preceding menses. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), the symptoms must be severe enough to interfere with occupational and social functioning, as opposed to the more common premenstrual syndrome (PMS). PMDD is a severely distressing and disabling condition that requires treatment.

Hippocrates described a group of conditions that occurred prior to the onset of menses, in which women might develop suicidal ideation and other severe symptoms. In 1931, Frank described 15 women experiencing severe premenstrual symptoms and coined the term premenstrual tension syndrome. Although Frank first described PMS 70 years ago, PMDD is a relatively new concept.

In 1987, the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) included criteria for late luteal phase dysphoric disorder (LLPDD). In the DSM-IV, published by the American Psychiatric Association, the name was changed from LLPDD to PMDD, with criteria that were almost identical to those of LLPDD (only 1 item was added). The DSM-IV included PMDD as an example of a depressive disorder not otherwise specified. 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. Several treatment options for PMDD have been investigated and developed in the past few years.

Pathophysiology

Major theories to explain the pathophysiology of PMDD are the (1) ovarian hormone hypothesis, (2) serotonin hypothesis, (3) psychosocial hypothesis, (4) cognitive and social learning theory, and (5) sociocultural theory.

The ovarian hormone theory hypothesizes that PMDD is caused by an imbalance in the ratio of estrogen to progesterone, with a relative deficiency in progesterone. Based on this theory, Dalton treated her PMS patients with progesterone suppositories in the 1960s. However, recent studies of the level of estrogen and progesterone among women with PMS were inconclusive because of methodological difficulties. The current consensus seems to be that the normal fluctuations in gonadal hormones trigger central biochemical events related to PMDD symptomatology 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 and other target tissues. PMDD shares many of the phenomenologic features of depression and anxiety states that have been linked to serotonergic dysregulation. Increasing evidence suggests that 5-hydroxytryptamine 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. The sensitivity to perturbations of the central serotonin system in women with PMDD is altered premenstrually. The administration of the serotonin agonist m-chlorophenylpiperazine may induce mood elevation. 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. They then develop maladaptive coping strategies, such as 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.

The sociocultural theory hypothesizes that PMDD is a manifestation of the conflict between the societal expectation of the dual role of women as both 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.

Among the theories described above, the serotonin theory is increasingly popular. 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 GABA systems.

Frequency

United States

Epidemiological studies indicate that as many as 80% of women experience emotional, behavioral, or physical premenstrual symptoms. From 3-8% of women meet the diagnostic criteria for PMDD.

International

PMDD affects 3-8% of women in their reproductive years worldwide, imposing an enormous burden on women, their families, and the health care system. A recent study from India reported a similar frequency.

Mortality/Morbidity

PMDD is a multifactorial syndrome that affects 3-8% of women in their reproductive years and has varying degrees of severity that interfere with work, social activities, or interpersonal relationships.

Race

Although premenstrual clinics are reported to be almost exclusively attended by white women, community-based studies found no difference in the prevalence or severity of premenstrual symptoms between black women and white women. Some isolated reports indicate varying individual symptoms but not the overall prevalence of premenstrual symptoms among different racial groups. Black women tend to have a higher prevalence of food cravings than white women. White women are more likely than black women to report premenstrual mood changes and weight gain. Pain featured most highly in a sample of Chinese women in Hong Kong.

Age

Apparently, women in the late third to middle fourth decades of life are most vulnerable to experiencing PMDD.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

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

The PMDD criteria of the DSM-IV require the presence of 5 of 11 symptoms to make the diagnosis of PMDD (see DSM-IV symptoms). At least 1 of the first 4 symptoms must occur during the last week of the luteal phase, begin to remit within a few days of the onset of menstrual flow, and be absent in the week after menses. The symptoms must be severe enough to interfere with social, occupational, sexual, or scholastic functioning. Symptoms must be discretely related to the menstrual cycle and must not merely be a worsening of preexisting depression, anxiety, or personality disorder. All of the above criteria must be confirmed prospectively by daily ratings of at least 2 consecutive menstrual cycles. The diagnosis may be made provisionally before this confirmation.

Of the symptoms listed in the DSM-IV, 10 of 11 are emotional and behavioral in nature. Only one includes multiple common physical symptoms. As such, 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 criterion excludes many women presenting with predominantly physical premenstrual symptoms and women with premenstrual exacerbation of underlying axis I or II disorders. Interestingly, DSM-IV criteria state that PMDD may be superimposed on axis I or II disorders. However, how to differentiate between exacerbation of and superimposition on symptoms of an axis I or II disorder is unclear. The 11 symptoms described in the DSM-IV are listed below.

Several scoring systems are available for symptom quantification. A recent suggestion is 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 merit psychopharmacologic intervention. The within-cycle percentage change is calculated by subtracting the follicular score from the luteal score, divided by the luteal score, and multiplied by 100.

(luteal - follicular / luteal) X 100

More than 60 instruments have been used for symptom recording. Visual analog scales have been used in some studies. The scoring of symptoms on a Likert scale from anchor points of "not present" to "severe" is also commonly used. A 24-item form called the Daily Record of Severity of Problems incorporates all DSM-IV symptoms of PMDD. As one may expect from this large number of instruments, a review of scoring methods used in most studies failed to identify a uniquely favorable method. DSM-IV symptoms are as follows:

• Depressive symptoms
• • Markedly depressed mood, feelings of hopelessness, self-depreciation
  • Suddenly feeling sad or tearful, with increased sensitivity to personal rejection
  • Decreased interest in usual activities
  • Lethargy, fatigue, marked lack of energy
  • Accompanying depressive symptoms there is always the danger for suicidal ideation and behavior.
  • Marked changes in appetite and cravings for certain foods
  • Insomnia or hypersomnia
• Anxiety symptoms
• • Marked anxiety, tension, feeling of being keyed-up or on-edge
  • Persistent or marked irritability, anger, increased interpersonal conflicts
  • Feeling overwhelmed or out of control
• Cognitive symptoms - Subjective sense of having difficulty concentrating
• Physical symptoms - Breast tenderness or swelling, headaches, joint or muscular pain, weight gain, bloated feeling

Physical

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

Causes

Risk factors for PMDD include the following:

• Personal history of a major mood disorder
• A family history of mood disorder
• Premenstrual depression
• Premenstrual mood changes
• Past history of sexual abuse
• Past, present, or current domestic violence

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Eating disorder
Disorders of adrenal system
Catamenial migraine
Catamenial epilepsy
Collagen-vascular disease

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The role of laboratory studies is limited to screening for medical conditions considered in the differential diagnosis. While some tests may be needed to reassure the patient, excessive testing can be counterproductive by making the patient more anxious.
• The initial steps in evaluating a patient for PMDD are aimed at excluding organic syndromes with manifestations similar to those of PMDD, such as thyroid disorders, anemia, perimenopause, and menopause. Laboratory studies should include the following:
• • Thyroid function tests
  • Complete blood cell count
  • Follicle-stimulating hormone level

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The treatment of PMDD includes both nonpharmacological and pharmacological treatment. Nonpharmacological treatment includes aerobic exercise (see Activity), consumption of complex carbohydrates and frequent meals (see Diet), relaxation training, light therapy, sleep deprivation, and cognitive-behavioral approaches.

• Nonpharmacological treatment
• • Relaxation therapy: Relaxation response is a physiological response that results in decreased metabolism, decreased heart rate, decreased blood pressure, decreased 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 an adjunct to other modalities of therapy. Available trials of relaxation treatment showed conflicting results. In one study, twice-daily relaxation therapy was superior to keeping a daily symptoms chart and leisure reading for improving physical symptoms of PMDD. In another study, relaxation therapy was less effective than coping skills training.
  • Light therapy: 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 these lamps with full-spectrum fluorescents (bright light) that are more similar to sunlight. A recent, randomized, double-blinded, crossover study compared the effect of bright light therapy and dim light therapy (placebo). The study demonstrated that 30 minutes of evening bright light therapy during the luteal phase was superior to placebo in 14 women with PMS. The effect of bright light was postulated to be mediated through the serotonin system. An open study reported that daily photic stimulation reduced emotional and physical premenstrual symptoms.
  • Sleep deprivation: Most patients with major depressive disorder respond to a night of total sleep deprivation. Treatments for major depressive disorder also may be effective for PMDD because of the relationship of major depressive disorder to PMDD. A randomized crossover trial of early-night sleep deprivation versus late-night sleep deprivation on 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. The healthy comparison subjects showed no clinically important mood changes. The efficacy of sleep deprivation in reducing depressive symptoms in PMDD parallels the efficacy of sleep deprivation in major depressive disorder.
  • Cognitive-behavioral treatment: Cognitive therapy views that behavioral disorders are influenced by negative or extreme thought patterns. These patterns are so habitual that they become automatic and are unnoticed by the individual. Cognitive treatment teaches patients ways to examine these negative patterns and replace them with more adaptive ways of viewing life events. Cognitive-behavioral therapy for PMDD includes anger control, thought stopping, and reduction of negative emotions through cognitive restructuring. Results from randomized controlled trials comparing cognitive-behavioral treatment with a dummy treatment or placebo are conflicting. A recent study reported that cognitive therapy was superior to a wait-list control situation in 23 women with prospectively confirmed PMS. Another controlled study reported that group cognitive-behavioral therapy was as effective as group information-focused therapy in 33 women with prospectively confirmed PMS.
• Pharmacological treatment
• • Vitamins and minerals
    • The use of pyridoxine (vitamin B-6) has had varying success described in the literature. One systematic review reported that no high-quality randomized controlled trials comparing pyridoxine and placebo were found. Limited poor-quality data favor the use of pyridoxine. An initial dose of 50-100 mg/d may be beneficial, without the risk of peripheral neuropathy, which is associated with doses of 200 mg/d or higher.
    • Data on the effects of dietary supplements on improving premenstrual symptoms are insufficient.
    • One recent nonrandomized trial found that a low-fat vegetarian diet reduced premenstrual symptoms.
    • Calcium supplementation during the luteal phase has proven beneficial with regard to bloating, pain, mood, and food cravings. The use of calcium carbonate (TUMS-EX, 2 tablets twice daily) has been described. In a trial of more than 400 women with documented PMS, subjects were assigned randomly to receive either placebo or 1200 mg of elemental calcium per day. The regimen was started 7-10 days after the onset of menses and continued for 3 complete cycles. More than 50% of women in the calcium group had significant decreases in depression, water retention, pain, food cravings, fatigue, and insomnia. Although the possibility of urolithiasis has been a concern with calcium supplementation, in this study, only one patient in each group developed a stone.
    • One study reported that luteal phase administration of magnesium was helpful for premenstrual emotional and physical symptoms. However, a more recent study reported that daily administration of magnesium was helpful only for reducing premenstrual fluid retention and was not helpful for emotional symptoms. Note that the dose of magnesium supplementation in the latter study was 200 mg/d, as opposed to 360 mg/d in the former study.
    • A systemic review of 8 small, randomized, controlled trials reported a small beneficial effect of evening primrose oil in relieving premenstrual symptoms. However, the number of patients enrolled in these studies was quite low. 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 (see Special Concerns).
  • Hormones
    • One systematic review of 14 randomized controlled trials (search date, July 2000) found no improvement in premenstrual symptoms with progesterone over placebo. Of the trials, 3 of 14 used oral progesterone and 11 used progesterone suppositories. Adverse effects included abdominal pain, nausea, headache, pruritus vulvae, dizziness, drowsiness, excessive vaginal bleeding, and dysmenorrhea.
    • Data from randomized controlled trials of synthetic progesteronelike drugs (medroxyprogesterone acetate and dydrogesterone) for premenstrual symptoms are conflicting. The adverse effects are 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, no data prove this approach.
    • Danazol suppresses the ovarian cycle in most women. Many randomized controlled trials showed beneficial effects of danazol on premenstrual symptoms. 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 danazol.
    • Randomized controlled trials have shown the beneficial effect of gonadotropin-releasing hormone analogues on premenstrual symptoms. However, use of gonadotropin-releasing hormone 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.
    • Anecdotal evidence suggests that oral contraceptives, by suppressing ovulation, may be beneficial in relieving premenstrual symptoms. Adverse effects of bloating, appetite changes, and depressive symptoms can occur and mimic the symptoms of PMDD.
    • Limited data are available on the beneficial effect of bromocriptine in relieving breast tenderness. Rare reports exist of stroke and death following 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.
    • In 1976, Werch and Kane reported the beneficial effect of metolazone.
    • Adverse effects include nausea, dizziness, palpitations, excess diuresis, and weakness.
  • Nonsteroidal anti-inflammatory drugs
    • Five randomized controlled trials found improvement of premenstrual symptoms, except breast pain, with mefenamic acid compared with placebo.
    • One placebo-controlled trial with naproxen sodium found it more effective than placebo for physical symptoms. Another trial with naproxen sodium reported significant improvement in mood changes and headache with naproxen sodium over placebo.
    • Adverse effects include nausea, vomiting, epigastric pain, gastrointestinal bleeding, and rash.
  • Anxiolytics, antidepressants, and mood stabilizers: Most trials of nonselective serotonin reuptake inhibitor (non-SSRI) antidepressants (eg, bupropion, clomipramine, nortriptyline, desipramine) and anxiolytics (eg, alprazolam, buspirone) reported positive effects on one or more symptoms compared with placebo.
  • • Bupropion can lower the convulsive threshold.
    • Clomipramine is a tricyclic antidepressant that inhibits norepinephrine and serotonin reuptake.
    • Buspirone has been shown to be efficacious in the treatment of PMS and PMDD. Adverse effects include nausea, headache, nervousness, and dizziness. Buspirone may be administered throughout the cycle or during the late luteal phase.
    • Alprazolam reduces depression, irritability, and anxiety. Tolerance and dependence are potential adverse effects.
    • Adverse reactions of the above medicines led to problems with therapy compliance in most trials.
    • Two trials of beta-blockers (atenolol and propranolol) found favorable effects.
    • Two trials of lithium reported no significant difference in symptoms compared with placebo.
    • The serotonergic system is in close relationship with the gonadal hormones, and it has been identified as the most plausible target for intervention. SSRIs are emerging as the most effective treatment option for PMDD.
    • Several randomized controlled trials in women with PMDD have clearly demonstrated that SSRIs have excellent efficacy and minimal adverse effects. One preliminary systemic review (search date, July 2000) of 15 randomized controlled trials found significant improvement in overall symptoms in patients on SSRIs compared with placebo. The SSRIs used in these trials were fluoxetine, sertraline, citalopram, fluvoxamine, and paroxetine. More recently, several preliminary studies indicate that intermittent treatment with SSRIs limited to the premenstrual phase is equally effective. Fluoxetine, sertraline, and paroxetine controlled release are FDA-approved SSRIs for PMDD.
    • 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. 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. 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.
    • In a 1995 large double-blinded trial, Steiner et al reported that fluoxetine at 20 or 60 mg/d through 6 menstrual cycles improved mood symptoms in 53% of the cycles compared with improvement in 28% of the cycles with placebo.
    • Two randomized controlled trials, one using daily dosing and another using luteal phase dosing, demonstrated the effectiveness of sertraline in subjects with PMDD. In 1998, Young et al reported that sertraline administered intermittently was significantly more effective than placebo in reducing both behavioral and physical symptoms as assessed by the Calendar of Premenstrual Experiences.
    • A multicenter, randomized, double-blind, placebo-controlled, 3-arm, fixed-dose study of luteal phase dosing with paroxetine CR in the treatment of PMDD showed that luteal phase dosing with 12.5 mg and 25 mg of paroxetine CR is effective and generally well tolerated.
    • 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. 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. Response to treatment was relatively rapid, noted to sometimes occur in the first treatment cycle.
    • A recent preliminary study showed that PMDD improved significantly with either luteal phase or symptom-onset dosing of escitalopram.

Surgical Care

• Randomized controlled trials demonstrated that hysterectomy plus bilateral oophorectomy was curative.
• 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 laparoscopic bilateral oophorectomy and endometrial ablation in the treatment of PMDD.

Diet

Dietary advice constitutes an important aspect of nonpharmacological 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.
• Consumption of complex carbohydrates and restriction or moderation of caffeine and alcohol intake have not been consistently beneficial in alleviating the symptoms of PMDD.

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, whether aerobic exercise is more effective than nonaerobic exercise is unclear.
• The efficacy of exercise could be because of raised endorphin levels, physiologic changes, and psychological changes.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goal of pharmacotherapy is to relieve symptoms.

Drug Category: Vitamins and minerals

Varying success described in the literature.

Drug Name	Calcium carbonate (Caltrate, TUMS)
Description	Calcium supplementation during luteal phase has proven beneficial with regard to bloating, pain, mood, and food cravings.
Adult Dose	600 mg elemental calcium PO bid
Pediatric Dose	Not established
Contraindications	Renal calculi; hypercalcemia; hypophosphatemia; digitalis toxicity
Interactions	May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; large intake of dietary fiber may decrease calcium absorption and levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in digitalized patients and respiratory failure or acidosis

Drug Category: Hormones

Danazol suppresses the ovarian cycle in most women. Many randomized controlled trials showed beneficial effects on premenstrual symptoms.

Drug Category: Diuretics

Widely used on the assumption that many symptoms are secondary to fluid retention.

Drug Name	Metolazone (Zaroxolyn)
Description	Thiazide diuretic with reported beneficial effect in PMDD. Increases excretion of sodium, water, potassium, and hydrogen ions by inhibiting reabsorption of sodium in distal tubules.
Adult Dose	5-20 mg/dose PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hepatic coma; anuria
Interactions	Thiazides may decrease effect of anticoagulants, sulfonylureas, and gout treatments; anticholinergics and amphotericin B may increase toxicity of thiazides; effects of thiazides may decrease when used concurrently with bile acid sequestrants, NSAIDs, or methenamine; when administered concurrently, thiazides increase toxicity of anesthetics, diazoxide, digitoxin, lithium, loop diuretics, antineoplastics, allopurinol, calcium salts, vitamin D, and nondepolarizing muscle relaxants
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in hepatic or renal disease, diabetes mellitus, gout, or lupus erythematosus

Drug Category: Nonsteroidal anti-inflammatory drugs

Reported to improve some physical and mental symptoms in PMDD.

Drug Name	Mefenamic acid (Ponstel)
Description	Reported to improve premenstrual symptoms, except breast pain.
Adult Dose	500 mg PO initially, followed by 250 mg q4h prn
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding
Interactions	Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Category D in third trimester of pregnancy; may have adverse effects in fetus; caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in anticoagulation abnormalities or during anticoagulant therapy

Drug Category: Antidepressants

Reported to have positive effects on one or more symptoms of PMDD compared with placebo. Antidepressant drug is indicated if PMDD symptoms of depression are moderate to severe.

Drug Name	Clomipramine (Anafranil)
Description	Affects serotonin uptake. Affects norepinephrine uptake when converted into its metabolite desmethylclomipramine.
Adult Dose	25 mg/d PO initially, followed by gradual increase to 100 mg/d the first 2 wk; not to exceed 250 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; recent myocardial infarction; use within 14 d of MAOIs
Interactions	Barbiturates, phenytoin, and carbamazepine decrease effects; increases effects of anticholinergics, sympathomimetics, alcohol, and CNS depressants; toxicity of MAOIs increases
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in severe cardiopulmonary or renal impairment and in those unable to metabolize sorbitol

Drug Name	Nortriptyline (Aventyl, Pamelor)
Description	Inhibits reuptake of serotonin and/or norepinephrine by presynaptic neuronal membrane.
Adult Dose	25 mg PO tid/qid, not to exceed 150 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; narrow-angle glaucoma; use within 14 d of MAOIs
Interactions	Cimetidine may increase levels when used concurrently; may increase PT in patients stabilized with warfarin
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in cardiac conduction disturbances and history of hyperthyroidism or renal or hepatic impairment; because of pronounced effects in cardiovascular system, avoid in elderly patients

Drug Name	Fluoxetine (Sarafem, Prozac)
Description	Selectively inhibits presynaptic serotonin reuptake with minimal or no effect on reuptake of norepinephrine or dopamine.
Adult Dose	10 mg/d PO initially, increase in 10-mg/d increments prn; dose changes should occur at intervals of at least 1 wk; usual dose range is 10-60 mg/d; not to exceed 60 mg; lower or less frequent dose in patients with hepatic cirrhosis
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; concurrent administration with MAOIs or within 14 d of MAOIs
Interactions	Increases toxicity of diazepam and alprazolam by decreasing clearance; increases toxicity of highly protein-bound drugs; increases plasma level and toxicity of phenytoin and carbamazepine; fatal reactions reported with concurrent or sequential administration of MAOIs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in history of seizures, mania, suicide, hepatic disease, and cardiac disease

Drug Name	Sertraline (Zoloft), Paroxetine (Paxil CR)
Description	Selectively inhibits presynaptic serotonin reuptake.
Adult Dose	Sertraline: 50 mg/d PO qam initially, increase in 50-mg/d increments q2-3d to 100 mg/d, if tolerated; not to exceed 200 mg/d Paroxetine: 12.5 mg PO qd initially, may increase to 25 mg/d if needed
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; concurrent administration with MAOIs or within 14 d of discontinuing an MAOI; coadministration with thioridazine
Interactions	Serotonin syndrome (ie, myoclonus, rigidity, confusion, nausea, hyperthermia, autonomic instability, coma, eventual death) occurs with simultaneous use of other serotonergic agents (eg, anorectic agents, tramadol, buspirone, trazodone, clomipramine, nefazodone, tryptophan), discontinue other serotonergic agents at least 2 wk prior to using other SSRIs Sertraline: Inhibits CYP450 isoenzymes 3A3/4, 2C9, 2C19, and 2D6, resulting in possible decreased clearance of isoenzyme substrates (eg, metoprolol, thioridazine, imipramine, haloperidol, phenytoin, barbiturates, glyburide, warfarin); increases toxicity of MAOIs, diazepam, tolbutamide, and warfarin Paroxetine: Inhibits CYP450 2D6, thus may increase toxicity of 2D6 substrates (eg, phenothiazines, propafenone, flecainide and encainide, other SSRIs, TCAs); phenobarbital and phenytoin decrease effects; alcohol, cimetidine, sertraline, phenothiazines, and warfarin increase toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in preexisting seizure disorders and in those who have experienced a recent myocardial infarction, have unstable heart disease, and have hepatic or renal impairment

Drug Category: Beta-adrenergic blocking agents

One 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.

Drug Category: Anxiolytics

Reported to have positive effects on one or more symptoms of PMDD compared with placebo. Anxiolytics should be used in PMDD if anxiety is prominent symptom, with dysphoria occurring secondarily.

Drug Name	Buspirone (BuSpar)
Description	5-HT1 agonist with serotonergic neurotransmission and some dopaminergic effects in CNS.
Adult Dose	15 mg/d PO divided tid, increase by 5 mg/d q2-4d; not to exceed 60 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Toxicity is increased with MAOIs, phenothiazines, and CNS depressants; increases toxicity of digoxin and haloperidol
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in hepatic or renal impairment

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

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

Prognosis

• 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.
• Symptoms do not usually recur after oophorectomy.

Patient Education

• Educate women to seek help for PMDD. Emphasize the following reasons for the need to seek help:
• • Problems tend to recur each cycle.
  • Problems may become more severe over time.
  • Problems can be quite disabling to women and their families.
  • Problems may not go away if ignored.
  • Problems can be readily diagnosed and effectively treated.
• Educate both the patient and the family/spouse as this disorder impacts on the entire family context.
• For excellent patient education resources, visit eMedicine's Women's Health Center. Also, see eMedicine's patient education article Premenstrual Syndrome (PMS).

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• PMDD is underdiagnosed and undertreated. No definitive laboratory or ancillary procedure aids in the diagnosis, and no definitive treatment is available for the symptoms associated with the syndrome; however, many options are available.
• Identifying and treating PMDD is quite a challenge for a primary care physician. A patient with another mood disorder might have preconceptions that she has PMS or PMDD, and, consequently, the diagnosis of PMDD may be incorrect. On the other hand, a patient may not have intellectually connected her symptoms to her menstrual cycle. The correct diagnosis depends on extended patient education and correcting previously received misinformation.

Special Concerns

• The studies that have 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 and/or oral contraceptives for other reasons. No major adverse reactions have been reported with this combination; however, awaiting further studies before prescribing SSRIs for PMDD in younger girls is sensible. Relatively low-risk therapy such as calcium supplements or nonsteroidal anti-inflammatory drugs 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.
• Women with premenstrual symptoms often explore alternative therapies that have not been proven effective. 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 and herbal formulations often used by women in self-treatment of PMS symptoms are listed below.
• Nutritional supplements
• • Calcium with magnesium chloride
  • Evening primrose oil
  • Kelp
  • L-tyrosine
  • Multivitamin-mineral complex with manganese
  • Vitamin B complex
  • Vitamin C with bioflavonoids
• Herbal formulations
• • Cayenne
  • Dong quai
  • Siberian ginseng
  • Pulsatilla
  • Raspberry leaves
  • St John's wort
  • Sepia
  • Blessed thistle
  • American valerian
  • Wild yam

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Apr 13, 2006