commonly asked questions about premenstrual dysphoric disorder

REVIEW

K A T H R Y N S. M U Z I N A , MD Department of Psychiatry and Psychology, Cleveland Clinic.

L I L I A N G O N S A L V E S , MD Vice chair, Department of Psychiatry and Psychology; and Department of Gynecology and Obstetrics, Cleveland Clinic.

Commonly asked questions about premenstrual dysphoric disorder

ABSTRACT

Although the etiology of premenstrual dysphoric disorder (PMDD), a severe form of premenstrual syndrome, is as yet unconfirmed, it is a biological condition that responds to biological therapies. With education, psychotherapy, and somatic and psychotropic treatment, women with PMDD can attain improved health and quality of life.

KEY POINTS Mos t w o m e n of reproduct ive age have some symptoms of premenstrua l syndrome (PMS), bu t on ly approx imate ly 2 . 5 % to 5 % have symptoms severe enough to af fect func t ion and qual i fy for a diagnosis of premenstrual dysphoric disorder (PMDD).

PMDD is d iagnosed by rul ing out organic causes of symptoms, and then asking pat ients to record their dai ly symptoms and basal body tempera tu re dur ing t w o or three cycles to conf i rm tha t symptoms occur in the luteal phase.

Treatment for PMDD depends on severity and type of symptoms; mi ld cases may respond to educat ion, l i festyle modi f icat ions, and somat ic t rea tments alone.

Severe cases of PMDD may require hormona l and psychotropic drugs such as oral contracept ives and selective serotonin reuptake inhibi tors, and may also require a psychiatr ic consult . Surgical ovar iec tomy is a last resort.

REMENSTRUAL SYNDROME (PMS) is a m o n g

the more common and puzzling prob-lems that primary care physicians and gynecol-ogists encounter. Too often, physicians dismiss premenstrual complaints as functional or psy-chosomatic, thereby invalidating the patient's symptoms and depriving her of treatment that can be c]Liite helpful and relatively easy to pre-scribe and manage.

Most women experience PMS to some degree, and to most it is a nuisance at worst. However, some women have a severe variety of PMS called premenstrual dysphoric disorder (PMDD) that can disrupt their life. This article reviews common questions about the definition of P M D D and its prevalence, risk factors, dif-ferential diagnosis, diagnostic evaluation, etio-logic theories, and current treatment strategies.

• WHAT IS PMDD? HOW IS IT DIFFERENT FROM PMS?

PMS is a group of physical, cognitive, and emo-tional symptoms that occurs in the late luteal phase of the menstrual cycle. It was described in ancient times as a virgin's disease, because in those times any woman who was married was generally pregnant and therefore not cycling. And from ancient times it was recognized that in a subset of women, PMS is severe enough to interfere with social and occupational func-tioning. Pliny the Elder, horn in A D 23, wrote in his Historia Naturalis that:

" O n the approach of a woman in this state, milk will turn sour, seeds which are touched by her become sterile, grafts writhe away.. .her very look, even, will dim the brightness of mirrors, blunt the edge of steel, and take the polish from ivory."

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Previously known as late luteal phase dys-phoric disorder, this severe variety of PMS is described in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders1 under its new name, in an appendix of diagnoses warranting further study.

Symptoms of PMDD include: • Depressed mood • Anxiety • Affective lability • Anger or irritability • Decreased interest in usual activities • Difficulty concentrating • Decreased energy • Appetite changes • Hypersomnia or insomnia • A sense of being overwhelmed • Other physical symptoms such as

breast swelling or tenderness, headaches, joint or muscle pain, a sensation of bloating, and weight gain.

Diagnostic criteria for PMDD. These symptoms must:

• Be present in most of the menstrual cycles in the past year, and five or more symp-toms must be present during the last week of the luteal phase.

• Begin to remit several days after the onset of menses, and be absent during the week after menses ceases.

• Markedly interfere with school, work, social activities, or relationships.

• Not be an exacerbation of the symp-toms of another disorder such as major depres-sive disorder.

• Be confirmed by prospective daily rat-ings through a minimum of two consecutive symptomatic menstrual cycles.

In contrast, the term PMS is generally used to describe milder physical symptoms such as breast changes, headaches, bloating, and minor changes in mood that do not inter-fere with daily functioning.

• HOW COMMON IS PMDD?

A n estimated 75% of women with regular menstrual cycles note some symptoms of pre-menstrual dysphoria, and these women are usually seen by primary care physicians or gynecologists.2

PMDD, in contrast, is significantly less

TABLE 1 Differential diagnosis of premenstrual dysphoric disorder Anemia

Endometriosis

Menopause

Pelvic inf lammatory disease

Premenstrual magnif ication of a primary psychiatric condit ion

Primary or secondary dysmenorrhea

Seizure disorder

Thyroid disease

Uterine fibroids

common, affecting perhaps 2.5% to 5% of women of reproductive age.' Women with P M D D generally do not respond to the usual treatments for PMS, and thus are frequently referred to psychiatrists or tertiary care cen-ters. O f these women, approximately 60% have "true" PMDD, another 8% are thought to have magnification of symptoms of anoth-er major psychiatric disorder or physical con-dition during the luteal phase of their cycle, and the remainder either have only mild symptoms or meet criteria for another major psychiatric diagnosis at the time of the eval-uation, thereby not qualifying as having PMDD.4

• PREDISPOSING FACTORS FOR PMDD

R e p r o d u c t i v e age. Because P M D D is a phenomenon of the menstrual cycle, it affects only women of reproductive age. Freeman et al,5 in a study of 332 women ages 20 to 44, found symptoms to be most severe in women in their late 20s through mid-30s.

D e p r e s s i o n . Numerous studies have linked the premenstrual syndrome to depres-sion. Approximately 80% of women with PMDD have depression at some time in their lives. Further, 65% of women with major

PMDD interferes with function; PMS does not

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P R E M E N S T R U A L D Y S P H O R I C D I S O R D E R M U Z I N A A N D GONSALVES

PMS and PMDD are linked to depression

depressive disorder experience premenstrual exacerbation of their symptoms.6 In one study, Harrison et al7 found a higher lifetime preva-lence of depression, suicide attempts, panic disorder, and substance abuse in women seek-ing treatment for PMDD than in a control group. However, the difference disappeared after women with a primary psychiatric diag-nosis were excluded.

Additional risk factors include a family history of mood disorders and a personal his-

tory of postpartum depression.

• DIFFERENTIAL DIAGNOSIS

T h e differential diagnosis of P M D D is exten-sive ( T A B L E 1 ) ; therefore it is important to rule out organic causes of symptoms. T h e follow-ing case report illustrates the type of case where P M D D might be suspected, but in which a detailed investigation unearthed another organic cause.

CASE REPORT

A 3 9 - y e a r - o l d w o m a n w i t h PMS

• A 3 9 - y e a r - o l d w o m a n w a s r e f e r r e d t o t h e P M S c l i n i c a t t h e C l e v e l a n d C l i n i c F o u n d a t i o n . Fo r t h e p a s t 6 m o n t h s , s h e h a d e x p e r i e n c e d d i m i n i s h e d c o n c e n t r a t i o n , d e c r e a s e d e n e r g y , n a u s e a , d i z z i n e s s , a n d o c c a s i o n a l f a i n t i n g d u r i n g t h e 2 d a y s b e f o r e t h e o n s e t o f h e r p e r i o d . T h e s e s y m p t o m s w e r e d o c u m e n t e d o n d a i l y s y m p t o m - r a t i n g f o r m s .

A p p r o x i m a t e l y 1 m o n t h p r e v i o u s l y , t h e p a t i e n t f a i n t e d w h i l e d r i v i n g ; h e r ca r h i t a t r e e , a n d she f r a c t u r e d h e r r i g h t a r m . T h e w o r k u p a t a c o m m u n i t y h o s p i t a l i n c l u d e d a n e l e c t r o e n c e p h a l o g r a m , e c h o c a r d i o g r a m , a n d c o m p u t e d t o m o g r a p h i c (CT) scan o f h e r h e a d , a l l o f w h i c h w e r e n o r m a l . S h e h a d n o h i s t o r y o f m e d i c a l o r p s y c h i a t r i c d i s o r d e r s o r c h e m i c a l d e p e n d e n c y . H e r f a m i l y h i s t o r y w a s n e g a t i v e f o r p s y c h i a t r i c a n d n e u r o l o g i c i l l nesses . T h e o n l y m e d i c a t i o n s h e u s e d w a s v i t a m i n B 6 . H e r m e n t a l s t a t u s w a s w i t h i n n o r m a l l i m i t s .

B e c a u s e h e r s y m p t o m s w e r e n o t t y p i c a l o f P M D D , t h e p a t i e n t w a s r e f e r r e d f o r f u r t h e r n e u r o l o g i c a n d c a r d i a c e v a l u a t i o n . S e r u m leve l s o f t h y r o i d - s t i m u l a t i n g

h o r m o n e (TSH), t h y r o x i n e (T4) , t r i -i o d o t h y r o n i n e (T3), f o l l i c l e -s t i m u l a t i n g h o r m o n e , l u t e i n i z i n g h o r m o n e , a n d e l e c t r o l y t e s w e r e n o r m a l . H o l t e r m o n i t o r i n g s h o w e d s h o r t r u n s o f v e n t r i c u l a r t a c h y c a r d i a , w h i c h w e r e p r e s u m e d t o b e t h e c a u s e of h e r s y n c o p e a n d f o r w h i c h p r o p r a n o l o l 2 0 m g f o u r t i m e s a d a y w a s s t a r t e d . H o w e v e r , t h e s y m p t o m s c o n t i n u e d .

T w e n t y - t w o days a f t e r h e r i n i t i a l e v a l u a t i o n , t h e p a t i e n t ' s h u s b a n d w i t n e s s e d h e r h a v i n g a 2 0 - s e c o n d s e i z u r e w h i l e she s l ep t . She w a s a d m i t t e d t o t h e hosp i t a l , w h e r e s h e d e s c r i b e d a s t r a n g e o d o r t h a t h a d p r e c e d e d t h e se izure . F u r t h e r t e l e m e t r i c m o n i t o r i n g f a i l e d t o d e m o n s t r a t e a n a r r h y t h m i a w i t h w h i c h h e r s y m p t o m s m i g h t b e c o r r e l a t e d . A m a g n e t i c r e s o n a n c e i m a g i n g scan o f her h e a d w a s n o r m a l . She w a s e v e n t u a l l y d i a g n o s e d b y he r n e u r o l o g i s t w i t h a c o m p l e x p a r t i a l se izure d i s o r d e r . C a t a m e n i a l ep i l epsy is a g r o u p i n g o f se i zu res a r o u n d the p e r i m e n s t r u a l o r p e r i o v u l a t o r y phases o f t h e m e n s t r u a l cyc le . C a r b a m a z e p i n e t h e r a p y w a s s t a r t e d , a n d a t last r e p o r t t h e p a t i e n t r e m a i n s s y m p t o m - f r e e .

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N A M E : M O N T H / Y E A R Scale f o r s y m p t o m s : 1 - N o t p r e s e n t 2 - M i n i m a l 3 - M i l d 4 - M o d e r a t e 5-Severe 6 - E x t r e m e

DATE: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 BASAL BODY TEMPERATURE (ALSO CHECK EACH DAY OF MENSTRUAL PERIOD) ACNE OR PIMPLES ANGRY/IRRITABLE CRAMPS CRYING/FEELING LIKE CRYING DEPRESSED DISTURBING THOUGHTS EMPTY FEELING ENERGY DECREASED ENERGY INCREASED FOOD CRAVINGS

SUGAR SALT

HALLUCINATIONS HEADACHES HELPLESSNESS HOPELESSNESS NERVOUS NEED TO BE ALONE NOISE SENSITIVITY OUT OF CONTROL SEXUAL INTEREST INCREASED SEXUAL INTEREST DECREASED SLEEP DISTURBANCE SUICIDAL TENSION UNREAL FEELING VIOLENT FEELING

FIGURE 1. S y m p t o m c a r d u s e d b y p a t i e n t s a t t h e C l e v e l a n d C l i n i c . A s p a c e f o r c o m m e n t s f o r e a c h d a y is p r o v i d e d o n t h e b a c k .

• CLINICAL EVALUATION

Rule ou t organic syndromes The initial steps in evaluating a patient for P M D D are aimed at ruling out organic syn-dromes presenting as PMDD, such as thyroid disorders, perimenopause, and menopause.

T h e history should include the medical, gynecologic, and psychiatric areas, with care-ful attention to responses to pregnancy (ie, postpartum depression) and any psychiatric disorders. Patients should also be asked about current drug and alcohol use.

T h e physical examination should include a pelvic examination.

Laboratory studies should include thyroid function tests, a complete blood count, and estrogen and progesterone levels.

Record and rate the symptoms Next, patients are asked to:

• Rate their symptoms every day for two or three menstrual cycles, and record them on

a "symptom card" (FIGURE 1 ) .

• Take and record their basal body tem-peratures on the symptom card before getting out of bed every morning; the basal body tem-perature typically reaches a nadir at ovulation and then rises approximately 1 °F.

• Take a psychological test such as the Minnesota Multiphasic Personality Inventory or the Beck Depression Inventory, a week prior to menses and repeated a week after menses; this can lend objective evidence to support the patient's subjective reporting of symptoms.

The diagnosis is made after examining the symptom cards to confirm that the symptoms occur in the luteal phase based on basal body temperature, ruling out medical or gynecolog-ical disease, and ruling out primary psychiatric diagnoses.

• WHAT ARE POSSIBLE CAUSES OF PMDD?

Many women with P M D D who enter menopause prematurely as the result of surgi-

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P R E M E N S T R U A L D Y S P H O R I C D I S O R D E R M U Z I N A A N D G O N S A L V E S

T A B L E 2

Therapy for premenstrual dysphoric disorder Fi rs t -s tep t r e a t m e n t s

Education and lifestyle modif ications Diet modif ications Exercise Vitamins and minerals

Somatic treatments Acetaminophen Bromocriptine Diuretics Nonsteroidal ant i - inf lammatory drugs

Second-s tep t he rap ies Hormonal therapies

Oral contraceptives (mild symptoms) Gonadotropin-releasing hormone analogs or danazol (severe or refractory symptoms)

Psychotropic drugs Alprazolam Buspirone Selective serotonin reuptake inhibitors Tricyclic antidepressants

Th i rd -s tep t r e a t m e n t Psychotherapy

cal ovariectomy or medical therapy subse-quently experience a dramatic reduction in their symptoms. This implies that some part of the menstrual cycle goes awry in PMDD, but which one? Theories abound, but none have been conclusively verified.

Progesterone deficiency, a theory pro-posed by Dalton8 and once popular, has not been confirmed in prospective studies.9-10

Ovarian steroid imbalance. The impor-tance of ovarian steroids in the pathophysiolo-gy of PMDD was first demonstrated by Muse et al,11 who gave a gonadotropin releasing hor-mone (GnRH) agonist to women with PMDD, after which ovarian stimulation ceased and pre-menstrual symptoms resolved. Recently, Schmidt et al12 studied the different behavioral effects of gonadal steroids in 20 women with PMS and 15 women without PMS. They con-cluded that in women with PMS, the occurence of symptoms represented an abnor-mal response to normal hormonal changes.

A n abnormal thyroid-stimulating hor-

mone response to thyrotropin-releasing hor-mone was demonstrated in one study13; how-ever, most other studies did not support this finding.

Dysregulation in central neurotransmis-sion, due to ovarian steroid flux, is a more recent theory. Estrogen, progesterone, and their metabolites are known to alter function in the noradrenergic and gamma-aminobu-tyric acid ( G A B A ) systems.H

Serotonin dysfunction. Still more recent-ly, interest has turned to the effects of estrogen and progesterone on the serotoninergic sys-tem. Rapkin15 found diminished levels of serotonin in whole blood and platelets during the late luteal phase in women with PMDD. Furthermore, patients with P M D D have responded dramatically to the selective sero-tonin reuptake inhibitor, f luoxetine. 1 6 - 1 8

• FIRST-STEP TREATMENTS

Many treatments for P M D D have been devised over the years, all aimed at the possi-ble causes discussed above. These have included exercise, vitamin supplementation, dietary changes, various hormones, diuretics, psychotropic medications, nonsteroidal anti-inflammatory drugs (NSAlDs) , medical and surgical oophorectomy, light therapy, and sleep deprivation. However, most of these have proved ineffective in prospective studies.

T A B L E 2 outlines the current treatments for P M D D and the milder syndrome, PMS. The first step is to review the individual patient's symptoms and then select treatment that addresses her specific complaints. T h e first line of treatment consists of education, lifestyle changes, and somatic therapies. These steps provide adequate relief for PMS, and at least some relief from less severe forms of PMDD.

Educat ion and l i festy le changes Patients should be told that P M D D is a legit-imate syndrome, and that anticipating it and responding appropriately can decrease its severity considerably. T h e patient's spouse, children, and significant friends may also need to hear this message and be more supportive. Support groups for women with P M D D also provide education and psychological support,




and participants in such groups may enjoy greater symptom relief than nontreated con-trols, as noted by Pearlstein et al.19

D i e t a r y m o d i f i c a t i o n s may modulate some symptoms. A dietitian can assess whether dietary factors may be contributing to the symptoms. General recommendations:

• Reduce consumption of caffeine and its equivalents (theophyll ine, theobro-mine, and other methylxanthines) dur-ing the late luteal phase; these have been linked to more severe premen-strual symptoms, including irritability and insomnia.20

• Reduce salt intake to minimize tempo-rary water weight gain.

• Increase intake of complex carbohy-drates.

• Decrease consumption of refined sugars. • Eat frequent small meals to avoid

hypoglycemia. E x e r c i s e may improve mood, perhaps by

increasing circulating endorphin levels.2 1

Several studies22-24 found exercise beneficial in nonclinical settings. Increasing the fre-quency of exercise was found to reduce symptoms related to fluid retention.2 2 A pro-gram of regular aerobic exercise produced greater symptom relief than did strength training.2 3 One recent prospective study showed both low-intensity and moderate-intensity aerobic training to be beneficial over three menstrual cycles.2 4 These studies were not controlled and therefore lacked sci-entific rigor. However, at the very least, reg-ular aerobic exercise will contribute to improved general health and will likely pro-vide some relief from P M D D .

Vitamin and mineral supplements. Pyridoxine (vitamin B^), a cofactor in the production of several neurotransmitters thought to be related to P M D D , is a popular treatment discussed in the lay press. Low doses (50 tng daily) may reduce depression, irritability, and fatigue.25 However, very large doses may produce neurotoxicity, marked by muscle weakness, numbness, paresthesias, and clumsiness. Calcium (80 mg daily) and magnesium (360 mg daily) have been exam-ined in clinical trials, and have both been found helpful in reducing premenstrual symptoms.26 '27

Trea tment o f somat ic symp toms Some treatments are aimed at specific somatic symptoms such as bloating, weight gain, swelling, headaches, breast tenderness, and joint or muscle pain.

Fluid retention can be addressed by a low-salt diet and calcium and magnesium supple-ments. Diuretics can be prescribed if these conservative measures fail. Spironolactone is preferred over the thiazides, as it is less likely to produce dependence on diuretics or rebound cyclic edema.28

Headaches, joint and muscle pain, and b r e a s t t e n d e r n e s s can be treated with N S A I D s or acetaminophen. Breast tenderness can also be reduced by wearing a supportive bra. More severe breast tenderness can be treated with bromocriptine, beginning at 2.5 mg daily and increased according to severity of symptoms and as tolerated; the common side effects are nausea and constipation.28

S SECOND-STEP THERAPIES

If the measures described above do not pro-vide adequate relief, the next step is to modi-fy the menstrual cycle and to give a psy-chotropic medication. A good option would be to begin with an oral contraceptive and then, if it provides no benefit after 2 months, switch to a selective serotonin reuptake inhibitor (SSRI).

Hormona l therap ies A s previously noted, early attempts to treat P M D D with progesterone were not particular-ly beneficial. There are currently four hor-monal alternatives available.

Oral contracept ives have been found use-ful in treating PMDD, particularly the symp-tom of painful menses; however, they have also been reported to worsen dysphoric symp-toms in some patients.29 Oral contraceptives that are estrogen dominant rather than andro-gen dominant are recommended.

Estradiol has been used successfully in PMDD; however, coadministration of prog-estins is required to prevent endometrial hyperplasia.30

G n R H agonists and danazol can be used to eliminate the menstrual cycle, and both have led to significant reductions in P M D D

Patients should consume less caffeine during the late luteal phase




P R E M E N S T R U A L D Y S P H O R I C D I S O R D E R M U Z I N A A N D G O N S A L V E S

Exercise may improve mood by increasing endorphin levels

symptoms.11 >31 Commonly used G n R H ago-nists include leuprolide, goserelin, and nafare-lin. Hot flashes, mood swings, and bone loss are some of the common side effects. These drugs should not be prescribed alone for longer than 6 months because of the risk of osteoporosis.

Surgica l ovar iectomy also eliminates the menstrual cycle—permanently. Al though it eradicates PMDD, it may lead to decreased libido and accelerated osteoporosis (compara-ble to that which can occur after natural menopause), and many other unwanted effects ascribed to low estrogen states. It is a last resort in women with severe symptoms for whom conservative therapies have failed.

Anx io ly t i c med ica t ions A multitude of studies have demonstrated the benefits of treating P M D D with anxiolytic and antidepressant medications.

Alprazolam (0.25 mg four times a day) has been demonstrated effective in double-blind s t u d i e s . T h e most common side effect is sedation. O n e advantage of alprazo-lam is that patients need to take it only during the symptomatic phase of the cycle, not con-tinuously. This dosing schedule may reduce the risk of addiction to this highly potent ben-zodiazepine.

Busp i rone was noted to produce improve-ments in symptoms at a dose of 5 to 10 mg three times a day during the luteal phase.35

Ant idepressan t med ica t ions Fluoxet ine , a selective serotonin reuptake

inhibitor (SSRI), has been demonstrated effective in several prospective studies, including double-blind, placebo controlled trials,1 5 - 1 7 producing significant reductions in affective and behavioral symptoms. T h e usual dose is 20 mg daily. Side effects include headaches, nausea, changes in appetite, and sexual dysfunction.

Sertraline, a second SSRI, produced similar results at doses of 50 to 150 mg daily in a recent controlled trial.36 T h e side effect profile of sertraline is similar to that of flu-oxetine. Our clinical experience reveals that all the SSRIs ( f luoxet ine , f l u v o x a m i n e , paroxetine, and sertraline) are equally effec-tive in treating P M D D and that they are

more similar than different in their side effect profiles.

Tricyclic antidepressants such as nor-triptyline and clomipramine are also effec-tive.37.38 Their side effects are predominantly anticholinergic, ie, dry mouth and sedation.

Venlafaxine and nefazodone, two novel antidepressants, remain in preliminary trials.

Unlike alprazolam and buspirone, the antidepressants are most effective if taken continuously.

Psychotherapy Should symptoms persist, patients should receive a psychiatric referral, especially if they have a personal or family history of mood dis-order or if substance abuse is suspected. Psychiatrists are uniquely qualified to treat severe or treatment-resistant cases, given the close ties between PMDD and depression, and the training that psychiatrists receive in psy-chotherapy. But regardless of clinical special-ty, clinicians need to be aware of psychologi-cal issues specific to women, and the increased risk of depression in women in general.

PMDD and the chang ing roles o f w o m e n in society Women today function in a myriad of com-plex roles. They may be wives and mothers in traditional nuclear families or single parents. Blended families (merged by divorce and remarriage) and stepparenting are common. Many women also care for aging parents.

A t the same time, increasing numbers of mothers work outside the home in ever-more-demanding jobs. Women run companies, uni-versities, states, day care centers, and police precincts, and also manage their homes day-to-day. These conflicting roles can produce considerable stress, which, left unrecognized, can lead to depression—and depression has close ties to PMDD. Therefore, the primary care clinician should be alert and sensitive to the stresses a woman may be under, and take these into account in their treatment.

A diagnosis of P M D D can also have legal ramifications. Women accused of murder and child abuse have used P M D D as a defense.39

Conversely, husbands have attempted to use the diagnosis of PMDD as a means of declar-ing a woman an unfit parent. C3




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4 . S t e i n e r M . P r e m e n s t r u a l d y s p h o r i c d i s o r d e r . A n u p d a t e . G e n H o s p P s y c h i a t r y 1 9 9 6 ; 1 8 : 2 4 4 - 2 5 0 .

5. F r e e m a n E W , R i c k e i s K, S c h w e i z e r E, T i n g T. R e l a t i o n s h i p s b e t w e e n a g e a n d s y m p t o m s e v e r i t y a m o n g w o m e n s e e k i n g m e d i c a l t r e a t m e n t f o r p r e m e n -s t r u a l s y m p t o m s . Psycho l M e d 1 9 9 5 ; 2 5 : 3 0 9 - 3 1 5 .

6 . E n d i c o t t J, H a l b r e i c h U . C l in ica l s i g n i f i c a n c e o f p r e m e n -s t r u a l d y s p h o r i c c h a n g e s . J C l in P s y c h i a t r y 1 9 8 8 ; 4 9 : 4 8 6 - 4 8 9 .

7 . H a r r i s o n W M , E n d i c o t t J, N e e J, G l i c k H , R a b k i n JG. C h a r a c t e r i s t i c s o f w o m e n s e e k i n g t r e a t m e n t f o r p r e -m e n s t r u a l s y n d r o m e . P s y c h o s o m a t i c s 1 9 8 9 ; 3 0 : 4 0 5 - 4 1 1.

8 . D a l t o n K. T h e p r e m e n s t r u a l s y n d r o m e a n d p r o g e s -t e r o n e t h e r a p y . 2 n d e d i t i o n . C h i c a g o : C h i c a g o Y e a r b o o k ; 1 9 8 4 .

9 . R a p k i n A , C h a n g LH, R e a d i n g A E . P r e m e n s t r u a l syn-d r o m e : A d o u b l e - b l i n d p l a c e b o c o n t r o l l e d s t u d y o f t r e a t -m e n t w i t h p r o g e s t e r o n e v a g i n a l s u p p o s i t o r i e s . J O b s t e t G y n e c o l 1 9 8 7 ; 7 : 2 1 7 - 2 2 0 .

10 . F r e e m a n E, R icke is K, S o n d h e i m e r SJ, P o l a n s k y M . I n e f f e c t i v e n e s s o f p r o g e s t e r o n e s u p p o s i t o r y t r e a t m e n t f o r p r e m e n s t r u a l s y n d r o m e . J A M A 1 9 9 0 ; 2 5 4 : 3 4 9 - 3 5 3 .

1 1 . M u s e K N , C e t e l IMS, F u t t e r m a n LA. T h e p r e m e n s t r u a l syn -d r o m e : e f f e c t s o f m e d i c a l o v a r i e c t o m y . N E n g l J M e d 1 9 8 4 ; 4 4 : 3 1 7 - 3 1 8 .

1 2 . S c h m i d t PJ, N i e m a n LK, D a n a c e a u M A , e t a l . D i f f e r e n t i a l b e h a v i o r a l e f f e c t s o f g o n a d a l s t e r o i d s in w o m e n w i t h a n d in t h o s e w i t h o u t p r e m e n s t r u a l s y n d r o m e . IM E n g l J M e d 1 9 9 8 ; 3 3 8 : 2 0 9 - 1 6 .

1 3 . R u b i n o w D R , H o b a n M C , G r o v e r G N , G a l l o w a y DS , R o y -B y r n e PP. A n d e r s e n R, M e r r i a m G R . C h a n g e s in p l a s m a h o r m o n e s across t h e m e n s t r u a l cyc le in p a t i e n t s w i t h m e n s t r u a l l y - r e l a t e d m o o d d i s o r d e r a n d in c o n t r o l s u b -j e c t s . A m J O b s t e t G y n e c o l 1 9 9 6 ; 1 5 8 : 5 - 1 1 .

1 4 . M c E w e n BS. Basic r e s e a r c h p e r s p e c t i v e : o v a r i a n h o r -m o n e i n f l u e n c e o n b r a i n n e u r o c h e m i c a l f u n c t i o n s . In: G i s e LH, K a s e N G , B e r k o w i t z RL, e d i t o r s . T h e P r e m e n s t r u a l S y n d r o m e s . N e w Y o r k : C h u r c h i l l L i v i n g s t o n e , 1 9 8 8 : 2 1 - 3 3 .

1 5 . R a p k i n A . T h e r o l e o f s e r o t o n i n in p r e m e n s t r u a l syn -d r o m e . C l i n O b s t e t G y n e c o l 1 9 9 2 ; 3 5 : 6 2 9 - 6 3 6 .

1 6 . S t o n e A B , P e a r l s t e i n TB , B r o w n W A . F l u o x e t i n e in t h e t r e a t m e n t o f l a t e l u t e a l p h a s e d y s p h o r i c d i s o r d e r . J C l i n P s y c h i a t r y 1 9 9 1 ; 5 2 : 2 9 0 - 2 9 3 .

1 7 . W o o d S H , M o r t o l a JF, C h a n YF, M o o s s a z a d e h F, Y e n SS. T r e a t m e n t o f p r e m e n s t r u a l s y n d r o m e w i t h f l u o x e t i n e : a d o u b l e - b l i n d , p l a c e b o - c o n t r o l l e d , c r o s s o v e r s t u d y . O b s t e t G y n e c o l 1 9 9 2 ; 8 0 ( 3 , p a r t 1 ) : 3 3 9 - 3 4 4 .

1 8 . S t e i n e r M , S t e i n b e r g S, S t e w a r t D , C a r t e r D , B e r g e r C, R e i d R, e t a l . F l u o x e t i n e in t h e t r e a t m e n t o f p r e m e n s t r u a l d y s p h o r i a . N E n g l J M e d 1 9 9 5 ; 3 3 2 : 1 5 2 9 - 1 5 3 4 .

1 9 . P e a r l s t e i n TB, R i v e r a - T o v a r A , F r a n k E, T h o f t J, J a c o b s E, M i e c z k o w s k i T. N o n m e d i c a l m a n a g e m e n t o f l a t e l u t e a l p h a s e d y s p h o r i c d i s o r d e r . J P s y c h o t h e r a p y Prac t Res 1 9 9 0 ; 1 : 4 9 - 5 5 .

2 0 . R o s s i g n o l A M , Z h a n g JY, C h e n Y Z , e t a l . T e a a n d p r e m e n -

s t r u a l s y n d r o m e in t h e P e o p l e ' s R e p u b l i c o f C h i n a . A m J P u b l i c H e a l t h 1 9 8 9 ; 7 9 : 6 7 - 6 9 .

2 1 . P r io r JC, V i g n a Y. C o n d i t i o n i n g e x e r c i s e a n d p r e m e n s t r u a l s y m p t o m s . J R e p r o d M e d 1 9 8 7 ; 3 2 : 4 2 3 - 4 2 8 .

2 2 . Pr ior JC, V i g n a Y, S c i a r r e t t a D , e t a l . C o n d i t i o n i n g e x e r c i s e d e c r e a s e s p r e m e n s t r u a l s y m p t o m s : a p r o s p e c t i v e , c o n -t r o l l e d 6 - m o n t h t r i a l . Fé r t i l S te r i l 1 9 8 7 ; 4 7 : 4 0 2 - 4 0 8 .

2 3 . S t e e g e JF, B l u m e n t h a l J A . T h e e f f e c t s o f a e r o b i c e x e r -c ise o n p r e m e n s t r u a l s y m p t o m s in m i d d l e - a g e d w o m e n : a p r e l i m i n a r y s t u d y . J P s y c h o s o m Res 1 9 9 3 ; 3 7 : 1 2 7 - 1 3 3 .

2 4 . B ib i K W . T h e e f f e c t s o f a e r o b i c e x e r c i s e o n p r e m e n s t r u a l s y n d r o m e s y m p t o m s . D i s s e r t a t i o n A b s t r a c t s I n t e r n a t i o n a l . 1 9 9 5 ; 5 6 : 6 6 7 8 .

2 5 . D o l l H , B r o w n S, T h u r s t o n A , V e s s e y M . P y r i d o x i n e ( v i t -a m i n B 6 ) a n d t h e p r e m e n s t r u a l s y n d r o m e : a r a n d o m -i z e d c r o s s o v e r t r i a l . J R o y a l C o l l G e n P r a c t 1 9 8 9 ; 9 : 3 6 4 - 3 6 8 .

2 6 . F a c c h i n e t t i F, B o r e l l a P, S a n e e s G , F i o r i n i L, N a p p i RE, G e n a z z a n i A R . O r a l m a g n e s i u m successfu l ly r e l i e v e s p r e m e n s t r u a l m o o d c h a n g e s . O b s t e t G y n e c o l 1 9 9 1 ; 7 8 : 1 7 7 - 1 8 1 .

2 7 . T h y s - J a c o b s S, C e c c a r e l l i S, B i e r m a n A , W e i s m a n H, C o h e n M A , A l v i r J. C a l c i u m s u p p l e m e n t a t i o n in p r e m e n s t r u a l s y n d r o m e . J G e n I n t e r n M e d 1 9 8 9 ; 4 : 1 8 3 - 1 8 9 .

2 8 . J o h n s o n S. C l in ic ian 's a p p r o a c h t o t h e d i a g n o s i s a n d m a n -a g e m e n t o f p r e m e n s t r u a l s y n d r o m e . C l in O b s t e t G y n e c o l 1 9 9 2 ; 3 5 : 6 3 7 - 6 5 7 .

2 9 . B a n c r o f t J, R e n n i e D . T h e i m p a c t o f o r a l c o n t r a c e p t i v e s o n t h e e x p e r i e n c e o f p e r i m e n s t r u a l m o o d c l u m s i n e s s , f o o d c r a v i n g a n d o t h e r s y m p t o m s . J P s y c h o s o m Res 1 9 9 3 ; 3 7 : 1 9 5 - 2 0 2 .

3 0 . M a n g o s A L , B r i n c a t M , S t u d J W W . T r e a t m e n t o f t h e p r e -m e n s t r u a l s y n d r o m e by s u b c u t a n e o u s o e s t r a d i o l i m p l a n t s a n d cycl ical o r a l n o r e t h i s t e r o n e : a p l a c e b o c o n t r o l l e d s tudy . Br M e d J 1 9 8 6 ; 2 9 2 : 1 6 2 9 - 1 6 3 3 .

3 1 . W a t t s JF, B u t t W R , E d w a r d s RL. A c l in ica l t r i a l u s i n g d a n a -z o l f o r t h e t r e a t m e n t o f p r e m e n s t r u a l t e n s i o n . Br J O b s t e t G y n a e c o l 1 9 8 7 ; 9 4 : 3 0 - 3 4 .

3 2 . F r e e m a n E W , R icke ls K, S o n h e i m e r SJ, P o l a n s k y M . A d o u -b l e - b l i n d t r i a l o f o r a l p r o g e s t e r o n e , a l p r a z o l a m , a n d p l a c e b o in t r e a t m e n t o f s e v e r e p r e m e n s t r u a l s y n d r o m e . J A M A 1 9 9 5 ; 2 7 4 : 5 1 - 5 7 .

3 3 . H a r r i s o n W M , E n d i c o t t J, N e e J. T r e a t m e n t o f p r e m e n s t r u a l d y s p h o r i a w i t h a l p r a z o l a m : a c o n t r o l l e d s t u d y . A r c h G e n P s y c h i a t r y 1 9 9 0 ; 4 7 : 2 7 0 - 2 7 5 .

3 4 . S m i t h S, R i n e h a r t JS, R u d d o c k V E , S c h i f f I. T r e a t m e n t o f p r e m e n s t r u a l s y n d r o m e w i t h a l p r a z o l a m : r e s u l t s o f a d o u -b l e - b l i n d , p l a c e b o - c o n t r o l l e d , r a n d o m i z e d c r o s s o v e r c l in i -cal t r i a l . O b s t e t G y n e c o l 1 9 8 7 ; 7 0 : 3 7 ^ 1 3 .

3 5 . R icke ls K, F r e e m a n E, S o n d h e i m e r S. B u s p i r o n e in t r e a t -m e n t o f p r e m e n s t r u a l s y n d r o m e ( l e t t e r ) . L a n c e t 1 9 8 9 ; 4 : 7 7 7 .

3 6 . Y o n k e r s K, H a l b r e i c h U , F r e e m a n E, e t a l . S y m p t o m a t i c i m p r o v e m e n t o f p r e m e n s t r u a l d y s p h o r i c d i s o r d e r w i t h s e r t r a l i n e t r e a t m e n t . J A M A 1 9 7 7 ; 2 7 8 : 9 8 3 - 9 8 8 .

3 7 . H a r r i s o n W M , E n d i c o t t J, N e e J. T r e a t m e n t o f p r e m e n -s t r u a l d e p r e s s i o n w i t h n o r t r i p t y l i n e : a p i l o t s t u d y . J C l i n Psych ia t ry 1 9 8 9 ; 5 0 : 1 3 6 - 1 3 9 .

3 8 . S u n d b l a d C, M o d i g h K, A n d e r s c h B, e t a l . C l o m i p r a m i n e e f f e c t i v e l y r e d u c e s p r e m e n s t r u a l i r r i t a b i l i t y a n d d y s p h o -ria: a p l a c e b o - c o n t r o l l e d t r i a l . A c t a P s y c h i a t r S c a n d 1 9 9 2 ; 8 5 : 3 9 - 4 7 .

3 9 . L a w n o t e . P r e m e n s t r u a l s y n d r o m e : a c r i m i n a l d e f e n s e . N o t r e D a m e L a w R e v i e w 1 9 8 3 ; 5 8 : 2 5 3 .

ADDRESS: Lilian Gonsalves, MD, Department of Psychiatry and Psychology, P57, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195.

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