Diagnosis and treatment of premenstrual dysphoric disorder -- american family physician
Diagnosis and Treatment of Premenstrual Dysphoric Disorder SUBHASH C. BHATIA, M.D., and SHASHI K. BHATIA, M.D. Creighton University School of Medicine, Omaha, Nebraska 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 treat- tion handout on pre-menstrual dysphoricment. 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 intermit- tently 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 syn- drome. 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 con- sidered when other treatments are ineffective. However, the risk of serious side effects and the cost of these medications limit their use to short periods. (Am Fam Physician 2002;66:1239-48,1253-4. Copyright 2002 American Academy of Family Physicians.)
80 percent of women of reproductive age havephysical changes with menstruation; 20 to 40 percent of them experience symptoms of
ductive age have recurrentemotional, cognitive, andphysical symptoms related
PMS, while 2 to 10 percent report severe dis-
ruption of their daily activities. Menstruation-
These symptoms often recur discretely during
related physical discomfort, such as dysmenor-
the luteal phase of the menstrual cycle and
rhea, may begin with menarche. Often this
may significantly interfere with social, occu-
condition is superseded by PMS in late adoles-
cence or the early 20s. These syndromes gener-
(PMS), is diagnosed by the pattern of symp-toms. According to a report by the Committee
In the Diagnostic and Statistical Manual of
on Gynecologic Practice of the American Col-
Mental Disorders, 4th ed. (DSM-IV), PMDD is
lege of Obstetricians and Gynecologists,1 up to
classified as “depressive disorder not otherwisespecified” and emphasizes emotional and cog-nitive-behavioral symptoms.2 At least five ofthe 11 specified symptoms must be present for
In the Diagnostic and Statistical Manual of Mental Disorders,
a diagnosis of PMDD (Table 1).2 These symp-
4th ed., premenstrual dysphoric disorder is classified as
toms should be limited to the luteal phase and
“depressive disorder not otherwise specified,” emphasizing
should not represent amplification of preexist-
emotional and cognitive-behavioral symptoms.
ing depression, anxiety, or personality disorder. In addition, they must be confirmed prospec-
tively by daily rating for at least two consecu-
tive menstrual cycles. A symptom-free period
the DSM-IV PMDD diagnostic criteria.
during the follicular phase of the menstrual
Patients rate each symptom on a five-point
cycle is essential in differentiating PMDD from
scale, from zero (none) to 4 (severe). The scale
preexisting anxiety and mood disorders.
provides guidance for scoring the severity of
Researchers have developed a reliable and
each symptom and may be used in the office
valid self-reporting scale called the Daily
setting by primary care physicians for diagno-
Symptom Report (see patient informationhandout).3 The report consists of 17 common
cause of PMDD. Biologic, psychologic, envi-
Research Criteria for Premenstrual Dysphoric Disorder
ronmental and social factors all seem to play apart. Genetic factors are also pertinent: 70 per-
A. In most menstrual cycles during the past year, five (or more) of the following
symptoms were present for most of the time during the last week of the luteal
affected by PMS have PMS themselves, com-
phase, began to remit within a few days after the onset of the follicular phase,
pared with 37 percent of women whose moth-
and were absent in the week postmenses, with at least one of the symptoms
ers have not been affected.4 There is a 93 per-
cent concordance rate in monozygotic twins,
1. Markedly depressed mood, feelings of hopelessness, or self-deprecating thoughts
compared with a rate of 44 percent in dizy-
2. Marked anxiety, tension, feelings of being “keyed up” or “on edge”
3. Marked affective lability (e.g., feeling suddenly sad or tearful or increased
gotic twins.4 Genetic influences mediated
4. Persistent and marked anger or irritability or increased interpersonal conflicts
and neuroreceptors seem to play a significant
5. Decreased interest in usual activities (e.g., work, school, friends, hobbies)
6. Subjective sense of difficulty in concentrating
7. Lethargy, easy fatigability, or marked lack of energy
ders—specifically atypical depression—over-
8. Marked change in appetite, overeating, or specific food cravings
depression (i.e., depressed mood, interper-
10. A subjective sense of being overwhelmed or out of control
sonal rejection hypersensitivity, carbohydrate
11. Other physical symptoms, such as breast tenderness or swelling, headaches,
joint or muscle pain, a sensation of “bloating,” or weight gain
craving, and hypersomnia) are similar tothose of PMDD. Thirty to 76 percent of
B. The disturbance markedly interferes with work or school or with usual social
activities and relationships with others (e.g., avoidance of social activities,
women diagnosed with PMDD have a lifetime
decreased productivity and efficiency at work or school).
history of depression,5 compared with 15 per-
C. The disturbance is not merely an exacerbation of the symptoms of another
disorder, such as major depressive disorder, panic disorder, dysthymic disorder, or a
PMDD. A family history of depression is com-
personality disorder (although it may be superimposed on any of these disorders).
D. Criteria A, B, and C must be confirmed by prospective daily ratings during at least
severe PMS.6 There is significant comorbidity
two consecutive symptomatic cycles. (The diagnosis may be made provisionally
between depression and PMDD. Despite this
relationship, many patients with PMDD donot have depressive symptoms; therefore,
NOTE: In menstruating females, the luteal phase corresponds to the period between ovu-
PMDD should not be considered as simply a
lation and the onset of menses, and the follicular phase begins with menses. In non-menstruating females (e.g., those who have had a hysterectomy), the timing of lutealand follicular phases may require measurement of circulating reproductive hormones.
The effectiveness of selective serotonin reup-
take inhibitors (SSRIs), administered only dur-
Reprinted with permission from the American Psychiatric Association. Diagnostic andstatistical manual of mental disorders. 4th ed. Washington, D.C.: American Psychiatric
ing the luteal phase of the menstrual cycle,8-14
Association, 1994:717-8. Copyright 1994.
highlights the difference between PMDD anddepressive disorder. Acute treatment with SSRIs
increases synaptic serotonin without the down-regulation of serotonin receptors needed for
The goals of treatment of premenstrual dysphoric disorder
improvement in overt depression. This finding
are symptom reduction and improvement in social and occu-pational functioning, leading to an enhanced quality of life.
altered sensitivity in the serotoninergic systemin response to phasic fluctuations in femalegonadal hormone. Other studies also favor theserotonin theory as a cause of PMDD. In par-
changes and/or nutritional supplements as a
ticular, the efficacy of L-tryptophan,15 a precur-
first step in the treatment of PMDD.
sor of serotonin, and of pyridoxine,16 whichserves as a cofactor in the conversion of trypto-
phan into serotonin, also favors serotonin defi-
ciency as a cause of PMDD. Carbohydrate crav-
described in Table 24,15,16,19-22 have proven effi-
cacy. A meta-analysis16 of nine randomized,
mediated through serotonin deficiency.
placebo-controlled trials was conducted to
ascertain the effectiveness of vitamin B6 in PMS
reproductive age, it is reasonable to assume
management. The researchers concluded that
that female gonadal hormones play a causative
vitamin B6, in dosages of up to 100 mg per day,
role, possibly mediated through alteration of
is likely to benefit patients with premenstrual
serotoninergic activity in the brain. Estrogen
and progesterone seem to modulate levels of
another study,21 research literature (from Janu-
monoamines, including serotonin. Eliminat-
ary 1967 to September 1999) was reviewed to
ing the effect of ovarian gonadal hormones
evaluate the effectiveness of calcium carbonate
through the use of a gonadotropin-releasing
in patients with PMS. The reviewers concluded
that calcium supplementation in a dosage of
symptoms.17 Subsequent administration ofestrogen and progesterone causes symptomsto return in women with PMS but not in those
Treatment Approaches to PMDD Treatment Lifestyle changes Nonpharmacologic treatments
Regular, frequent, small balanced meals rich
in complex carbohydrates and low in salt, fat,
improvement in social and occupational func-
tioning, leading to an enhanced quality of life.
Available treatment options are summarized
Nutritional supplements LIFESTYLE CHANGES
Calcium carbonate, 1,200 to 1,600 mg per day21,22
benefit their overall health. Aerobic exercise
strual symptoms.19,20 Decreasing caffeineintake can abate anxiety and irritability, and
PMDD = premenstrual dysphoric disorder; PMS = premenstrual syndrome.
reducing sodium decreases edema and bloat-
Information from references 4, 15, 16, and 19 through 23.
ing. Many patients prefer to try lifestyle
TABLE 3 Herbal Therapies for PMDD
Most-studied of all herbs used in treatment of PMS
May provide a precursor for prostaglandin synthesis
Benefits breast tendernessSafety data in pregnancy and lactation lackingNot approved for this use by the FDA
Inhibits prolactin productionSafety data lackingNot approved for this use by the FDA
PMDD = premenstrual dysphoric disorder; PMS = premenstrual syndrome; FDA = U.S. Food and Drug Administration.Information from references 24 through 26.
1,200 to 1,600 mg per day is a treatment option
tion, assertiveness training, and anger man-
agement can reduce symptoms and interper-
tion (using Tums E-X) was found to reduce
sonal conflicts. Women with negative views of
core premenstrual symptoms by 48 percent in
themselves and the future caused or exacer-
466 patients.22 Vitamin E, an antioxidant,
bated by PMDD may benefit from cognitive-
seems to reduce the affective and physical
behavioral therapy.23 This kind of therapy can
symptoms of PMS.20 Tryptophan,15 a substrate
enhance self-esteem and interpersonal effec-
for serotonin, may also benefit some patients.15
tiveness, as well as reduce other symptoms.23Educating patients and their families about
the disorder can promote understanding of it
Almost invariably, psychosocial stressors
and reduce conflict, stress, and symptoms.20
should be addressed, either as a cause or aresult of PMDD. Psychosocial stressors are
A recent study24 reviewed efficacy and safety
stress-related hormonal activity. Stress reduc-
data on herbal supplements marketed forwomen. The author concluded that two herbalproducts, evening primrose oil and chaste treeberry, have been effective in treating PMS
(Table 3).24-26 Other researchers25 have arrived
SUBHASH C. BHATIA, M.D., is chief of the Mental Health and Behavioral Science
at variable conclusions about the efficacy of
Department at the Department of Veterans Affairs, Nebraska–Western Iowa Health
evening primrose oil. It is thought to provide
Care System, Omaha. He is also professor of psychiatry at Creighton University School
the gamma-linolenic acid required for synthe-
of Medicine and clinical associate professor at the University of Nebraska College ofMedicine, both in Omaha. A medical graduate of Panjab University, Chandigarh, India,
sis of prostaglandin E1,24 one of the anti-
Dr. Bhatia received a graduate degree from the Postgraduate Institute of Medical Edu-
cation and Research, also in Chandigarh, and completed a residency in psychiatry at
berry may reduce prolactin levels,24,25 thereby
Creighton University. Dr. Bhatia is board-certified in psychiatry, geriatric psychiatry,addiction psychiatry, and forensic psychiatry.
reducing symptoms of breast engorgement. These herbal therapies have not been approved
SHASHI K. BHATIA, M.D., is director of child and adolescent residency education andtraining at Creighton University School of Medicine, where she is also associate professor
of psychiatry, child and adolescent psychiatry, and pediatrics. In addition, she serves as clin-
(FDA) for use in PMDD, and their safety in
ical associate professor at the University of Nebraska College of Medicine. A medical grad-
pregnancy and lactation has not been estab-
uate of Panjab University, Dr. Bhatia completed a residency in obstetrics and gynecologyat the Postgraduate Institute of Medical Education and Research and a residency in psy-
lished. Moreover, manufacturing standards for
chiatry and child psychiatry at Creighton University. Dr. Bhatia is board-certified in psychi-
atry, child and adolescent psychiatry, addiction psychiatry, and forensic psychiatry. Address correspondence to Subhash C. Bhatia, M.D., Chief, Mental Health and Behav-PHARMACOLOGIC INTERVENTIONS ioral Science Department, Department of Veterans Affairs, Nebraska–Western IowaAntidepressant and Anxiolytic Medications.Health Care System, 4101 Woolworth Ave., Omaha, NE 68105 (e-mail: subhash.b[email protected]). Reprints are not available from the authors.
The serotoninergic antidepressants are the
TABLE 4 Pharmacologic Interventions: Antidepressant and Anxiolytic Medications
Benefits physical, cognitive, and emotional symptoms
Administration during luteal phase Luteal-phase use is superior to continuous treatmentNot approved by FDA for this use
Decreased libido or delayed orgasm is most common
side effect in long-term, continuous use
Transient GI and sexual side effectsSuperior to maprotilineNot approved by FDA for this use
Transient GI and sexual side effectsApproved by FDA for this use
Other serotoninergic antidepressants
Anticholinergic and sexual side effectsNot approved by FDA for this use
Interrupted use during the luteal phase can
Use only if SSRIs are ineffectiveNot approved by FDA for this use
SSRIs = selective serotonin reuptake inhibitors; FDA = U.S. Food and Drug Administration; GI = gastrointestinal. Information from references 8 through 14, and 27 through 37.
first-line treatment of choice for severe
30 mg per day was effective in one random-
PMDD (Table 4).8-14,27-37 Fluoxetine, in a
ized, placebo-controlled trial.13 Interestingly,
dosage of 20 mg per day, has been shown to be
intermittent administration of citalopram
superior to placebo, whether used only during
during the luteal phase was found to be supe-
the luteal phase12 or throughout the full men-
rior to continuous treatment. Clomipramine,
strual cycle.27-29 In a review29 of seven con-
a serotoninergic tricyclic antidepressant that
trolled and four open-label clinical trials of
affects the noradrenergic system, in a dosage
of 25 to 75 mg per day used during the full
cycle34 or intermittently during the luteal
In one placebo-controlled study,30 paroxe-
phase,11 significantly reduced the total symp-
In a recent meta-analysis35 of 15 random-
patients with PMDD. Paroxetine was moreeffective than the noradrenaline reuptakeinhibitor maprotiline.30 Sertraline in a dosage
The serotoninergic antidepressants are the first-linetreatment of choice for patients with severe premenstrual
placebo whether used during the full men-strual cycle31-33 or only during the luteal
phase.8-10,14 Citalopram in a dosage of 10 to
weight gain), minimize discontinuation syn-
Alprazolam should be used as a second-line drug only if
drome, and reduce the cost of care. SSRIs ben-efit the total symptom complex of PMDD, not
selective serotonin reuptake inhibitors fail to bring about an
only the mood-related symptoms. It should
also be noted that fluoxetine and sertraline arethe only two SSRIs with FDA approval for usein the treatment of PMDD.
ized, placebo-controlled studies of the efficacy
azepine with mood-enhancing and anxiolytic
SSRIs are an effective and safe first-line ther-
effects, has been shown to be somewhat effec-
apy and that there is no significant difference
tive in patients with PMS.28,36,37 Because of the
potential for drug dependence, alprazolam
and intermittent dosing. Because fluoxetine,
should be considered a second-line drug and
used only if SSRIs fail to achieve an optimal
were effective if administered during the luteal
response. Therapy should be limited to the
phase only, these drugs may be used as first-
luteal phase, and the agent should be given in
line therapy and taken intermittently only
low dosages—0.375 to 1.5 mg per day. The
during the luteal phase. Such an approach can
risk of drug dependence with alprazolam can
reduce the risk of long-term side effects (e.g.,
be minimized by administering it only during
TABLE 5 Hormonal Therapies for PMDD
Pregnancy category XSignificant relief from symptoms but can induce
Less likely to induce menopause; PMDD symptoms
may return, making this combination less effective
Less likely to induce menopause; PMDD symptoms
may return, making this combination less effective
Pregnancy category XUse nonhormonal contraception during therapy and for 12 weeks
after discontinuation of drug or until menses resume
May cause masculinization from weak androgenic propertiesPregnancy category X
Variable response; may not benefit patients with significant
mood symptoms; in some patients, may make mood
PMDD = premenstrual dysphoric disorder; IM = intramuscularly; SC = subcutaneously; OCPs = oral contraceptive pills.Information from references 18, 20, and 38 through 43.
TABLE 6 Miscellaneous Pharmacologic Interventions for PMDD Diuretics
Aldosterone antagonistPotassium-sparing diureticCould improve physical and
evaluate hepatic and renal functions before initiation
PMDD = premenstrual dysphoric disorder; NSAIDs = nonsteroidal anti-inflammatory drugs.Information from references 4, 20, 44, and 45.
the luteal phase of the menstrual cycle in
suppress ovulation, they are not reported to be
patients without a history of substance abuse.
consistently effective in the treatment of
Hormonal Therapies. It has been shown that
PMDD (perhaps because the studies had vari-
able samples). OCPs may not suffice if mood
GnRH agonists, leuprolide, histrelin, and
goserelin provide significant relief of symp-
patients, these drugs may worsen dysphoria (a
toms in patients without comorbid depres-
known side effect of some birth control pills)
sion.38-40 However, these medications can
Efficacy studies of progesterone have shown
flushes, vaginal dryness, fatigue, irritability,
limited benefits. One study42 found proges-
cardiac problems, and osteopenia. In women
terone to be superior to placebo; however,
another study43 reported efficacy equal to or
induced menopause with estrogen39 or estro-
less than that of placebo. Currently, ovarian
gen plus progestational agents18 can induce
gonadal hormones are thought to be of lim-
ited usefulness in the treatment of PMDD,
supports the theory of an etiologic role for
and none of the drugs has FDA approval for
this indication (Table 5).18,20,38-43
Miscellaneous Pharmacologic Interventions.
prescribed for patients with endometriosis,
In a double-blind, placebo-controlled, cross-
fibrocystic breast disease, and hereditary
over study,44 spironolactone in a dosage of 100
angioneurotic edema, is sometimes used to
mg per day was more effective than placebo in
reducing irritability, depression, somatic
twice a day. Such treatment can reduce symp-
symptoms, feelings of swelling, breast tender-
toms but may result in anovulation and mas-
ness, and craving for sweets. Bromocriptine in
culinization, either of which may limit regular
a dosage of up to 2.5 mg three times per day
use.41 Because of the potential for serious side
may be beneficial in patients with cyclic
effects and significant costs, GnRH agonists
mastalgia,4,20 although in one study45 it was not
and danazol should be tried as a last resort.
found to be effective. Ibuprofen, in a dosage of
These medications must be initiated during
up to 1,000 mg per day, can reduce breast pain,
menstruation to prevent teratogenicity if there
headaches, back pain, and other pain symp-
toms,20 but seems to have limited effect on
mood symptoms (Table 6).4,20,44,45
Management of PMS/PMDD
checklist prospectively for two consecutive menstrual cycles and assess severity of symptoms
intermittent use of SSRI during luteal phase with lifestyle changes
therapy or luteal-phase–specific,low-dose alprazolam and/or symptom-focused therapy andlifestyle changes
alprazolam intermittentlyor other therapies
FIGURE 1. Algorithm for the management of PMS/PMDD. (PMS = premenstrual syndrome; PMDD = premenstrual dys-phoric disorder; SSRI = selective serotonin reuptake inhibitor; GnRH = gonadotropin-releasing hormone.)
TABLE 7 Efficacy Rating of Current Treatments for PMS/PMDD
Dosage > 100 mg per day may cause peripheral neuropathy
Placebo-controlled study supports benefits in moderate to severe PMS
Safety in pregnancy and lactation not documented; not FDA-approved
Well-designed, randomized, placebo-controlled studies and meta-
Low-dose, luteal phase treatment; long-term use may cause tolerance
Menopausal syndrome/masculinization/cost limit its use
Symptom-focused efficacy; spironolactone efficacy supported by
Anecdotal efficacy or not consistently effective
PMS = premenstrual syndrome; PMDD = premenstrual dysphoric disorder; FDA = U.S. Food and Drug Administration; GnRH = gonadotropin-releas-ing hormone.*—Efficacy rating key: A = first line; B = second line; C = third line; D = symptomatic efficacy; E = efficacy anecdotal or not consistently effective;F = not recommended; G = general or adjunctive treatments.Information from references 8 through 16, 19 through 25, 28 through 39, and 41 through 45.Other Medical Interventions. Historically,
surgical and radiation oophorectomies have
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Análisis de la cooperación tecnológica España - Argentina mediante indicadores de patentes Luis Manuel Plaza y Esther García-Carpintero* Este trabajo tiene el propósito de analizar las actividades de cooperación en el ámbitotecnológico entre España y Argentina, a la luz del análisis de las patentes argentinas y,entre ellas, las que surgen de la colaboración con España. El
Desarrollado por Bristol-Myers Squibb, REYATAZ® (atazanavir) es un antirretroviral que se utiliza en combinación con otros medicamentos para tratar la infección del Virus de la Inmunodeficiencia Humana (VIH) en pacientes adultos 1. En el año 2004, atazanavir fue el primer inhibidor de la proteasa autorizado en la Unión Europea en una sola dosis al día indicado para pacientes previament