The new england journal of medicine

clinical practice

Premenstrual Dysphoric Disorder

Tana A. Grady-Weliky, M.D.
This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the authors clinical recommendations.

A 33-year-old woman without a history of psychiatric illness presents with marked ir-
ritability, periods of crying, mood swings, severe fatigue, and increased appetite asso-
ciated with a craving for carbohydrates. These symptoms begin one week before the
start of menses and end within three days after the onset of menses. The symptoms
have begun to interfere with her usual social functioning. How should the clinician
treat this patient?
the clinical problem
Emotional and physical symptoms are common during the premenstrual phase of the From the Department of Psychiatry, Uni-
menstrual cycle. Premenstrual syndrome includes a constellation of mild-to-moderate versity of Rochester School of Medicine and
Dentistry, Rochester, N.Y. Address reprint
emotional and physical symptoms, which typically do not interfere with patients usual requests to Dr. Grady-Weliky at the Uni-
level of functioning. As many as 75 percent of women of reproductive age report having versity of Rochester School of Medicine,
premenstrual symptoms at some time during their lives.1 Premenstrual dysphoric dis- 601 Elmwood Ave., Box 601, Rochester,
NY 14642, or at tana_gradyweliky@urmc.
order is a severe form of premenstrual syndrome that affects 3 to 8 percent of women of rochester.edu.
reproductive age. Premenstrual symptoms usually begin when women are in their early
20s, but women often do not seek medical treatment for up to 10 years. Thus, many
women initially present for treatment in their mid-to-late 30s, with a long-standing his-
tory of premenstrual symptoms that may have progressively worsened. Clinical experi-
ence suggests that premenstrual symptoms continue through menopause. It is often
difficult to distinguish perimenopausal symptoms from premenstrual dysphoric dis-
order in women in their late 30s and early 40s.
Premenstrual dysphoric disorder is characterized by some combination of marked
mood swings, depressed mood, irritability, and anxiety, which may be accompanied by
physical symptoms. These symptoms occur exclusively during the luteal phase of the
menstrual cycle, with remission generally within three days after the onset of menses.
In addition, there is substantial impairment of personal functioning, generally more in
social than occupational domains.2
In order to make the diagnosis of premenstrual dysphoric disorder, a comprehen-
sive history and physical examination are required to rule out other possible causes of
the emotional and physical symptoms. Specific diagnostic criteria for premenstrual
dysphoric disorder, as outlined in the research section of the Diagnostic and Statistical
Manual of Mental Disorders, fourth edition, text revision,3 are shown in Table 1.
It is important to distinguish the marked emotional symptoms observed in premen-
strual dysphoric disorder from those seen in other major mood or anxiety disorders
(e.g., major depressive disorder, dysthymia, or panic disorder), because treatments dif-
fer. Prospective daily recording of the presence and severity of symptoms for at least two
menstrual cycles is used to confirm the diagnosis of premenstrual dysphoric disorder.
A number of valid and reliable diagnostic instruments are available to document
symptoms in premenstrual dysphoric disorder, including the Calendar of Premenstru-

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 The new england journal
Table 1. Criteria for Premenstrual Dysphoric Disorder.*
In most menstrual cycles during the past year, presence of 5 of the following
symptoms for most of the last week of the luteal phase, with remission be-
ginning within a few days after the onset of the follicular phase, and
absence of symptoms during the week after menses; inclusion of 1 of the
first 4 symptoms:
Markedly depressed mood, feelings of hopelessness, or self-deprecating
thoughts
Marked anxiety, tension, feelings of being keyed up or on edge lifestyle interventions
Marked affective lability (e.g., feeling suddenly sad or tearful or having in-
creased sensitivity to rejection)
Persistent and marked anger or irritability or increased interpersonal conflicts
Decreased interest in usual activities (e.g., work, school, friends, and hobbies)
Subjective sense of difficulty in concentrating
Lethargy, easy fatigability, or marked lack of energy
Marked change in appetite, overeating, or specific food cravings
Hypersomnia or insomnia
Subjective sense of being overwhelmed or out of control
Other physical symptoms, such as breast tenderness or swelling, headache,
joint or muscle pain, a sensation of bloating, weight gain
Marked interference with work or school or with usual social activities and re-
lationships with others (e.g., avoidance of social activities or decreased
productivity and efficiency at work or school)
Disturbance not a mere exacerbation of the symptoms of another disorder, such
as major depressive disorder, panic disorder, dysthymic disorder, or a
personality disorder (although possibly superimposed on any of these
disorders)
Confirmation of three criteria above by prospective daily ratings during at least two
consecutive symptomatic menstrual cycles (diagnosis may be made pro-
visionally before such confirmation)
* The criteria are from the Diagnostic and Statistical Manual of Mental Disorders,
fourth edition, text revision.3 In menstruating women, the luteal phase corresponds
to the period between ovulation and the onset of menses, and the follicular phase
begins with menses. In nonmenstruating women (e.g., women who have had a
hysterectomy), determination of the timing of the luteal and follicular phases may
require measurement of circulating reproductive hormones.
al Experiences,4 the Premenstrual Syndrome Dia-
ry,5 and the Daily Record of Severity of Problems.6
Patients record emotional, physical, and functional
symptoms daily using one of these tools, which typ-
ically use a Likert-type scale to assess the presence,
timing, and severity of symptoms. The diagnosis of
premenstrual dysphoric disorder is confirmed if
there is demonstrated evidence of a relative absence
of symptoms during the follicular phase of the men-
strual cycle; a substantial increase in emotional
symptoms, physical symptoms, or both during the
luteal phase of the menstrual cycle; and functional
impairment during the luteal phase.
strategies and evidence
Therapeutic strategies for the management of pre-
menstrual symptoms can be divided into two phas-
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of medicine
es. First, the patient records or charts her symptoms
for two menstrual cycles, during which lifestyle-
related interventions may be started. If she remains
symptomatic after the charting period and initial
interventions, pharmacologic therapy should be
strongly considered.
Anecdotal data suggest that reducing the intake of
caffeine, refined sugars, or sodium can be helpful in
women with mild-to-moderate premenstrual symp-
toms. However, there have been no controlled trials
to support these anecdotal reports.1 Increased exer-
cise has been found to alleviate symptoms of major
depressive disorder,7 but there is no definitive
evidence that it results in the improvement of symp-
toms of premenstrual dysphoric disorder. Nonethe-
less, some clinicians recommend these interven-
tions, given their other benefits and their safety.
Some studies have shown a benefit of vitamin
B6 supplementation in women with premenstrual
syndrome. A meta-analysis of studies of vitamin B6
concluded that daily doses of 50 to 100 mg may re-
duce the severity of premenstrual depressive and
physical symptoms as compared with placebo.8 Cal-
cium carbonate may also be effective against pre-
menstrual symptoms of moderate severity. In a ran-
domized, controlled trial involving 497 women with
premenstrual syndrome, 1200 mg of calcium car-
bonate administered daily resulted in a clinically
significant reduction in clusters of physical premen-
strual symptoms (water retention, food cravings,
and pain) and in emotional premenstrual symptoms
(negative affect) as compared with placebo.9 Data
also support the effectiveness of spironolactone, a
diuretic and aldosterone antagonist, for the man-
agement of negative emotions during the premen-
strual period and the alleviation of such physical
symptoms as bloating and weight gain.10 The im-
provement in the emotional symptoms appears to
be independent of the reduction of physical symp-
toms with spironolactone. Moreover, limited data
suggest the potential usefulness of an oral contra-
ceptive combined with drospirenone, an analogue
of spironolactone, for the management of premen-
strual symptoms.11
Clinical experience has shown that by charting
symptoms daily, women learn more about when
their symptoms occur and what may exacerbate or
diminish them. This close monitoring may facilitate
changes in lifestyle that lead to a limited but mean-
ingful reduction of symptoms. However, improve-
january 30, 2003
 clinical practice

ment of symptoms is rarely complete, so further most in women with premenstrual dysphoric dis-
therapeutic intervention is generally necessary. order.
In a study involving 277 patients who would meet
psychopharmacologic interventions the current criteria for premenstrual dysphoric dis-
If a diagnosis of premenstrual dysphoric disorder is order, fluoxetine at a dose of 20 mg or 60 mg daily
confirmed and lifestyle interventions have not been was superior to placebo in reducing premenstrual
effective, treatment with psychotropic medication emotional and physical symptoms.12 This study
is generally indicated in order to alleviate symptoms found a significant difference in the rate of response
and enhance the quality of life. during the first treatment cycle, with moderate im-
provement (defined as at least 50 percent reduction
Selective Serotonin-Reuptake Inhibitors in the severity of symptoms from base line) in 52
Selective serotonin-reuptake inhibitors are first-line percent of the patients receiving fluoxetine, as com-
agents for the treatment of premenstrual dysphoric pared with 22 percent of patients receiving place-
disorder (Table 2). Several double-blind, random- bo.12 The 60-mg daily dose, however, was associat-
ized, controlled clinical trials have shown that vari- ed with more side effects and higher dropout rates
ous selective serotonin-reuptake inhibitors are su- than the 20-mg daily dose, without superior efficacy.
perior to placebo for treatment of the emotional and Other randomized, controlled trials of fluoxetine
physical symptoms of premenstrual dysphoric dis- have also shown that 20 mg daily is effective in the
order.12-23 In the majority of these trials, symptoms treatment of severe premenstrual syndrome.13-15
have improved within three menstrual cycles during Similar efficacy has been reported for sertra-
which patients received active treatment. Fluoxe- line.16-21 In a study involving 243 women with pre-
tine12-15 and sertraline16-21 are the selective seroto- menstrual dysphoric disorder, sertraline at a dose
nin-reuptake inhibitors that have been studied the of 50 to 150 mg daily (mean [SD] daily dose at the

Table 2. Recommended Treatment Strategies for Premenstrual Dysphoric Disorder.*

Starting Therapeutic
Medication Dose Dose Common Side Effects

mg
First-line selective serotonin-
reuptake inhibitors
Fluoxetine 1020 20 Sexual dysfunction (anorgasmia and decreased libido),
sleep alterations (insomnia, sedation, or hypersomnia),
and gastrointestinal distress (nausea and diarrhea)
Sertraline 2550 50150 Same as fluoxetine
Paroxetine 1020 2030 Same as fluoxetine
Citalopram 1020 2030 Same as fluoxetine
Second-line
Clomipramine 25 5075 Dry mouth, fatigue, vertigo, sweating, headache, nausea
Alprazolam 0.500.75 1.252.25 Drowsiness, sedation
Third-line
Leuprolide 3.75 3.75 Hot flashes, night sweats, headache, nausea

* For selective serotonin-reuptake inhibitors and clomipramine, the starting and therapeutic doses are administered once daily
and are the same with luteal-phase and continuous administration. For luteal-phase administration, the medication should be
initiated at time of ovulation (usually approximately two weeks before the expected onset of menses) and discontinued on the
first day of menses. The therapeutic doses given for selective serotonin-reuptake inhibitors are those that were reported in the
randomized clinical trials. However, clinical experience has shown that a subgroup of patients with premenstrual dysphoric dis-
order may require slightly higher doses (up to 60 mg of fluoxetine; up to 150 mg of sertraline; up to 40 mg of paroxetine; and up
to 40 mg of citalopram). If a patient is taking another selective serotonin-reuptake inhibitor and tolerating it well but has a partial
response at the doses listed, it would be appropriate to increase the dose of the specific selective serotonin-reuptake inhibitor be-
fore switching to another agent. Alprazolam is administered three times a day; treatment should begin at 0.25 mg three times a
day. Clinical trials of leuprolide used the depot form; leuprolide should be administered intramuscularly each month.

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 The new england journal
end of the final treatment cycle, 10635 mg) was
more effective than placebo against premenstrual
emotional and physical symptoms.16 The overall
response rate (defined by a rating by a clinician-
observer of much improved or very much im-
proved) was significantly higher in the sertraline
group than in the placebo group (62 percent vs. 34
percent).16 The results of other double-blind, ran-
domized trials confirm the effectiveness of sertra-
line at daily doses of 50 to 150 mg in the alleviation
of a range of premenstrual symptoms.17-21
Paroxetine22 and citalopram23 are also effec-
tive alternatives. Although one double-blind study
found no difference between fluvoxamine and pla-
cebo,24 a more recent open-label trial suggested
that fluvoxamine might be useful in premenstrual
dysphoric disorder.25
Although the majority of clinical trials of selec-
tive serotonin-reuptake inhibitors have examined
continuous administration of medication through-
out the menstrual cycle, these agents may also be
administered only when the patient has symptoms.
This method, called luteal-phase or intermittent ad-
ministration, involves initiating medication at the
time of ovulation and discontinuing it at the onset
of menses. Several double-blind, controlled trials
have documented the effective use of strategies of
luteal-phase administration of such selective se-
rotonin-reuptake inhibitors as fluoxetine,13 sertra-
line,19-21 and citalopram.23
There are some data to support the use of inter-
mittent doses as the preferred strategy. One study
compared several strategies for the administration
of citalopram continuous (throughout the men-
strual cycle), semi-intermittent (a low dose during
the follicular phase and a higher dose during the
luteal phase), and intermittent (the full dose dur-
ing the luteal phase only) to patients with severe
premenstrual syndrome.23 As compared with place-
bo (given throughout the menstrual cycle), all the
active treatments significantly reduced the severity
of premenstrual symptoms, but intermittent admin-
istration and semi-intermittent administration were
more effective than continuous administration. The
efficacy of intermittent administration is an impor-
tant finding, because many patients would prefer to
take medication only when they have symptoms.26
Studies of both the continuous and intermittent
administration of selective serotonin-reuptake in-
hibitors have demonstrated the alleviation of symp-
toms during the initial treatment cycle, with further
improvement over the course of active treat-
ment.12,16,20,21
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of medicine
Alternative Psychotropic Agents
Other antidepressant agents have been studied for
the treatment of premenstrual dysphoric disorder
but are currently considered second-line therapies
because they have lower tolerability than those dis-
cussed above. Several comparative studies have
found that antidepressant agents with increased
serotonergic activity are more effective than agents
whose primary action is noradrenergic (such as
desipramine18 and maprotiline22) or dopaminergic
(such as bupropion).14 Medications with minimal
serotonergic activity have limited or no efficacy in
the management of premenstrual dysphoric disor-
der, as compared with placebo.14,18,22 Clomipra-
mine, a tricyclic antidepressant, has been found to
be more effective than placebo for premenstrual
dysphoric disorder in studies involving continuous
administration or luteal-phase administration.27,28
Open-label studies have suggested that nortrip-
tyline29 and nefazodone30 are effective against pre-
menstrual symptoms, but these agents have not
been tested in randomized, controlled trials.
Alprazolam, a triazolobenzodiazepine anxiolytic
agent, has also been studied for the treatment of
moderate-to-severe premenstrual syndrome. Of five
randomized, controlled trials,31-35 four found alpra-
zolam to be more effective than placebo, particu-
larly for the management of premenstrual anxiety.
Clinicians should remain cautious when prescrib-
ing alprazolam, given the risks it carries of devel-
opment of tolerance and dependence.
Hormonal Interventions
If treatment with a selective serotonin-reuptake in-
hibitor or a second-line psychotropic agent (e.g.,
clomipramine or alprazolam) is unsuccessful, hor-
monal therapies are an alternative approach. Al-
though oral contraceptives are used for treatment
of mild-to-moderate symptoms, there has been only
one controlled trial supporting the efficacy of an
oral contraceptive combined with drospirenone for
moderate-to-severe symptoms.11 Progesterone has
also been used for the treatment of premenstrual
syndrome, but a recent meta-analysis found that
progesterone and other progestogens were no more
effective than placebo.36 In contrast, gonadotropin-
releasing hormone agonists, including leuprolide
and buserelin, were superior to placebo in the alle-
viation of premenstrual emotional symptoms (such
as irritability and depression) and physical symp-
toms (such as bloating and breast tenderness) in
four double-blind, controlled studies.37-40 Although
gonadotropin-releasing hormone agonists may be
january 30, 2003
 clinical practice

effective against premenstrual dysphoric disorder,
the parenteral route of administration (for leupro-
lide), cost, and potential side effects, including hot
flashes and vaginal dryness, make them a third-line
treatment strategy.
areas of uncertainty
The efficacy of lifestyle interventions such as diet,
exercise, and vitamin supplementation, as well as
psychotherapeutic interventions for premenstrual
dysphoric disorder, remains unclear. Studies of cog-
nitivebehavioral therapy for premenstrual syn-
drome have yielded inconsistent results.41-44 In
addition, the most appropriate strategy for admin-
istration (intermittent or luteal-phase vs. continu-
ous administration) and the optimal duration of
pharmacologic treatment for premenstrual dys-
phoric disorder remain uncertain.
guidelines
The American College of Obstetricians and Gyne-
cologists is the only organization of medical pro-
fessionals that has developed clinical-practice
guidelines for premenstrual syndrome.45 These
guidelines identify diagnostic and treatment strat-
egies for the full spectrum of clinical presentations,
including both premenstrual syndrome and pre-
menstrual dysphoric disorder. The importance of
prospective daily ratings to verify the diagnosis and
the first-line role of selective serotonin-reuptake in-
hibitors for treatment of premenstrual syndrome
are highlighted as top-level recommendations.
conclusions and
recommendations
sive assessment of symptoms, including prospec-
tive daily ratings of symptoms for at least two
consecutive menstrual cycles, is needed in order to
confirm the diagnosis of premenstrual dysphoric
disorder. During the period when the patient is re-
cording her symptoms, I would recommend a trial
of vitamin B6 supplementation or calcium carbon-
ate therapy.
Once premenstrual dysphoric disorder has been
identified and if treatment with calcium or vitamin
B6 has not been effective, I would recommend a trial
with a selective serotonin-reuptake inhibitor admin-
istered during the luteal phase. Because testing for
ovulation may be too burdensome and costly, it is
reasonable for patients to begin taking the pre-
scribed selective serotonin-reuptake inhibitor two
weeks before the expected onset of menses, which
should approximate the onset of the luteal phase in
women with a regular menstrual cycle. Patients
should complete a course of medication lasting at
least three menstrual cycles before an alternative
treatment strategy is considered. Typically, patients
will begin to notice an alleviation of symptoms with-
in three to five days of the start of pharmacologic
therapy administered during the luteal phase. How-
ever, in some patients, medication for several cycles
may be required before any substantial change is
noticed. Although there are currently no data to sup-
port a switch to a different selective serotonin-
reuptake inhibitor or a switch from luteal-phase to
continuous administration if initial therapy fails,
clinical experience suggests that either of these
strategies may be useful in some patients. Although
data are limited, once the patient has had a demon-
strated response, I would recommend continuing
the effective treatment for at least 9 to 12 months.
I am indebted to Eric D. Caine and Edward M. Hundert for their
comments on the manuscript.

Premenstrual dysphoric disorder affects 3 to 8 per-

cent of women of reproductive age. A comprehen-

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