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 dysphoric ment. 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- Diagnosis
(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 information handout).3 The report consists of 17 common Etiology
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- NUTRITIONAL SUPPLEMENTS
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 NONPHARMACOLOGIC TREATMENTS
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 HERBAL THERAPIES
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 Iowa Antidepressant and Anxiolytic Medications. Health Care System, 4101 Woolworth Ave., Omaha, NE 68105 (e-mail: [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 Anxiolytics
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-line treatment 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 Dopamine agonist
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 1. Premenstrual syndrome. ACOG committee opinion.
No. 155-April 1995 (replaces no. 66, January 1989).
modalities have no role in the current man- 2. American Psychiatric Association. Diagnostic and sta- tistical manual of mental disorders. 4th ed. Wash- ington, D.C.: American Psychiatric Association,1994:715-8.
3. Freeman EW, DeRubeis RJ, Rickels K. Reliability and PMDD are described in Table 7,8-16,19-25,28-39,41- validity of a daily diary for premenstrual syndrome.
Psychiatry Res 1996;65:97-106.
45 while an algorithm for the management of 4. Parry BL, Rausch JL. Premenstrual dysphoric disorder.
these conditions is outlined in Figure 1. In: Kaplan HI, Sadock BJ, Cancro R, eds. Compre-hensive textbook of psychiatry. 6th ed. Baltimore:Williams & Wilkins, 1995:1707-13.
The authors thank Daniel Richard Wilson, M.D., 5. Yonkers KA. The association between premenstrual Ph.D., Professor and Chair, Creighton University dysphoric disorder and other mood disorders. J Clin School of Medicine, Department of Psychiatry, for constructive suggestions for the manuscript. 6. Endicott J, Amsterdam J, Eriksson E, Frank E, Free- man E, Hirschfeld R, et al. Is premenstrual dysphoricdisorder a distinct clinical entity? J Womens Health Dr. Shashi Bhatia is a member of the speakers bureaus of Abbot Laboratories and Forest Pharma- 7. Kendler KS, Karkowski LM, Corey LA, Neale MC. Longi- ceutical, Inc. Dr. Subhash Bhatia is a member of the tudinal population-based twin study of retrospectivelyreported premenstrual symptoms and lifetime major speakers bureaus for Eli Lilly and Co., Pfizer US Phar- depression. Am J Psychiatry 1998;155:1234-40.
maceutical Group, and Forest Pharmaceutical, Inc. 8. Freeman EW, Rickels K, Arredondo F, Kao LC, Pollack Sources of funding: none reported. SE, Sondheimer SJ. Full- or half-cycle treatment of severe premenstrual syndrome with a serotonergic 27. Steiner M, Steinberg S, Stewart D, Carter D, Berger C, antidepressant. J Clin Psychopharmacol 1999;19:3-8.
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