Premenstrual Dysphoric Disorder
A Guide for the Treating Clinician
For many years, doctors have recognized the link of men- Diagnosis
strual cycle to behavior and mood changes in women. In the1930s, RT Frank used the term “premenstrual tension syn- Diagnosis of PMDD is based on the presence of at least five drome” to describe the premenstrual mood problems that he of the symptoms listed in Table 1. Essential to diagnosis is noted in 15 women; by the 1950s, terminology had evolved the occurrence of symptoms during the post-ovulatory, into the now-familiar “premenstrual syndrome” or PMS.1 In premenstrual period; symptoms typically begin in the late 1987, the Diagnostic and Statistical Manual of Mental luteal phase (occasionally at ovulation) and remit by the end Disorders, Third Edition, Revised (DSM-III-R) listed cri- of menstrual flow. Because patients can misinterpret or teria for diagnosis of what it called “late luteal phase dyspho- overemphasize the relationship of symptoms to their men- ric disorder” or LLPDD.2 This cumbersome and unfamiliar strual cycle, it can be useful to have them chart symptoms name never became part of popular jargon, but the diagnostic throughout the month. A number of instruments (the Daily criteria associated with it are used in research and for clinical Rating Form, the Menstrual Distress Questionnaire, the treatment. In 1993, DSM-IV changed the name to “pre- Premenstrual Assessment Form, the Calendar of Premen- menstrual dysphoric disorder”(PMDD), and modified the strual Experiences, and the Prospective Record of the Impact and Severity of Menstrual Symptoms) are available to help As the name implies, PMDD is a cyclical disorder identify and quantify the timing and impact of symptoms consisting of distressing mood and behavioral symptoms during the menstrual cycle. As an alternative to formal rating arising during the late luteal (premenstrual) phase of a scales, patients may keep an informal diary of symptoms woman’s ovulatory cycle. Women with PMDD experience throughout the month. Charts allow clinicians to differenti- marked irritability as well as dysphoria, mood lability, anxi- ate PMDD from other psychiatric or medical disorders, and ety, fatigue, change in appetite, and a sense of feeling to distinguish it from mood changes expected during normal overwhelmed. Up to 75% of women experience some physi- cal and emotional symptoms before menses, but in only 3-8% Many women report that disorders like depression, are symptoms severe enough to qualify as PMDD.
bipolar disorder, panic disorder, generalized anxiety disor- The exact nature of PMDD continues to be debated, but der, and attention deficit disorder are exacerbated during the it is generally agreed that it is a distinct psychiatric and late luteal phase of their menstrual cycle. Patients with “pure” medical syndrome rather than an exacerbation of an under- PMDD will generally be free of symptoms except in the post- lying psychiatric disorder.3 A hormonal basis of PMDD is ovulatory period of their cycle. As always, other medical suggested by twin studies indicating that PMDD is inher- causes of dysphoria should be considered. A good history and ited,4 and by the observation that medical or surgical suppres- physical examination and routine laboratory tests can help sion of ovulation eliminates premenstrual symptoms.5,6 The exclude conditions like hypothyroidism, autoimmune disor- predictable, cyclical recurrence and remission of symptoms is ders, diabetes, anemia, parathyroid disorders, seizure disor- further evidence that PMDD is a distinct, biologically driven ders, sleep disorders, and endometriosis, which also can Dr. Elliott is Assistant Professor in the Department of Psychiatry and Behavioral Medicine, Wake Forest University School of Medicine.
He can be reached there at: 8th Floor Clinical Sciences Building, Wake Forest University Baptist Medical Center, Medical CenterBoulevard, Winston-Salem, NC 27157, or by email at [email protected].
NCMJ March/April 2002, Volume 63 Number 2 Etiology
Table 1. Symptoms associated with PMDD
Severe PMS and PMDDare closely linked to func- imbalance.7 Rather, it ap-pears that PMDD is theresult of heightened centralnervous system sensitivity to normal hormonal cycling, which Treatment
leads to reduced levels of the neurotransmitter serotonin or5-hydroxy tryptamine (5-HT). As women with PMDD Many regimens for treating PMS and PMDD have been enter the late luteal phase of their menstrual cycle, available proposed and tried over the years. Currently, the SSRIs have 5-HT is reduced, triggering symptoms associated with 5- the best record of efficacy and appear to be effective in up to HT depletion (irritability, dysphoria, impulsivity, and carbo- 70% of PMDD patients. Sertraline (Zoloft), fluoxetine hydrate craving). Several studies point to altered 5-HT (Prozac), paroxetine (Paxil), and citalopram (Celexa) have all metabolism in the genesis of PMDD. Blood levels8 and been successful in controlled trials of treating PMS and platelet uptake of 5-HT9 are low in PMDD patients, and PMDD symptoms. Because women often see improvement acute depletion of tryptophan, the precursor of serotonin, in PMS/PMDD symptoms a day or two after beginning an SSRI, several studies have investigated the use of these drugs The current consensus holds that dysregulation of sero- only in the late luteal phase, and indeed SSRIs appear to be tonin is the primary cause of PMDD symptoms, but there is effective when taken just during the week or so prior to evidence that other neurotransmitters may play a significant menses. In fact, a 1998 study by Wikander et al suggested role. Levels of gamma aminobutyric acid (GABA) are low in that intermittent dosing of citalopram might be even better patients with PMDD and PMS.11 Studies of the opiate than continuous dosing in relieving PMDD symptoms.15 A antagonists naltrexone and naloxone suggest a possible acute surprising finding has been that SSRIs can decrease physical withdrawal of endogenous opioids in the late luteal phase of symptoms of PMS like breast tenderness and bloating. This the menstrual cycle, which would produce the irritability and further suggests that their effectiveness is due to more than mood lability characteristic of such withdrawal.12,13 just inhibition of central serotonin re-uptake. Intermittent Finally, in PMDD, selective serotonin reuptake inhibi- and post-ovulatory dosing may decrease the adverse side tor (SSRI) drugs are effective, and their onset of action is effects of SSRIs, including sexual dysfunction and weight usually much quicker than the two to four weeks needed to treat depression, panic disorder, or obsessive-compulsive It is noteworthy that non-serotonin enhancing antide- disorder. This has led to the theory that SSRIs work by a pressants like bupropion or the tricyclic antidepressants are different mechanism in PMDD than in depressed or anxious not effective in the treatment of PMS/PMDD symptoms. If patients. One suggestion is that SSRIs work in PMDD by SSRIs cannot be used or are ineffective, ovulation suppres- indirectly increasing synthesis of allopregenolone from proges- sion can be used to halt menstrual cycling. Gonadotropin- terone; the binding of allopregenolone to GABA receptors releasing hormone (GnRH) agonists act on the hypothala- would account for the rapid relief of PMDD symptoms by mus to decrease secretion of follicle stimulating and lutein- izing hormones. This causes anovulation and decreased Regardless of uncertainty about the exact biochemical estrogen and progesterone synthesis. GnRH agonists can mechanism, it appears that the symptoms of PMDD are help some women with PMDD, but they do not work well caused by central sensitivity rather than peripheral hormonal in women who have severe dysphoria or exacerbation of pre- abnormality. Therefore, it makes sense that treatment should existing major depression in the late luteal phase.16 Danazol focus on correcting or compensating for central sensitivity, or suppression of the HPG axis has been used to treat PMDD/ on stopping the cycle altogether, rather than modifying the PMS. Results have been mixed, but positive responses appear to be the result of suppressed ovulation.17 Danazolmay cause acne, increased facial hair, weight gain, and NCMJ March/April 2002, Volume 63 Number 2 Table 2. An approach to caring form patients with PMS/PMDD
Establish the diagnosis by having the patient chart her symptoms throughout the course of the menstrualcycle.
Rule out other medical or underlying psychiatric disorders with a thorough history, physical and laboratoryexaminations.
Consider nonintrusive interventions such as calcium carbonate, multivitamin with magnesium, and pyridoxine; increase intake of complex dietary carbohydrates; increase exercise; decrease caffeine intake.
If symptoms persist, consider using an SSRI in the late luteal phase; if intermittent dosing is ineffective or ifthere are depressive or anxiety symptoms throughout the cycle, use an SSRI on a continuous schedule(increase in dosage in the late luteal phase if needed).
Consider referral for cognitive behavioral therapy or relaxation therapy, especially if external stressorsexacerbate symptoms.
Benzodiazepines can sometimes be useful as adjunctive treatment, but are generally less effective than SSRIs.
They should be used with caution in patients with a history of substance abuse or impulse control problems.
If symptoms remain refractory to treatment or if the PMDD is so severe as to be life-threatening, psychiatricconsultation is indicated.
Medical or surgical suppression of ovulation is a last resort because of the risks associated with long-term lackof estrogen.
depression; long-term reduction of estrogen has been linked proved compared to 30% of those taking placebo.19 This rate to an increased incidence of heart disease and decreased bone of response is less than that for SSRIs, but calcium does offer a cheap and non-intrusive option for treating PMS/PMDD Other proposed treatments for PMS/PMDD include symptoms. At least one study indicated that PMDD symp- oral contraceptives or addition of progesterone during the toms improved with magnesium supplementation, but a luteal phase. Unfortunately, despite widespread use, there is more recent study indicated only a decrease in fluid reten- no real evidence that oral contraceptives alleviate PMS/ tion.20 Vitamin B6 (pyridoxine) in doses of 50-100 mg per PMDD symptoms. Estrogen may worsen mood symptoms day may produce a very mild benefit; larger doses should be in women with significant PMS/ PMDD, and at least one avoided to minimize the risk of neurotoxicity.
study found that continuous use of oral contraceptives in- Nonpharmacological treatment—with diet, exercise, creased PMDD symptoms.18 The steroid hormone and cognitive and relaxation therapy—can be of significant allopregenolone, on the other hand, has anxiolytic proper- benefit. Increased dietary intake of complex carbohydrate ties, and so there has been interest in using its precursor, foods, a decrease in caffeine, and frequent meals in the late progesterone, during the luteal phase. Unfortunately, several luteal phase can be helpful; there is speculation that the controlled trials have shown progesterone to be no more carbohydrate craving noted during the premenstrual period is a result of a need to increase brain tryptophan, the precursor Because benzodiazepines act on GABA receptors, they of serotonin. Exercise can increase endogenous endorphins, have been used to treat PMS/PMDD symptoms. The results alleviating anxiety and dysphoria. Finally, both relaxation are mixed. Some studies show mild efficacy compared to and cognitive therapy have been reported to lessen PMS/ placebo and others do not. Several studies have found that PMDD symptoms and improve coping with those symp- low-dose alprazolam improved severe PMS symptoms some- what, but the improvement rate was less than that of SSRIs.
Because of the risk for abuse, benzodiazepines should be usedwith caution in patients with a history of substance abuse.
Also, benzodiazepines can cause disinhibition in some pa-tients, and so should be used with caution in those with Up to 75% of women report some premenstrual symptoms, but less than 10% have symptoms severe enough to qualify for Studies of vitamin and mineral supplementation have a diagnosis of PMDD. A key to diagnosis is establishing a also given mixed results. The best evidence suggests that pattern of typical PMDD symptoms that recur during the calcium supplementation is helpful. A large 1998 study late luteal phase of the menstrual cycle and remit after showed that 48% of women taking calcium carbonate im- menses. Underlying psychiatric and medical disorders that NCMJ March/April 2002, Volume 63 Number 2 might mimic PMDD should be ruled out or addressed. The some evidence that GABA, endogenous opiates, clinician should recognize that severe PMS and PMDD are allopregenolone, and various vitamins and minerals might most likely caused by sensitivity to hormonal cycling rather play roles in severe PMS and PMDD. Treatment with oral than an abnormality of hormone levels.
contraceptives or supplementary progesterone or estrogen Current treatment is based on the hypothesis that sero- has not been effective. For the treating clinician, a reasonable tonin depletion is responsible for the premenstrual irritabil- approach to the patient with severe PMS or PMDD is shown ity, dysphoria, and poor impulse control in PMDD. There is References
1 Frank RT. The hormonal basis of premenstrual tension. Arch 12 Rapkin AJ, Shoupe D, Reading A, et al. Decreased central opioid activity in premenstrual syndrome: leuteinizing hor- 2 American Psychiatric Association. Diagnostic and Statistical mone response to naloxone. J Soc Gynecol Investig 1996;3:93- Manual of Mental Disorders, Third Edition, Revised. Wash- ington, DC: American Psychiatric Association; 1987 13 Chuong CJ, Coulam CB, Bergstralh EJ, et al. Clinical trial of 3 Endicott J, Amsterdam J, Eriksson E, et al. Is premenstrual naltrexone in premenstrual syndrome. Obstet Gynecol dysphoric disorder a distinct clinical entity? J Womens Health 14 Guidotti A, Costa E. Can the antidysphoric and anxiolytic 4 Condon, JT. The premenstrual syndrome: a twin study. Br J profiles of selective serotonin reuptake inhibitors be related to their ability to increase brain 3alpha, 5 alpha- 5 Schmidt PJ, Nieman LK, Danaceau MA, et al. Differential tetrahydroprogesterone (allopregenolone ) availability? Biol behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. Am J Obstet Gynecol 15 Wikander I, Sundblad C, Andersch B, et al. Citalopram in premenstrual dysphoria: is intermittent treatment during luteal 6 Casson P, Hahn PM, Van Vugt DA, Lasting response to phases more effective than continuous medication throughout ovariectomy in severe intractable premenstrual syndrome. Am the menstrual cycle? J Clin Psychopharmacol 1998;18:390-8.
16 Freeman EW, Sonheimer SJ, Rickels K. Gonadotropin-re- 7 Roca CA, Schmidt PJ, Bloch M, et al. Implications of endo- leasing hormone agonist in treatment of premenstrual symp- crine studies of premenstrual syndrome. Psychiatr Ann toms with and without ongoing dysporia: a contolled study.
8 Rapkin AJ, Edelmuth E, Chang LC, et al. Whole blood 17 Halbreich U, Rojansky N, Palter S. Elimination of ovulation serotonin in premenstrual syndrome. Obstet Gynecol and menstrual cyclicity (with Danazol) improves dysphoric premenstrual syndromes. Fert Steril 1991;56:1066-9.
9 Taylor DL, Mathew RJ, Ho BT, et al. Serotonin levels and 18 Bancroft J, Rennie D. The impact of oral contraceptives on the platelet uptake during premenstrual tension.
experience of perimenstrual mood, clumsiness, food craving and other symptoms. J Psychosom Res 1993;37:195-202.
10 Menkes DB, Coates DC, Fawcett JP. Acute tryptophan deple- 19 Thys-Jacobs S, Starkey P, Bernstein D, et al. Calcium carbon- tion aggravates premenstrual syndrome. J Affect Disord ate and the premenstrual syndrome: effects on premenstrual and menstrual symptoms. Am J Obstet Gynecol 1998;179:444- 11 Halbreich U, Petty F, Yonkers K, et al. Low plasma gamma- aminobutyric acid levels during the late luteal phase of women 20 Walker AF, De Souza MC, Vickers MF, et al. Magnesium with premenstrual dysphoric disorder. Am J Psychiatry supplementation alleviates premenstrual symptoms of fluid retention. J Womens Health 1998;7:1157-65.
NCMJ March/April 2002, Volume 63 Number 2


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