Exploring New Treatment Options. case study on PMDD and the current recommendations for treatment. A Case Study on PMDD

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1 M A N A G I N G PMS& PMDD Exploring New Treatment Options Most women of reproductive age some 85 percent experience recurrent mood and somatic symptoms with their menstrual cycles (ACOG, 2000). The symptoms that typically occur during the luteal phase or last 14 days of the menstrual cycle constitute premenstrual syndrome (PMS). Approximately 5 percent to 10 percent of these women suffer from premenstrual dysphoric disorder (PMDD), a disabling form of PMS characterized by depressed or labile mood, anxiety, irritability, anger and impaired function. PMDD is distinguished from PMS and other medical conditions by the pattern and severity of symptoms and their interference with occupational and social functioning. For more than a decade, theorists have alluded to the possible relationship between PMDD and other psychiatric disorders. Consider the following case study on PMDD and the current recommendations for treatment. A Case Study on PMDD Many women use the Internet to research health issues of personal concern. They analyze their health condition and often select a treatment plan before being evaluated by a health care professional. For health care practitioners, this presents a unique challenge: keep ahead of those clients who expect treatment with the latest therapies although the scientific evidence for such therapy is sketchy. 430 AWHONN Lifelines Volume 6 Issue 5

2 Ursula A. Pritham, MS, WHCNP

3 This was the case approximately three years ago when a woman in her mid-40s presented with a history of PMS. She thought her PMS warranted treatment with a prescribed antidepressant that she would take intermittently with the onset of symptoms each month. Her request for an intermittently dosed antidepressant as a remedy for PMS was based on knowledge acquired through the Internet and media. Of all the PMS symptoms (see Table 1), those most concerning for her was the anger and irritability felt each month before menses. These severe mood changes interfered with her work as a business office manager and affected her relationships with family members and friends. Confirmation of her worsening premenstrual mood swings and behavioral changes occurred when her partner complained of the discord in their relationship due to PMS. They were both hopeful that effective treatment was finally available. Her history, physical exam and laboratory tests ruled out other causes for the PMS symptoms (see Table 2). Daily symptom monitoring was advised for at least two months to help establish a diagnosis of PMS. She was advised to incorporate lifestyle changes such as aerobic exercise, a complex carbohydrate diet and to take nutritional supplements such as calcium and a daily multivitamin. Meanwhile, a clinician researched the latest pharmacologic interventions for PMS and PMDD to determine whether intermittent dosing with an antidepressant was effective. It s important for clinicians to note that the ultimate diagnosis and treatment plan for this particular woman was highly individualized, as is the case with most women who seek help with PMS or PMDD. Gaining Knowledge In the past decade, our knowledge of PMS and PMDD has greatly improved. Recent research suggests that severe PMS and PMDD are associated with affective disorders (Steiner, 2000). Web sites with information on PMS and PMDD clearly convey these latest findings to the consumers. A PMDD guide for patients and families developed through expert consensus is a valuable online reference (Moline, Kahn, Ross, Cohen, & Altshuler, 2001). In addition, direct consumer marketing by the pharmaceutical companies has increased the public s awareness of new medications, specifically antidepressants, and their use with PMS or PMDD. As such, more women than ever before are requesting pharmacologic treatment of their premenstrual symptoms. Clinicians need to know what treatment strategies are best and when to prescribe medications. Ursula A. Pritham, MS, WHCNP, is a women s health nurse practitioner at the Family Practice Center at the Eastern Maine Medical Center in Bangor, ME. DOI: / Evaluation and management of premenstrual disorders typically occur in a primary care setting where clinicians must distinguish premenstrual symptoms from a spectrum of other conditions with similar symptoms. Staying up to date on PMDD and treatment is essential for clinicians who care for women of reproductive age (see Box 1. Getting All the Facts). Table 1. Symptom Clusters Commonly Noted With PMS Affective Depression or sadness Irritability Tension Anxiety Tearfulness or crying easily Restlessness or jitteriness Anger Loneliness Appetite change Food cravings Changes in sexual interest Pain Headache or migraine Back pain Breast pain Abdominal cramps General muscular pain Cognitive or Performance Mood instability or mood swings Difficulty in concentrating Decreased efficiency Confusion Forgetfulness Accident-prone Social avoidance Temper outbursts Energetic Fluid Retention Breast tenderness or swelling Weight gain Abdominal bloating or swelling Swelling of extremities General Somatic Fatigue or tiredness Dizziness or vertigo Nausea Insomnia Source: Adapted from Daugherty (1998). 432 AWHONN Lifelines Volume 6 Issue 5

4 Premenstrual Dysphoric Disorder (PMDD) Endicott (2000) summarized the history, evolution and diagnosis of PMDD as far back as Hippocrates. Even then, women were noted to have a group of conditions that included mood changes and suicidal thoughts that occurred before the onset of menstruation. Descriptions of women with premenstrual problems have been found in many different cultures over time. Formal investigations of these premenstrual problems began in the 1930s by an American gynecologist, R. T. Frank, who coined the term premenstrual tension syndrome. In the 1950s, Dr. Katharina Dalton, a world-renowned medical researcher from England and pioneer in PMS research and treatment began to use the term premenstrual syndrome or PMS. Her work in developing natural hormone replacement therapy for PMS resulted in several self-help publications for women with PMS and the opening of the first PMS clinic in London (Women s Health Access, 2001). Table 2. Differential Diagnosis for PMS/PMDD Psychiatric Disorders Major depression Dysthymia Generalized anxiety Panic disorder Bipolar illness (mood irritability) Medical Disorders Anemia Autoimmune disorders Chronic fatigue syndrome Collagen vascular disease Diabetes Endometriosis Hypothyroidism Seizure disorder Premenstrual Exacerbation Of psychiatric disorders Of seizure disorders Of endocrine disorders Of cancer Of systemic lupus erythematous Of anemia Of endometriosis Psychosocial Spectrum Past history of sexual abuse Past, present, or current domestic violence Source: Adapted from Ling (2000). By the late 1970s and early 1980s, experts believed that ovulation triggered PMS although the precise causes of PMS remained an enigma. Because PMS occurs only in women who have ovulatory menstrual cycles, factors involving hormonal control of those cycles were suspected in the etiology of premenstrual disorders (Frackiewicz & Shiovitz, 2001). Cyclic changes in reproductive hormones occur normally throughout the menstrual cycle because of interaction between the hypothalamus, pituitary gland, ovaries and uterus (Frye & Silverman, 2000). During the follicular phase (typically the first 14 days of a 28-day cycle), an ovarian follicle matures and estrogen production peaks, causing the endometrium to become engorged with blood. Around midcycle, ovulation occurs as the egg emerges from the follicle, marking the start of the luteal phase. During the luteal phase, the corpus luteum also produces progesterone to prepare the uterus to receive a fertilized egg. If conception does not occur, the corpus luteum degenerates and progesterone and estrogen levels decline. This causes the uterine lining to slough off in menstruation, starting a new cycle. Hormones involved in the ovarian menstrual cycle were believed to be factors of premenstrual disorders. The list of proposed theories of the biological cause of PMS included progesterone deficiency, excessive estrogen production, falling estrogen levels, abnormal ratio of estrogen to progesterone levels, hormonal imbalances that involved fluid regulation, vitamin deficiencies and thyroid dysfunction (Dickerson, 2002). In the early 1980s, many investigators were focusing on mood and behavioral changes in addition to the physical symptoms of PMS. By 1983, the National Institute of Mental Health recommended that the cyclic symptoms experienced by women need to be documented with at least a 30 percent difference in severity between the mid-follicular (maturation of follicle) and late-luteal phases of the menstrual cycle for changes in mood, behavior or physical condition to be considered PMS. Identification of a symptom-free, mid-follicular phase was emphasized as the major means of differing PMS from other conditions (Endicott, 2000). In 1987, criteria for late luteal phase dysphoric disorder (LLPDD) were proposed and published in the appendix of the Diagnostic and Statistical Manual of Mental Disorders ( DSM ), Third Edition (Critchlow, Bond, & Wingrove, 2001). Although the term LLPDD never gained widespread use by clinicians, many clinicians used the criteria to identify research subjects with significant premenstrual mood change. When the DSM was updated in 1994, a change in name from LLPDD to PMDD occurred and PMDD was listed as an example of a mood disorder not otherwise specified. Diagnostic criteria for PMDD (see Figure 1) was outlined by the American Psychiatric Association (1994). October November 2002 AWHONN Lifelines 433

5 Nearly 10 years later, a panel of 16 experts from the United States and abroad came together and decided that the concept of PMDD was a distinct clinical disorder closely linked to mood (affective) disorders (Endicott, 2000). Although the etiology of PMS and PMDD is still uncertain, clinicians and researchers generally agree that PMS and PMDD are physiologic phenomena, biologically determined and only partially influenced by psychosocial events (Steiner & Pearlstein, 2000). This has been highlighted by recent evidence of the family history in relationship with PMS and PMDD, as well as the fact that suppression of ovulation or surgical menopause will eliminate premenstrual complaints. Patients with PMDD have increased episodes of mood disorder and a family history of mood disorder (Critchlow et al., 2001). PMDD is associated not only with major depressive disorder but also with puerperal depression (Hartlage, Arduino, & Gehlert, 2001). Furthermore, patients with seasonal affective disorder have been shown to possess more of the diagnostic Box 1. Getting All the Facts Academy of Family Physicians: www/familydoctor.org/healthfacts American College of Obstetricians and Gynecologists: Medem and the American Psychiatric Association Medical Library: MEDLINEplus: Women s health topics: s MEDLINEplus: Drug Information: National Library of Medicine s PubMed: National Guideline Clearinghouse: National Institute of Health Office of Research on Women s Health: University of Kentucky Chandler Medical Center: Women s Health Resources on the Internet: symptoms of PMDD than other healthy females (Praschak- Reider et al., 2001). Another interesting finding by Maskall et al. (1997) is that patients with PMDD have substantial seasonal patterns in mood and premenstrual symptoms. These seasonal patterns have implications for the clinical assessment and treatment of PMDD. For instance, light therapy may be beneficial for women with fall and winter seasonal worsening of PMDD. Pathophysiology of PMDD According to Steiner and Pearlstein (2000), the pathophysiology of severe PMS and PMDD is closely linked to an active hypothalamic-pituitary-gonadal (HPG) axis. The ovarian hormones are most likely the triggers for psychological as well as the somatic premenstrual symptoms. A misconception that some women have is that abnormal levels of circulating female hormones are the underlying cause of PMS/PMDD. Normal ovarian function, not abnormal fluctuations, is the cyclic trigger for symptoms. Normal ovarian function triggers biochemical events in the brain and peripherally that cause premenstrual symptoms in vulnerable or predisposed women. Ovarian steroids affect neurotransmitters in a variety of ways, including synthesis, release, reuptake, enzymatic inactivation and pre- and postsynaptic receptor sensitivity (Ling, 2000). The neurotransmitter serotonin, 5-HT, is thought to be in a reciprocal relationship with the HPG axis, and evidence now suggests that 5-HT is pivotal in the pathogenesis of PMDD. Dysfunction in 5-HT or reduction in brain 5-HT is believed to be associated with mood and anxiety disorders and poor impulse control, respectively. Other studies have found that women with PMS and PMDD have abnormal serotonergic function during the luteal phase as evidenced by lower whole blood serotonin concentrations and decreased platelet uptake of serotonin (Frackiewicz & Shiovitz, 2001). Decreased serotonergic transmission has been connected with depressed mood irritability anger aggression poor control of impulses increased craving for carbohydrates Observations that serotonergic drugs such as the selective serotonin reuptake inhibitors (SSRIs) are highly effective in reducing the symptoms of PMDD also suggests that serotonin plays a role in the etiology of premenstrual mood changes (Freeman, Rickels, Sondheimer, & Polansky, 1999). Not all women with PMS/PMDD respond to SSRIs; therefore, other causes are likely factors. For example, other neurotransmit- 434 AWHONN Lifelines Volume 6 Issue 5

6 ters have been aberrant in PMS, including the opioid, catecholaminergic and the y-aminobutyric acid (GABAergic) systems. In a review of the literature on PMDD, it was found that the depressive disorders and PMDD share a biological substrate. Both conditions are aggravated by acute tryptophan depletion, each share neuroendocrine markers of reduced serotonergic function as a trait marker and they both generally respond to SSRIs (Critchlow et al., 2001). Therefore, PMDD is more likely to respond to serotonergic antidepressants than to other antidepressants (FitzGerald et al.,1997; Freeman et al., 2001). Table 3. Premenstrual Dysphoric Disorder (PMDD) DSM-IV Criteria Symptoms occur in the late luteal phase of most menstrual cycles during the past year and remit within a few days of menses. At least five of these symptoms have been present most of the time during each symptomatic phase, at least one of those being item 1, 2, 3 or 4: 1. Markedly depressed mood, feelings of hopelessness or self-depreciating thoughts 2. Marked anxiety, tension, feelings of being keyed up or on edge 3. Marked affective lability 4. Persistent and marked anger, irritability or increased interpersonal conflicts 5. Decreased interest in usual activities 6. Subjective sense of difficulty in concentrating 7. Lethargy, easy fatigue ability, or lack of energy 8. Marked change in appetite 9. Hypersomnia or insomnia 10. Subjective sense of being overwhelmed or out of control 11. Other physical symptoms Markedly interferes with work, school or usual social activities and relationships. Not merely an exacerbation of the symptoms of another disorder, such as major depressive disorder. Criteria must be confirmed by prospective daily ratings during at least two consecutive symptomatic cycles. Source: American Psychiatric Association (1994). Diagnosis of PMDD A diagnosis of PMDD requires prospective daily ratings and the presence premenstrually of at least five symptoms mainly related to mood that disappear within a few days of the onset of menses (see Table 3). The pattern of symptoms must always include a symptom-free interval after the menstrual flow and prior to ovulation (Ling, 2000). There must be marked interference with social, occupational and vocational functioning, and the symptoms must not be an exacerbation of a preexisting disorder. The criteria required to make the diagnosis of PMDD points to the timing, nature and severity of the symptoms plus the need for symptoms to be present for at least two consecutive symptomatic cycles documented by daily ratings (Endicott, 2000). Treatment of PMDD Treatment usually begins with a two- to three-month trial of lifestyle modifications while the patient prospectively charts her symptoms (Frackiewicz & Shiovitz, 2001). Lifestyle changes that have been proven to be beneficial include a dietary plan that increases blood levels of the amino acid tryptophan, a precursor of serotonin (Ling, 2000). This can be accomplished by eating smaller, more frequent meals that are high in complex carbohydrates and fiber. A commercially available carbohydrate-rich beverage known to increase tryptophan can be taken in the late luteal phase. Other dietary modifications include, reducing or eliminating intake of salty foods, sugar, caffeine, chocolate, red meat, dairy products and alcohol calcium supplementation with two Tums-EX tablets twice a day during the luteal phase to reduce bloating, pain, mood and food cravings The use of pyridoxine and vitamin B6 supplements has had varying degrees of success and is no longer recommended (Wyatt, 2000). However, a daily multivitamin would be a reasonable suggestion with low likelihood of adverse effects. Other lifestyle modifications should include moderate exercise for 20 to 30 minutes, three to four times per week, October November 2002 AWHONN Lifelines 435

7 yoga, relaxation techniques, stress management, adherence to consistent bedtimes and waking times and cognitive therapy. Lam et al. (1997) suggest using bright light therapy for premenstrual depression. For women whose symptoms are severe or not adequately relieved by nonpharmacologic approaches, medications may be considered. Drug selection should be based on the woman s most troublesome symptom. If the PMS symptoms are predominately physical discomfort, nonsteroidal anti-inflammatory drugs (NSAIDs) or diuretics may be prescribed (Stearns, 2001). If the patient meets the diagnostic criteria for PMDD or has significant depression, antidepressants, especially SSRIs, would be first line therapy. In 1999, the Food and Drug Administration approved fluoxetine (Sarafem) for treatment of the mood and physical symptoms of PMDD. Sarafem is available as 10 mg or 20 mg capsules. The initial dose is 20 mg per day, not to exceed a maximum daily dose of 80 mg per day. Continuous treatment with Sarafem throughout a 28-day menstrual cycle costs about $80 (The Medical Letter, 2001). The most common adverse effects associated with SSRIs are nausea, headache, nervousness, insomnia, rash, fatigue and sexual dysfunction including decreased libido and anorgasmia. For the treatment of PMDD, SSRIs have a faster onset of action (usually 1 or 2 days) than when used to treat depression or anxiety disorders. Since the symptoms of PMS and PMDD occur only during the luteal phase, some researchers have evaluated intermittent dosing of the antidepressants (Frackiewicz & Shiovitz, 2001). Researchers have evaluated clomipramine (Anafranil), citalopram (Celexa), fluoxetine (Prozac & Sarafem) and sertraline (Zoloft) and suggest that intermittent dosing with these medications during the luteal phase may be as effective as full cycle dosing (Steiner & Pearlstein, 2000). Dosing from the presumed time of ovulation until the second day of the next menstrual cycle minimizes cost and may reduce sexual dysfunction and other adverse effects such as insomnia and fatigue. According to Pearlstein and Steiner (2000), other pharmacologic options for PMS and PMDD include anxiolytics, oral contraceptives and various gonadotropin-releasing hormones (GnRH). Alprazolam (Xanax) is the anxiolytic medication that has been evaluated the most in PMS. Recent studies report different pharmacodynamic and behavioral responses to benzodiazepines at different menstrual cycle phases in women with PMS. They are prescribed cautiously and only for women whose primary symptoms are agitation and anxiety. Although oral contraceptives (OCs) are one of the most frequently prescribed treatments for women with PMS, small randomized trials have not indicated relief via their use. Since OCs suppress ovulation, they may relieve some physical symptoms, with triphasic OCs noted as more effective than monophasic OCs. On the other hand, the side effects of OCs such as bloating, appetite changes and depressive symptoms might simulate PMS/PMDD. The use of a GnRH agonist such as Goserelin, Leuprolide (Lupron) or Nafarelin (Synarel) to cause anovulation is less effective in managing premenstrual dysphoria and severe PMS than the SSRIs. Although ovulation suppression alleviates some premenstrual symptoms, the low estrogen levels that result from these medications lead to long-term health concerns of cardiac disease and decreased bone density. Another medication that suppresses ovulation is Danazol, a weak synthetic androgen. Danazol has been shown to be effective in relieving premenstrual migraines but also has a significant adverse effect profile. Based on the benefit-risk ratio, many clinicians consider Danazol a poor choice for women with PMS (Pearlstein & Steiner, 2000). Additional treatments for PMDD The most common adverse effects associated with SSRIs are nausea, headache, nervousness, insomnia, rash, fatigue and sexual dysfunction including decreased libido and anorgasmia. are being explored. The first trial of a unique OC containing a combination of drospirenone (DRSP, 3 mg) and ethinyl estradiol (EE, 30 mcg) for the treatment of PMDD has shown a reduction of symptoms. DRSP is a spironolactone-like progestin with antiandrogenic and antimineralocorticoid activity. Spironolactone has been shown to be beneficial in PMS, whereas OCs have shown conflicting results (Freeman et al., 2001). Other upcoming strategies for the evaluation and management of PMDD will be available through a number of Web sites (see Box 1). Many women suffering from premenstrual symptoms can be effectively and satisfactorily treated with conservative therapies such as lifestyle changes (diet and exercise), cognitive behavioral therapies and calcium supplementation (Dimmock, Wyatt, Jones, & O Brien, 2000). However, for the minority who experience PMDD, pharmacological intervention is needed. Since PMDD can be expected to last until menopause, the pharmacologic intervention selected must be effective, safe for long-term use and free from side effects. SSRIs have been shown to be effective in the treatment of PMDD. Their long-term safety has been proven in studies on affective disorders. The side effects are usually manageable and can be reduced with intermittent dosing regimens. SSRIs should be the first-line therapy for PMDD. 436 AWHONN Lifelines Volume 6 Issue 5

8 References American College of Obstetricians and Gynecologists. (2000, March 31). ACOG issues guidelines on diagnosis and treatment of PMS. Retrieved March 22, 2002, from lease/nr html American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: Author. Critchlow, D., Bond, A., & Wingrove, J. (2001). Mood disorder history and personality assessment in premenstrual dysphoric disorder. Journal of Clinical Psychiatry, 62(9), Daugherty, J. (1998, July). Treatment strategies for premenstrual syndrome. American Academy of Family Practice. Retrieved March 7, 2002, from American Academy of Family Practice from daughert.html Dickerson, V. (2002). PMS and PMDD: The diagnostic spectrum. In PMS/PMDD and Quality of Life: Advances in Management. Montvale, NJ: Thomson Medical Economics. Dimmock, P., Wyatt, K., Jones, P., & O Brien, P. (2000). Efficacy of selective serotonin-reuptake inhibitors in premenstrual syndrome: A systematic review. The Lancet, 356, Endicott, J. (2000). History, evolution, and diagnosis of premenstrual dysphoric disorder. Journal of Clinical Psychiatry, 61(Suppl. 12), 5-7. FitzGerald, M., Malone, K., Li, S., Harrison, W., McBride, A., Endicott, J., et al. (1997). Blunted serotonin response to fenfluramine challenge in premenstrual dysphoric disorder. American Journal of Psychiatry, 154(4), Frackiewicz, E., & Shiovitz, T. (2001). Evaluation and management of premenstrual syndrome and premenstrual dysphoric disorder. Journal of the American Pharmaceutical Association, 41(3), Freeman, E., Kroll, R., Rapkin, A., Pearlstein, T., Brown, C., Parsely, K., et al. (2001). Evaluation of a unique oral contraceptive in the treatment of premenstrual dysphoric disorder. Journal of Women s Health & Gender- Based Medicine, 10(6), Freeman, E., Rickels, K., Sondheimer, S., & Polansky, M. (1999). Differential response to antidepressants in women with premenstrual syndrome/premenstrual dysphoric disorder: A randomized controlled trial. Archives of General Psychiatry, 56, Freeman, E., Rickels, K., Yonkers, K., Kunz, N., McPherson, M., & Upton, V. (2001). Venlafaxin in the treatment of premenstrual dysphoric disorder. Obstetrics & Gynecology, 98(5), Frye, G., & Silverman, S. (2000). Is it premenstrual syndrome? Keys to focused diagnosis therapies for multiple symptoms. Postgraduate Medicine, 107(5), Hartlage, S., Arduino, K., & Gehlert, S. (2001). Premenstrual dysphoric disorder and risk for major depressive disorder: A preliminary study. Journal of Clinical Psychology, 57(12), Lam, R., Carter, D., Misri, S., Yatham, L., Kuan, A., & Ziz, A. (1997). A controlled study of light therapy for premenstrual depression. Retrieved April 7, 2002, from Ling, F. (2000). Recognizing and treating premenstrual dysphoric disorder: The obstetric and gynecologic, and primary care practices. Journal Clinical Psychiatry (suppl 61): 9-16 Maskall, D., Lam, R., Misri, S., Carter, D., Kuan, A., Yatham, L., et al. (1997). Seasonality of symptoms in women with late luteal phase dysphoric disorder. American Journal of Psychiatry, 154(10), Moline, M., Kahn, D., Ross, R., Cohen, L., & Altshuler, L. (2001, March). Premenstrual dysphoric disorder: A guide for patients and families. Postgraduate Medicine Special Report, Pearlstein, T., & Steiner, M. (2000). Non-antidepressant treatment of premenstrual syndrome. Journal of Clinical Psychiatry, 61(Suppl. 12), Praschak-Reider, N., Willeit, M., Neumeister, A., Hilger, E., Stastny, J., Thierry, N., et al. (2001, March). Prevalence of premenstrual dysphoric disorder in female patients with seasonal affective disorder. Journal of Affective Disorder, 63(1-3), Steiner, M. (2000). Recognition of premenstrual dysphoric disorder and its treatment. Lancet, 356, Steiner, M., & Pearlstein, T. (2000). Premenstrual dysphoria and the serotonin system: Pathophysiology and treatment. Journal of Clinical Psychiatry, 61(Suppl. 12), Stearns, S. (2001). PMS/PMDD in the domain of mental health nursing. Journal of Psychosocial Nursing, 39(1), The Medical Letter on Drugs and Therapeutics. (2001, January 22). Fluoxetine (Sarafem) for premenstrual dysphoric disorder. The Medical Letter, pp Women s Health Access. (2001). Specialized prescription compounding: Traditional practice comes of age. Women Health American Group. Retrieved April 6, 2002, from Wyatt, K. (2000). Poor quality studies suggest that vitamin B6 use is beneficial in premenstrual syndrome. Western Journal of Medicine, 172, 245. Retrieved March 4, 2002, from American Family Physician Tips from other journals at October November 2002 AWHONN Lifelines 437