PMDD

A short course on PMDD

By Neil S. Skolnik, MD, and Harris B. Cohen, MD

Many women are more impaired by premenstrual symptoms such as depression, anxiety, mood swings, and anger than by physical changes. Lower and luteal-phase dosing with selective serotonin reuptake inhibitors can effectively treat the problem.

Premenstrual dysphoric disorder (PMDD) is a serious condition that affects women of reproductive age. It is characterized by cyclic symptoms of severely depressed mood, anxiety, affective lability, and irritability that start in the second half or luteal phase of the menstrual cycle and resolve with the onset of menstrual flow. It is important to distinguish PMDD from the less severe premenstrual syndrome (PMS), which does not significantly interfere with a woman's lifestyle. Researchers do not yet know whether PMS and PMDD are two points on a continuum or represent biologically distinct conditions. They have noted that many women meet the diagnostic criteria for PMDD only during some cycles and have less severe premenstrual symptoms during other cycles.

Who is affected?

As many as 75% of women with regular menstrual cycles experience some symptoms of PMS, according to epidemiologic surveys. PMDD is much less common, affecting only 3% to 8% of women of reproductive age.¹ In one prospective study of the prevalence of PMDD at a single point in time in 513 women aged 36 to 44 in a large community, approximately 6% of the population met criteria for PMDD; of these women, half also had a history of depression.² In another study of members of a large northern California HMO, 1,194 women aged 21 to 45 completed daily ratings of symptom severity for two menstrual cycles; approximately 5% met the criteria for PMDD.³

To quantify the economic burden associated with PMDD, the researchers assessed health-care service use and related costs, work loss, and work productivity by this group.⁴ They found that the economic burden associated with PMDD manifests itself primarily as lower productivity but not higher health-care costs or time away from work.

Clinical presentation and criteria

PMDD is distinguished from PMS by its severity. PMS is characterized by physical and psychological symptoms that occur on a monthly basis prior to the menstrual period. The symptoms, which often include irritability, fatigue, mood lability, breast tenderness, a feeling of bloating, and food cravings, tend to be mild to moderate in severity and do not interfere with daily functioning.^5,6

In contrast, PMDD leads to significant disruption of quality of life and often interferes with a woman's ability to maintain her usual level of function during the luteal phase of the menstrual cycle. Symptoms include marked depression of mood, anxiety, affective lability, decreased interest in usual activities, difficulty concentrating, fatigue, changes in appetite and sleep pattern, and physical symptoms of breast tenderness or swelling, headaches, and bloating. The American Psychiatric Association's DSM-IV criteria recommend confirming symptoms by prospective daily rating for two cycles to make the diagnosis (Table 1). Importantly, the symptoms must be cyclic in nature, occur prior to the menstrual period, and should resolve with the onset of the period. The symptoms cannot be an exacerbation of symptoms that are present during the whole cycle, as would be the case with depression that gets worse premenstrually. Clinicians can instruct their patients to keep a 28-day diary in which they note symptoms and their severity, rating them from 0 for no symptoms to 4 for severe and interfering with daily routine.⁷

Nonpharmacologic treatment

Clinical experience indicates that patient education and support, stress reduction, a healthy diet, regular exercise, and vitamin supplements may help many women understand and feel more in control of their symptoms. Scientific evidence demonstrating the benefit of these interventions is scant. Even so, lifestyle modifications might be worth trying. Unless the patient has severe PMDD, have her try nonpharmacologic strategies for several months before proceeding to drug therapy.

Dietary modifications. The American College of Obstetricians and Gynecologists recommends a complex carbohydrate diet and nutritional supplements, includingmagnesium, vitamin E, and calcium to help with premenstrual symptomatology.⁸ Patients taking 1,200 mg of elemental calcium (calcium carbonate 1,500 mg/d in two divided doses) showed significant improvement in PMDD symptoms.⁹ Several trials have been conducted to evaluate the efficacy of pyridoxine (vitamin B₆); results suggest that dosages of up to100 mg/d show a reduction in the physical and emotional symptoms of PMDD.¹⁰

Other dietary recommendations include decreasing the intake of caffeine, alcohol, salt, fat, and refined sugar. Note that most dietary studies have been conducted in patients with PMS, and their applicability to those with PMDD has not been extensively studied.

Exercise. While the effects of aerobic exercise have not been studied specifically in patients with PMDD, patients with PMS have benefited. The benefits of exercise stem from the release of endorphins, alterations in estrogen and progesterone levels, changes in self-esteem, and emotional well-being, or a combination of these.

Complementary and alternative medicine. Relaxation techniques such as meditation and yoga, bright-light therapy, and cognitive behavior therapy have all been studied on a limited basis. While evidence is scarce, a recent study found that 30 minutes of light therapy given daily during the luteal phase of the menstrual cycle was effective in reducing PMDD symptoms.¹¹ The premise that light therapy boosts melatonin levels, which directly increase serotonin levels, supports the mechanism behind the use of selective serotonin reuptake inhibitors (SSRIs) in PMDD therapy.

Pharmacologic therapy

SSRIs are considered state-of-the-art treatment for PMDD. Other drug options include anxiolytics, oral contraceptives, non-SSRI antidepressants, and nonsteroidal anti-inflammatory drugs (NSAIDs). Gonadotropin-releasing hormone (GnRH) agonists, including leuprolide, may be used to suppress the menstrual cycle when symptoms are severe and unresponsive to other therapy.^12-15 Note that drugs discussed in this article may not be FDA-approved for PMDD.

SSRIs. Results from several randomized, controlled clinical trials document the efficacy of SSRIs in treating PMDD. The effectiveness of SSRIs as a class in the treatment of PMDD has been confirmed in a meta-analysis where SSRIs were found to be seven times more effective than placebo, showing benefit for both physical and affective symptoms.¹⁶ Women with PMDD show decreased serotonin levels during the luteal phase of the menstrual cycle. In addition, it is believed that postsynaptic serotonergic responsivity might be altered during the late-luteal-premenstrual phase of the menstrual cycle.¹⁷

PMDD is a distinctly different disorder from major depression andis distinguished by its cyclic nature and the fact that it does not ap-pear either during pregnancy or after menopause. In addition, with PMDD there is normal function of the hypothalamic-pituitary-adrenal axis, which is often abnormal in patients with major depressive disorder. Not all antidepressants are effective for PMDD. Antidepressants that have a predominant effect on the serotonin system have been shown to improve PMDD symptoms, and the effect of SSRIs on PMDD is rapid, as compared with the often delayed response in major depressive disorder.¹⁸ Intermittent dosing has been shown to be as effective as daily dosing.¹⁹ Dosing options for fluoxetine, for example, include taking the drug daily(20 mg/d) or intermittently during the luteal phase of the menstrual cycle. Luteal-phase dosing is an attractive treatment option for those who do not want to take a daily medication for a cyclic condition, so this regimen decreases the cost of treatment.²⁰

SSRIs are used at lower dosages for PMDD compared to the dosages used in treating depression. Two SSRIs—fluoxetine and sertraline—are FDA-approved for treatment of PMDD, and paroxetine is under consideration for approval by the FDA for use in PMDD. Citalopram and fluvoxamine have been evaluated and, compared to placebo, demonstrate an ability to improve symptoms. In one report, SSRIs led to a moderate-to-marked improvement in up to 70% of patients compared with response rates of about 20% with placebo.¹⁸

Patients can expect to see positive results from an SSRI in 1 month, and 2 to 3 months should be allowed before considering the use of another SSRI or another class of drug. Common side effects with SSRIs include insomnia, fatigue, GI disturbances, and sexual complaints such as decreased libido and anorgasmia. Side effects are more common at higher dosages (Table 2). Since the SSRIs are probably equally effective, choose among them based on symptoms and side-effect profiles. Side effects can lead to medication discontinuation at a rate of approximately 2 1/2 times that seen in the placebo groups.¹⁶

In a recent retrospective study, investigators looked at data from two multicenter clinical trials to see whether PMDD symptoms worsened after patients discontinued fluoxetine. Researchers noted a rapid return of symptoms when women with PMDD stop treatment.²¹ To date, the effect of SSRIs for PMDD in patients younger than 18 has not been studied, and caution is urged before treating this age group with an SSRI.²²

Other medications. Other drugs that have been used to treat PMDD include anxiolytics, hormonal agents, NSAIDs, and non-SSRI antidepressants.

Anxiolytics. Alprazolam, clonazepam, and lorazepam have all been studied in PMDD. These agents act on gamma-aminobutyric acid (GABA) receptors. GABA is a major inhibitory transmitter in the brain and the spinal cord, and levels are low in patients with PMDD and PMS.²³ Results with the anxiolytics have been mixed. While severe symptoms may be improved, the improvement rate is less than that produced by SSRIs. In addition, due to the risk of abuse, their safety profile is not as strong as that of other medicines.²⁴

Non-SSRI antidepressants. Other antidepressants have been shown to be less effective than SSRIs in treating PMDD. Venlafaxine was shown to be significantly more effective than placebo in reducing PMDD symptoms, with response to treatment occurring in the first treatment cycle. Luteal-phase dosing and long-term treatment with venlafaxine have not been evaluated.²⁵ In one study comparing sertraline with desipramine and placebo, daily symptom scores were decreased by more than 50% in 65% of patients in the sertraline group, compared with 36% of patients in the desipramine group and 29% in the placebo group (P<0.001). This study showed an important effect of sertraline, but no difference between desipramine and placebo.²⁶

Hormonal agents. OCs may be beneficial because they inhibitovulation through suppression of FSH and lutein-stimulating hormone. While studies of the effects of OCs on PMDD are few, the limited evidence is not consistent with regard to effect and there may be some weak class effect. A unique OC containing a combination of drospirenone and ethinyl estradiol showed a trend toward a reduction of PMDD symptoms.²⁷ In a study evaluating prescribing patterns of general practitioners in the United Kingdom, the most widely prescribed medications for treating premenstrual symptoms were progestogens, including progesterone; however, there is no evidence supporting their efficacy.²⁸ Leuprolide, a GnRH agonist, is given as a once-a-month IM injection. Though probably effective for PMDD, because of its route of administration, it is neither a first nor second therapeutic choice.

NSAIDs. Through prostaglandin inhibition, NSAIDs can effectively treat many premenstrual symptoms, including breast tenderness, cramping, headaches, and joint pain and muscle aches that are thought to be mediated by prostaglandins. Therapy should be initiated prior to the onset of discomfort and continued until menstruation begins.

REFERENCES

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2. Cohen LS, Soares CN, Otto MW, et al. Prevalence and predictors of premenstrual dysphoric disorder (PMDD) in older premenopausal women: the Harvard Study of Moods and Cycles. J Affect Disord. 2002;70:125-132.

3. Sternfeld B, Swindle R, Chawla A, et al. Severity of premenstrual symptoms in a health maintenance organization population. Obstet Gynecol. 2002;99:1014-1024.

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10. Wyatt KM, Dimmock PW, Jones PW, et al. Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: systematic review. BMJ. 1999;318:1375-1381.

11. Lam RW, Carter D, Mistri S, et al. A controlled study of light therapy in women with late luteal phase dysphoric disorder. Psychiatry Res. 1999;86:185-192.

12. Brown CS, Ling FW, Andersen RN, et al. Efficacy of depot leuprolide in premenstrual syndrome: effect of symptom severity and type in a controlled trial. Obstet Gynecol. 1994;84:779-786.

13. Freeman EW, Sondheimer SJ, Rickels K. Gonadotropin-releasing hormone agonist in the treatment of premenstrual symptoms with and without ongoing dysphoria: a controlled study. Psychopharmacol Bull. 1997;33:303-309.

14. Schmidt PJ, Nieman LK, Danaceau MA, et al. Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. N Engl J Med. 1998;338:209-216.

15. Hammarback S, Backstrom T. Induced anovulation as treatment of premenstrual tension syndrome: a double-blind, cross-over study with GnRH-agonist versus placebo. Acta Obstet Gynecol Scand. 1988;67:159-166.

16. Dimmock PW, Wyatt KM, Jones PW, et al. Efficacy of selective serotonin-reuptake inhibitors in premenstrual syndrome: a systematic review. Lancet. 2000;356:1131-1136.

17. Halbreich U, Tworek H. Altered serotonergic activity in women with dysphoric premenstrual syndromes. Int J Psychiatry Med. 1993;23:1-27.

18. Recognition of premenstrual dysphoric disorder and its treatment. Lancet. 2000;356:1126.

19. Lin J, Thompson DS. Treating premenstrual dysphoric disorder using serotonin agents. J Womens Health Gend Based Med. 2001;10:745-750.

20. Cohen LS, Miner C, et al. Premenstrual daily fluoxetine for premenstrual dysphoric disorder: a placebo-controlled, clinical trial using computerized diaries. Obstet Gynecol. 2002;100:435-444.

21. Pearlstein T, Joliat MJ, Brown EB, et al. Recurrence of symptoms of premenstrual dysphoric disorder after the cessation of luteal-phase fluoxetine treatment. Am J Obstet Gynecol. 2003;188:887-895.

22. Batra P, Harper DM. Recognizing and treating premenstrual dysphoric disorder. J Clin Outcomes Manage. 2002;9:87-98.

23. Halbreuch U, Petty F, Yonkers K, et al. Low plasma gamma-aminobutyric acid levels during the late luteal phase of women with premenstrual dysphoric disorder. Am J Psychiatry. 1996;153:718-720.

24. Elliott H. Premenstrual dysphoric disorder: a guide for the treating clinician. N C Med J. 2002;63:72-75.

25. Freeman EW, Rickels K, Yonkers KA, et al. Venlafaxine in the treatment of premenstrual dysphoric disorder. Obstet Gynecol. 2001;98:737-744.

26. Freeman EW, Rickels K, Sondheimer SJ, et al. Differential response to antidepressants in women with premenstrual syndrome/premenstrual dysphoric disorder: a randomized controlled trial. Arch Gen Psychiatry. 1999;56:932-939.

27. Freeman EW, Kroll R, Rapkin A, et al. Evaluation of a unique oral contraceptive in the treatment of premenstrual dysphoric disorder. J Womens Health Gend Based Med. 2001;10:561-569.

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DR. SKOLNIK is Associate Director, Family Practice Residency Program, Abington Memorial Hospital, Abington, Pa., and Professor of Family and Community Medicine, Temple University School of Medicine, Philadelphia, Pa.

DR. COHEN practices at Buckingham Family Medicine, Buckingham, Pa.

Take-home messages

• Researchers do not yet know whether PMS and PMDD are two points on a continuum or represent biologically distinct conditions.

• The American Psychiatric Association's DSM-IV recommends confirming symptoms by prospective daily rating for two cycles in order to make the diagnosis.

• Unless the patient has severe PMDD, try nonpharmacologic strategies for several months before proceeding to drug therapy.

• SSRIs are considered state-of-the-art treatment for PMDD.

• Lower dosages than those for depression and luteal-phase dosing are effective SSRI treatment options.

 

Neil Skolnik, Harris Cohen. A short course on PMDD. Contemporary Ob/Gyn May 1, 2004;49:56-65.