The menstrual cycle–mood disorder tandem: Screening, diagnosis, and treatment

Distinguishing PMDD from an underlying mood disorder is just one of the challenges you face when a woman complains of depression, irritability, anxiety, or other mood changes

Dr. Pinkerton is Professor of Obstetrics and Gynecology and Director of The Women’s Place Midlife Health Center at the University of Virginia Health System, Charlottesville, Va. She serves on the OBG Management Board of Editors.

Dr. Pinkerton reports that she has served as a consultant to Teva, Novo Nordisk, Amgen, Wyeth, DepoMed, Pfizer, and Boehringer Ingelheim (fees to the University of Virginia). She serves on the boards of the National Women’s Health Resource Center, is a council member on the Hormone Foundation for The Endocrine Society, and is past president of the North American Menopause Society. She has been involved in multicenter trials with Wyeth, Pfizer, DepoMed, and Endoceutics (fees to the University of Virginia).

The menstrual cycle and its attendant hormonal changes can exacerbate mental health disorders or trigger new disorders, such as premenstrual dysphoric disorder (PMDD) and perimenopausal depression. The mechanism is unclear, although it appears to be related to complex changes in the immune and endocrine systems.

As ObGyns, we are in a unique position to screen for menstrual cycle–related mood disturbances. Routine screening for mental health disorders is critical for accurate diagnosis and effective treatment. Management options include pharmacotherapy with antidepressant or anti-anxiety agents; hormonal suppression or supplementation; and referral to, or consultation with, a mental health specialist.

Is it PMS or PMDD?

About 75% of women experience premenstrual symptoms at some point in their reproductive life. When these symptoms occur during the luteal phase only, they constitute premenstrual syndrome (PMS). The lifetime prevalence of PMS is thought to be 13% to 18% in women of reproductive age.¹ Common symptoms of PMS include anxiety, irritability, mood changes, acne, breast tenderness, fatigue, bloating, constipation or diarrhea, headache or backache, and food cravings. These changes are present during the luteal phase of the cycle and usually resolve completely with the start of menses.

Premenstrual dysphoric disorder (PMDD) is more severe than PMS, affecting only 3% to 6% of premenopausal women. To meet diagnostic criteria for PMDD, a woman must have at least five of the following mood symptoms (one of which must be depression, anxiety, lability, or anger), and they must be severe enough to interfere with social or occupational functioning, or both, for at least two consecutive menstrual cycles:

• depression, feelings of hopelessness, or self-deprecating thoughts

• anxiety

• lability

• anger or irritability

• diminished interest in regular activities

• impaired concentration

• lethargy or excessive fatigue

• changes in appetite

• sleep disturbance

• somatic symptoms.^2,3

Women who have PMDD are typically symptom-free between menses and ovulation.

It is important to differentiate between PMDD and premenstrual exacerbation of an underlying mood disorder to develop the optimal treatment plan.

A preexisting anxiety disorder increases the probability of developing PMDD by a factor of 2.5.⁴ Of women given a diagnosis of PMDD, 30% to 70% have a history of a major mood disorder.⁵ PMDD may be triggered by life stressors, such as marital discord, smoking cessation, or hormonal changes.

Neuroimaging studies using functional magnetic resonance have found a diminished premenstrual response in the amygdala in women with PMDD, leading to enhanced processing of negative emotions, diminished processing of positive emotions, and reduced control of limbic activity (FIGURE).⁶

Is it new or preexisting depression?

During the luteal phase, there is an elevated risk of either a new depressive episode or worsening of ongoing depression.⁷

The fluctuating hormone levels seen during the menopausal transition have also been associated with a new onset of depression, affecting 15% to 50% of women.^8-14 Although most women do not experience a significant mood disturbance during the menopausal transition, studies have shown that they are more vulnerable to depression at this time.^11-15 Cohen and colleagues found a twofold increase in the risk of developing depressive symptoms with the onset of perimenopause in women without a history of depression.⁹ Another study found a fourfold increase in the risk of depressive symptoms and an increase of 2.5 times in the risk of being given a diagnosis of depression.¹⁶

Fluctuations and variability in reproductive hormones were significantly associated with the onset of depression in perimenopausal women.¹⁶

Cardinal symptoms of major depressive disorder (MDD) are feelings of sadness or unhappiness and loss of interest in normal activities for at least 2 weeks.

During perimenopause, the triggers of depression are many

Women who have a history of depression are more likely to experience depressive symptoms or be given a diagnosis of MDD during the menopausal transition than women without such a history—particularly if the earlier episode was associated with a reproductive event, such as postnatal blues, postpartum depression, or PMDD.^15,17

In the Study of Women’s Health Across the Nation (SWAN), the risk of depressive symptoms was significantly increased during perimenopause and early menopause or when a woman used hormone therapy (HT), independent of potential confounding factors, such as poor perceived health or stressful events.¹⁸

Regardless of menopausal status, symptoms such as hot flushes, night sweats, sleep disturbances, mood swings, and impaired memory, have been related to an increased risk of perimenopausal depression in some, but not all, studies.^9,10,19,20

Symptoms of perimenopausal depression include:

• emotional flatness

• conversely, emotional lability

• “inability to cope”

• irritability

• social isolation

• tearfulness

• decreased energy

• weight gain

• sleep disturbances

• failure to enjoy normal activities.

Any woman who reports depressed mood during the menopausal transition should be evaluated for an underlying mood or a stress-related disorder.²¹

Some mood disorders may become worse premenstrually

For example, anxiety symptoms may worsen premenstrually, with increasing intensity during the perimenopausal transition. Some small studies have reported a premenstrual increase in panic attacks in women who have panic disorder,^22,23 although other investigations have found no significant change in the frequency of panic attacks during the late luteal phase of the menstrual cycle, compared with the follicular phase.

Premenstrual exacerbation of generalized anxiety disorder has also been reported in women with and without chronic depression,^23,24 as has worsening of obsessive-compulsive disorder.²⁵

Women who have bipolar disorder may be increasingly vulnerable to mood shifts during hormonal fluctuations, such as the postpartum period or perimenopause.^26,27

No clear evidence of worsening eating disorders has been found, but an increase in binge eating has been reported, particularly during the 5 days preceding menses. No studies have evaluated menstrual cycle effects on anorexia, although an association has been found between the severity of eating disorders and depression.²⁸

Exacerbation of schizophrenia in relation to the menstrual cycle has also been reported.²³ In one study, more than 40% of women who were hospitalized for a psychotic or bipolar episode during pregnancy were hospitalized again during the post-partum period—90% of them within the first 4 weeks after delivery.²⁹ Clearly, ObGyns need to identify women who have psychiatric illness or a history of mental disorders early in pregnancy and work with a psychiatrist to reduce the risk of postpartum hospitalization. We also need to recognize the risk of worsening of these disorders during the perimenopausal transition.

Screening tools are plentiful

When screening for menstrual cycle–related mood disorders, focus on the patient’s history as well as the duration and intensity of symptoms. When taking a history, review not only the recent and distant medical history but also the psychiatric history. Screening tools are available to assess the number and type of mood symptoms, as well as their duration and associated impairment, during three critical reproductive phases: premenstrual, postpartum, and perimenopausal. For detail on specific screening tools, see my earlier article on menstrual cycle–related exacerbation of disease.³⁰

Because “many practitioners find the numerous case-finding and screening questionnaires for depression too cumbersome and time-consuming for routine use,”³¹ Arroll and colleagues proposed two simple, verbal questions for use in primary care:

“During the past month, have you often been bothered by feeling down, depressed, or hopeless?”

“During the past month, have you often been bothered by feeling little interest or pleasure in doing things?”

They then validated the questions in 15 practices in Auckland, New Zealand. If the answer to either question was “Yes,” the test was considered positive. Of the 157 patients who screened positive, 28 (18%) were determined, via composite interview, to be depressed, whereas only one of the 264 patients who screened negative was found to be depressed. The relatively high false-positive rate is not a concern in depression screening, the investigators point out, because “further clarification can be obtained by asking more questions (the reference standard)” or by referring the patient to another health professional.³¹

Anxiety is common in women who have PMDD and generalized depression and may worsen or intensify during perimenopause. Tools to identify anxiety disorders are available as hand-scored or Web-based tests.³⁰

Before a diagnosis of PMDD can be made, prospective daily ratings of mental health symptoms for at least one consecutive menstrual cycle are essential; there must be a symptom-free period after menses begin until the time of ovulation.³

How to manage anxiety and depression

Anxiety and depression are the two most commonly clustered symptoms. In many cases, anxiety is the presenting complaint for women who have both depression and anxiety.³¹ Decisions about treatment should be made on an individual basis.

Treatment for anxiety may improve both anxiety and depression. For generalized anxiety disorder and MDD, serotonin-norepinephrine reuptake inhibitors (SNRIs) and serotonin reuptake inhibitors (SRIs) are options. These agents have approval from the US Food and Drug Administration (FDA) to treat a broad spectrum of disorders, including MDD, panic disorder, social anxiety disorder, and post-traumatic stress disorder.

Psychotherapy also appears to be beneficial when used in combination with pharmacotherapy for major mood disorders. During perimenopause, stress-management skills and coping strategies are very helpful for significant midlife stressors, such as aging parents, teenage children, employment, marital or partner issues, and financial concerns.

Psychiatric consultation may be most appropriate for generalized anxiety disorder, bipolar disorder, eating disorders, and complicated or severe depression.

For depression that worsens during the luteal phase or perimenopausal transition, antidepressant agents are recommended as first-line therapy. The dosage can be increased during times of vulnerability, such as the luteal phase, late perimenopause, and periods of high stress.

In perimenopause, hormone therapy (HT) may be helpful, particularly in improving or accelerating the response to antidepressants.^32-34 In the absence of contraindications, and if benefits outweigh risks, short-term HT may be an option, although it lacks FDA approval for this indication.³⁵ Psychiatrists may request gynecologic consultation for addition of HT when antidepressants alone are not effective.

Complementary and alternative therapies may also be beneficial, although they are not regulated by the FDA for safety or efficacy. Black cohosh and St. John’s wort have demonstrated short-term benefits, as have light therapy, S-adenosylmethionine, and folate.³⁶

Regular exercise, a healthy diet, regular sleep, and decreased caffeine and alcohol consumption are all recommended and may help improve premenstrual mood symptoms. However, a recent large longitudinal study found that the risk of depression decreased with increasing consumption of caffeine.³⁷

Consider lifestyle changes

For PMS or mild PMDD, changes in lifestyle or diet may be helpful, including regular exercise, smoking cessation, reduced alcohol intake, regular sleep, and the eating of small, frequent, regular meals. Over-the-counter products may provide some relief, as well. Short-term benefits have been found with vitamin B6, vitamin E, calcium carbonate, magnesium, tryptophan, evening primrose oil, and chaste tree berry. However, these products lack FDA approval or oversight and have limited efficacy data.

OCs and antidepressants are the main medical therapies for PMDD

The only FDA-approved hormonal therapy for PMDD is drospirenone/ethinyl estradiol (Yaz), which is approved to treat PMDD symptoms in women who need contraception. Other cyclic or continuous oral contraceptives (OCs) help maintain consistent hormone levels through ovarian suppression and are considered acceptable alternatives. The choice of OC depends on the patient; some progestins have been associated with negative mood effects. In postmenopausal women, medroxyprogesterone has more negative mood effects than norethindrone, with micronized progesterone appearing to have the least negative effects on mood.³⁸

Also approved for PMDD are three SRIs: fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft). These agents may be given intermittently (during the luteal phase) or continuously.

Other effective agents for PMDD (but that lack that FDA indication) are citalopram (Celexa), clomipramine (Anafranil, a tricyclic agent), and venlafaxine (Effexor, an SNRI), as well as the anxiolytic agents alprazolam (Xanax) and buspirone (Buspar).

Long-acting gonadotropin-releasing hormone GnRH agonists and danocrine (Danazol) also have been shown to be effective, but lack that FDA indication.

For women who experience significant mood changes that fail to respond to hormonal suppression or an antidepressant, it may be appropriate to combine an OC with an SRI/SNRI, but data supporting this approach are limited.

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