From The Carlat Psychiatry Report, February 2014, Women’s Psychiatry

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Topics: Women's Issues in Psychiatry

Of all the factors that contribute to mood, hormonal variations, such as those found in premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) can have a particularly strong effect. I’ve heard some people, for instance, describe PMS as a “powerful spell” that women are put under once every month.

But while it might feel like a mysterious force to women—and to their significant others—we now know much more about its biological basis. And since most of our patients are women, it’s important for us to be asking about these symptoms, as it can dictate our treatment.

PMDD versus PMS

So what’s the difference between PMS and PMDD? PMS is very common, affecting 80% of women with regular menstrual cycles. These are usually mild to moderate emotional fluctuations. When I ask women about premenstrual symptoms and they shrug it off and tell me, “I’m a little more moody the week before my period, but it’s not a big deal,” then it’s probably PMS.

PMDD, on the other hand is a severe form of PMS. The symptoms of PMDD are similar to those of PMS, but are severe enough to interfere with work, social activities, and/or relationships. PMDD affects 3% to 8% of women and feels like a “hell on earth” period.

The typical story I hear is that for one to two weeks before menses, a woman’s life is dramatically derailed: fights with her significant other, missing work or school, suicidal thoughts. Then, right when her period starts, these symptoms are suddenly lifted and she feels “great” again. In fact, a lot of women I see for a PMDD evaluation come to see me prompted by their significant other, with the couple on the verge break-up or divorce.

Diagnostic Criteria for PMDD

PMDD involves severe mood swings, depressed mood, irritability or anxiety, and four other emotional or physical symptoms occurring exclusively during the luteal phase (the one to two weeks before menses) and lifting within a few days of the onset of menses. To meet the PMDD diagnostic criteria, the symptoms must cause clinically significant distress or interfere with work, school, usual social activities, or relationships.

PMDD was made an official diagnosis in DSM-5 in 2013. Although diagnostic criteria may look complicated and overwhelming, I find it helpful to think of PMDD as a woman meeting criteria for a MDE (major depressive episode) one to two weeks before menses (with or without physical symptoms like breast tenderness, cramps, or bloating), but then feeling 100% normal the other two or three weeks.

Pathophysiology

So what is going on here? There’s good evidence that biology plays a key role. For starters, more women are admitted to psychiatric hospitals in the week immediately prior to menses than on any other week. In one study, 47% of admissions occurred during this week (Targum SD et al, J Affect Disorders 1991;22(1–2):49–53).

Before going further, it helps to understand basic biology. In the first half of the menstrual cycle, a follicle grows into an egg (hence the term follicular phase for this part of the cycle). Then, after 14 days, the egg is released (ovulation). What is left behind is a structure called the corpus luteum (hence the term luteal phase), which then starts producing progesterone to thicken the uterine lining to prepare for implantation.

If the egg is not fertilized, then the corpus luteum stops secreting progesterone and decays. Thus, there is a drop in progesterone one to two weeks before menses, and this drop is what triggers the uterine lining to shed (menstruation). Recent research suggests that some women are more sensitive than others to this fall in progesterone, and this sensitivity causes the mood symptoms of PMDD.

A groundbreaking 1999 study found that progesterone gets converted into another hormone called allopregnanolone, which binds the GABA-A receptor—the same receptor to which benzodiazepines and alcohol bind—and acts as a powerful anxiolytic, anticonvulsant, and anesthetic agent that decreases anxiety and depression (Griffin L and Mellon S, Proceedings Natl Acad Sci USA 1999;96(23):13512–7).

Think of allopregnanolone as a soothing, calming hormone. When the progesterone level drops, the allopregnanolone level also falls. For women who are sensitive to this drop, it’s similar to experiencing diazepam (Valium) or alcohol withdrawal.

You might be tempted to measure levels of progesterone or allopregnanolone, but such tests probably wouldn’t tell you very much. They would most likely be normal, as would the rate of the progesterone or allopregnanolone drop during the luteal phase. PMDD is a clinical diagnosis and the current hypothesis is that it has to do with a woman’s sensitivity to this drop in hormones—not to abnormal hormone levels themselves.

Treatment

SSRIs. So what can we do about PMDD? We all know the SSRI’s mechanism of action related to the increase in receptor sensitivity to serotonin after four to six weeks. But it turns out that a second mechanism of action involves helping to accelerate the conversion of progesterone to allopregnanolone. Research has found that fluoxetine, sertraline, and paroxetine decrease the K_m (energy of activation needed for the reaction) of the enzyme 10- to 30-fold (Griffin ibid).

This means that progesterone is converted much faster into allopregnanolone and there is more of it around to act on GABA receptors. Imipramine (a tricyclic antidepressant) appears to have no such effect, and this effect seems to be specific to SSRIs alone.

Amazingly, this second mechanism of action works quickly, often within several days. In fact, many of my patients tell me that their symptoms completely go away within an hour of taking an SSRI. Typically, only a low dose SSRI is needed (fluoxetine 10 to 20 mg daily or sertraline 25 to 50 mg daily, for example).

The SSRI can be started seven to 10 days prior to menses (or whenever your patient’s PMDD symptoms come on), or daily if the woman is also depressed or anxious at baseline on the other days. Or, if there is baseline depression or anxiety that is exacerbated the week before menses each month, the SSRI dose can be increased just during the week before menses.

This is an important distinction: if a woman doesn’t return to baseline during the other two to three weeks of the month, it’s not true PMDD and would be considered premenstrual exacerbation (PME). I often record this as MDD with PME, or GAD with PME, for example.

Some women really like the idea of intermittent dosing, especially if they are weary of side effects. Surprisingly, I have never seen withdrawal or discontinuation symptoms with intermittent dosing, likely due to the low doses needed for PMDD.

Hormones. Another possible treatment is hormones, specifically oral contraceptive pills (OCPs). OCPs work by “flattening out” the body’s hormone levels (keeping the levels consistent without any peaks or troughs), as the patient takes the exact same dose of progesterone and estrogen daily.

Some women are fine with the standard placebo week (the week in which the daily pill contains no active hormone), while others get a mood drop shifted to the placebo week when there is a drop in hormones. These women do best by taking the active pill continuously and cutting out the placebo week altogether.

It is also important to mention that women are sensitive to hormones in different ways—some to the hormone fluctuation, some to the amount, and others to the specific progestin type. Therefore, you might have to try a few different OCPs. Women who are sensitive to hormonal fluctuations should avoid triphasic OCPs. It usually takes about two cycles to see if an OCP will work.

The combination drospirenone/ethinyl estradiol (Yaz), the only OCP studied for PMDD, has shown good results for both physical and mood symptoms (Yonkers KA et al, Obstet Gynecol 2005;106:492–501). It shortens the placebo week to four days instead of the usual seven, which, in practice, could be done with any OCP. Keep in mind that OCPs, like SSRIs, can lower libido—especially Yaz, since the progestin it uses (drospirenone) has antiandrogenic activity.

I am often asked what it is better to try first, SSRIs or OCPs? It depends on the individual. Women who don’t like the idea of hormones or have a history of worsening mood with OCPs might prefer SSRIs, while women who aren’t keen about taking psychiatric medications might wish to try OCPs first. In my practice, I have found that it’s usually easier to start with an SSRI since you know pretty much immediately if it will work or not.

Benzodiazepines. As you might imagine, benzodiazepines can also be an effective treatment for PMDD or PME since they work on the GABA receptor. Sometimes I’ll give patients a small amount of both fluoxetine and lorazepam (Ativan), for example, and ask them to try both during their premenstrual week to see which is more effective for them (Freeman E et al, Prim Care Companion J Clin Psychiatry 2003;5(1):30–39).

Other antidepressants. Although SSRIs are the gold standard for PMDD, there has been some evidence that serotonin-norepinephrine reuptake inhibitors (SNRIs) and clomipramine (a tricyclic antidepressant) show some efficacy for PMDD (see, for instance, Mazza M et al, Expert Opin Pharmacother 2008;9(4):517–521).

Non-pharmacological treatments. It can be helpful to simply walk a woman through the pathophysiology of PMDD or PME so that she and her family are more aware of the biological explanation of her symptoms. I often have women track their symptoms on a mood chart for at least two months. This serves two functions: (1) it can ensure that we are dealing with a premenstrual pattern, and (2) it can often help decrease distress by predicting when the bad days are coming.

Although there is no consensus about the best tracking tools, two well-validated scales include the Calendar of Premenstrual Experiences (COPE) and the Prospective Record of the Severity of Menstruation (PRISM), both of which ask the patient to measure a variety of symptoms on each day of her cycle.

Other helpful things to try are diet and lifestyle changes: eliminating caffeine, sugar and sodium use, cutting out nicotine and alcohol use, getting good sleep and regular exercise (for more information, see http://bit.ly/KJrg1N).

In terms of psychotherapy, one study found that cognitive-behavioral therapy (CBT) was as effective as fluoxetine (20 mg daily) in the treatment of women with PMDD at the end of six months, as measured by a prospective daily diary (Hunter MS et al, J Psychosom Res 2002;53(3):811–817).

Certain nutritional supplements have also shown promise in various studies for physical and emotional symptoms of PMDD, including calcium (1,200 mg/day) and Vitamin B6 (50 to 100 mg/day). Make sure to caution patients that Vitamin B6 in doses above 100 mg/day can cause peripheral neuropathy. There is also some limited evidence that magnesium (200 to 360 mg/day) and Vitamin E (400 IU/day) can provide modest relief of symptoms.

Herbal remedies may also be helpful. Placebo-controlled studies have shown that extracts of Agnus castus fruit, also known as chasteberry, can significantly decrease emotional and physical PMS symptoms, and that Gingko biloba can also improve symptoms of PMS.

Light therapy has also been explored as a possible treatment for PMDD (see http://bit.ly/KJrg1N). More work must be done to determine optimal doses and treatment durations for these alternative interventions.

TCPR’s Verdict: Mood changes are common during the menstrual cycle and probably arise from fluctuations of hormones and their metabolites throughout the cycle. PMDD may result from sensitivity to rapid changes in estrogen and progesterone levels. Oral contraceptives, SSRIs, and other interventions can be effective treatments.