Abstract
‘It is assumed that ovulation-related mechanisms trigger premenstrual symptoms in women with a vulnerability to CNS dysregulation. Several studies have identified abnormal serotonergic parameters during the entire menstrual cycle and the luteal phase in women with premenstrual dysphoric disorder.’
Premenstrual dysphoric disorder (PMDD) is a combination of emotional, behavioral and physical symptoms that occur in the luteal phase of the menstrual cycle, abate shortly after the onset of menses, and cause impairment in social and role functioning [1]. The hallmark emotional symptoms of PMDD include irritability, anxiety or tension, mood swings and depressed mood. PMDD occurs in approximately 5% of menstruating women and is considered the severe end of the spectrum of clinically significant premenstrual symptoms. Reduced quality of life (QoL), increased healthcare costs and reduced productivity at work have been documented in women with PMDD [2,3]. Recent reviews and expert guidelines summarize the diagnostic criteria, recommended forms for the prospective daily charting of symptoms and the importance of identifying a premenstrual exacerbation of an underlying mood or medical illness prior to the initiation of treatment [4–7].
The etiology of PMDD is likely to be multifactorial, and many possible etiological factors have been reviewed [8]. It is assumed that ovulation-related mechanisms trigger premenstrual symptoms in women with a vulnerability to CNS dysregulation [9]. Several studies have identified abnormal serotonergic parameters during the entire menstrual cycle and the luteal phase in women with PMDD [8]. Studies also suggest an abnormal response to allopregnanolone and other γ-aminobutyric acid (GABA)-ergic agonists during the luteal phase of the cycle [10]. The suppression of ovulation (e.g., with gonadotropin-releasing hormone [GnRH] analogs) and the enhancement of serotonin (e.g., with selective serotonin reuptake inhibitors [SSRIs]) both have substantial research findings supporting their use in the effective treatment of PMDD. Due to medical concerns with the long-term hypoestrogenic state induced by anovulatory agents, SSRIs have become the first-line drugs recommended for the treatment of PMDD. There is also some research supporting cognitive–behavioral therapy, calcium carbonate, spironolactone, alprazolam and chasteberry [5,7,11,12]. Until recently, there have been no research studies supporting the efficacy of oral contraceptives (OCs) for PMDD.
All SSRIs have been reported to be beneficial in reducing the emotional, behavioral and physical symptoms of PMDD, and antidepressants that are predominantly serotonergic are differentially effective compared with nonserotonergic antidepressants (e.g., bupropion and desipramine) [7,13,14]. Fluoxetine, sertraline and paroxetine controlled-release (CR) are approved by the US FDA for the treatment of PMDD using both daily and intermittent dosing (medication administered from ovulation until menses only). The efficacy of daily dosing has been reported in double-blind, placebo-controlled trials for fluoxetine [15], sertraline [16,17], paroxetine CR [18,19], citalopram [20] and venlafaxine [21]. The efficacy of intermittent dosing has been reported in double-blind, placebo-controlled trials for fluoxetine [22], weekly fluoxetine [23], sertraline [24–26], paroxetine CR [27] and citalopram [20]. Some studies have suggested less improvement of premenstrual physical symptoms with intermittent dosing and lower doses [22–24].
The advantages of intermittent dosing include popularity with women who only want to take medication during the symptomatic half of the cycle and reduced cost and risk of adverse effects. The efficacy of intermittent dosing has predominantly been demonstrated with medication administered throughout the luteal phase. However, a recent study suggested that the administration of escitalopram starting at symptom onset was as effective as administration through the full luteal phase for women with milder symptoms of PMDD [28]. This study was not placebo controlled and replication is needed. Although SSRIs are a clear first-line treatment for PMDD, up to a third of women will not achieve a satisfactory response, and long-term adverse effects such as weight gain and sexual dysfunction may lead to SSRIs being poorly tolerated [29]. In addition, the use of SSRIs in adolescent women with PMDD necessitates close monitoring for worsening mood and suicidality [30].
‘Both selective serotonin reuptake inhibitors and the new oral contraceptive formulation EE/DRSP effectively treat the emotional, behavioral and physical symptoms of premenstrual dysphoric disorder over at least 3 months.’
Studies have reported that OCs can improve mood, have no effect on mood, or cause dysphoria in menstruating women [10,12,31]. Until the publication of two recent studies, the research literature on OCs as a treatment for PMDD was not encouraging. These studies have suggested the efficacy of a new OC formulation containing ethinyl estradiol 20 μg and drospirenone 3 mg (EE/DRSP) administered in a 24-day active-hormone/4-day hormone-free regimen in women with PMDD [32,33]. DRSP is a unique progestin that is an analog of spironolactone, with progestogenic, antiandrogenic and antimineralocorticoid activity. These properties may contribute to its efficacy in decreasing premenstrual symptoms, particularly irritability and bloating. The shorter pill-free interval maintains ovulation suppression with fewer adverse symptoms during the hormone-free interval compared with the traditional 21-day active-hormone/7-day hormone-free regimen [34]. The OC formulation EE/DRSP is not currently approved by the US FDA for oral contraception or PMDD.
A large, double-blind, placebo-controlled, parallel-design study reported a significantly superior response rate for EE/DRSP versus placebo for emotional, behavioral and physical symptoms with accompanying improvements in QoL and functioning [33]. A smaller double-blind, placebo-controlled, crossover-design study reported a positive response in 62% of women receiving EE/DRSP versus 32% receiving placebo, with accompanying improvements in QoL and functioning [32]. The improvement in emotional, behavioral and physical symptoms reported in these two studies with EE/DRSP approximate the spectrum of action and effect size of the SSRIs. As with the SSRIs, approximately a third of women with PMDD did not respond to EE/DRSP, and contraindications (e.g., smoking and an age of over 35 years) and adverse effects, such as intermenstrual bleeding, may limit the utility of this new OC formulation in some women. However, women with PMDD who also desire contraception may find the off-label use of this new OC formulation helpful for both symptom relief and contraception. Potential risks of long-term use of EE/DRSP, as well as extended OC regimens, which have anecdotally been used to treat PMDD, have not been studied to date [34].
Both SSRIs and the new OC formulation EE/DRSP effectively treat the emotional, behavioral and physical symptoms of PMDD over at least 3 months. The substantial number of studies documenting SSRI efficacy and the US FDA approval of fluoxetine, sertraline and paroxetine CR for PMDD establish SSRIs as a clear first-line treatment option. With the recent publication of two positive studies, a new OC formulation, EE/DRSP, may now offer an additional, off-label treatment option. This option may be particularly suitable for women with PMDD who do not respond to SSRIs, or women who desire contraception in addition to treatment for PMDD. Further studies are needed to assess the long-term efficacy and safety of both SSRIs and OCs. Comparator studies of SSRIs and OCs are also indicated to potentially identify the subsets of women with PMDD who may differentially respond to SSRIs versus EE/DRSP. Studies of combined SSRI and EE/DRSP treatments compared with single treatments would also be of interest. At this point, it appears that the new OC formulation EE/DRSP offers women with PMDD a new treatment option in addition to the already established SSRIs.