Imagine a mood disorder in which intense mood swings come predictably every month, wreaking havoc on any idea of calm normalcy. Depressed mood, lethargy, decreased interest and hopelessness occur along with marked irritability, anger, agitation and insomnia. One has the sense of being overwhelmed and “out of control.” Arguments and heightened tearfulness ensue. Then everything returns to normal for the next week or two, only to be turned upside down by the dreaded monthly roller-coaster.
The intensity of what I have described sounds similar to bipolar disorder in its dramatic presentation. However, it is actually a fairly typical description of Premenstrual Dysphoric Disorder (PMDD), which has recently been recognized as a mood disorder in the DSM-V (1). The criteria for PMDD is strict in terms of timing, duration, and degree of functional impairment. Symptoms begin during the luteal phase (days 15-28 of the menstrual cycle) and peak around the time of onset of menses. While symptoms can linger into the first few days of menses, there must be a symptom-free period in the follicular phase after the menstrual period begins. The diagnosis needs to be confirmed by prospective charting of at least two symptomatic cycles, and cannot be an exacerbation of symptoms of another disorder (such as depression or bipolar disorder), though PMDD can co-occur with these disorders (1).
PMDD is considered less common than PMS, with an estimated prevalence rate of 3-8% (2) compared with 75% of women for PMS (2,3). The hormonal fluctuations of the menstrual cycle are themselves not the cause of the mood dysregulation. Rather, certain subpopulations of women have been observed to develop sensitivity to the normal hormonal fluctuations of the menstrual cycle (5). Clinically, we have observed such women to include those who have a personal or family history of mood disorders, or those who seem to have a heightened response to environmental stress.
Multiple mechanisms have been proposed for PMDD. Estrogen (primarily E2, or Estradiol), can affect the serotonin system in ways that are similar to SSRIs. In both rodent and human studies, E2 receptors have been found to be plentiful in the hippocampus and amygdala and modulate the affective response to stress (6). In the normal luteal phase in humans, levels of E2 drop dramatically, which, in some women, could trigger a heightened negative response to stress through several proposed mechansisms. For example, E2 normally decreases MAO (monoamine oxidase) activity, which increases the availability of serotonin (5-HT), dopamine (DA) and norepinephrine (NA). A decrease in E2 could thus trigger a depressive reaction by increasing the breakdown of these neurotransmitters by MAO (2). Attention has also been focused on the role of E2 in the formation of dendritic spines on pyramidal cells in the hippocampus and prefrontal cortex of the brain. Dendritic spine formation is considered to enhance both mood and cognition, with E2 and brain-derived neurotrophic factor (BDNF) working in concert (7). During the follicular phase of the menstrual cycle, when E2 is rising, spines form. During the late luteal phase, however, with E2 falling, the spines become dismantled, resulting in depressed mood and poor concentration (8).
The above mechanism of dendritic spine deterioration is also thought to be promulgated by progesterone, which, like estrogen, rises but then falls during the luteal phase of the menstrual cycle (8). Progesterone is also thought to increase MAO activity, decreasing neurotransmitter activity by causing their breakdown (2). Perhaps for this reason, progesterone has been thought of as a “depressogenic” hormone. However, recent research has highlighted another role for progesterone, in the form of its metabolite, the “neurosteroid” allopregnanolone (Allo-P) (9-11). Neurosteroids are endogenous steroids synthesized in the brain and nervous system from cholesterol that are potent modulators of the two major neurotransmitter systems that govern CNS activity – glutamate, the major excitatory neurotransmitter, and GABA (gamma-aminobutyric acid), the major inhibitory neurotransmitter (10). Too little GABA, too much glutamate (the main “excitatory” neurotransmitter) is considered to be a possible mechanism for depression, anxiety, mania and other disorders. In general, Allo-P is thought to be a GABAa receptor enhancer (10).
The drop in progesterone during the late luteal phase of the menstrual cycle causes rapid withdrawal from Allo-P and may be responsible for PMDD symptoms (11). Recent animal studies have shown that low-dose SSRIs such as fluoxetine given during the late luteal phase can stimulate the production of Allo-P, resulting in a rapid improvement in mood symptoms (over hours to days). This is via a separate mechanism from the slower process of selective serotonin reuptake inhibition, in which the patient may not notice a clinical effect for a longer period (at least two weeks). Indeed, the author proposes calling fluoxetine a “selective brain steroidogenic stimulant” (11). The mechanism by which fluoxetine rapidly generates Allo-P production is unclear, but it supports clinical observations of improvement in PMDD symptoms in some patients with intermittent, luteal-phase only dosing of SSRIs (3).
So Allo-P is generally a good thing, correct? Here we run up against seemingly conflicting data – for 3-8% of menstruating women (interestingly, the same prevalence of women who have PMDD), Allo-P causes “paradoxical” effects on the GABAa receptor system (4). The Allo-P-induced negative mood symptoms are dependent on how much Allo-P is present – very low and very high concentrations have less of an effect on mood. However, during endogenous luteal phase levels, negative mood occurs. Women with PMDD are thought to have a “supersensitive” GABAa receptor in which Allo-P actually changes the configuration of the receptor so that it no longer functions as an inhibitory receptor and instead causes “paradoxical” heightened anxiety, depression, and irritability during the luteal phase of the menstrual cycle (4).
So what are the clinical implications of these findings? It appears that for women who have true PMDD, a “less is more” approach applies to treatment, especially use of SSRIs. The trick appears to be how to find and hit the “sweet spot” of just enough Allo-P produced to keep the GABAa receptor working the way it’s supposed to. The desired result – relief from the emotional vicissitudes of PMDD – may be a few steps closer. However, more research must be done to fully clarify the pathophysiology of this elusive illness. Doing so may also shed some light on why some women, but not others, are susceptible to mood shifts in response to the wide ranges of hormone levels found in a typical reproductive lifespan.