Premenstrual Syndromes : PMS and PMDD - Rutuja :: The site ...

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Future directions in the pathophysiology
of premenstrual dysphoric disorder: steps
to future treatments
Peter J Schmidt and David R Rubinow
INTRODUCTION
Premenstrual dysphoric disorder (PMDD) represents
an affective syndrome, the symptoms of which are confined
to the luteal phase of the menstrual cycle and are
of sufficient severity to interfere with normal life activities.
PMDD causes substantial suffering to the approximately
5–10% of women of reproductive age with this
disorder. The degree of functional impairment is at
least equivalent to that seen with dysthymia (i.e. chronic
depression) and, in some aspects (e.g. social/leisure and
parental impairment) is equivalent to chronic or recurrent
major depression. Given the prevalence of PMDD
(almost four million women), the years at risk, and an
average of 6 days of severe symptoms per cycle, the
World Health Organization’s model calculates the
burden of PMDD in the United States alone as 14.5
million disability adjusted life years. Two forms of
treatment have demonstrated efficacy in PMDD (i.e.
selective serotonin reuptake inhibitors [SSRI] and
ovarian suppression); however, neither treatment is effective
in all women with PMDD, and predictors of response
to either treatment are not known, nor are the mechanisms
of their therapeutic actions.
The timing of symptoms of PMDD both distinguishes
this condition and leads to speculation about its
underlying pathophysiology. Since the menstrual cycle
is a series of hormonal events involving endocrine
activity at the hypothalamus, pituitary, and ovary, it
was presumed that the symptoms of PMDD must result
from abnormal levels of some ovarian or menstrual
cycle-dependent factor, much in the way that depression
may result from other endocrinopathies involving
thyroid or adrenal dysfunction. Studies reviewed in
previous chapters in this textbook, however, have overwhelmingly,
refuted the presumption that circulating
gonadal steroid levels are abnormal in women with
PMDD. Thus, traditional hormone deficiency-based
models of behavioral regulation do not provide adequate
explanations for PMDD. Speculation about the
pathophysiology of PMDD may be informed by those
characteristics of women with this disorder that are
consistently demonstrated in the literature: evidence of
altered serotonergic system function in women with
PMDD compared with controls, the therapeutic efficacy
of SSRIs but not other antidepressants, and the
provocation of PMDD symptoms by physiological
levels of ovarian steroids. Nonetheless, to propose that
PMDD simply reflects an interaction between a hormonal
signal and an abnormality of neurotransmitters
(e.g. serotonergic dysfunction) is not adequate, since
neither the nature of the signal nor the nature of the
neurotransmitter abnormality is understood. Moreover,
there are several characteristics of PMDD that
need to be included in efforts to develop a disease
model for PMDD. First, PMDD involves symptoms of
both affective dysregulation and cognitive disturbance
and, therefore, it is in large part a brain disease. Thus,
in addition to understanding the nature of the hormonal
signal, the brain regions targeted by this signal and
the relevant neurocircuitry of PMDD need to be identified.
Finally, an appropriate disease model for PMDD
must not only account for the timing of the symptoms
during the luteal phase but also their emergence with
time (appearing commonly in the late 20s or 30s) and
their minimal expression in most women (only 5–10%
of women have PMDD). An attempt to model these
characteristics not only results in a reconceptualization
of PMDD that will generate new hypotheses to be
examined but also permits the development of theoretically
derived and evidence-based treatment strategies
for this condition.