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

22 THE PREMENSTRUAL SYNDROMES
pharmacological data: whereas drugs facilitating brain
serotonergic transmission effectively reduce the symptoms
of PMS, treatments counteracting serotonergic activity
may aggravate them. In addition to these findings, there
are however also reports, though difficult to interpret,
suggesting that women with PMS differ from controls
with respect to serotonergic activity. In this chapter, the
different arguments supporting an involvement of serotonin
in PMS will be presented and discussed.
HOW IS HUMAN BEHAVIOR INFLUENCED
BY SEROTONIN?
Serotonin is a monoamine, formed from the essential
amino acid tryptophan, with 5-hydroxytryptophan as
intermediate. 6 Whereas the cell bodies of the neurons
using serotonin as transmitter are all localized to the
brainstem, serotonergic nerve terminals are found in
most parts of the brain. The effects of this transmitter
on adjacent neurons are mediated by at least 15 receptor
subtypes, the different functions of which are as yet
poorly understood.
Serotonin has long since been assumed to be of importance
for the regulation of mood and behavior, partly
because of observations made in preclinical studies,
and partly because of the antidepressant and anxietyreducing
effect exerted by serotonin-facilitating drugs,
such as the serotonin reuptake inhibitors (SRIs) (see
below). Recently, the importance of serotonin for depression
and anxiety has been reinforced by studies applying
brain imaging 4 and/or molecular genetics. 5,7,8
Although serotonin has been implicated in psychiatric
conditions as disparate as depression, obsessive compulsive
disorder, and panic disorder, little is known regarding
the normal, physiological role of this transmitter. Interestingly,
however, the most clear-cut changes in the
behavior of rodents exposed to serotonin depletion is
an increase in aggression and sexual activity, 6 i.e. those
aspects of behavior that are most clearly sex steroiddriven.
These findings may suggest that a major physiological
task for serotonin in rats and mice is to modulate
or dampen sex steroid-driven behavior. That this may
be the case not only in rodents but also in humans gains
support from the fact that reduced libido is probably
the most common side effect of long-term treatment
with SRIs. 9
Studies showing sex steroids to influence serotonin
transmission in rodents 10–14 and non-human primates 15,16
suggest that the effects of gonadal hormones on behavior
may be mediated in part by an influence on serotonergic
pathways. However, an alternative scenario
would be that sex steroids influence neuronal circuits
regulating mood and behavior, which do not constitute
serotonergic neurons per se, but are under the dampening
influence of serotonergic terminals. Reinforcing the
notion that interactions between sex steroids and serotonin
may be of clinical importance, almost all indications
for SRIs – including depression, dysthymia, social
phobia, panic disorder, generalized anxiety disorder, and
eating disorders – display a marked gender difference in
prevalence, being considerably more common in women
than in men.
If it is true that a major role for serotonin is to dampen
the influence of sex steroids on behavior, the theory that
serotonin is of importance for PMS, one of the most
obvious examples of sex steroids influencing behavior,
is not farfetched, and even less so given the fact that
enhanced irritability is a cardinal symptom of PMS, and,
at the same time, one of the most characteristic features
of serotonin-depleted animals. Given what we know
from animal studies regarding the neurochemical
regulation of aggression, for any condition in which
irritability and anger are prominent symptoms, an
involvement of serotonin should in fact be suspected.
SEROTONIN REUPTAKE INHIBITORS
IN PMS
The most well-established way of facilitating brain serotonergic
neurotransmission is to block the serotonin
transporter, i.e. the protein inactivating serotonin by
transporting this molecule from the synaptic cleft back
into the presynaptic neuron. Such an effect may be
achieved by SRIs, some of which selectively inhibit the
reuptake of serotonin only (selective SRIs � SSRIs), and
some of which inhibit the reuptake of both serotonin
and norepinephrine (tricyclic antidepressants and serotonin/norepinephrine
reuptake inhibitors � SNRIs).
To a large extent, the notion that serotonergic neurons
are part of – or capable of influencing – the neuronal
networks that generate premenstrual changes in mood
and behavior stems from the observation that SRIs very
effectively reduce such symptoms. This has now been
shown with the tricyclic antidepressant clomipramine,
the selective SRIs citalopram, escitalopram, fluoxetine,
paroxetine, and sertraline, and the SNRI venlafaxine. 17–19
In addition to reducing the symptoms of PMS, the SRIs
are also antidepressants. Whereas studies aiming to reveal
an effect of these treatments in depression however
sometimes fail to show a difference between active drug
and placebo, due to insufficient statistical power, the
superiority of SRIs over placebo in PMS/PMDD has
been robustly replicated in a large number of consecutive
studies, one small early trial being the sole exception. 17–19
In PMS patients with irritability or depressed mood as
the most prominent symptoms, the response rate to an