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

134 THE PREMENSTRUAL SYNDROMES
Weekly luteal phase dosing with enteric-coated fluoxetine
90 mg tablets has been reported to be efficacious
in one RCT, 27 but to our knowledge this dosage
regimen has not been widely disseminated into clinical
practice.
Semi-intermittent dosing is a more complicated
regimen and involves continuous administration of the
SSRI throughout the menstrual cycle, with increased
doses during the luteal phase. Although intuitive, particularly
for patients who experience premenstrual worsening
of underlying mood and/or anxiety disorders, this
intervention has not been widely assessed in controlled
trials. To date, only one randomized, placebo-controlled
study has examined the efficacy of semi-intermittent
treatment. 39
Several studies have also compared intermittent vs
continuous dosing and found either no differences or
advantage of the intermittent dosing 39–44 (Table 15.3).
The extent to which different subgroups of women who
suffer from severe PMS/PMDD could preferably benefit
from either continuous or intermittent dosing remains
to be investigated.
So far, clinicians and patients have opted for intermittent
vs continuous dosing primarily based on the patient’s
symptom profile and treatment tolerability. Good candidates
for intermittent therapy are patients who wish
to limit the amount of medication they take, are not
able to adhere properly to the continuous regimen, have
no mood symptoms during the follicular phase, or are
concerned about long-term adverse effects (e.g. sexual
dysfunction). 45 Treatment cost may also play a role in
the option for intermittent treatment. Other alternatives
for patients who are treated intermittently and do not
achieve a robust clinical response include increasing the
dose of the intermittently administered SSRI or switching
to continuous SSRI treatment. If mood or anxiety
symptoms emerge during the follicular phase of the
menstrual cycle, strong consideration should be given
to switching to continuous SSRI therapy. Finally, intolerable
adverse effects that occur during intermittent
SSRI therapy may be addressed in one of two ways: by
watchful waiting to determine if they resolve over time
or by a reduction in dose. For patients treated with continuous
SSRIs and who only achieve suboptimal clinical
response, the dose should be increased after the
second menstrual cycle. Adverse effects are managed by
watchful waiting; if this approach is not effective or if
the adverse effect is intolerable, the dose should be
reduced. When dosage reduction is not successful, consideration
should be given to switching to intermittent
SSRI administration.
The specificity of the serotonergic antidepressants in
the treatment of PMS/PMDD has been demonstrated in
several comparative RCTs. Sertraline has been compared
to desipramine, 20 fluoxetine to bupropion, 11 and paroxetine
to maprotiline, 16 all clearly demonstrating the
lack of efficacy of the non-SSRIs. Preliminary results
have also shown that L-tryptophan, a serotonergic precursor,
is an effective treatment for PMS, 37 whereas
lithium is not. Treatment with nefazodone, a serotonin
modulator, has been shown initially to have some beneficial
effect 25 but in a subsequent RCT, nefazodone
was not more effective than placebo. 29 The effectiveness
of milnacipran, a presynaptic SNRI, has recently been
demonstrated in three women with PMDD who were
intolerant to SSRIs. 46 Overall, the response rate in most
RCTs for clomipramine, the SSRIs and the SNRIs is
�60% with a standardized mean difference in favor of
the active drug (for reviews see also References 45,
47–49). To date, no evidence supports a differential treatment
response to either SSRIs or SNRIs for patients
with PMDD.
Several of the larger RCTs have also clearly demonstrated
that the improvement is not only in the
behavioral/psychological symptoms of PMS/PMDD
(in particular irritability) but also in the physical symptoms
(breast tenderness and bloating) (e.g. References
16, 17, 19, 44, 49, and 50) as well as in the psychosocial
domain. 44,51,52 Interestingly, premenstrual headaches
do not appear to benefit from treatment with these
agents. The side-effect profile and compliance reported
in these studies do not differ significantly from those
reported in studies using the same medications for other
indications. Nonetheless, intermittent and low doses of
clomipramine, SSRIs, and SNRIs, when used in the treatment
of PMS/PMDD, seem to reduce the burden of side
effects. The concern that intermittent dosing, especially
of the antidepressants with a relatively short half-life,
might cause withdrawal symptoms or the discontinuation
syndrome has also been evaluated. The studies of
intermittent dosing report neither a high frequency of
initial side effects each time the medication is restarted
nor any marked discontinuation symptoms. 53 The lack
of significant withdrawal or discontinuation symptoms
seen with intermittent dosing may be related to its unique
mechanism of action (possibly GABA-a mediated), by
which no prolonged exposure is needed to promote the
therapeutic effect. In fact, subjects treated with intermittent
dosing of SSRIs and SNRIs not only fail to
experience discontinuation symptoms but also show
improvement of symptoms that continues into the early
follicular phase. 38,54
Adverse drug–drug interactions, especially with drugs
competing for the same microsomal systems in the liver,
are nevertheless potentially dangerous during intermittent
dosing, as much as when used continuously. Given
that PMS/PMDD affects women during their reproductive
years, it is important to note that there is no