Although the exact etiology of premenstrual syndrome (PMS) remains unknown, it appears to be a chronic mood disorder that continues for many years in reproductive-age women. Approximately 2% to 10% of cycling women report severe symptoms resulting in a disruption of work or relationships (Logue and Moos, 1986). Identifying appropriate treatments and the optimal dosing of medications is important for the large number of women who experience marked disruptions of their work relationships, productivity and quality of life because of distressing premenstrual symptomatology.
Research has shown that serotonergic antidepressants taken daily throughout the menstrual cycle are effective for severe PMS. This efficacy is based on continuous daily dosing of the antidepressant medications, thus treating the asymptomatic phase as well as the symptomatic premenstrual phase of the cycle.
Several preliminary studies discussed in this article have reported that half-cycle dosing of a serotonergic antidepressant in the symptomatic premenstrual phase is effective for severe PMS and its DSM-IV diagnosis of premenstrual dysphoric disorder (PMDD). These results suggest that PMS/PMDD patients do not require continuous daily dosing. The findings are important because intermittent dosing may spare PMS patients unnecessary medication and reduce the risks and costs of treatment.
The most recent report of intermittent dosing for premenstrual symptoms comes from the University of Pennsylvania PMS Program (Freeman et al., 1999). This study used sertraline (Zoloft), a selective serotonin reuptake inhibitor (SSRI), in a flexible dosing schedule and compared half-cycle with full-cycle dosing regimens. More subjects improved in half-cycle treatment than in full-cycle treatment. These preliminary data add support to other pilot studies reporting the efficacy of sertraline, clomipramine (Anafranil) and fluoxetine (Prozac) administered only premenstrually to PMS patients who had no other comorbid disorders.
The women in the University of Pennsylvania Study fulfilled criteria for severe PMS when they entered a preceding three-arm treatment trial, in which daily administration of two antidepressant medications and a placebo were compared. At the end of this short-term treatment trial, the double-blind protocol was not compromised. Thirty-one volunteers, half of whom were improved and half of whom were unimproved, were randomized in double-blind fashion to receive either full-cycle or half-cycle sertraline for three additional months. All study participants took capsules daily, with the half-cycle treatment group receiving placebo capsules in the first two weeks of the cycle, both to control for placebo effects and to maintain the double-blind protocol.
The results showed that more subjects improved with half-cycle treatment as compared with full-cycle treatment (89% versus 46%, respectively; p-02). Response to the previous treatment was not associated with response in the half-cycle dosing study. Of the subjects who were improved when they entered the second study, 88% (14 of 16) remained improved for the study duration, regardless of whether the sertraline was taken throughout the cycle or only premenstrually. Of the subjects who were unimproved with previous treatment, 53% (8 of 15) improved. The subjects who were unimproved at the outset either improved swiftly in the first month of treatment or remained unimproved throughout the study. A greater percentage of initially unimproved subjects improved with half-cycle dosing than with full-cycle dosing (80% versus 40% respectively), though the small numbers in this comparison were not statistically significant.
The sertraline dose was 50 mg/day (one capsule) in the first month. In the absence of improvement or dose-limiting side effects, the dose was raised to 100 mg/day (two capsules) for the second month and to 150 mg/day (three capsules) for the third month of treatment. The mean sertraline dose at the end of three months was 80 mg/day in the half-cycle group and 100 mg/day in the full-cycle group-a nonsignificant difference.
Side effects were reported by 81% (25 of 31) of the subjects; there were no statistically significant differences between the full- and half-cycle dosing groups. The side effects (nausea, dry mouth, headache, dizziness, fatigue and decreased libido) were typically transient and diminished in the second and third months of treatment. No subject reported symptoms after discontinuation of sertraline, though the half-cycle dosing group discontinued active drug on day 3 and resumed active drug on day 14 in each treatment cycle.
These results of half-cycle dosing with sertraline for premenstrual symptoms are consistent with recent findings reported for the SSRI citalopram (Celexa) (Wikander et al., 1998). Intermittent treatment of premenstrual dysphoria with citalopram was more effective than placebo, and intermittent treatment also appeared more effective than continuous or semi-intermittent administration of the drug.
Two other studies reported that intermittent treatment with sertraline was superior to placebo for dysphoric premenstrual symptoms. Sertraline administered for two weeks premenstrually produced improvement significantly greater than placebo, and appeared equivalent in efficacy to sertraline given during the entire menstrual cycle (Halbreich and Smoller, 1997). In this fixed-dose study using 100 mg/day of sertraline, only subjects who improved after a month of daily sertraline were randomized to intermittent dosing.
Another fixed-dose study examined the response to half-cycle sertraline without first establishing improvement with daily treatment (Young et al., 1998). Again, sertraline was significantly better than the placebo, with 50 mg sertraline administered in a randomized, double-blind, placebo-controlled crossover design for 14 days before menses.
Successful intermittent administration of an antidepressant for premenstrual symptoms was first reported for clomipramine, a potent but nonselective serotonin reuptake inhibitor, at daily doses of 25 mg to 75 mg (Sundblad et al., 1993). Twenty-nine subjects were randomized for three months of treatment with either clomipramine or placebo for 14 days before menses. Treatment response was significantly better with clomipramine than the placebo. This intermittent treatment trial demonstrated a short onset of action when using clomipramine for premenstrual symptoms.
An open study of fluoxetine at 20 mg/day compared continuous and intermittent treatment for three menstrual cycles (Steiner et al., 1997). Seventy-one percent of the subjects improved. Again, more women responded in the intermittent dosing group than in the continuous dosing group, though the difference was small and not statistically significant.
More research and investigation is necessary, as all intermittent dose studies thus far have been preliminary. Some have investigated intermittent dosing only after establishing a treatment response with daily dosing. Some have compared intermittent dosing to continuous dosing, while other studies have compared only half-cycle dosing to placebo. Nonetheless, the consistent results suggest that half-cycle dosing with an SSRI can control PMS symptoms.
Which women will respond to half-cycle dosing and which will require continuous dosing is not known. However, it should be noted that the existing information on half-cycle dosing is based entirely on women who were free of premenstrual symptoms in the follicular phase of the cycle and did not have other comorbid diagnoses.
The psychopharmacologic reasons for the possible efficacy of intermittent dosing are not known. Possibly SSRIs have a more rapid onset of action when used to treat PMS, i.e., several days rather than the one to four weeks when used to treat depression. The mechanisms underlying PMS may differ from those of depression, the model for studies of serotonergic actions. The predominant PMS symptoms such as irritability and mood swings are not exclusively depressive symptoms, and the syndrome frequently includes anxiety and physical symptoms. The onset (and remission) of PMS symptoms is typically rapid, rather than gradual as in depression.
Nonetheless, evidence is accumulating that alterations in serotonin transmission may be important in PMS. For example, administration of tryptophan, an essential amino acid that serves as a dietary precursor for serotonin, and d-fenfluramine, which stimulates serotonin neurotransmission, reduced symptoms in PMS subjects. Alternatively, depletion of tryptophan aggravated PMS symptoms. In addition, short-term improvement of PMS subjects in response to administration of the serotonin agonist meta-chlorophenylpiperazine suggested that dysregulation of either the hypothalamic-
pituitary-adrenal (HPA) axis or serotonin control of the HPA axis may be associated with the symptoms of PMS (Su et al., 1997).
These preliminary studies of half-cycle dosing for PMS patients suggest that administration of a serotonergic antidepressant in the symptomatic half of the menstrual cycle may effectively control premenstrual symptoms. This is an important clinical issue for patients who might control symptoms with less medication, for medical costs, and for an increased understanding of PMS mechanisms and its relationship with depression and other mood disorders. Additional well-designed studies with sample sizes sufficient for definitive and statistically significant results are needed to support or refute these intriguing findings.
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