Intermittent and Continuous Sertraline Equally Effective for PMS

Mindy Hung

March 03, 2004

March 3, 2004 — Intermittent and continuous dosing of the selective serotonin reuptake inhibitor (SSRI) sertraline are equally effective for the treatment of severe premenstrual syndrome (PMS), according to the results of a study published in the February edition of the American Journal of Psychiatry.

Ellen W. Freeman, PhD, and colleagues from the University of Pennsylvania in Philadelphia conducted a stratified, randomized, double-blind, parallel-treatment trial that compared full-cycle and premenstrual dosing regimens of sertraline with a placebo.

The researchers included patients aged 18 to 45 years with regular menstrual cycles, persistent premenstrual symptoms for at least six months, and global report of moderate to severe impairment in work, family life, or social activity. Women met the stated PMS criteria with confirmation by prospective daily symptom ratings. Sixty percent of the patients also met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for premenstrual dysphoric disorder (PMDD).

Exclusion criteria were any major axis I psychiatric diagnosis, use of psychotropic medications that could not be discontinued for the duration of the study; prescription, nonprescription, herbal, or other therapies for PMS; pregnancy and breast-feeding; hysterectomy; symptomatic endometriosis; not using medically approved contraception; serious health problems; risk of suicide; or alcohol or drug abuse within the past year.

The primary outcome measure was the total score on the premenstrual Daily Symptom Rating Form, which was calculated from the daily symptom ratings that were maintained throughout the study. The secondary outcome measure was the Subject Global Ratings of Functioning.

The investigators assigned 167 subjects, stratified for severity of postmenstrual symptoms and history of major depression, to a treatment condition: 56 patients received full-cycle dosing, 56 patients received luteal-phase dosing, and 55 patients were given placebo. All subjects received two bottles of medication at each visit. Patients took tablets daily during the three cycles of dosing.

The initial dose for all subjects was 1 tablet per day continued through day 2 of the next cycle. Starting at day 3, subjects switched to bottle B and received either 50 mg sertraline (the daily-dosing group) or placebo. At 14 days before menses, subjects in the premenstrual dosing group were switched from placebo to 50 mg sertraline. In the absence of clear improvement or dose-limiting adverse effects, the dose was raised to two tablets per day (100 mg sertraline or placebo) in the second or third double-blind treatment cycles.

Dosage increases started with bottle B at day 14. Subjects who increased to two tablets during the second cycle continued with two tablets through the third cycle. To maintain the study blind, all subjects taking two tablets per day at end point were tapered to one tablet per day for seven days before stopping medication.

In the third treatment cycle, mean dose levels in the full-cycle sertraline group were 74 mg/day (standard deviation [SD] = 25), 76 mg/day (SD = 25) in the luteal-phase sertraline group, and a dose equivalent for the placebo tablets of 85 mg/day (SD = 23) (F = 2.30, df = 2, 114; P = .11).

Twenty-four subjects discontinued before providing treatment response data. Another 25 subjects discontinued after providing at least one treatment response.

The sertraline groups showed significantly more improvement than the placebo group (full-cycle dosing vs. placebo: t = -2.39, df = 137; P = .02); luteal-phase dosing vs. placebo: t = -2.65, df = 137; P = .009). Results were similar between the two sertraline groups (t = 0.31, df = 137; P = .76).

Significant improvement was seen in Daily Symptom Rating Form scores over three treatment cycles with last observation carried forward (F = 3.83, df = 2, 137; P = .02). Treatment groups demonstrated greater improvement than the placebo group (full-cycle dosing vs. placebo: t = -1.93, df = 137; P = .055; luteal-phase dosing vs. placebo: t = -2.67, df = 137; P = .009). The researchers found no significant difference between the two sertraline groups (t = 0.78, df = 137; P = .44).

Mean Daily Symptom Rating Form scores by cycles showed that the greatest decrease in Daily Symptom Rating Form scores from baseline took place in the first month of double-blind treatment: 42% in the full-cycle group and 45% in the luteal-phase dosing group compared with 26% in the placebo group.

The placebo-treated group improved more slowly, and it remained less improved but not significantly different from the sertraline-treated groups at end point.

Subjects with more severe postmenstrual symptoms before treatment remained more symptomatic regardless of the dosing regimen. Patients did not report any serious adverse events that required medical intervention or withdrawal symptoms that required medication adjustments. Adverse effects included gastrointestinal problems, decreased libido or orgasm, headache, insomnia, dry mouth, and nausea.

"'The results clearly demonstrate the more rapid efficacy of medication but also indicate the importance of nondrug factors in clinical care and suggest the potential for cognitive therapy or supportive treatments as options for severe PMS,"' write Dr. Freeman and colleagues.

"'While this is a very high response rate and consistent with all other reports of SSRI treatments for PMS/PMDD, further evidence-based information about treatments and underlying mechanisms remains essential for increasing scientific understanding of the disorder and relieving the distress that it incurs."'

The study was supported by a grant from the National Institute of Child Health and Human Development.

Am J Psychiatry. 2004;161:343-351

Reviewed by Gary D. Vogin, MD

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