Sometimes placebo effects can be superior to those of standard drug therapy. Placebo effects in the treatment of premenstrual syndrome (PMS) and its more severe form, premenstrual dysphoric disorder, have not been studied in randomized controlled trials. However, a meta-analysis of controlled trials of the treatment of premenstrual dysphoric disorder showed that the rates of placebo responses varied from 6 to 35 percent. To characterize the frequency and duration of placebo responses in the treatment of PMS, Freeman and Rickels analyzed placebo responses in patients in two identically designed clinical trials of the treatment of PMS.

One of the studies was a double-blind trial of oral progesterone, alprazolam and placebo for the treatment of severe PMS in 185 subjects. The other study was a double-blind trial that compared serotonergic and noradrenergic antidepressants in the treatment of PMS in 145 subjects. Each study began with a single-blind placebo cycle, followed by randomization to three months of treatment. The outcome measure was the premenstrual symptom score derived from the daily symptom report (DSR), a validated 17-item scale. Improvement was defined as a decrease of 50 percent or more in the score for premenstrual symptoms.

During the placebo run-in phase of the study, the greatest number of subjects who initially reported a 50 percent reduction in premenstrual symptoms occurred in the first month of placebo treatment, when 17 percent reported this degree of improvement in PMS symptoms. The maximum number of subjects with improvement in PMS symptoms while receiving placebo was reached in the second month of the double-blind treatment, when 29 percent noted improvement. Twenty percent of the subjects had sustained improvement, 42 percent had partial improvement and 39 percent had no improvement throughout the six-month placebo period.

The mean DSR scores significantly worsened during the screening period in each study and returned to baseline levels in the single-blind placebo lead-in phase. When the changes in symptom severity during the screening period were compared among the groups with sustained improvement, partial improvement and no improvement, subjects in the unimproved and partial improvement groups accounted for the observed worsening of PMS symptoms during screening. In contrast, subjects with sustained improvement while receiving placebo showed slight improvement in the screening month and increased improvement in the following month. Subjects who experienced improvement of symptoms for at least two months were likely to remain improved at a level similar to that achieved with drug treatment.

The authors conclude that approximately 20 percent of patients with severe PMS experience sustained improvement with placebo medication. If improvement occurs for at least two months, the subjects are likely to remain improved at a level comparable to that achieved with drug treatment.