Approximately half the improved subjects relapsed within 6 to 8 months after discontinuing sertraline. Overall, longer treatment was marginally better in preventing relapse, but more importantly, both the rate of relapse and time to relapse were highly associated with symptom severity at baseline. Subjects with severe baseline symptoms were significantly more likely to relapse after discontinuing drug, relapsed after a shorter time period, and were significantly more likely to relapse during extended drug treatment compared to subjects in the low symptom group. The subjects with low to moderate baseline symptoms were less likely to relapse regardless of the treatment duration, and the time to relapse was significantly longer.
The rate of relapse during extended drug treatment was high. Forty-one percent of the improved subjects relapsing during months 5-12 of drug continuation. The reasons for relapse on drug are unclear.18
The subjects were maintained at their improvement dose and took the medication as prescribed in the protocol and confirmed by pill counts. We observed that this group was more likely to have increased their sertraline dose in the initial treatment period (54% versus 18% who remained on the lower sertraline dose), possibly indicating that their initial improvement was less stable or less responsive to sertraline and thus more susceptible to relapse. Another possible reason for the loss of treatment response is a loss of a placebo response, as has been identified in maintenance studies of depression.19,20
The present study was not designed to determine a loss of placebo effects, but the findings suggest that the “true” drug effect of sertraline in PMS treatment may be lower than observed in short-term clinical trials.4
A third possibility is that luteal phase dosing may be insufficient for patients with severe symptoms, who were the most likely to relapse. Although luteal phase dosing is a current standard of care for PMS and PMDD treatment, these findings suggest that further study is needed of the role of symptom severity in treatment response.
The subjects who reached remission as defined in the study were significantly less likely to relapse than the improved subjects with less complete recovery, regardless of the duration of treatment or the severity of baseline symptoms. These findings indicate that partial recovery is associated with a rapid return of symptoms, while a more complete recovery, where symptoms are reduced to approximately the “normal” postmenstrual level, is associated with a longer delay in symptom recurrence, similar to previous studies of depressed patients.21,22
Numerous clinical and demographic variables were examined for an association with relapse, but only two variables retained significance in multivariable analysis. Subjects with a history of depression, which was reported by approximately half the sample, were about twice as likely to relapse within 6 months of discontinuing sertraline compared to those with no history of depression. This association has been previously observed in depressed patients, where both the chronicity and the severity of depression predict relapse after SSRI treatment.18
Current OC users were less likely to relapse, and the treatment association with relapse became non-significant when OC use was added to the multivariable model. However, there was no significant interaction between OC use and treatment, indicating that the response to sertraline was not different in OC users. Nonetheless, the indication that OC use is a potential confounder of treatment warrants further studies.
Several limitations of the study are considered. There are no established definitions of improvement, remission and relapse in PMS or PMDD treatment, and results may vary according to the definitions of these conditions. Our definition of improvement yielded results consistent with the proportions of improved subjects reported in clinical trials of SSRIs for this disorder. Our definition of relapse is conservative in requiring that symptoms return to the study eligibility level and may underestimate the rate of relapse if less stringent definitions were used.
Our pre-study estimates for the sample size assumed a 25% difference in relapse between the two treatment groups with 90% power and alpha at P=0.05. However, the observed difference in the relapse rate between short-term and long-term treatment was only 18% to 19%, which resulted in a marginal P value for treatment in Model 2.
Although the considerable relapse that was observed on continued drug treatment clearly impacts the number of survivors in the long-term treatment group, there is no direct way to account for this when the primary objective of the study is to compare discontinuing drug at different time intervals. However, our hypothesis that discontinuing drug after longer treatment would delay relapse was tested in two different ways and yielded consistent results. Both models favored long-term treatment, particularly for subjects with severe symptoms.
The subjects were without comorbidities, in their late twenties to mid-thirties, and predominantly Caucasian, and results may not be generalizeable to all women with premenstrual symptoms. Finally, the study did not address alternative dosing regimens or other treatment strategies for the subjects who relapsed or remained unimproved, and further studies that examine treatment approaches for these conditions are needed.
The strengths of this study include randomized, placebo-controlled comparisons of short-term and long-term treatment of PMS using luteal phase administration of an SSRI, which is the current gold-standard for this disorder. Both improvement and relapse were systematically identified in daily symptom reports that were maintained by the subjects throughout the study. The findings indicated that there is a high likelihood of relapse when medication is discontinued, particularly for patients with severe premenstrual symptoms at baseline. Inasmuch as the subjects with severe symptoms were less likely to relapse with long-term treatment compared to short-term treatment, patients with severe symptoms might be advised to continue medication for at least a year after initial improvement. However, the considerable relapse during continued drug treatment raises an important question of whether luteal phase dosing is sufficient for patients with severe symptoms and should be further evaluated. Relapse was not associated with the duration of treatment among the subjects with low to moderate symptoms, suggesting that for these patients, the continued use of medication could be evaluated after initial improvement. Although the premenstrual symptoms may eventually return, a medication-free interval that reduces the side effects and costs of drugs may be an acceptable benefit for patients with low to moderate symptoms. Finally, subjects who achieved remission were much less likely to relapse, regardless of the treatment duration or the severity of baseline symptoms. This is a compelling indication of the importance of seeking remission as the goal of PMS treatment.