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The duration of treatment after achieving a satisfactory response is an unanswered question in the treatment of premenstrual syndrome (PMS). This information is needed given the improvement provided by medication versus the side effects and costs of drugs.
Compare rates of relapse and time to relapse between short-term and long-term sertraline treatment administered in the luteal phase.
An 18-month survival study with a randomized, double-blind switch to placebo after 4 months or 12 months of sertraline treatment.
Academic medical center.
174 PMS/PMDD patients.
Relapse, defined as symptoms returned to the entry criterion level assessed by daily ratings.
The relapse rate was 41% during long-term treatment compared to 60% after short-term sertraline treatment, with a median time to relapse over 8 months versus 4 months (hazard ratio 0.58; CI 0.34, 0.98; P=0.04). Subjects with severe baseline symptoms were more likely to relapse compared to the low-moderate group (hazard ratio= 2.02, CI 1.18, 3.41; P=0.01) and were more likely to relapse with short-term treatment (P=0.03). Length of treatment did not affect relapse for subjects with low to moderate symptoms (P=0.50). Subjects who reached remission were least likely to relapse (hazard ratio= 0.22; CI 0.10, 0.45; P<0.001). Further analysis comparing relapse in the first 6 months on placebo in each treatment group had similar results.
The relapse rate was significantly greater after short -term treatment compared to long-term treatment. The relapse rate was also high during extended drug treatment. Subjects with severe symptoms at baseline were most likely to relapse and relapsed more swiftly, regardless of treatment duration. The findings suggest that the severity of symptoms at baseline and symptom remission with treatment should be considered in determining the duration of treatment.
Premenstrual syndrome (PMS) continues to be one of the most common health problems reported by reproductive age women. The morbidity of PMS is due to the severity of the symptoms, the resulting impairment of work, personal relationships and activities and its chronicity over many years of menstrual cycling, 1,2 but its etiology remains uncertain. Treatment of the severe form of PMS termed premenstrual dysphoric disorder (PMDD) with sertonergic reuptake inhibitors has consistently demonstrated efficacy, and the FDA has approved sertraline, fluoxetine and paroxetine for this indication.3,4
Clinical trials have addressed only acute treatment of PMS and PMDD, typically about 3 months duration. There is little information about the optimal duration of treatment, although anecdotal reports and small pilot investigations suggest that premenstrual symptoms return rapidly in the absence of effective medication.5-8 How long medication should be continued after achieving a satisfactory response, and the risk of relapse after discontinuing treatment are important questions for women and clinicians, given the possible side effects and cost of drugs versus the benefit of medication that improves symptoms, functioning and quality of life.1
The purpose of this study was to compare the rate of relapse and time to relapse between short-term treatment (ST) and long-term (LT) sertraline treatment administered in the luteal phase. Both treatment groups continued for the 18 months of study, using a double-blind switch to placebo when sertraline was discontinued. We hypothesized that the time to relapse would be longer and the rate of relapse lower when discontinuing drug after 12 months compared to discontinuing after 4 months of treatment.
The study was conducted at the University of Pennsylvania Medical Center, Philadelphia, PA from 2002 to 2007. The study was approved by the Institutional Review Board of the University, and subjects provided written informed consent.
Inclusion criteria were ages 18-45 years; regular menstrual cycles of 22-35 days for at least 6 months; persistent premenstrual symptoms for at least 1 year; a positive urine test indicating probable ovulation; and general good health as determined by physical and pelvic examination and laboratory tests of complete blood count and chemistry profile.
Exclusion criteria were any major axis I psychiatric diagnosis, currently or within the past year as determined by the Structured Clinical Interview for DSM-IV Axis I disorders (SCID),9 alcohol or substance abuse in the past year; lifetime history of psychosis or bipolar disorder; current use of psychotropic medications or any current prescription, over-the-counter, herbal or non-medical therapies for PMS; pregnancy, breast feeding, hysterectomy, symptomatic endometriosis, irregular menstrual cycles, lack of medically approved contraception, or any severe or unstable medical illness.
Diagnosis of severe PMS was based on prospective rating of the validated Daily Symptom Report (DSR)10 and patient global ratings of functioning. Subjects rated the 17 DSR symptoms daily from 0=none to 4=very severe. A total premenstrual score >=80 with an increase of at least 50% from the postmenstrual score was required for the mean of the screen cycles and for the third single-blind, placebo-treated screen cycle. The premenstrual DSR scores were calculated by summing the 17 symptom ratings for 6 days before menses. The postmenstrual DSR scores were the sum of the 17 symptoms ratings for days 5-10 (day 1 was the first day of menses). Subjects rated functioning in work, family life, social activity and overall interference on a 10-point scale, with at least moderate disruption (a rating of >=4) on one or more scales required for eligibility.11 These symptom criteria are the same as the criteria to establish a PMDD diagnosis, with the exception of requiring a specific number of symptoms, e.g., 5 of the 11 specified PMDD symptoms.
This is a randomized, stratified, double-blind, placebo-controlled study to examine rate of relapse and time to relapse compared between short-term (ST) and long-term (LT) sertraline treatment, using a double-blind switch to placebo (Figure 1). After a 3-month screen period that included 1 month of single-blind placebo medication to confirm a stable PMS diagnosis, all eligible subjects were randomized double-blind to the ST or LT treatment groups and were administered sertraline in the luteal phase for 4 months. After 4 months of drug treatment, the ST group switched to placebo and the LT group continued sertraline for 8 more months. After 12 months of sertraline, the LT group was switched to placebo, and the ST group continued placebo (all switches were double-blind). Both treatment groups had 18 total months of study. Symptom assessments were monthly and timed to the menstrual cycle.
Random allocation to the study groups was generated by computerized random-number tables prior to the start of the study and implemented by the use of numbered containers with identical tablets. Randomization codes were kept in locked files, and neither the clinicians nor the subjects knew the treatment assignments. Stratification was used to assure equal distributions of premenstrual symptom severity in the ST and LT groups. Symptom severity was determined from the subject's average of the premenstrual DSR scores in the screen period, and subjects were allocated to one of three groups at randomization: high severity (>169), mid severity (169-122) or low severity (121-80).
Power calculations prior to the study indicated that a sample size of 180 subjects (90 per group) assuming relapse rates of 0.65 in the ST group and <0.40 in the LT group would provide over 90% power with alpha=0.05 and 2-tailed tests.
Treatment was administered in the luteal phase of the menstrual cycle, starting on day 14 before the expected date of menses and continuing through menstrual day 2. Sertraline and placebo tablets were prepared by the manufacturer and were identical in appearance. Medication bottles were labeled for each visit with the code number assigned at randomization. All subjects started at 50 mg/day sertraline. In the absence of clear improvement in the second or third months of treatment (defined as premenstrual DSR scores >=80 and CGI improvement scores >2) or dose-limiting side effects, the dose was increased to 100 mg/day. The dose in the fourth month of sertraline treatment was maintained for the remainder of the study. The equivalent number of placebo tablets was used when subjects were switched to placebo. Subjects with an increased dose took 50 mg/day for the first 3 days of the dosing interval, increased to 100 mg/day until day 2 of menses and then tapered to 50 mg/day before stopping. Medication compliance was monitored by pill counts (the number used and returned at each visit) and by subject report as recorded daily on the DSR. The mean (SD) luteal phase dose after 4 months of sertraline treatment was 89 (SD 21) mg/day, with no significant difference between the ST and LT groups.
Improvement and relapse were assessed using the total premenstrual DSR scores (above). Improvement was defined by a premenstrual DSR score <80 and at least 50% decrease from the subject's average baseline DSR score. Relapse was defined as return of premenstrual DSR scores to the entry criterion of 80 or more, as documented by the daily symptom ratings for one or more menstrual cycles. Time to relapse was measured for an 8-month time period, comparing the ST group on placebo versus the LT group on drug in months 5-12 of the study. In the second analysis, time to relapse was measured for a 6-month time period after the switch to placebo in each treatment group (months 5-10 in the ST group and months 13-18 in the LT group).
Possible covariates of treatment response were selected, based on reports in the literature and the goals of the study: adverse events in months 2-4 of sertraline treatment (yes, no); symptom remission (yes, no) as defined by premenstrual DSR scores <=40 after 4 months sertraline (the mean postmenstrual score in previous studies 12); perceived stress at baseline (Cohen et al);13 duration of PMS (<10 years, >=10 years); history of major depression (yes, no as assessed in SCID interview); Hamilton Depression Rating Scores (HAM-D) at the postmenstrual and premenstrual screen visits;14 and the demographic variables listed in Table 1.
Survival analysis was used to compare the time to relapse between short-term and long-term treatment. The time to relapse was compared between the two treatment groups in two different ways. First, we compared discontinuing drug after short-term treatment versus continued drug treatment in the same 8-month time period (Model 1). We then addressed the research question of whether there were differences in relapse if drug was stopped after 4 months compared to 12 months treatment with a direct comparison of relapse in the 6 months following the switch to placebo (months 5-10 in the ST group and months 13-18 in the LT group) (Model 2).
The statistical analyses used Kaplan Meier curves,15 log-rank tests16 and Cox proportional hazards models17 to compare time to relapse between the ST and LT treatment groups. The data from all improved subjects in the specified time interval were included as appropriate for each model; unimproved subjects were excluded. The log rank test was used to detect differences in the distribution of time to relapse between the two treatment groups or multiple groups defined by the covariates of interest. Multivariable models utilized Cox proportional hazards models to estimate the ratio of the hazard of relapse between the groups defined by each covariate, allowing for adjustment for baseline severity and other risk factors. The hazard ratio indicates the chance of relapse in the current month provided the subject has not had a relapse in the past month.
Bivariable associations between covariates and time to relapse were examined. The primary covariate of interest was baseline symptom severity, which was the stratification variable described above. After inspection of the distributions of relapse in the three stratified severity groups, the moderate and low groups were collapsed into a single group and termed the low severity group.
The covariates with a bivariable association with relapse at P<=0.15 were entered simultaneously in the multivariable model. The final selection of covariates for multivariable models was guided by whether the variable was associated with the response variable at P<=0.05 or whether its inclusion in the model modified other significant associations by 15% or more.
Analysis of symptom levels used the premenstrual DSR scores and Student's t test or ANOVA to compare treatment groups at the end of each study phase. All randomized subjects with treatment response data were included, using the last observation in each phase for study discontinuers (intent-to-treat analysis). A second analysis included only the subjects who remained active throughout the phase.
Baseline characteristics of all randomized subjects were compared between the treatment groups using t tests or chi square tests as appropriate for the data. In all analyses, results with P<=0.05 for a two-tailed interpretation were considered statistically significant. The statistical software package was SAS, Version 9 (SAS Institute Inc., Cary, NC).
One hundred seventy four subjects were randomly assigned to the short-term (ST, N=87) or long-term (LT, N=87) groups. Figure 1 depicts subject progress and study discontinuations throughout the study. There were no significant differences in discontinuation rates between the ST and LT groups. At baseline the clinical and demographic variables of the study did not differ between the two treatment groups (Table 1).
Seventy-two percent of the subjects (125/174) improved (defined by a >=50% decrease in premenstrual DSR scores from the average baseline to a score below the entry criterion of 80). Nearly all improvement occurred in the first months of treatment: 37% of the subjects (64/174) improved in the first month, 62% were improved in the second month, 69% in the third month, and 70 % in the fourth month of sertraline treatment. Only 3 additional subjects improved during extended sertraline treatment, one in each of months 5, 6, and 9. There was no significant difference in the proportion of women who improved in the ST and LT groups.
We first compared time to relapse between the ST group switched to placebo and the LT group that continued sertraline (months 5-12 of the study) (Model 1). In this 8- month time period, 60% (32/53) relapsed in the ST group versus 41% (24/58) in the LT treatment group. The median time to relapse was 4 months versus over 8 months, respectively. The chance of relapse was significantly lower in the LT group on sertraline compared to the ST group on placebo in this 8-month period (hazard ratio 0.58; CI 0.34, 0.98; P=0.04) (Table 2).
Baseline symptom severity was strongly associated with relapse independent of treatment. In the high severity group, the relapse rate was 70% (26/37) compared to 41% (30/74) in the low severity group, with a median time to relapse of 2 months versus greater than 8 months, respectively. The chance of relapse was 2-fold greater in the high severity group compared to the low severity group in this 8-month time period (hazard ratio =2.02; CI 1.18, 3.41; P=0.01) (Table 2)
Table 3 shows the significant differences in relapse across the 4 strata of treatment and severity (log-rank P=0.001). In the high severity group, 83% off the ST group relapsed after switching to placebo compared to 58% of the LT group that continued sertraline. In the low severity group, 49% of the ST group relapsed after switching to placebo, compared to 33% of the LT group that continued sertraline. Among subjects with severe symptoms, the rate of relapse was significantly greater with short-term treatment compared to long-term treatment (P=0.03). In the low symptom group, the rate of relapse did not differ between ST and LT treatment (P=0.19) (Table 3 and illustrated in Figure 2, Panels A and B).
We then examined time to relapse for the first 6 months on placebo in each treatment group (months 5-10 in the ST group and months 13-18 in the LT group). The results were consistent with Model 1. In the LT group, 33% (13/39) relapsed versus 51% (27/53) in the ST group. The median time to relapse was over 6 months and 4 months, respectively. The chance of relapse was lower with long-term treatment compared to short-term treatment in the first 6 months after going off drug (hazard ratio 0.55; CI 0.28, 1.11; P=0.09) (Table 4).
In Model 2, symptom severity was significantly associated with relapse independent of treatment duration. In the high severity group, 66% relapsed compared to 32% in the low severity group, with a median time to relapse of 2 months and over 6 months, respectively. The chance of relapse in the first 6 months after switching to placebo was over 2 times greater in the high severity group compared to the low severity group (HR 2.22; CI 1.15, 4.29; P=0.02).
In Model 2, the differences in relapse across the 4 strata of treatment and severity were significant (log-rank P=0.001) and consistent with the first model. In the high severity group, 83% relapsed after ST treatment compared to 43% after LT treatment, with a median time to relapse of 1 month versus over 6 months, respectively. In the low severity group, 34% relapsed after ST treatment compared to 28% after LT treatment, with the median time to relapse over 6 months in both groups (shown in Figure 2, Panels C and D). Among subjects with severe symptoms, the rate of relapse was significantly lower with long-term treatment (P=0.02). Among subjects with low to moderate symptoms, the rate of relapse did not differ between ST and LT treatment (P=0.50).
We defined symptom remission as a premenstrual DSR score <=40, which was the mean postmenstrual score in previous studies. Twenty-four percent (41/174) of the subjects reported remission after 4 months of sertraline treatment. The rate of remission did not differ significantly between the high versus low severity groups (P<0.14). In Model 1, 22% (9/41) of the subjects who reached remission relapsed compared to 67% among the subjects with less complete recovery (hazard ratio= 0.22; CI 0.10, 0.45; P<0.0001). In Model 2, 16% (6/37) of subjects who reached remission relapsed compared to 62% among the remaining improved subjects (hazard ratio= 0.22; CI 0.09, 0.52; P<0.001). The median time to relapse of the remitted subjects extended beyond the observation periods in both models. There was no interaction between remission and treatment group, indicating that relapse was not different in the two treatment groups when remission was taken into account.
When remission was included in a multivariable analysis, only remission remained significantly and inversely associated with relapse, while treatment and baseline severity had no significant association with relapse. This indicated that the subjects who reached remission were significantly less likely to relapse regardless of the duration of treatment or the severity of symptoms. Figure 3 shows that the DSR scores were significantly lower in the remission group at 12 months and 18 months regardless of whether they were on drug or switched to placebo.
All baseline characteristics (shown in Table 1) and a variable for adverse events (yes, no) during initial sertraline treatment were examined with relapse in bivariable analysis. Only 3 of these variables were associated with relapse at the level of P<=0.15: PMDD, history of depression and OC use. PMDD subjects had a greater rate of relapse in bivariable analysis in Model 1 (P=0.02). However, PMDD was highly correlated with symptom severity (corr = 0.51)and could not be retained in the multivariable model. History of depression was significantly associated with relapse in bivariable analysis in Model 2 (P=0.005). Women with a history of depression were nearly twice as likely to relapse after switching to placebo, regardless of the duration of sertraline treatment (hazard ratio 1.92; 95% CI 1.00, 3.66; P=0.05). The addition of OC use (25% in each treatment group) reduced the estimated association between treatment group and relapse, indicating confounding in Model 1. However, there was no significant interaction between OC use and treatment, indicating that the response to sertraline was not different in OC users.
To determine whether symptom scores differed after short-term or long-term treatment, we compared the premenstrual DSR scores for all available subjects at the beginning of each study phase using the last observation of the discontinuers during the phase (LOCF). We had hypothesized that subjects who continued through long-term treatment would have lower symptom scores but found no significant difference in the premenstrual DSR scores compared between the ST and LT groups after 4, 12, or 18 months in LOCF analysis. When only the continuers were examined in each phase, the DSR scores were significantly lower at 12 months in the LT group that continued drug compared to the ST group on placebo (22 +/- SE 7 versus 62 +/-SE 9, P=0.03). However, at 18 months when both groups were on placebo, there was no significant difference in DSR scores of the completers (25 +/- SE 5 in the LT group vs 38 +/- SE 8 in the ST group, P=0.17).
Adverse events were reported at each visit in response to general clinical questioning and subject reports on the daily symptom rating form (DSR). There were no serious adverse events due to treatment that required medical intervention or withdrawal from the study. There were no reports of withdrawal symptoms that resulted in medication adjustments. Ten percent (17/174) of the randomized subjects stated that adverse events were the reason for withdrawing from the study (shown in Figure 1).
The most frequent adverse events were insomnia (23%), nausea (22%), fatigue (18%), headache (13%), decreased libido or orgasm (10%) and appetite changes (9%). Adverse events usually diminished with time and adjustment to the medication. For example, 60% (105/174) of the subjects reported adverse events in the first two months of sertraline treatment, but only 16 subjects reported adverse events in month 4. Of the 17 subjects who reported decreased libido or orgasm during the 12 months of sertraline administered in the luteal phase, only one subject reported this adverse event at more than one visit, and none stated that discontinuation was due to this adverse event.
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.
Naseem Kerr, MPH served as the study coordinator with responsibility for the data collection. The statistical analyses were conducted by Hui Lin, MS, a member of the research team. Sertraline and placebo tablets were provided by Pfizer, Inc. Pfizer had no role in the conduct of the study, including design, analysis and interpretation of the data, and had no role in the preparation, review or approval of the manuscript.
Funding: This study was supported by a grant from the National Institutes of Health, Bethesda, MD, #RO1 HD18633.
The authors report financial disclosures as follows (none had involvement with this study):
Dr. Freeman: During the past 5 years received honoraria, served as a consultant or on an advisory board: Wyeth, Xanodyne Pharmaceuticals, Forest Research, Pherin Pharmaceuticals, Berlex Laboratories, Pfizer. Received research support (issued to the University of Pennsylvania) from Wyeth, Xanodyne Pharmaceuticals, Forest Research, Pherin Pharmaceuticals, Berlex Laboratories, Pfizer.
Dr. Rickels: During the past 5 years received honoraria, served as a consultant or on an advisory board: Cephalon, Inc., DOV Pharmaceuticals, Eli Lilly, Hoffman-LaRoche, Jazz Pharmaceuticals, Johnson and Johnson, Novartis, Pfizer, Epix (PreDix) Pharmaceuticals, Sanofi-Synthelabo Research. Received research grants (issued to the University of Pennsylvania): AstraZeneca, Bristol-Meyers Squibb, Cephalon, Inc., Epix Pharmaceuticals, Genaissance Pharmaceuticals, Inc., GlaxoSmithKline, Merck, Pamlab, Pfizer, Somerset Pharmaceuticals, Wyeth.
Dr Sondheimer: During the past 5 years received honoraria, served as a consultant or on a advisory board: Forest Laboratories, Pfizer.
Dr. Sammel and Ms. Lin report no financial interests.