Effects of Metergoline on Symptoms in Women With Premenstrual Dysphoric Disorder

Women with severe premenstrual syndrome/premenstrual dysphoric disorder were either self-referred in response to advertisements in local newspapers or referred by their physician. Comparison women were recruited through local advertisements. All subjects were without current medical illness (as determined by a medical history review, physical examination, laboratory tests, and an ECG), were medication free, and had no axis I diagnosis within the past 2 years, including alcohol and substance abuse, as determined by the Structured Clinical Interview for DSM-III-R or DSM-IV (SCID) (13, 14). Premenstrual syndrome was confirmed by prospective ratings for three consecutive cycles. In order to be confirmed as having a diagnosis of premenstrual syndrome, subjects had to show at least a 30% increase in mean negative mood (e.g., depression, anxiety, or irritability) on a 100-mm analogue rating scale in the week before menses compared with the week after menses (unpublished guidelines from the NIMH Premenstrual Syndrome Workshop, Rockville, Md., 1983). Patients also met criteria for DSM-IV premenstrual dysphoric disorder.

A group of unmedicated healthy comparison women participated as well in order to control for symptoms that might be secondary to side effects of the metergoline. Comparison women also completed 2 months of prospective ratings, were without premenstrual mood symptoms, and did not meet criteria for either current or past psychiatric illness as determined by the SCID.

All subjects had regular menses, ranging between 21 and 34 days in length. Pregnancy tests were performed before the beginning of the study, and all participants were required to use barrier forms of contraception throughout the course of the study. The protocol was reviewed and approved by the NIMH Institutional Review Board, and all subjects gave both written and verbal consent to study participation. Since metergoline has been shown in other patient populations to produce clinically significant worsening, for ethical reasons patients who had been suicidal within the last year were excluded from participation. None of the women with premenstrual dysphoric disorder had any history of psychiatric hospitalization.

Metergoline, fluoxetine, and diphenhydramine were purchased from commercial sources. Metergoline (Farmitalia Carlo Erba SRL, Milan, Italy) was analyzed by the National Institutes of Health Pharmaceutical Development Service (Bethesda, Md.) to verify its identity and purity. The 8-mg dose was selected on the basis of previous studies (8) that demonstrated that this dose produced behavioral effects in selected populations and was generally well tolerated.

After acceptance into the study, participants with premenstrual dysphoric disorder (N=13) were given a trial of open fluoxetine for a period of 3 months. We used a flexible-dosing schedule titrated to symptom relief (doses ranged from 7.5 mg/day to 40 mg/day). Subjects who exhibited a response to fluoxetine (i.e., failed to meet the aforementioned 30% increase in mean negative mood) (N=11) then participated in a randomized, double-blind, placebo-controlled, crossover study 6–8 days after their luteinizing hormone surge during two consecutive menstrual cycles as determined by Ovuquick test kits (Quidel Corp., San Diego). The timing and nature of the procedure were identical in the unmedicated healthy comparison group (N=9).

Participants came to the clinic between 8:00 a.m. and 9:00 a.m. after fasting from midnight the night before. After baseline vital signs and mood ratings (Beck Depression Inventory [15], self-report and clinician-rated forms of the Premenstrual Tension Symptom Scale [16], Hamilton Anxiety Rating Scale [17], Hamilton Depression Rating Scale [18], a measure of side effects [19], and a visual analogue scale [20, 21]) were obtained, a heparin lock was inserted for blood drawing purposes. Metergoline (8 mg) or diphenhydramine (50 mg) was administered orally 40 minutes after insertion of the heparin lock. Diphenhydramine was used as an active placebo to maintain the blind and to control for the sedative effects of the metergoline. Baseline blood samples were obtained at –20 and –5 minutes and then at 30, 60, 90, 120, 180, and 240 minutes after administration of the medication. Mood ratings were obtained at baseline, at the end of the procedure (4 hours after administration of medication), and 24 hours after the procedure.

Vital signs (temperature, pulse, and blood pressure) were obtained at baseline and after 30, 60, 90, 120, 180, and 240 minutes.

Blood samples were collected for the measurement of plasma levels of prolactin (22) (a measure of the central activity of metergoline) at baseline and 30, 60, 90, 120, 180, and 240 minutes (4 hours) after metergoline/active placebo administration. Metergoline levels were obtained at baseline and 60 minutes, 4 hours, and 24 hours after metergoline administration. Additionally, patients had fluoxetine and norfluoxetine levels drawn at the end of the procedure (i.e., after 4 hours) and after 24 hours.

Plasma prolactin assays were performed at Covance Laboratories (Vienna, Va.) by methods previously described (23). The prolactin assay had an intraassay coefficient of variation of 4.6% and an interassay coefficient of variation of 8.2%. Fluoxetine and norfluoxetine assays were performed by high-performance liquid chromatography by Quest Diagnostics (Baltimore). Metergoline levels were assayed by a high-performance liquid chromatography method developed in the Laboratory of Clinical Sciences, NIMH (Bethesda, Md.) (T. Toliver et al., personal communication). The intraassay and interassay coefficients of variation were 5.8% and 8.8%, respectively.

Participants completed the following symptom ratings at baseline, at the end of the procedure (4 hours), and at 24 hours: the Beck Depression Inventory (15), self-report Premenstrual Tension Symptom Scale (16), and a physical symptoms rating scale (19). Visual analogue scales (100-mm) of mood measures—mood stability, irritability, sadness, and anxiety—were also completed by the subjects at the same time points. In addition, the following objective measures were obtained (at the same time points mentioned for the self-ratings): the Hamilton depression and anxiety scales (18) and the clinician-rated Premenstrual Tension Symptom Scale (16).

Symptom ratings were analyzed by repeated-measures analysis of variance (ANOVA) with Systat 8 (SPSS, Chicago, 1998), with drug treatment (metergoline versus diphenhydramine) and time (baseline, 4 hours [postprocedure], and 24 hours) as the within-group variables and diagnosis the between-group variable. Significant differences in these measures were analyzed with post hoc Bonferroni t tests. Pearson correlation coefficients were calculated to determine if symptoms at 4 and 24 hours after the procedure were predicted either 1) by plasma levels of fluoxetine or norfluoxetine at the end of the procedure or after 24 hours or 2) by metergoline levels at 60 minutes (peak) and at the end of the procedure (metergoline levels at 24 hours were negligible).

There was no significant difference between the ages of the women with premenstrual dysphoric disorder (mean age=40.4 years, SD=3.9) and the comparison women (mean age=36.9 years, SD=7.7) (t=1.2, df=18, p=0.20). There was one African American woman with premenstrual dysphoric disorder and two African American healthy comparison subjects. The remaining participants were Caucasian. Four of the women with premenstrual dysphoric disorder had a history of major depression. The average dose of fluoxetine taken by the women with premenstrual dysphoric disorder was 24 mg (SD=10.7).

ANOVA revealed significant diagnosis and diagnosis-by-time effects on a variety of mood measures that reflected an increase in symptoms after 24 hours in the patients but not in the comparison subjects. As seen in Table 1, the source of these effects was further clarified by the identification of significant interactive effects of diagnosis, drug condition, and time for scores on the self-report and clinician-rated Premenstrual Tension Symptom Scale, Hamilton anxiety scale, Hamilton depression scale, and the visual analogue scale ratings of anxiety and mood lability. Post hoc Bonferroni t tests indicated that the significant results were due to an increase in symptoms 4 hours after administration of metergoline (but not active placebo) in the patients relative to the comparison subjects as measured by the clinician-rated Premenstrual Tension Symptom Scale (t=3.3, df=54, p<0.05) and the visual analogue scale rating of anxiety (t=3.1, df=54, p<0.05) and symptom increases after 24 hours for the following measures: Premenstrual Tension Symptom Scale (self-report: t=4.9, df=54, p<0.01; clinician-rated: t=4.7, df=54, p<0.01), Hamilton anxiety scale (t=7.6, df=54, p<0.01), Hamilton depression scale (t=7.6, df=54, p<0.01), and the visual analogue scale rating of anxiety (t=6.5, df=54, p<0.01). For the patients, scores 24 hours after metergoline administration were higher than at baseline for the Premenstrual Tension Symptom Scale (self-report: t=6.4, df=72, p<0.01; clinician-rated: t=7.8, df=72, p<0.01); Hamilton anxiety scale (t=9.5, df=72, p<0.01); Hamilton depression scale (t=6.1, df=72, p<0.01); and visual analog scale rating of anxiety (t=6.5, df=72, p<0.01). In addition, scores for the patients were higher 24 hours after metergoline administration compared with placebo for the Premenstrual Tension Symptom Scale (self-report: t=3.7, df=54, p<0.01; clinician-rated: t=6.0, df=54, p<0.01); Hamilton anxiety scale (t=7.2, df=54, p<0.01); Hamilton depression scale (t=6.2, df=54, p<0.01); and the visual analogue scale rating of anxiety (t=5.0, df=54, p<0.01). The significantly higher scores on the Hamilton anxiety scale in the patients (but not in the comparison women) 4 hours and 24 hours after metergoline administration are depicted in Figure 1. Patients and comparison subjects did not differ in their experience of side effects during metergoline or active placebo administration, both of which induced sedation.

There was no significant change in oral temperature or systolic blood pressure in patients or comparison women receiving metergoline versus active placebo (ANOVA data not shown). However, since it has been previously shown that metergoline significantly decreases temperature 4 hours after its administration (8), we also performed a comparison specifically at that time point and found that there was a significant decrease in oral temperature 4 hours after metergoline administration compared with baseline (t=2.5, df=18, p=0.02) and active placebo (t=2.3, df=18, p=0.03).

There was no significant difference in baseline plasma prolactin levels in either patients or comparison women receiving metergoline versus active placebo. Plasma prolactin levels significantly decreased following metergoline administration compared with active placebo (ANOVA F=2.2, df=1, 14, p<0.004) in both patients and comparison subjects.

In patients there was no difference in fluoxetine levels at any time point with metergoline compared with active placebo days; a significant metergoline-associated decrease in norfluoxetine levels (t=6.9, df=10, p<0.01) was observed at 4 hours (metergoline: mean=122.0 ng/ml [SD=57.7]; placebo: mean=230.0 ng/ml [SD=45.8]) but not at 24 hours (metergoline: mean=165.9 ng/ml [SD=56.8]; placebo: mean=147.5 ng/ml [SD=57.5]). Metergoline levels were significantly lower at both 60 minutes and 4 hours in the comparison subjects (mean=23 ng/ml [SD=12.4] and 11.6 ng/ml [SD=2.9], respectively) than patients (mean=132.1 ng/ml [SD=71.5] and 68.0 ng/ml [SD=39.6]), most likely indicating an interference by fluoxetine with the metabolism of metergoline, an observation previously seen in fluoxetine-treated patients with OCD (8). In the patient group, the severity of symptoms at 24 hours as measured by the Hamilton anxiety scale and clinician-rated Premenstrual Tension Symptom Scale was significantly correlated with metergoline levels after 60 minutes (r=0.68, df=10, p<0.01 and r=0.45, df=10, p<0.05, respectively) and after 4 hours (r=0.79, df=10, p<0.01 and r=0.77, df=10, p<0.01). There was no correlation between symptoms experienced at 4 or 24 hours and levels of fluoxetine or norfluoxetine at any of the timepoints.