131

Psychiatry Research, 37: I3 I- 138 Elsevier

Atenolol in Premenstrual Melatonin Hypothesis Barbara L. Parry, Norman Thomas A. Wehr Received

November

Syndrome:

E. Rosenthal,

Stephen

A Test of the

P. James, and

26, 1990: revised version received March 7, 1991; accepted April 7, 1991.

Abstract. Eleven patients with prospectively documented premenstrual depression were given 100 mg atenolol or placebo daily to suppress melatonin secretion during the symptomatic premenstrual phase of the menstrual cycle. There was no significant improvement in mood following treatment with atenolol

vs. placebo. These findings suggest that bright light may exert antidepressant effects in patients with premenstrual syndrome through mechanisms other than melatonin suppression and that atenolol does not appear to be a viable treatment modality for the majority of patients with premenstrual depression. Key Words. Atenolol,

premenstrual

syndrome,

light therapy,

melatonin.

Bright light has been used to treat both seasonal affective disorder (SAD) (Rosenthal et al., 1985) and nonseasonal depression (Kripke, 1981). Recently, preliminary findings have suggested its potential efficacy in premenstrual syndrome (PMS) (Parry et al., 1989). Though the mechanism by which bright light exerts its antidepressant properties is unknown, two major theories have been proposed to explain its therapeutic efficacy: (1) the melatonin hypothesis advanced by Rosenthal et al. (1986) and (2) the phase-shift hypothesis proposed by Lewy et al. (1987). The melatonin hypothesis is based on the coupled observations that both the suppression of nocturnal melatonin secretion in humans and the antidepressant effects of light therapy in SAD require light that is considerably brighter than ordinary indoor lighting (Lewy et al., 1980; Rosenthal et al., 1985). Thus, bright light may exert its antidepressant effects by suppressing nocturnal melatonin secretion. Alternatively, Lewy et al. (1987) observed that bright light altered the timing of the onset of melatonin secretion, a proposed marker for circadian phase. They hypothesized that in patients with winter depression, correcting underlying circadian phase disturbances with bright light therapy was the mechanism by which light exerted its antidepressant effects. In this study, we wished to test the hypothesis that bright light may exert its potential antidepressant effects in PMS patients (Parry et al., 1989) by suppressing

Barbara L. Parry, M.D., is Assistant Professor of Psychiatry, University of California at San Diego, La Jolla, CA. Norman E. Rosenthal, M.D., is Director of Outpatient Research Program, Clinical Psychobiology Branch, National Institute of Mental Health, Bethesda, MD. Stephen P. James, M.D., is Medical Director, Yorba Hills Hospital and Medical Center, Yorba Linda, CA. Thomas A. Wehr, M.D., is Chief, Clinical Psychobiology Branch, National Institute of Mental Health, Bethesda, MD. (Reprint requests to Dr. B.L. Parry, UCSD T-004, La Jolla, CA 92093, USA.) 0165-1781/91/$03.50

@ 1991 Elsevier Scientific

Publishers

Ireland

Ltd.

132 melatonin. Some PMS patients, similar to patients with both seasonal and nonseasonal depression, may respond to phototherapy (Parry et al., 1989). Also, many of the atypical symptoms such as hyperphagia, hypersomnia, lethargy, and weight gain that are characteristic of SAD also characterize PMS. Increasing evidence suggests that PMS may be related to major nonseasonal depressive disorders (MDD) (Hallman, 1986; MacKenzie et al., 1986) since many women with a history of PMS later develop MDD (Schuckit et al., 1975; Wetzel et al., 1975), and women with a lifetime risk of MDD are more likely to be diagnosed with premenstrual depression (Endicott et al,, 1981; Halbreich et al., 1983). One way to test the hypothesis that bright light may exert antidepressant effects in PMS patients by suppressing nocturnal melatonin secretion is to administer a drug that mimics the effects of light on melatonin secretion and to evaluate whether such a drug has antidepressant effects. The nocturnal secretion of melatonin can be suppressed pharmacologically by means of P-adrenergic antagonists. Melatonin is ordinarily released from the pineal gland in response to the stimulation of Padrenergic receptors on the surface of pinealocytes, which are outside the bloodbrain barrier (Lewy, 1983). The long-acting P-adrenergic antagonist atenolol has been shown to suppress the nocturnal secretion of melatonin in humans when administered in the afternoon hours (Cowen et al., 1983). Atenolol appears to be a good choice of drug for the present study since it is relatively lipid-insoluble and does not readily cross the blood-brain barrier (Cruickshank et al., 1980). Thus, any observed behavioral effects would be less likely the result of a direct effect on the brain than of a peripheral action, such as the suppression of melatonin. In studies examining the role of atenolol and melatonin in SAD, Rosenthal et al. (1986) administered melatonin to SAD patients and found that it reversed the antidepressant effects of light on the atypical symptoms but not the typical symptoms of depression. In another study (Rosenthal et al., 1988), atenolol was administered to SAD patients, and though its antidepressant efficacy was no greater than that of placebo, it was reported to be effective for at least several years in certain individuals. In studies of atenolol in PMS, we had found previously that atenolol was as effective as bright light in reducing depressive symptoms in a patient with seasonal PMS (Parry et al., 1987). Thus, we wondered whether atenolol might similarly be effective in patients with nonseasonal PMS. Rausch et al. (1988) testing an angiotensin therory of PMS, initially reported some efficacy of atenolol administered in the morning to PMS patients. A recent report (Parry et al., 1990) suggests that nocturnal secretion of melatonin is lower, the duration is shorter, and the offset occurs earlier in patients with premenstrual depression compared to normal controls, a finding which suggests melatonin suppression-whether a result of atenolol, bright light. or a dampened circadian oscillator-might exacerbate premenstrual symptoms. In this study, we administered atenolol to PMS patients in the late afternoon as a test of the hypothesis that the antidepressant effects of bright light in PMS were due to suppression of melatonin secretion. We also evaluated the clinical efficacy of atenolol in the treatment of PMS.

133

Methods Subjects. Patients were recruited from local gynecologists and psychiatrists; from information centers of the National Institutes of Health (NIH) and the University of California, San Diego (UCSD); and from advertisements placed in local newspapers. Subjects completed screening questionnaires, provided medical and psychiatric histories, and underwent physical examinations by a psychiatrist. Routine laboratory tests (chemistry panel, complete blood count, urinalysis, and thyroid indices) were performed. If, on the basis of these screening procedures, the patient did not have major medical, gynecologic, or psychiatric illness; had regular menstrual cycles; appeared to have premenstrual symptoms sufficiently severe to disrupt social or occupational functioning; and was willing to endure the rigors of a long-term research study, she was admitted to a 2-month evaluation phase. This evaluation consisted of twice-daily self-ratings of mood using a segmented lOO-mm visual analogue scale, daily sleep logs, weekly mood inventories, and weekly clinic visits for a psychiatric rating on the 21-item Hamilton Rating Scale for Depression (HRSD; Hamilton, 1967) and an addendum to the HRSD which assessed atypical depressive symptoms (Rosenthal and Heffernan, 1986). On the basis of these 2-month prospective measures, subjects were included in the study if the nature, timing, and severity of symptoms met either proposed research criteria developed for PMS by an NIH conference (April 1983) or the later published DSMIII-R criteria for late luteal phase dysphoric disorder (American Psychiatric Association, 1987). At the time of study, patients had been free of psychoactive medications for at least 2 months. Procedure. Patients who met diagnostic criteria were randomly assigned to a 2-month double-blind crossover trial of placebo and atenolol, each administered in the symptomatic premenstrual phase of separate menstrual cycles. HRSD assessments were done weekly by two psychiatrists without knowledge of medication assignment. Patients continued to complete daily mood analogue rating scales. When the HRSD score met entry criteria (2 12) in the luteal phase of the cycle (as determined by previous documentation of cycle length, and in the UCSD patients also by a urinary luteinizing hormone assay [Ovustick, CA]), patients took 100 mg atenolol or placebo by mouth at 4 p.m. daily for I week before the anticipated onset of the next menses. Two 24-hour urine samples were obtained during both the placebo and atenolol treatment phases to measure the degree of melatonin suppression by determining the effect of medication on urinary 6-sulphatoxy melatonin secretion. These urine samples were obtained at least 1 day after medication began and before the onset of the next menses. Blood pressure was checked on days 1, 2, and 7 after the initial dose of medication to assess hypotensive side effects. Statistical the results treatment. (before vs.

Analysis. A repeated measures analysis of variance (ANOVA) was used to assess of the HRSD and atypical depressive ratings obtained before and after each The ANOVA examined main effects of treatment (placebo vs. atenolol), condition after medication), and interaction.

Results Eight patients approximately follows: irregular and not meeting phase dysphoric HRSD ratings cycle.

Thus,

from the NIH and five patients from UCSD were selected from 60 subjects recruited for the study. Reasons for exclusion were as menstrual cycles; use of medication, including oral contraceptives; either NIH conference or DSM-III-R criteria for PMS or late luteal disorder, respectively. One patient was excluded because of elevated during the medication trials in the follicular phase of the menstrual

she did not have

PMS

because

she was depressed

during

the follicular

134 phase. Another patient dropped out of the study after the placebo trial and did not return for the atenolol trial. The mean age of the subjects was 32 (SD = 8) years. Most subjects had suffered from their disorder for more than 5 years. Eight women were employed outside the home, six were married, six had children, six had had previous (more than 1 year ago) episodes of depression for which they had sought professional help, four reported suffering from significant untreated post-partum depressions, and none had been on oral contraceptives. Results are reported for typical (21-item HRSD) and atypical (Rosenthal and Heffernan, 1986) symptoms of depression. HRSD Scores (see Table 1). For the HRSD, the results of a two-factor (treatment: atenolol vs. placebo; condition: before vs. after) ANOVA showed a trend (F= 3.76; c@’= 1, 10; p = 0.08) for a main effect of condition but no significant effect of treatment (F= 0.01; df= I, 10; NS). The interaction was not statistically significant (F= 0.01; df= 1, 10; NS). There were no statistically significant order effects (ANOVA for first treatment vs. second treatment: F = 0.08; 4f = 1, 2 1; NS, no statistically significant interaction). Depression Ratings (see Table 1). ANOVA revealed no statistically significant effect of treatment (atenolol vs. placebo) (F = 0.11; df = 1, 1 1; NS) or of condition (before vs. after) (F = 2.51; df = 1, 11; NS). There was no statistically significant interaction (F = 0.85; df= 1, 1 1; NS). There also were no significant order effects regardless of whether atenolol or placebo was administered first (ANOVA: F= 0.35; df = 1, 23; NS, no statistically significant interaction). Atypical

Table 1. Effects of atenolol ratings in PMS subjects Before

vs. placebo on HRSD and atypical A

atenolol

After atenolol

17.5

15.2

1.8

4.6

7.2

5.7

Mean

9.4

6.5

SD

7.2

6.7

atenolol

Before Dlacebo

After Dlacebo

19

depression A DlaCebO

HRSD ratings Mean SD

15.7

3.3

4.4

9.6

8.7

2.9

8.18

6.5

1.6

5.9

5.4

4.5

3.5

Atypical ratings

Note. Depression ratings are presented on the 21.item Hamilton Rating Scale for DepressIon (HRSD) and an addendum to the HRSD assessing atyplcal symptoms (maxlmum 23 points) before and after atenolol vs. placebo In subjects with premenstrual syndrome (PMS). The A atenolol and placebo entries refer to the differences in ratings (change score) before vs. after treatment.

Daily Mood and Sleep Self-Ratings. There were no statistically significant effects of atenolol vs. placebo on daily mood self-ratings (see Table 2) or on sleep variables (see Table 3). The only variable that approached significance @ = 0.07) was number of awakenings.

135

Table 2. Daily mood self-ratings during atenolol vs. placebo treatment Depression

Anxiety

Fatigue

Best/worst felt

Energy

Mean

5.0

5.7

4.3

4.0

4.3

SD

2.7

2.1

0.6

1.7

1.5

Mean

6.0

4.3

4.7

5.0

5.0

SD

1.0

0.6

0.6

1.0

1.0

Atenolol

Placebo

Note. On each of the mood ratings (depression, anxiety, fatigue, best/worst felt, energy), a value of I represents feeling the W0rs.t or the most symptomatic; a value of 10 represents feeling the best or the least symptomatic.

Analysis of Urinary Melatonin. It was not possible to analyze the 24-hour urine samples collected on the NIH patients. From 24-hour urine samples collected from the UCSD patient population (5 patients, 4 complete urine sample collections from placebo and atenolol conditions), results of the 6-sulphatoxy melatonin assay (Arendt et al., 1985; Aldbous and Arendt, 1988) showed that the mean (k SD) melatonin levels after atenolol (2.7 + 2.4 pg/24 hours) were significantly 0, < 0.04) lower than after placebo (7.3 f 4.9 pug/24 hours) (t = 3.3, df = 3). There was an insufficient number of samples to permit the amount of melatonin suppression on atenolol vs. baseline levels to be correlated with clinical response.

Table 3. Sleep variables during atenolol vs. placebo treatment Number of awakenings

Duration of awakenings

Onset

Offset

Duration

1l:OO p.m.

630 a.m.

7 hr, 32 min

0.64

52 min

40 min

36 min

24 min

0.19

27 min

Midnight

7:30 a.m.

8 hr, 2 min

0.34

40 min

43 min

70 min

37 min

0.17

10 min

Atenolol Mean SD Placebo Mean SD

Note. Self-reported sleep variables are as follows: time of sleep onset, time of sleep offset, sleep duration In hours, number of awakenings, and estimated duration of awakenings.

Discussion The results of our study, in which we administered atenolol at a time of day designed to suppress nocturnal melatonin secretion, suggest that PMS patients do not significantly improve with atenolol treatment vs. placebo treatment. These findings lend support to the hypothesis that light treatment in PMS patients may exert its putative antidepressant effects through mechanisms other than the nocturnal suppression of melatonin. This finding is in contrast to our earlier observation that atenolol was effective in reducing a patient’s seasonal premenstrual symptoms (Parry et al., 1987). This patient with seasonal PMS developed severe suicidal depressions pre-

136 menstrually only in the fall and winter. She was asymptomatic in the spring and summer and during the first half or follicular phase of her menstrual cycle in the winter. On the basis of our previous experience using phototherapy in SAD (Rosenthal et al., 1985), we treated this patient with high intensity light. Melatonin, when administered in conjunction with the light treatment, blocked the therapeutic effect of the light. Propranolol and atenolol, P-adrenergic antagonists which lower human melatonin secretion (Hanssen et al., 1977; Cowen et al., 1983) had a therapeutic effect similar to light in her case. Thus, we hypothesized that in this patient with seasonal PMS, melatonin was mediating the symptoms that improved with treatments such as phototherapy, propranolol, and atenolol. all of which suppress melatonin secretion. It is possible that melatonin may mediate the symptoms of seasonal premenstrual syndrome, and that bright light therapy or atenolol, by suppressing melatonin secretion, may provide clinical benefit. In contrast, bright light treatment in nonseasonal PMS may exert its antidepressant effects through mechanisms other than melatonin suppression. Thus, the two disorders, seasonal and nonseasonal PMS, may involve different underlying pathophysiologic processes. In sheep, and in Djungarian and Siberian hamsters, evidence suggests that the duration of nocturnal melatonin secretion controls reproductive, physiologic. and behavioral responses to seasonal changes in the photoperiod (Bittman et al.. 1983: Carter and Goldman, 1983). If- melatonin secretion is important in inducing the symptoms of nonseasonal PMS, then bright light and atenolol should induce remissions by suppressing its secretion for part of the night, thereby decreasing its duration. Since bright light also is capable of altering the timing of melatonin secretion (Lewy et al.. 1985), it may be the timing rather than the duration of melatonin secretion that is the critical factor mediating the antidepressant effects of bright light in PMS patients. The duration of melatonin elevation, as Illnerova and Vanecek (1982, 1986) suggest, may be determined by the phase angle between morning and evening oscillators, which are theoretically synchronized by light at dawn and dusk, respectively. Thus, it is conceivable that bright light treatment in PMS patients may be exerting its antidepressant effects by altering the phase relationship between morning and evening oscillators, rather than by melatonin suppression. Indeed. preliminary evidence from our laboratory (Parry et al.. 1990) suggests that the morning oscillator is phase-advanced (shifted earlier) in PMS patients compared with normal controls, as measured by profiles of nocturnal melatonin secretion. To address this hypothesis, we currently are investigating the effects of morning vs. evening bright light treatment on the waveform of plasma nocturnal melatonin secretion. Phototherapy might also exert its therapeutic effects by altering circadian amplitude (Czeisler et al., 1987) or through some other mechanisms, as yet undefined. Although a few of our patients did appear to respond to atenolol, our findings do not suggest that atenolol is a viable treatment for the majority of PMS patients. However, two patients had elevated depression ratings after atenolol treatment. Further investigations into the particular physiologic responses of the patients who did respond to atenolol would be of interest as well as more extended trials to rule nut placebo responses. However, on the basis of our findings, a more fruitful area of

137

research mediators

may be to focus of the potential

on mechanisms other than melatonin suppression as therapeutic efficacy of bright light treatment in PMS

patients. Acknowledgments. and R29 MH-42831.

This work was supported

in part by NIH grant number

MO1 RR-00827

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lllnerova, H., and Vanecek, J. Effect of light on the N-acetyltransferase rhythm in the rat pineal gland. Advances in Pineal Research, 1:69-76, 1986. Kripke D.F. Photoperiodic mechanisms for depression and its treatment. In: Perris, C.; Struwe, G.; and Jansson, B., eds. Biological Psychiatry 1981. Amsterdam:Elsevier/NorthHolland, 1981. pp. 1249-1252. Lewy, A.J. Biochemistry and regulation of mammalian melatonin production. In: Relkin, R., ed. The Pineal Gland. New York: Elsevier/North-Holland, Inc., 1983. pp. 77-128. Lewy A.J.; Sack R.L.; Miller S.; and Hoban T.M. Antidepressant and circadian phaseshifting effects of light. Science, 235:352-354, 1987.

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Atenolol in premenstrual syndrome: a test of the melatonin hypothesis.

Eleven patients with prospectively documented premenstrual depression were given 100 mg atenolol or placebo daily to suppress melatonin secretion duri...
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