Atenolol in Seasonal Affective Disorder: A Test of the Melatonin Hypothesis

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1 Atenolol in Seasonal Affective Disorder: A Test of the Melatonin Hypothesis Norman E. Rosenthal, M.D., Frederick M. Jacobsen, M.D., David A. Sack, M.D., Josephine Arendt, Ph.D., Stephen P. James, M.D., Barbara L. Parry, M.D., and Thomas A. Wehr, M.D. To test the hypothesis that the antidepressant effects of bright light in seasonal affective disorder are mediated by the suppression of melatonin, 1 patients with this disorder were given atenolol, which suppresses melatonin secretion, and placebo in a double-blind crossover study. No difference in antidepressant efficacy was found between drug and placebo in the sample as a whole, which argues against the melatonin hypothesis of phototherapy. However, in three of the patients atenolol provided repeated, marked, and sustamed relief of symptoms, suggesting that it may be useful in treating the winter depressive symptoms of some patients with seasonal affective disorder. (Am J Psychiatry 88; 5:52-5) S easonal affective disorder is a condition in which the symptoms exhibit a characteristic annual pattern (depression in fall and winter and euthymia or hypomania in spring and summer) (1). These changes are reminiscent of the seasonal rhythms in behavior commonly found among animals (2). Just as seasonal rhythms in animals can be changed by modifying patterns of exposure to environmental light (3), so can the symptoms of winter depression be ameliorated by exposing patients with seasonal affective disorder to bright environmental light during the winter (1, 4-). The use of bright (00 lux) light was initially inspired by the finding of Lewy et at. (10) that such light was capable of suppressing nocturnal melatonin secretion in humans, whereas ordinary room light was not. In a similar fashion we have shown in several studies (1, 4, 5) that bright light is capable of producing powerful antidepressant responses in patients with seasonal affective disorder, whereas dim light (0 lax or less) is not. These observations led us to hypothesize that, just as melatonin is important in mediating the seasonal response to photopeniod in many other species (1 1), Received Aug. 8, 8; revised Feb. 10 and June, 8; accepted July, 8. From the Clinical Psychobiology Branch, NIMH. Address reprint requests to Dr. Rosenthal, Clinical Psychobiology Branch, NIMH, Bldg. 10, Rm. 45-, 000 Rockville Pike, Bethesda, MD changes in the pattern of melatonin secretion might be responsible for the seasonal changes in patients with seasonal affective disorder. We suggested further that the effects of bright light on melatonin secretion might be responsible for its antidepressant properties (). One way to test this hypothesis would be to administer a drug that mimics the effects of light on melatonin secretion and to evaluate whether such a drug has antidepressant effects in seasonal affective disorder. Besides the direct suppressant effect of bright light on melatonin that we have mentioned, there are data which suggest that bright light is also capable of influencing the timing of the nocturnal rise and diurnal fall in melatonin secretion (8). Which specific property of melatonin secretion is critical for mediating the seasonal effects of photoperiod has not been fully ascertained for most species. However, in two species in which this has been well studied-sheep (13) and Djunganian hamsters ()-the duration of melatonin secretion is the critical seasonal time cue. These observations led us to hypothesize that, if melatonin secretion is in fact important in inducing the symptoms of seasonal affective disorder, then perhaps bright light produces remissions by suppressing melatonin secretion for part of the night, thereby decreasing its duration. The nocturnal secretion of melatonin can be suppressed pharmacologically by means of 3-adrenergic antagonists. Melatonin is ordinarily released from the pineal gland in response to the stimulation of 3- adrenergic receptors on the surface of pinealocytes, which are outside the blood-brain barrier (). The long-acting 3-adrenergic antagonist atenotol has been shown to suppress the nocturnal secretion of melatonm in humans when administered in the afternoon hours (). Peak levels of atenolol appear in the blood within 2-4 hours after ingestion, its elimination halflife is approximately - hours, and its 3-blocking effect persists for at least hours (Physicians Desk Reference). Atenolol appeared to be a good choice of drug for the present study because it is relatively lipid-insoluble and does not readily cross the bloodbrain barrier (). Thus, any observed behavioral effects would be less likely to be the result of a direct effect on the brain than of a peripheral action, such as 52 Am J Psychiatry 5:1, January 88

2 ROSENTHAL, JACOBSEN, SACK, ET AL the suppression of metatonin. In this study we tested the hypothesis that the antidepressant effects of bright light in seasonal affective disorder are due to suppression of melatonin secretion by administering atenolol to seasonal affective disorder patients in the late afternoon. In doing so we also evaluated the clinical efficacy of atenolol in the treatment of this condition. METHOD Subjects were recruited by means of a newspaper article or were referred by local therapists. In order to be admitted into the program they were required to meet the criteria for seasonal affective disorder of Rosenthal et at. (1 ), namely, a lifetime history of major depression according to the Research Diagnostic Cnitenia (RDC) (), recurrent episodes of fall and winter depression (at least two during consecutive winters) that remitted during the spring and summer, no other DSM-III axis I psychiatric disorder, and no clear-cut psychosocial explanations for their seasonal mood changes. Patients were excluded from the study if they were not in reasonably good medical health or if they had specific contraindications for the use of atenolol, such as low blood pressure or asthma. All patients who participated in the study provided informed consent. Once admitted into the program, patients were followed regularly in an outpatient clinic. Their mood was evaluated by means of the -item Hamilton Rating Scale for Depression () and a seven-item supplement specifically designed to evaluate atypical symptoms that are characteristic of seasonal affective disorder and other forms of bipolar illness (). Ratings were made by two raters blind to the patients treatment status, and a single consensus rating was obtained. When the total Hamilton depression score (excluding the supplement) reached on more for 2 consecutive weeks, the drug study was initiated. Patients were randomly assigned to either atenolol, 100 mg, or placebo in identical capsules administered once daily at 4:00 p.m. for a week. This was followed by a week of withdrawal, the alternate treatment for the next week, and a final week of withdrawal. Patients were rated on the last day of each treatment week. A scone of at least 10 on the Hamilton scale was required for admission into the second treatment condition. Both the minimum Hamilton entry scores ( and 10) and the duration of treatment (1 week) were the same as those used by our group in phototherapy studies of seasonal affective disorder (1, 4, 5, ). Pulse and blood pressure (sitting and standing) were measured on days 1, 3, and of each treatment week. If the pulse rate fell below 0 beats/minute or if patients experienced symptomatic postural hypotension, they were evaluated clinically and a decision was made about whether the drug should be discontinued. Patients were asked to complete a side effects checklist at the end of each week of treatment. At the same time they were asked whether they thought they had been taking atenolol or placebo capsules and how sure they were of their guess. After the final week of withdrawal, while the patients were still blind to their treatment conditions, each patient was offered the opportunity to resume treatment with whichever capsule had been found to be most helpful or to receive another type of treatment. Patients continued to be rated on a weekly basis during this informal part of the study. During each week of the study two -hour urine collections were made and the quantity of the major melatonin metabolite -hydroxymelatonin sulfate secreted per -hour period was determined by the radioimmunoassay method of Anendt et at. (). Results of the Hamilton mood ratings were analyzed by analysis of variance (ANOVA) with one grouping factor (sequence of administration) and two repeated measures (atenolol versus placebo and pretreatment versus posttreatment). Similar analyses were performed on pulse, blood pressure, and -hydroxymelatonin sulfate measurements. Correlations between Hamilton scale change scones and the melatonin metabolite values for both atenotol and placebo conditions were also done. RESULTS Twenty-two patients ( women and three men) with seasonal affective disorder entered the study. The mean± age of the sample was 38.±. years; the mean age at onset was.2±8.1 years. All patients met lifetime RDC for major depression with hypomania (bipolar II), except for one patient who had a history of recurrent unipolar depression. Three patients failed to complete the course of treatment: one developed symptomatic hypotension while taking atenolol, one failed to comply with the first treatment condition (atenolol), and one did not relapse following withdrawal of the first treatment condition (atenolol). The mean± reduction in Hamilton score following atenolol treatment was.3±.5 points, compared with 5.1 ±. points following administration of ptacebo capsules. An ANOVA revealed a significant treatment effect for both treatment conditions, with no superiority of atenolol over placebo for the group as a whole (see table 1). Analysis of the supplementary Hamilton depression items yielded similar results. In general, the active drug was well tolerated, and there was no statistically significant difference in side effects between the atenolol and the placebo conditions. However, there was a significant reduction in pulse rate and blood pressure in the atenolol condition compared with the placebo condition (see table 2). The urinary excretion of -hydnoxymelatonin sulfate was significantly lower in the atenolol condition than with placebo (see table 2). There was no correlation between the lower -hydroxymelatonin sulfate secretion and the change in Hamilton mood ratings. Analysis of patients opinions showed that 1 0 of 1 8 patients guessed correctly when given atenolol (one missing Am J Psychiatry 1 45: 1, January 88 53

3 ATENOLOL IN SEASONAL AFFECTIVE DISORDER TABLE 1. Hamilton Depression Scores of Patients With Seasonal Affective Disorder Given Atenolol or Placebo in a Crossover Designa Patient Atenolol first Placebo first All patients Hamilton Score With Atenolol Hamilton Score With Placebo Baseline Treatment Withdrawal Baseline Treatment Withdrawal asignificant difference between atenolol and placebo in treatment effect (F=., df= 1,, p<o.oo1); nonsignificant interaction between treatment and condition (F=0.13, df=1,, p<o.3) TABLE 2. Effects of Atenolol and Placebo on Blood Pressure, Pulse, and Urinary Excretion of -Hydroxymelatonin Sulfate of Patients With Seasonal Affective Disorder Measure Baseline Atenolol Placebo Difference Between Atenolol and Placebo t (df= ) p Blood pressure (mm Hg) Lying down Systolic <0.03 Diastolic <0.01 Standing Systolic <0.001 Diastolic <0.001 Pulse (beats/minute) Lyingdown <0.001 Standing <0.001 Urinary -hydroxymelatonin sulfate (mg/ hours) <0.01 value) and nine of patients guessed correctly when they were given placebo (four missing values). Since patients were aware of the crossover design of the study, the group was divided into those who guessed correctly both times and those who guessed incorrectly both times. There was no significant correlation between the patients degree of certainty that they were taking the active drug and their degree of antidepressant response as measured by the Hamilton depression scale (Spearman s correlation). After the formal crossover study was completed, nine patients, while still blind to their treatment conditions, chose to resume treatment with atenolol, which they believed had helped them. Of these nine patients, five responded to treatment with atenolol a second time, with a median reduction in Hamilton score of points. Three of these patients chose to continue to take atenolol for extended periods with continued beneficial effects. During the next two winters these three patients requested that they be treated again with atenolol, and they again reported antidepressant effects throughout the winter months. There was no difference in clinical or demographic details between atenolol responders and nonresponders. There was some difference in time course of response in the three patients who continued to take atenolol: one patient responded within 2-4 hours and the other two between 2 and 3 days of starting to take atenolol. One patient found that he had to take his medicine between 5:00 p.m. and : p.m. in order to observe a clinical effect. In the other two cases the timing of administration did not appear to be critical. 54 Am J Psychiatry 5:1, January 88

4 ROSENTHAL, JACOBSEN, SACK, ET AL After the crossover study was completed, two patients, while still blind to the study conditions, requested that they be allowed to return to placebo capsules, which they believed had been helpful. One of these patients remained symptom free but did not think that it was because of the capsules. Of the eight patients who chose not to restart either atenolol or placebo, recovery occurred spontaneously in two patients, after traveling south in three patients, and following phototherapy in two patients. For the one patient who remained depressed despite phototherapy, adjunctive antidepressants were added with moderately beneficial results. DISCUSSION The results of this study address three questions: first, whether the antidepressant effects of light are mediated by the suppression of melatonin secretion (); second, whether atenolol might be a clinically useful treatment for seasonal affective disorder; and third, the degree to which the antidepressant effects of light in earlier studies of seasonal affective disorder might have been mediated by the placebo effect. We will discuss these questions in turn. 1. The melatonin hypothesis. The significant neduction in pulse rate and blood pressure during the atenolol condition indicates that peripheral 3-adrenergic blockade did in fact occur. Similarly, the significantly lower excretion of -hydnoxymetatonin sulfate suggests that atenolol suppressed melatonin secretion. Since atenolot did not show an antidepressant effect significantly superior to that of placebo in the sample as a whole, it appears that suppression of melatonin is an unlikely explanation for the antidepressant effects of light in seasonal affective disorder. This conclusion is compatible with the finding of Wehr et at. () that bright light which was administered to seven patients with seasonal affective disorder at a time of day when melatonin is not being secreted, and which did not suppress melatonin, nonetheless produced significant antidepressant effects. Similarly, Jacobsen and colleagues (unpublished work, 8) found that 2 hours of bright light treatment given during the middle of the day, when melatonin is not normally secreted, produced clinically significant antidepressant effects in outpatients with seasonal affective disorder. Recently Thompson et at. () found that 4 hours of bright light in the middle of the day had more pronounced antidepressant effects than an equivalent amount of light applied in such a way as to extend the photoperiod and suppress melatonin secretion. We should note that whereas atenolol administration suppresses melatonin secretion, it may not reproduce all the effects of light treatment on melatonin secretion. Thus, the results of this study do not rule out the possibility that bright light treatment might exert its antidepressant effects in seasonal affective disorder by some effect on melatonin secretion other than direct suppression. For example, bright light is capable of altering the timing of melatonin secretion (8). Arendt and Broadway () recently suggested that it may be the timing rather than the length of melatonin secretion that serves as a critical influence on seasonal behavior responses in humans, and Lewy et at. () emphasized timing as an important factor in the efficacy of photothenapy. Other studies of the role of melatonin in seasonal affective disorder have also failed to support the hypothesis that melatonin plays a critical role in the pathogenesis of the disorder and in the response to phototherapy, even though they have not ruled out the possibility that melatonin may have some influence on the symptoms of the disorder. For example, the administration of oral melatonin to eight patients who had been treated successfully with bright light therapy reversed some, but not all, of the antidepressant effects of light (). Preliminary studies have failed to show a difference in melatonin secretion patterns between patients with seasonal affective disorder and normal subjects either in summer or in winter (Sack et al., unpublished work, 8). As we have noted, melatonin plays a critical role in seasonal rhythms of reproduction in many species (1 1). However, there are other types of seasonal rhythms in animals, for example, seasonal rhythms of energy utilization in hamsters, where melatonin is only one of several influences (). Most of the available evidence suggests that melatonin may play some note in the pathogenesis of seasonal affective disorder but that it is not a critical role. If this is the case, we should perhaps regard certain animal models, such as seasonal rhythms of energy utilization and weight in hamsters, as more useful for our understanding of the pathogenesis of seasonal affective disorder and the mechanism of action of photothenapy than seasonal rhythms of reproduction. 2. Possible clinical utility of atenolol. It is important to note that although there was no overall difference between the antidepressant effects of atenolol and placebo in the present study, a small subgroup of patients experienced considerable antidepressant effects when treated with atenolol. It is also noteworthy that after the formal crossover study was complete, nine patients chose to go back to taking atenolol, whereas only two patients chose to go back to placebo. This preference may reflect some subjective awareness in these patients that atenolol was superior, which was not detected on the format ratings. The three subjects with the most convincing clinical response to atenolol relapsed when treatment was discontinued, benefited again when it was resumed, requested atenolol the following winter, and reported further beneficial results over an extended period. Our clinical observations could be explained in several ways. First, they may have been due to a placebo effect. Second, melatonin may have been responsible for depressive symptoms in those who re- Am J Psychiatry 5:1, January 88 55

5 ATENOLOL IN SEASONAL AFFECTIVE DISORDER sponded. Finally, some other mechanism, as yet undefined, may have been involved. While f3 blockers have been reported to have therapeutic effects in patients with anxiety states and panic disorder (2, ), we should note that in the three atenolol responders, the therapeutic effects of the drug were observed for a wide range of depressive symptoms and not only for those reflecting anxiety. 3. The placebo effect. The results of this study may further our understanding of the placebo effect in the treatment of patients with seasonal affective disorder by phototherapy. Because such treatment studies cannot be carried out in a double-blind fashion, the question of whether all observed antidepressant effects have been due to placebo responses has concerned researchers in the field. Since the present study is the first double-blind drug study of patients with seasonal affective disorder, their response to placebo capsules is of particular interest. The statistically significant ptacebo effect represented a mean drop of 5.1 points on the Hamilton depression scale. This change is slightly higher than the responses we observed previously to treatment with control lighting conditions in studies of phototherapy, but it is considerably smaller than the changes we saw following treatment with bright light (). The results of this study suggest that people with seasonal affective disorder, like other patients, respond favorably to nonspecific placebo elements in a treatment study. However, the large discrepancy between the placebo effect seen here and the marked effects of phototherapy reported in earlier studies suggests that the phototherapy either has specific antidepressant effects or is an extraordinary placebo. In conclusion, the overall lack of antidepressant efficacy of atenolot in the treatment of seasonal affective disorder does not support the hypothesis that the suppression of melatonin secretion is the mechanism of action of phototherapy in most patients with seasonal affective disorder. This corroborates other evidence that melatonin secretion is not of pivotal importance in the pathogenesis of seasonal affective disorder (). However, in a few patients atenolol proved to be extremely helpful in treating the winter depressive symptoms of seasonal affective disorder, although the mechanism of action of this effect remains unknown. REFERENCES 1. Rosenthal NE, Sack DA, Gillin JC, et al: Seasonal affective disorder: a description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 84; 41: Gwinner E: Circannual systems, in Handbook of Behavioral Neurobiology, vol 4. Edited by Aschoff J. New York, Plenum, Hoffman K: Photoperiodism in vertebrates. Ibid 4. Rosenthal NE, Sack DA, Carpenter CJ, et al: Antidepressant effects of light in seasonal affective disorder. Am J Psychiatry 85; 2:3-0 S. James SP, Parry BL, Sack DA: Treatment of seasonal affective disorder with light in the evening. Br J Psychiatry 85; : 4-4. Hellekson CJ, Kline JA, Rosenthal NE: Phototherapy for seasonal affective disorder in Alaska. Am J Psychiatry 8; 3: Wirz-Justice A, Fisch H-U, Woggon B: How much light is antidepressant? Psychiatry Res 1 8; :5-8. Lewy AJ, Sack RL, Singer CM: Melatonin, light and chronobiological disorders, in Photoperiodism, Melatonin and the Pineal. Edited by Evered D, Clark S. London, Pitman, 85. Wehr TA, Jacobsen FM, Sack DA, et al: Timing of phototherapy and its effect on melatonin secretion do not appear to be critical for its antidepressant effect in seasonal affective disorder. Arch Gen Psychiatry 8; 43: Lewy AJ, Wehr TA, Goodwin FK, et al: Light suppresses melatonin secretion in humans. Science 80; 0:- 11. Lincoln GA: Melatonin as a seasonal time-cue: a commercial story. Nature 83; 2:55. Rosenthal NE, Sack DA, Jacobsen FM, et al: Melatonin in seasonal affective disorder and phototherapy. J Neural Transm 8; (suppl): Bittman EL, Dempsey J, Karsch FJ, et al: Pineal melatonin secretion drives the reproductive response to daylength in the ewe. Endocrinology 83; 113:-83. Carter DS, Goldman BD: Antigonadal effects of timed melatonm infusion in pinealectomized male Djungarian hamsters (Phodopus sungorus sungorus): duration is the critical parameter.endocrinology 83; 113:1-. Lewy AJ: Biochemistry and regulation of mammalian melatonin production, in The Pineal Gland. Edited by Relkin R. New York, Elsevier-North Holland, 83. Cowen PJ, Fraser S, Sammons R, et al: Atenolol reduces plasma melatonin concentration in man. BrJ Clin Pharmacol 83; : Cruickshank JM, Neil-Dwyer G, Cameron MM, et al: Betaadrenoceptor blocking agents and the blood-brain barrier. Clin Sci 80; 5(suppl ):453S-455S. Spitzer RL, Endicott J, Robins E: Research Diagnostic Criteria: rationale and reliability. Arch Gen Psychiatry 8; 35:3-82. Hamilton M: Development of a rating scale for primary depressive illness. Br J Social Clin Psychol ; :8-2. Rosenthal NE, Heffernan MM: Bulimia, carbohydrate craving and depression: a central connection? in Nutrition and the Brain, vol. Edited by Wurtman RJ, Wurtman JJ. New York, Raven Press, 8. Arendt J, Bojkowski C, Franey C, et al: Immunoassay of -hydroxymelatonin sulfate in human plasma and urine: abolition of the urinary -hour rhythm with atenolol. J Clin Endocrinol Metab 84; 0:1-13. Thompson C, Isaacs G, Miles A: Seasonal affective disorder: phototherapy and salivary melatonin: abstract 13b, in Proceedings of the Centennial Celebration of the Psychiatric University Clinic. Basel, Psychiatric University Clinic, June 8. Arendt J, Broadway J: Phase response of human melatonin rhythms to bright light in Antarctica. J Physiol (Lond) 8; 3:8. Lewy AJ, Sack RL, Miller LS, et al: Antidepressant and circadian phase-shifting effects of light. Science 8; 5: Hoffman RA, Davidson K, Steinberg K: Influence of photoperiod and temperature on weight gain, food consumption, fat pads and thyroxine in male golden hamsters. Growth 82; 4: Ballenger JC: Psychopharmacology of the anxiety disorders. Psychiatr Clin North Am 84; :5-1. Noyes R Jr: Beta-adrenergic blocking drugs in anxiety and stress. Psychiatr Clin North Am 85; 8: Rosenthal NE, Sack DA, James SP, et al: Seasonal affective disorder and phototherapy. Ann NY Acad Sci 85; 453: Am J Psychiatry 5:1, January 88