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Melatonin Suppression by Light in Euthymic Bipolar and Unipolar Patients

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Melatonin Suppression by Light in Euthymic Bipolar and Unipolar Patients ORIGINAL ARTICLE Melatonin Suppression by Light in Euthymic Bipolar and Unipolar Patients John I. Nurnberger, Jr, MD, PhD; Sherril Adkins, RN; Debomoy K. Lahiri, PhD; Aimee Mayeda, MD; Kuolung Hu, MS; Alfred Lewy, MD, PhD; Aaron Miller, MD; Elizabeth S. Bowman, MD; Marvin J. Miller, MD; N. Leela Rau, MD; Carrie Smiley, RN; Dawn Davis-Singh, BS Background: Previous studies have suggested that bi- Results: No group differences were seen in light sup- polar patients are supersensitive to light suppression of pression among bipolar patients, unipolar patients, and melatonin and that this may be a trait marker for ge- controls; an analysis of the whole group did not reveal netic vulnerability. The present study was an attempt to differences in propranolol effect, differences in cortico- replicate and extend this observation. Propranolol hy- tropin or cortisol levels, or evidence for a lithium effect. drochloride effects were compared with light effects be- However, patients with bipolar I affective disorder showed cause of the documented influence of b-adrenergic re- the following: (1) significantly lower melatonin levels on ceptors on melatonin production. Nighttime levels of the light night, at baseline and following light exposure; corticotropin and cortisol were also examined as poten- and (2) a later peak time for melatonin on the dark night. tial trait vulnerability markers. Conclusions: The general hypothesis of increased light Methods: Melatonin levels in euthymic bipolar pa- sensitivity in bipolar patients was not supported. How- tients (n=29) were tested before and after 500-lux light ever, melatonin secretion abnormalities were con- was administered between 2 and 4 AM and on a separate firmed in the subgroup with bipolar I disorder. Further night in the dark. Results were compared with those of assessments of circadian rhythm disruption as a vulner- a group of patients with unipolar depression (n=24) and ability marker in bipolar illness are indicated. with those of a group of non–psychiatrically ill control subjects (n=50). Lithium effects and propranolol ef- fects were tested in subgroups. Arch Gen Psychiatry. 2000;57:572-579 IPOLAR AFFECTIVE disorder Bright light can shift the phase of involves disruption of in- melatonin secretion in humans.24 The pho- trinsic biological rhythms, toperiodic control of melatonin makes it including the sleep-wake a potential marker of circadian rhythms. cycle, hormonal rhythms, Lewy25 has suggested use of the dim-light Band temperature regulation. A phase ad- melatonin onset as a marker of circadian vance in rhythms explains some of these rhythm phase and period. observations; a general phase instability has Melatonin is an indolamine derivative From the Department of also been hypothesized.1-7 of serotonin and is produced by the action Psychiatry, Indiana University The hormone melatonin has a time- of the enzymes N-acetyltransferase and School of Medicine keeping function in many mammals and hydroxyindole-O-methyltransferase,withthe (Drs Nurnberger, Lahiri, Mayeda, A. Miller, and appears to adjust the timing of circadian first step being rate limiting. Production is Bowman and Mss Adkins, Hu, rhythm information transmitted from the primarily within the pineal body; the hor- Smiley, and Davis-Singh), suprachiasmatic nucleus of the hypothala- mone is secreted into the blood and into the Department of Psychiatry, mus to entrain physiologic rhythms.8-16 A cerebrospinal fluid.23(pp40-66) Specific recep- Roudebush Veterans Affairs physiologic role for melatonin in hu- tors for melatonin are found in multiple Medical Center (Dr Mayeda), mans has yet to be clearly established. brain areas, including the hypothalamus, the Institute of Psychiatric Some apparently normal humans have low the cerebellum, and the pineal body itself. Research, Larue Carter to undetectable levels of melatonin.17 Pa- Melatonin is secreted into plasma at high Hospital (Dr M. J. Miller), and tients undergoing long-term treatment levels (60-100 pg/mL) at night and at low Department of Psychiatry, with b-blockers show suppressed mela- levels (3-10 pg/mL) during the daytime. Wishard Hospital (Dr Rau), 18,19 Indianapolis, Ind; and the tonin secretion without ill effects. Mela- The anatomic pathway mediating Department of Psychiatry, tonin levels decrease with chronological melatonin secretion is complex. Retinal 20,21 Oregon Health Sciences age. Administered melatonin is known stimulation by light produces a tonic in- University, Portland to lower body temperature at night22 and hibitory signal to the suprachiasmatic (Dr Lewy). may induce sleepiness.23(pp192-208) nucleus of the hypothalamus via the reti- (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 57, JUNE 2000 WWW.ARCHGENPSYCHIATRY.COM 572 ©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 SUBJECTS AND METHODS not be pregnant (determined by a urine screen). Premeno- pausal women were not tested during their menstrual period. Subjects were stratified by age, race, sex, and season of SUBJECTS testing. Each bipolar and unipolar patient was matched with a control of the same sex, race, age (within 5 years), and sea- Subjects consisted of 29 patients with bipolar I (n=21) or bi- son of testing (within 6 weeks). Women were also matched polar II (n=8) affective disorder, 24 patients with unipolar for menstrual status (premenopausal or postmenopausal). The affective disorder, and 50 controls. Patients were recruited clinical characteristics of patients and matched controls are from an Indiana University, Indianapolis, outpatient clinic, summarized in Table 1 and Table 2. Three additional un- and additional patients and controls were recruited by ad- matched controls were included in the total control sample. vertisement (primarily on campus). A Structured Clinical In- terview for DSM-III-R was administered by a nurse-clinician CLINICAL PROCEDURE (S.A.). Two psychiatrists ( J.I.N., M.J.M., E.S.B., N.L.R. and A.M.) then made the diagnosis in patients who met the cri- Subjects sitting up in bed and looking at a 500-lux light po- teria by DSM-III-R40 and by modified Research Diagnostic Cri- sitioned at the foot of the bed can vary the amount of light teria41 for the disorder indicated. Patients with bipolar II they receive by 20% by leaning forward or backward ( J.I.N., disorder (bipolar disorder, not otherwise specified by unpublished data, 1986). Nurnberger et al35 reduced this varia- DSM-III-R) and unipolar patients had recurrent episodes of tion by placing a seated subject in the center of an arc of lights. depression. Controls had no ongoing psychiatric illness and In the present study, we further modified the procedure by no history of major affective disorder, psychosis, or any other placing a bank of full-spectrum shielded fluorescent lights psychiatric impairment by Structured Clinical Interview for behind the subject in a small room, such that light was re- DSM-III-R. All subjects gave informed consent in writing. flected from the wall, floor, and ceiling. The participant was Patients were tested in the euthymic state, ie, function- thus exposed to a dispersed source of light, the intensity of ing at their usual interepisode level for several months and which was calibrated by handheld photometer to be 500 lux, scoring less than 3 on the Raskin Mood Scale.42 Twenty-two ±50 lux. Subjects were carefully monitored to ensure that they bipolar patients and 24 unipolar patients were tested after re- were awake, with eyes open, gazing in an appropriate direc- maining free from psychoactive medication for at least 2 weeks tion, during the 2-hour period of the testing. (5 weeks for fluoxetine and 3 weeks for carbamazepine and Subjects arrived at the Indiana University General Clini- for antidepressants other than fluoxetine). No patient took cal Research Center, Indianapolis, on the evening of test- other medications known to affect melatonin levels. Alco- ing, and retired between 11 PM and midnight. For the dark hol was not permitted for 3 days before the test. A urine drug night condition, subjects were allowed to sleep through the and alcohol screen was performed on the day of testing. Smok- night; blood samples were drawn through an indwelling cath- ing and eating were not permitted after admission to the re- eter with the aid of a small flashlight with a red filter. For search unit. A subgroup of bipolar patients was tested on their the light night condition, subjects were awakened at 2 AM ongoing therapeutic regimen of lithium (n=20), including and asked to sit in a cardiac chair between 2 and 4 AM. Blood 13 patients who were also tested while not taking lithium and was drawn at 1, 1:30, 2, 2:20, 2:40, 3, 3:20, 3:40, 4, 4:30, 5, 7 additional patients tested while taking lithium only. A sub- and 6 AM. After the 4 AM sample, the subject was allowed to group of bipolar patients not taking lithium (n=13) and con- return to bed; thus, the first 3 samples and the last 3 samples trols (n=41) were tested with a single 10-mg oral dose of were drawn from subjects recumbent in a dark room. Pilot propranolol or placebo given at 11 PM on the night of test- studies43 showed that posture and sleep per se did not sig- ing. Twenty-two controls were also retested on a second oc- nificantly affect melatonin values. Each subject was invited casion to provide a measure of reliability. to participate in a dark night and a light night study; study Female subjects were required to be using a reliable method of birth control (but not oral contraceptives) and to Continued on next page nohypothalamic tract. The signal in the suprachiasmatic ported that light suppression of melatonin (percentage re- nucleus of the hypothalamus appears to be mediated by duction in melatonin following light exposure) was greater glutamate, although prior studies26-28 implicated acetyl- in bipolar patients than in control subjects.
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