Psychiatry Research, 33: 129- 134
129
Elsevier
Melatonin Suppression Disorders
in Bipolar
and Unipolar
Mood
Raymond W. Lam, Alan L. Berkowitz, Sarah L. Berga, Campbell Daniel F. Kripke, and J. Christian Gillin Received
November
27, 1989;
revised
version
received
May 4. 1990: accepled
M. Clark,
June
2, 1990.
Abstract. Nocturnal melatonin suppression to 500 lux light was studied during an acute episode of illness in 8 patients with bipolar disorder, 7 patients with unipolar depression, and 15 age-, sex-, and season-matched normal controls. Unipolar patients did not differ from controls in melatonin suppression. In contrast to previous studies, controls showed greater melatonin suppression than bipolar patients. Baseline melatonin concentration, however, was significantly lower in the bipolar group compared to the unipolar and control groups.
Key Words.
Melatonin,
bipolar, unipolar, depression.
Human plasma melatonin was reported to be significantly suppressed by nocturnal exposure to 2500 lux light, but not by exposure to 500 lux light (Lewy et al., 1980). Significant melatonin suppression to 500 lux light was reported in actively ill bipolar patients as contrasted to normal controls, suggesting that bipolar patients are “supersensitive” to light (Lewy et al., 1981). Moreover, this melatonin supersensitivity was also found in euthymic bipolar patients (Lewy et al., 1985) and in at-risk, unaffected offspring of bipolar patients (Nurnberger et al., 1988). These findings led to the hypothesis that supersensitivity of melatonin suppression is a trait marker for bipolar disorders. Unipolar depressive patients do not have greater melatonin suppression to 500 lux light compared to matched controls (Cummings et al., 1989), suggesting that light supersensitivity might be specific for bipolar disorder. The present study compared nocturnal melatonin suppression to 500 lux light in bipolar patients, unipolar patients, and well-matched controls to test the hypothesis that light supersensitivity is specific to bipolar disorders.
Raymond W. Lam, M.D., F.R.C.P.(C.), is Assistant Professor and Consultant Psychiatrist, Mood Disorders Service, Department of Psychiatry, University of British Columbia, Vancouver. Alan L. Berkowitz, M.D., was a Fellow in Clinical Psychopharmacology and Psychobiology at the University of California, San Diego, when this research was conducted. Sarah L. Berga, M.D., is Assistant Professor, Department of Obstetrics and Gynecology, University of Pittsburgh. Campbell M. Clark, Ph.D., is Assistant Professor, Department of Psychiatry, University of British Columbia, Vancouver. Daniel F. Kripke, M.D., and J. Christian Gillin, M.D., are Professors, Department of Psychiatry, University of California, San Diego. (Reprint requests to Dr. R.W. Lam, Dept. of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, B.C., Canada V6T 2Al.) Ol6s-i7ll
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Scientific
Publishers
Ireland
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130
Methods Fifteen acutely ill patients and 15 age-and sex-matched control subjects were studied. The controls were also matched for season, with each control subject run within 4 weeks of the matched patient. All subjects underwent a Schedule of Affective Disorders and Schizophrenia (SADS; Endicott and Spitzer, 1978) interview conducted by a psychiatrist. Diagnoses were obtained by achieving research group consensus using the Research Diagnostic Criteria (RDC; Spitzer et al., 1978). Depressed patients were excluded if they had 21-item Hamilton Rating Scale for Depression (HRSD; Hamilton, 1960) scores < 16. Control subjects had an RDC diagnosis of “never mentally ill” and a negative family history of affective disorder. All subjects had been free of psychotropicdrugs for at least 2 weeks. Subjects taking P-blocking medications were excluded. Subjects were requested to avoid outdoor light as much as possible on the day of the protocol. At 2 lOOh, an i.v. catheter was inserted in a forearm vein and subjects were seated in a darkened room (< 15 lux). An HRSD was obtained by a psychiatrist, and the Beck Depression Inventory (BDI; Beck et al., 1961) was also completed. All subjects remained awake for the duration of the study. From OlOOh to 0215h, subjects were exposed to light from four cool-white fluorescent tubes mounted at eye level. Subjects were seated at a distance to produce illumination of 500 f 20 lux measured by digital photometer at the forehead level. Subjects were told to glance directly at the lights several times/min. The i.v. line was flushed every hour with 2 ml of EDTA and saline. Blood samples (7 ml) were drawn from the i.v. line every 15 min from 0030h to 0215h. There were three blood samples (MEL, to MEL,) taken before exposure to 500 lux light (-30, - 15, and - 1 min), and five samples (MEL, to MEL,) taken during light exposure (15, 30, 45, 60, and 75 min). Blood samples for melatonin determination were collected in EDTA-containing plastic tubes, stored immediately on ice, and centrifuged within 2 hours of collection. The plasma was immediately frozen and kept at -20 “C until assay. Plasma melatonin was measured directly, without extraction, by a previously described radioimmunoassay (RIA) (Fraser et al., 1983; Webley et al., 1985; Berga et al., 1988). The accuracy of the RIA has been validated by gas chromatography-mass spectroscopy methods by Lewy and Markey (1978). Assay sensitivity was 43 pmol/l (10 pg/ml). Samples from matched pairs were analyzed in duplicate in the same assay. The intra-assay and interassay coefficients of variation were 8.9% and 11.2%. respectively. Since the sensitivity of the melatonin assay was 10 pg/ml, all values < 10 pgjml were set to 10 pg/ml for the purpose of the statistical analysis. Analysis was done using a 3 x 8 (3 levels of diagnosis and 8 levels of time) repeated measures analysis of variance (ANOVA) with planned contrasts of the interaction term as follows: unipolars vs. controls over time (contrast l), and bipolars vs. controls over time (contrast 2).
Results The diagnostic breakdown was as follows: unipolar depression (n = 7); bipolar I, depressed (n = 2); bipolar I, manic (n = 2); and bipolar II, depressed (n = 4). None of the patients had seasonal patterns of illness. Table 1 presents the melatonin values for each time point. When the three baseline melatonin samples (MEL, to MEL,) were compared using a repeated measures ANOVA, there was no main effect of time (F = 0.84; df = 2,54; p = 0.44). The planned contrasts found that the unipolar group was not significantly different from the controls (F = 1.20; df = 1, 27; p = 0.28), but that the bipolar group was significantly different from the controls (F = 4.11; df= 1, 27; p = 0.05). The difference in the bipolar group was a result of lower baseline melatonin concentrations compared to the control and the unipolar groups. There were no significant differences in age among the three diagnostic groups
131 Table 1. Group melatonin
concentration
vs. sampling
time
Time
Unipolar
SE
Bipolar1
SE
MEL1
- 30
43.8
8.8
25.9
7.2
50.2
8.1
MEL2
-15
45.0
7.4
28.8
7.9
81.7
11.1
Sample
1
Control
SE
MEL3
-
49.8
11.2
25.4
7.7
52.6
8.3
MEL4
+15
40.9
8.1
28.7
7.1
50.7
8.3
MEL5
+30
42.8
7.4
24.5
5.7
45.6
8.7
MEL6
+45
31.8
4.6
28.0
5.9
45.4
10.1
MEL7
+60
25.7
3.4
26.4
6.7
41.7
7.0
MEL8
+75
34.6
6.4
27.4
6.3
44.9
8.4
Note. MEL= exposure.
melatonin
1. Diagnosis
X time interaction,
blood samples isamples
repeated
l-3 taken before light exposure;
measures
analysis
of variance,
samples4-8
bipolar
vs. control
takenduring
light
ip = 0.01 j.
(unipolar, bipolar, control) (F = 0.84; df = 2, 27; p = 0.44). The baseline melatonin concentration (mean of -30, -15, and -1 min samples) was not significantly correlated with age (r = -0.21, p = 0.14). There were also no significant differences between baseline melatonin and month of study (F 1.29; df = 8, 21; p = 0.30). Fig. 1 presents the melatonin results. The repeated measures ANOVA showed no significant main effect of diagnosis (F= 2.32; df = 2,27; p = 0.12) and a trend to a main effect of time (F= 1.98; df = 7, 189;~ = 0.06). Contrast 1 found no significant difference in melatonin suppression in unipolar patients compared to controls, although a trend toward greater suppression was noted (F = 3.20; df = 1, 189; p = 0.08). Contrast 2, however, did show a significant difference between the bipolar group and controls over time (F = 6.73; df = 1, 189; p = O.Ol), with controls showing greater melatonin suppression than bipolar patients. To reduce the probability of a Type II error, the maximal melatonin suppression of each subject was also analyzed. The maximum melatonin concentration (MAXB) during the dim-light baseline (MEL, to MEL,) was compared to the minimum q
Fig. 1. Group melatonin and normal controls
concentrations
5 -30
T
-15
-1
in bipolar patients,
-
Control
(n=15)
-
Unipolar
(n=7)
+15 +30 +45 +60 +75
(01 :OO)
Sampling time (minutes)
unipolar patients,
132 melatonin concentration (MINL) during the post-light period (MEL, to MEL,) using repeated measures ANOVA (Table 2). Results similar to those in our main analysis were found. There was no main effect of diagnosis (F= 2.48; df = 2, 27; p = 0. lo), but there was a main effect of time (F = 55.12; df = 1, 27; p < 0.001). There was also a significant time x diagnosis interaction (F= 6.53; df = 2,27;p = 0.005) with the planned contrasts again showing that unipolar patients did not differ from controls (F= 1.81; df = 1,27;p = 0.19), but controls suppressed melatonin more than bipolar patients did (F = 11.25; df = 1, 27; p = 0.002). Table 2. Maximal Sample
melatonin
suppression Bipolar1
during light exposure
Unipolar
SE
SE
Control
SE
MAXB
56.1
8.7
30.1
8.1
70.8
10.8
MINL
20.5
3.7
20.2
5.7
29.1
5.8
Note. Maximum (MAXB) melatonin during dim light baseline (MEL1 to MELs). Minimum (MlNLj melatonin during 500 Iux light exposure (MEL4 to MELs). 1. Diagnosis X time interaction,
repeated measures analysis of variance, bipolar vs. control (p = 0.002).
Discussion This study did not find significant differences in nocturnal melatonin suppression between depressed unipolar patients and controls, thus replicating the finding by Cummings et al. (1989). Although the sample size was small, the probability of a Type II error is lessened by analyzing the maximal melatonin suppression in the unipolar patients. Our data do not replicate the marked “supersensitive” suppression of melatonin in bipolar patients reported by other investigators (Lewy et al., 1981, 1985; Nurnberger et al., 1988). In fact, greater melatonin suppression occurred in the control group compared to the bipolar group. This study, however, cannot be directly compared to previous studies of melatonin suppression in bipolar patients because different methodologies were used. The onset of light exposure in this study occurred at an earlier time (OlOOh vs. 0200h in past studies). As previously described (Cummings et al., 1989), the OlOOh light onset was timed earlier to reduce the confounding effects of possible phase shifts in patient groups that might have earlier melatonin offset. Although the duration of light exposure in this study was also shorter (75 min vs. 120 min), most of the melatonin suppression in previous studies occurred during the first hour of exposure, so that significant differences in suppression could be expected even with the shorter exposure time. In contrast to previous reports, this study also carefully matched patients and controls on the factors thought to affect melatonin secretion such as age, sex, and season of study. In addition, we studied acutely ill patients rather than the euthymic patients in other studies. Melatonin suppression in the bipolar group may not have been demonstrated because of a “floor effect” due to the significantly lower baseline melatonin levels before light exposure. We cannot satisfactorily explain this finding. Nocturnal serum melatonin levels have not been previously compared in bipolar versus unipolar patients. Melatonin levels have been found to be lower in melancholia, with some investigators proposing a “low melatonin” hypothesis of depression (Claustrat et al.,
133 1984; Beck-Friis et al., 1985; Brown et al., 1985), although other studies comparing depressed patients with well-matched controls were unable to find differences in melatonin concentrations (Thompson et al., 1988). In a report of a single bipolar patient who was studied in three states (euthymic, manic, and depressed), nocturnal melatonin was highest during the manic state, intermediate during the euthymic state, and lower during the depressed state (Kennedy et al., 1989). Since six of the eight bipolar patients in this study were depressed, our results may be consistent with a depression-dependent decrease in melatonin secretion in bipolar patients. It is also possible that the lower baseline melatonin levels seen in the bipolar group resulted from a phase delay in the melatonin rhythm, although phase advances are more commonly reported in nonseasonal bipolar patients (Kripke et al., 1978). Finally, it is conceivable that daytime light exposure may affect nocturnal melatonin secretion in “supersensitive” bipolar patients. Thus, baseline melatonin levels in bipolar patients may be lower when sampled in San Diego compared to other research centers because of differences in daytime illumination. Although initial studies indicated that control subjects did not significantly suppress melatonin to 500 lux light exposure, subsequent work has demonstrated significant melatonin suppression with 300 lux light (Bojkowski et al., 1987) in healthy subjects. Our data show that melatonin suppression in controls has wide interindividual variability, and further emphasize the need for well-matched controls for comparison to patient groups. One of the major limitations of all melatonin suppression studies to date has been the absence of control nights without light exposure. Thus, phase or amplitude differences between groups in the melatonin rhythm are not adequately distinguished from effects of the light challenge. Future studies should incorporate a baseline (no-light) control night to control for melatonin phase differences between diagnostic groups. Acknowledgment. The research reported Research Foundation.
was supported,
in part, by the Canadian
Psychiatric
References Beck, A.T.; Ward, C.H.; Mendelson, M.; Mack, J.; and Erbaugh, J. An inventory for measuring depression. Archives of General Psychiatry, 4:561-571, 1961. Beck-Friis, J.; Kjellman, B.F.; Aperia, B.; Unden, F.; von Rosen, D.; Ljunggren, J.-G.; and Wetterberg, L. Serum melatonin in relation to clinical measures in patients with major affective disorders and a hypothesis of a low melatonin syndrome. Acta Psychiatrica Scandinavica, 71:319-330, 1985. Berga, S.L.; Mortola, J.F.; and Yen, S.S.C. Amplification of nocturnal melatonin secretion in women with functional hypothalamic amenorrhea. Journal of Clinical Endocrinology and Metabolism, 66~242-244, 1988. Bojkowski, C.J.; Aldhous, M.E.; English, J.; Franey, C.; Poulton, A.L.; Skene, D.J.; and Arendt, J. Suppression of nocturnal plasma melatonin and 6-sulphatoxymelatonin by bright and dim light in man. Hormone and Metabolic Research, 19:437-440, 1987. Brown, R.; Kocsis, J.H.; Caroff, S.; Amsterdam, J.; Winokur, A.; Stokes, P.E.; and Frazer A. Differences in nocturnal melatonin secretion between melancholic depressed patients and control subjects. American Journal of Psychiatry, 142:81 l-816, 1985. Claustrat, B.; Chazot, G.; Brun, J.; Jordan, D.; and Sassolas, G. A chronobiological study of melatonin and cortisol secretion in depressed subjects. Biological Psychiatry, 19: 1215-1229, 1984.
134
Cummings,M.A.;Berga,S.L.;Cummings,K.L.;Kripke,D.F.;Haviland,M.G.;Golshan,S.; and Gillin, J.C. Light suppression of melatonin in unipolar depressed patients. Psychiatry Research, 271351-355, 1989. Endicott, J., and Spitzer, R.L. A diagnostic interview: The Schedule for Affective Disorders and Schizophrenia. Archives of General Psychiatry, 35:837-844, 1978. Fraser, S.; Cowen, P.; Franklin, M.; Franey, C.; and Arendt, J. Direct radioimmunoassay for melatonin in plasma. Clinical Chemistry, 29:396-397, 1983. Hamilton, M. A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry, 23:56-62, 1960. Kennedy, S.H.; Tighe, S.; McVey, G.; and Brown, G.M. Melatonin and cortisol “switches” during mania, depression, and euthymia in a drug-free bipolar patient. Journal of Nervous and Mental Disease, 177:300-303, 1989. Kripke, D.F.; Mullaney, D.J.; Atkinson, M.; and Wolf, S. Circadian rhythm disorders in manic-depressives. Biological Psychiatry, 13:335-351, 1978. Lewy, A.J., and Markey, S.P. Analysis of melatonin in human plasma by gas chromatography-negative chemical ionization-mass spectroscopy. Science, 201:741-743, 1978. Lewy, A.J.; Nurnberger, J.I., Jr.; Wehr, T.A.; Pack, D.; Becker, L.E.; Powell, R.; and Newsome D.A. Supersensitivity to light: Possible trait marker for manic-depressive illness. American Journal of Psychiatry, 142~725-727, 1985. Lewy, A.J.; Wehr, T.A.; Goodwin, F.K.; Newsome, D.A.; and Markey, S.P. Light suppresses melatonin secretion in humans. Science, 210: 1267-1269, 1980. Lewy, A.J.; Wehr, T.A.; Goodwin, F.K.; Newsome, D.A.; and Rosenthal, N.E. Manic depressive patients may be supersensitive to light. Lancet, 1:383-384, 1981. Nurnberger, J.I., Jr.; Berrettini, W.H.; Tamarkin, L.; Hamovit, J.; Norton, J.; and Gershon, E. Supersensitivity to melatonin suppression by light in young people at high risk for affective disorder: A preliminary report. Neuropsychopharmacology, 1:217-223, 1988. Spitzer, R.L.; Endicott, J.; and Robins, E. Research Diagnostic Criteria: Rationale and reliability. Archives of General Psychiatry, 35~773-782, 1978. Thompson, C.; Franey, C.; Arendt, J.; and Checkley, S.A. A comparison of melatonin secretion in depressed patients and normal subjects. British Journalof Psychiatry, 152:260-265, 1988. Webley, G.E.; Mehl, H.; and Willey, K.P. Validation of a sensitive direct assay for melatonin for investigation of circadian rhythms in different species. Journal of Endocrinology, 106:387394. 1985.
129
Elsevier
Melatonin Suppression Disorders
in Bipolar
and Unipolar
Mood
Raymond W. Lam, Alan L. Berkowitz, Sarah L. Berga, Campbell Daniel F. Kripke, and J. Christian Gillin Received
November
27, 1989;
revised
version
received
May 4. 1990: accepled
M. Clark,
June
2, 1990.
Abstract. Nocturnal melatonin suppression to 500 lux light was studied during an acute episode of illness in 8 patients with bipolar disorder, 7 patients with unipolar depression, and 15 age-, sex-, and season-matched normal controls. Unipolar patients did not differ from controls in melatonin suppression. In contrast to previous studies, controls showed greater melatonin suppression than bipolar patients. Baseline melatonin concentration, however, was significantly lower in the bipolar group compared to the unipolar and control groups.
Key Words.
Melatonin,
bipolar, unipolar, depression.
Human plasma melatonin was reported to be significantly suppressed by nocturnal exposure to 2500 lux light, but not by exposure to 500 lux light (Lewy et al., 1980). Significant melatonin suppression to 500 lux light was reported in actively ill bipolar patients as contrasted to normal controls, suggesting that bipolar patients are “supersensitive” to light (Lewy et al., 1981). Moreover, this melatonin supersensitivity was also found in euthymic bipolar patients (Lewy et al., 1985) and in at-risk, unaffected offspring of bipolar patients (Nurnberger et al., 1988). These findings led to the hypothesis that supersensitivity of melatonin suppression is a trait marker for bipolar disorders. Unipolar depressive patients do not have greater melatonin suppression to 500 lux light compared to matched controls (Cummings et al., 1989), suggesting that light supersensitivity might be specific for bipolar disorder. The present study compared nocturnal melatonin suppression to 500 lux light in bipolar patients, unipolar patients, and well-matched controls to test the hypothesis that light supersensitivity is specific to bipolar disorders.
Raymond W. Lam, M.D., F.R.C.P.(C.), is Assistant Professor and Consultant Psychiatrist, Mood Disorders Service, Department of Psychiatry, University of British Columbia, Vancouver. Alan L. Berkowitz, M.D., was a Fellow in Clinical Psychopharmacology and Psychobiology at the University of California, San Diego, when this research was conducted. Sarah L. Berga, M.D., is Assistant Professor, Department of Obstetrics and Gynecology, University of Pittsburgh. Campbell M. Clark, Ph.D., is Assistant Professor, Department of Psychiatry, University of British Columbia, Vancouver. Daniel F. Kripke, M.D., and J. Christian Gillin, M.D., are Professors, Department of Psychiatry, University of California, San Diego. (Reprint requests to Dr. R.W. Lam, Dept. of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, B.C., Canada V6T 2Al.) Ol6s-i7ll
~YO/$O3.50 @I1990 El\evicr
Scientific
Publishers
Ireland
I.td
130
Methods Fifteen acutely ill patients and 15 age-and sex-matched control subjects were studied. The controls were also matched for season, with each control subject run within 4 weeks of the matched patient. All subjects underwent a Schedule of Affective Disorders and Schizophrenia (SADS; Endicott and Spitzer, 1978) interview conducted by a psychiatrist. Diagnoses were obtained by achieving research group consensus using the Research Diagnostic Criteria (RDC; Spitzer et al., 1978). Depressed patients were excluded if they had 21-item Hamilton Rating Scale for Depression (HRSD; Hamilton, 1960) scores < 16. Control subjects had an RDC diagnosis of “never mentally ill” and a negative family history of affective disorder. All subjects had been free of psychotropicdrugs for at least 2 weeks. Subjects taking P-blocking medications were excluded. Subjects were requested to avoid outdoor light as much as possible on the day of the protocol. At 2 lOOh, an i.v. catheter was inserted in a forearm vein and subjects were seated in a darkened room (< 15 lux). An HRSD was obtained by a psychiatrist, and the Beck Depression Inventory (BDI; Beck et al., 1961) was also completed. All subjects remained awake for the duration of the study. From OlOOh to 0215h, subjects were exposed to light from four cool-white fluorescent tubes mounted at eye level. Subjects were seated at a distance to produce illumination of 500 f 20 lux measured by digital photometer at the forehead level. Subjects were told to glance directly at the lights several times/min. The i.v. line was flushed every hour with 2 ml of EDTA and saline. Blood samples (7 ml) were drawn from the i.v. line every 15 min from 0030h to 0215h. There were three blood samples (MEL, to MEL,) taken before exposure to 500 lux light (-30, - 15, and - 1 min), and five samples (MEL, to MEL,) taken during light exposure (15, 30, 45, 60, and 75 min). Blood samples for melatonin determination were collected in EDTA-containing plastic tubes, stored immediately on ice, and centrifuged within 2 hours of collection. The plasma was immediately frozen and kept at -20 “C until assay. Plasma melatonin was measured directly, without extraction, by a previously described radioimmunoassay (RIA) (Fraser et al., 1983; Webley et al., 1985; Berga et al., 1988). The accuracy of the RIA has been validated by gas chromatography-mass spectroscopy methods by Lewy and Markey (1978). Assay sensitivity was 43 pmol/l (10 pg/ml). Samples from matched pairs were analyzed in duplicate in the same assay. The intra-assay and interassay coefficients of variation were 8.9% and 11.2%. respectively. Since the sensitivity of the melatonin assay was 10 pg/ml, all values < 10 pgjml were set to 10 pg/ml for the purpose of the statistical analysis. Analysis was done using a 3 x 8 (3 levels of diagnosis and 8 levels of time) repeated measures analysis of variance (ANOVA) with planned contrasts of the interaction term as follows: unipolars vs. controls over time (contrast l), and bipolars vs. controls over time (contrast 2).
Results The diagnostic breakdown was as follows: unipolar depression (n = 7); bipolar I, depressed (n = 2); bipolar I, manic (n = 2); and bipolar II, depressed (n = 4). None of the patients had seasonal patterns of illness. Table 1 presents the melatonin values for each time point. When the three baseline melatonin samples (MEL, to MEL,) were compared using a repeated measures ANOVA, there was no main effect of time (F = 0.84; df = 2,54; p = 0.44). The planned contrasts found that the unipolar group was not significantly different from the controls (F = 1.20; df = 1, 27; p = 0.28), but that the bipolar group was significantly different from the controls (F = 4.11; df= 1, 27; p = 0.05). The difference in the bipolar group was a result of lower baseline melatonin concentrations compared to the control and the unipolar groups. There were no significant differences in age among the three diagnostic groups
131 Table 1. Group melatonin
concentration
vs. sampling
time
Time
Unipolar
SE
Bipolar1
SE
MEL1
- 30
43.8
8.8
25.9
7.2
50.2
8.1
MEL2
-15
45.0
7.4
28.8
7.9
81.7
11.1
Sample
1
Control
SE
MEL3
-
49.8
11.2
25.4
7.7
52.6
8.3
MEL4
+15
40.9
8.1
28.7
7.1
50.7
8.3
MEL5
+30
42.8
7.4
24.5
5.7
45.6
8.7
MEL6
+45
31.8
4.6
28.0
5.9
45.4
10.1
MEL7
+60
25.7
3.4
26.4
6.7
41.7
7.0
MEL8
+75
34.6
6.4
27.4
6.3
44.9
8.4
Note. MEL= exposure.
melatonin
1. Diagnosis
X time interaction,
blood samples isamples
repeated
l-3 taken before light exposure;
measures
analysis
of variance,
samples4-8
bipolar
vs. control
takenduring
light
ip = 0.01 j.
(unipolar, bipolar, control) (F = 0.84; df = 2, 27; p = 0.44). The baseline melatonin concentration (mean of -30, -15, and -1 min samples) was not significantly correlated with age (r = -0.21, p = 0.14). There were also no significant differences between baseline melatonin and month of study (F 1.29; df = 8, 21; p = 0.30). Fig. 1 presents the melatonin results. The repeated measures ANOVA showed no significant main effect of diagnosis (F= 2.32; df = 2,27; p = 0.12) and a trend to a main effect of time (F= 1.98; df = 7, 189;~ = 0.06). Contrast 1 found no significant difference in melatonin suppression in unipolar patients compared to controls, although a trend toward greater suppression was noted (F = 3.20; df = 1, 189; p = 0.08). Contrast 2, however, did show a significant difference between the bipolar group and controls over time (F = 6.73; df = 1, 189; p = O.Ol), with controls showing greater melatonin suppression than bipolar patients. To reduce the probability of a Type II error, the maximal melatonin suppression of each subject was also analyzed. The maximum melatonin concentration (MAXB) during the dim-light baseline (MEL, to MEL,) was compared to the minimum q
Fig. 1. Group melatonin and normal controls
concentrations
5 -30
T
-15
-1
in bipolar patients,
-
Control
(n=15)
-
Unipolar
(n=7)
+15 +30 +45 +60 +75
(01 :OO)
Sampling time (minutes)
unipolar patients,
132 melatonin concentration (MINL) during the post-light period (MEL, to MEL,) using repeated measures ANOVA (Table 2). Results similar to those in our main analysis were found. There was no main effect of diagnosis (F= 2.48; df = 2, 27; p = 0. lo), but there was a main effect of time (F = 55.12; df = 1, 27; p < 0.001). There was also a significant time x diagnosis interaction (F= 6.53; df = 2,27;p = 0.005) with the planned contrasts again showing that unipolar patients did not differ from controls (F= 1.81; df = 1,27;p = 0.19), but controls suppressed melatonin more than bipolar patients did (F = 11.25; df = 1, 27; p = 0.002). Table 2. Maximal Sample
melatonin
suppression Bipolar1
during light exposure
Unipolar
SE
SE
Control
SE
MAXB
56.1
8.7
30.1
8.1
70.8
10.8
MINL
20.5
3.7
20.2
5.7
29.1
5.8
Note. Maximum (MAXB) melatonin during dim light baseline (MEL1 to MELs). Minimum (MlNLj melatonin during 500 Iux light exposure (MEL4 to MELs). 1. Diagnosis X time interaction,
repeated measures analysis of variance, bipolar vs. control (p = 0.002).
Discussion This study did not find significant differences in nocturnal melatonin suppression between depressed unipolar patients and controls, thus replicating the finding by Cummings et al. (1989). Although the sample size was small, the probability of a Type II error is lessened by analyzing the maximal melatonin suppression in the unipolar patients. Our data do not replicate the marked “supersensitive” suppression of melatonin in bipolar patients reported by other investigators (Lewy et al., 1981, 1985; Nurnberger et al., 1988). In fact, greater melatonin suppression occurred in the control group compared to the bipolar group. This study, however, cannot be directly compared to previous studies of melatonin suppression in bipolar patients because different methodologies were used. The onset of light exposure in this study occurred at an earlier time (OlOOh vs. 0200h in past studies). As previously described (Cummings et al., 1989), the OlOOh light onset was timed earlier to reduce the confounding effects of possible phase shifts in patient groups that might have earlier melatonin offset. Although the duration of light exposure in this study was also shorter (75 min vs. 120 min), most of the melatonin suppression in previous studies occurred during the first hour of exposure, so that significant differences in suppression could be expected even with the shorter exposure time. In contrast to previous reports, this study also carefully matched patients and controls on the factors thought to affect melatonin secretion such as age, sex, and season of study. In addition, we studied acutely ill patients rather than the euthymic patients in other studies. Melatonin suppression in the bipolar group may not have been demonstrated because of a “floor effect” due to the significantly lower baseline melatonin levels before light exposure. We cannot satisfactorily explain this finding. Nocturnal serum melatonin levels have not been previously compared in bipolar versus unipolar patients. Melatonin levels have been found to be lower in melancholia, with some investigators proposing a “low melatonin” hypothesis of depression (Claustrat et al.,
133 1984; Beck-Friis et al., 1985; Brown et al., 1985), although other studies comparing depressed patients with well-matched controls were unable to find differences in melatonin concentrations (Thompson et al., 1988). In a report of a single bipolar patient who was studied in three states (euthymic, manic, and depressed), nocturnal melatonin was highest during the manic state, intermediate during the euthymic state, and lower during the depressed state (Kennedy et al., 1989). Since six of the eight bipolar patients in this study were depressed, our results may be consistent with a depression-dependent decrease in melatonin secretion in bipolar patients. It is also possible that the lower baseline melatonin levels seen in the bipolar group resulted from a phase delay in the melatonin rhythm, although phase advances are more commonly reported in nonseasonal bipolar patients (Kripke et al., 1978). Finally, it is conceivable that daytime light exposure may affect nocturnal melatonin secretion in “supersensitive” bipolar patients. Thus, baseline melatonin levels in bipolar patients may be lower when sampled in San Diego compared to other research centers because of differences in daytime illumination. Although initial studies indicated that control subjects did not significantly suppress melatonin to 500 lux light exposure, subsequent work has demonstrated significant melatonin suppression with 300 lux light (Bojkowski et al., 1987) in healthy subjects. Our data show that melatonin suppression in controls has wide interindividual variability, and further emphasize the need for well-matched controls for comparison to patient groups. One of the major limitations of all melatonin suppression studies to date has been the absence of control nights without light exposure. Thus, phase or amplitude differences between groups in the melatonin rhythm are not adequately distinguished from effects of the light challenge. Future studies should incorporate a baseline (no-light) control night to control for melatonin phase differences between diagnostic groups. Acknowledgment. The research reported Research Foundation.
was supported,
in part, by the Canadian
Psychiatric
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