effect of light therapy on salivary melatonin in seasonal affective disorder

ELSEVIER Psychiatry Research 56 (I 995) 22 I-228

PSYCHIATRY

RESEARCH

Effect of light therapy on salivary melatonin in seasonal affective disorder

Jane Rice*“, Joan Mayora, H. Allen Tuckerb’“, Robert J. Bielski”

aDepartment of Psychiatry, Michigan State University, Bll5 West Fee Hall, Easi Lansing, MI 48824-1316, USA bDepartment of Animal Science, Michigan State University, East Lansing, Ml, USA

CDepartment of Physiology, Michigan State University, East Lansing, MI, USA

Received 25 February 1994; revision received 25 July 1994; accepted 25 October 1994

Abstract

To investigate the role of a light-induced advance in the timing of the melatonin rhythm in seasonal affective disorder, 11 depressed patients underwent 2 weeks of light therapy with full spectrum or cool white light. Evening saliva samples were collected before and after each week of treatment-and assayed for melatonin to determine the time of onset of nocturnal secretion. Both treatments reduced depression scores, advanced the timing of the melatonin rhythm, and increased melatonin concentrations. Time of onset of the nocturnal increase in melatonin did not differ between clinical responders and nonresponders, suggesting that a phase advance in the onset of nocturnal melatonin secretion is not sufficient to induce clinical remission in seasonal affective disorder.

Keyword: Major depression; Phototherapy; Circadian rhythm

1. Introduction

Seasonal affective disorder (SAD) is a syndrome of recurrent depressive episodes that occur on a seasonal basis during the autumn and winter, and remit spontaneously during spring and summer (Rosenthal et al., 1984; American Psychiatric Association, 1987). Daily administration of timed bright light, or phototherapy, induces a remission in 50-70% of depressed SAD patients (Terman et al., 1989). Alterations in the timing, or phase posi-

tion, of circadian rhythms may account for both the etiology of SAD and the therapeutic effect of light (Lewy et al., 1987). Preliminary evidence sug- gests that the timing of circadian rhythms is delayed in depressed SAD patients compared with control subjects (Avery et al., 1987; Lewy et al., 1987; Terman et al., 1988; Winton et al., 1989; Sack et al., 1990; Wirz-Justice et al,, 1993) and that morning phototherapy induces a corrective phase advance coincident with clinical improvement (Lewy et al., 1987; Terman et al., 1988; Sack et al., 1990).

* Corresponding author, Tel: +I 517 353 3070; Fax: +I 517 The circadian rhythm of melatonin is often used 336 2893. as an indicator of circadian phase position since it

0165-1781/95/$09.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0165-1781(95)02610-U

222 J. Rice et al. /Psychiatry Research 56 (1995) 221-228

is a well-defined, high-amplitude rhythm control- led by the hypothalamic suprachiasmatic nuclei (Shanahan and Czeisler, 1991). Moreover, the melatonin rhythm can be manipulated by light exposure (Lewy et al., 1987; Sack et al., 1990; Salinas et al., 1992). Serial blood sampling in the evening revealed a delay in the onset time of elevated nocturnal secretion of melatonin in depressed SAD patients compared with normal control subjects (Lewy et al., 1987). Although the necessity of fre- quent blood sampling limits the applicability of this procedure, sampling of saliva may yield com- parable information without the technical draw- backs. The concentration of melatonin in saliva is highly correlated with plasma concentrations, ex- hibiting a circadian rhythm with low daytime and high nocturnal values (Miles et al., 1985a).

In a crossover study, we compared the effect of two types of broad spectrum white light on depression scores and salivary melatonin. The clinical results were reported previously (Bielski et al., 1992). Here we report the effects of light therapy on the onset time of nocturnal melatonin secretion and the association between onset time and clinical improvement.

2. Methods

2.1. Subject selection Human subjects, aged 18-59, were recruited

through newspaper articles and clinician referrals. The admission criteria for the study included (1) a DSM-HI-R diagnosis of recurrent major depression, seasonal pattern (American Psychiatric As- sociation, 1987), and (2) a score of at least 18 on the 17-item Hamilton Rating Scale for Depression (HRSD; Hamilton, 1967). Exclusion criteria included pregnancy, concomitant treatment with antidepressant medications or fi-adrenergic antag- onists, and suicidal behavior. All subjects were free of psychopharmacological drugs for at least 12 days before beginning the study and remained so until the end of the study. Subjects entered the study at least 5 weeks before spontaneous remission was expected based on recall of previous episodes. The study was approved by the Univer- sity Committee for Research Involving Human Subjects. Written informed consent was obtained from each subject,

2.2. Experimental design The design of the study was a 2 x 2 crossover

design (two treatments in two stages) consisting of 7-day regimens of light therapy separated by a l- week withdrawal period (Jones and Kenward, 1989). Treatment assignment in stage 1 was by a balanced procedure. Stage 1 of the crossover con- sisted of pretreatment and treatment measures associated with the first treatment assignment; stage 2, pretreatment and treatment measures associated with the second treatment assignment.

2.3. Light therapy protocol

The two treatment conditions were full spectrum (FS; Vita-Lite F40Tl2; Duro-Test Corpora- tion, North Bergen, NJ) and cool white (CW; Sylvania F40Tl2CWSS) light. Illuminance (Gos- sen Panlux) for FS light was 2690 lx and 3013 lx for CW light. An acrylic diffusing lens (Lithonia) filtered out ultraviolet B radiation (< 325 nm). Ir- radiance (Kettering; 250-33 000 nm range) was 675 pW/cm2 for FS light and 600 pW/cm’ for CW light, yielding a calculated dose of 4.86 J/cm2 and 4.32 J/cm2, respectively. The spectral power distribution for each light source was published previously (Bielski et al., 1992). Light therapy was administered individually at an outpatient clinic from 06:OO to 08:OO h for 7 days. Subjects were monitored to ensure compliance with the light therapy protocol.

2.4. Saliva samples Saliva samples were collected in accordance

with biosafety regulations of the Center for Disease Control (U.S. Public Health Service, 1988). Saliva samples (2 ml) were collected without stimulation of salivary flow every 30 min from 18:OO to 24:00 h (Miles et al., 1985b). Subjects stayed in dim light (< 50 lx) during the procedure and refrained from eating, drinking, and smoking. Water was allowed, but not later than 15 min before sample collection. Samples were collected on four occasions (pretreatment and treatment in both stages of the crossover). Pretreatment profiles were obtained on the evening before day 1 of treatment; treatment profiles were obtained on day 7 of treatment.

Saliva was assayed for melatonin by radioimmunoassay (Fraser et al., 1983) with a double anti-

J. Rice et al. /Psychiatry Research 56 (1995) 221-228 223

body separation method (Webley et al., 1985) using tritiated melatonin tracer (New England Nu- clear) and antiserum G/S/704-6483 (Guildhay An- tisera). The sensitivity of the assay, defined as the apparent concentration at 2 SD from the counts at maximum binding, was 4 pg/ml. Intra-assay coefficients of variation were 10% at 8 pg/ml and 6% at 70 pg/ml; interassay coefficients of variation were 16% at 8 pg/ml and 11% at 63 pg/ml. Saliva samples containing high melatonin concentrations produced dilution curves parallel to the standard curve. Recovery of known amounts of melatonin (10 and 40 pg/ml) added to saliva was 106 f 7% and 103 f 7%, respectively.

2.5. Depression ratings The response to light therapy was measured

with the HRSD and the SAD Supplementary Rat- ing Scale (Rosenthal and Heffernan, 1986) by an investigator (J.M.) who was unaware of treatment assignments. Ratings were obtained between 18:OO and 20:00 h on four occasions that coincided with the collection of saliva samples. Subjects were re- quired to have an HRSD score of at least 16 to cross over to stage 2.

2.4. Data analysis The effect of FS and CW light therapy on mela-

tonin concentrations was modeled with a double split-plot crossover design’ (Gill, 1978, 1988) with subject, stage (first vs. second treatment assignment), and treatment (FS vs. CW) as main plot ef-

’ A double split-plot model was used to analyze melatonin data because of the existence of two layers of repeated information. The first layer of repeated information is the data from the four periods (i.e., pretreatment and treatment within each stage of the crossover). The second layer of information is the data from the I3 sampling times within each period. The double split-plot model gives rise to four error terms in the analysis of variance, each of which may be differentially affected by the correlations induced by repeated measurement. Thus, the selection of the proper error term as a denominator for the F statistic used in testing hypotheses about main effects is critical. To analyze trends within the data, appropriate standard errors were calculated from combinations of the four error terms. Bonferroni t tests were then used to compare trends within sampling times (20:00-2290 h) between different periods (pretreatment and treatment). Note that there is no four-way interaction term because treatment and stage are not indepen- dent effects.

fects, period (pretreatment vs. treatment) as the subplot, and sampling time (18:00-24:00 h) as the sub-subplot. Analysis of variance was used to determine differences between the various effects. Differences in melatonin concentrations between 20:00 and 22:00 h (the usual time of onset of nocturnal secretion) were compared between periods with the Bonferroni t test. Clinical response was defined as at least a 50% decrease in HRSD score to a value <8 (Terman et al., 1989). On the basis of clinical status on day 7 of treatment, subjects were divided into two groups (clinical responders and nonresponders), and differences between the groups within periods were assessed with the Bon- ferroni t test. All data are reported as mean f SD unless otherwise noted.

3. Results

Twelve subjects (nine women and three men) entered the study. Eleven subjects (mean age = 37 f 12 years) completed the crossover (one male subject failed to relapse during the withdrawal period following FS light). The two light sources were indistinguishable to subjects. As reported previously (Bielski et al., 1992), FS and CW light were equally effective in reducing HRSD and SAD scores and in inducing clinical remission. Individ- ually, three patients responded to both treatments, three responded only to FS light, two responded only to CW light, and three did not respond to either.

Table 1 presents the results of the analysis of variance of melatonin concentrations for 10 subjects. To balance the design, one subject was ran- domly discarded from the CW-FS sequence group to match the subject in the FS-CW sequence group who failed to complete the crossover.

Mean melatonin concentrations were unexpect- edly high early in the evening and then plummeted to a low value before beginning a steady rise over the remainder of the evening. Melatonin profiles were similar between the two treatments (FS vs. CW) at both pretreatment (Fig. 1) and on day 7 of treatment (Fig. 2). Treatment results were thus pooled in future analyses. Mean melatonin concentrations for the 6-h profiles increased (P < 0.05) following 1 week of light therapy compared with pretreatment (Fig. 3). Moreover, following


Table I Analysis of variance of melatonin levels

Source of variance

Subject Stage Treatment Error Period Period x subject Period x stage Period x treatment Error (period) Sample Sample x subject Sample x stage Sample x treatment Error (sample) Period x sample Period x sample x subject Period x sample x stage Period x sample x treatment Error (period x sample)

d’

9 1 1 8 I 9 I I 8

I2 108 I2 I2 96 12

108 I2 I2 96

F value P

4.28 0.03 1.36 0.28 0.95 0.36

8.53 0.02 1.16 0.42 0.00 0.95 0.43 0.53

32.14 0.0001 5.30 0.0001 0.53 0.89 0.62 0.82

2.06 0.03 2.34 0.0001 0.56 0.87 0.54 0.88

treatment, melatonin profiles showed a significant phototherapy, there was no difference (P > 0.25) rise between 20:00 and 2290 h, while melatonin in mean melatonin concentrations at pretreatment profiles at pretreatment did not. between subjects who eventually responded to

On the basis of clinical status on day ‘7 of light treatment and those who did not (Fig. 4). Ad-

Time of Day 6) Time of Day 6)

Fig. I. Salivary melatonin profiles at pretreatment. Unstimu- Fig. 2. Salivary melatonin profiles (mean * SEM) on day 7 of lated saliva samples were collected under dim (< 50 lx) light. treatment with morning (06:00-OS:00 h) light therapy. See leg- Each data point represents the mean (+ SEM) for IO patients. end for Fig. I.

J. Rice et al. /Psychiatry Research 56 (1995) 221-228 225

1 I - Pretreatment ._.. * .._. ql_abent

: : : r

0; l8oolmmoo2loo22cnm24m

Time of Day (h)

Fig. 3. Salivary melatonin profiles (mean f SEM) at pretreatment and after treatment (1 week of daily light therapy at 06:00~08:00 h). Data for full-spectrum and cool-white light have been pooled (a = 20).

Eo-

loo-

50’

- Remieaion

------- Depreeaed

Time of Day (h)

Fig. 5. Salivary melatonin profiles (mean f SEM) on day 7 of treatment. Subjects were divided into two groups based on clinical response on day 7 of treatment. There were nine observations for responders (remission) and I1 observations for nonresponders (depressed).

ditionally, melatonin profiles were similar (P > 0.25) on day 7 of treatment between responders and nonresponders (Fig. 5).

Mean melatonin concentrations were similar at pretreatment in stages 1 and 2, indicating that the l-week withdrawal period was adequate to prevent carryover effects of light. Melatonin concentrations were also similar between stages following 1 week of light therapy. Thus, there was no stage effect on melatonin concentrations.

4. Discussion

Time of Day (h)

Fig. 4. Salivary melatonin profiles (mean f SEM) at pretreatment with subjects divided into two groups based on clinical response on day 7 of treatment. There were nine observations for responders (remission) and 11 observations for nonresponders (depressed).

Melatonin is a small (MW 232) lipophilic hor- mone secreted primarily at night by the pineal gland. Approximately 70% of circulating melatonin is bound to plasma albumin (Cardinali et al., 1972). The remaining unbound fraction is free to diffuse across acinar cells of the salivary glands into saliva. Consequently, salivary melatonin concentrations are generally 30% of plasma concentrations, with a high correlation between paired


saliva and plasma samples (Miles et al., 1985a; Nowak et al., 1987). In the present study, melatonin concentrations increased steadily between 20:00 and 24:00 h, consistent with previous reports of circadian rhythmicity in salivary melatonin (Miles et al., 1985a, 1985b, 1989; McIntyre et al., 1987). Our results with saliva samples are also consistent with studies of plasma melatonin showing high interindividual variability (Waldhauser and Dietzel, 1985; Laasko et al., 1990). Subjects found saliva sampling easy to perform and preferable to blood sampling. Thus, measurement of melatonin in saliva provides an acceptable, noninvasive method for assessing circadian phase position in SAD patients.

Several studies of the melatonin rhythm in depressed SAD patients document a delay in the timing of the nocturnal onset of secretion (Lewy et al., 1987; Terman et al., 1988; Winton et al., 1989; Wirz-Justice et al., 1993) that can be advanced by morning phototherapy (Lewy et al., 1987). How- ever, determination of light-induced changes in the melatonin rhythm is difficult in SAD studies since 24-h profiles are often unavailable. Cosinor methods may not be appropriate when data sets are c 24 h (Minors and Waterhouse, 1988). Visual in- spection (Terman et al., 1988) and increases above daytime threshold values (Lewy et al., 1987; Sack et al., 1990) have been used to estimate onset time of nocturnal secretion in plasma samples. In the present study, high variability between subjects precluded the use of a threshold value in determin- ing onset time in saliva samples. Therefore, we defined onset as the presence of a significant rise in melatonin concentrations within the usual time frame (20:00-22:00 h) observed in normal control subjects (Waldhauser and Dietzel, 1985; Lewy et al., 1987; Rubin et al., 1992). We found a significant increase in melatonin concentrations in this time frame only in profiles obtained following 1 week of light therapy. While this method does not yield an exact time of onset of nocturnal secretion, it does allow us to conclude that 1 week of morning light therapy advanced the onset time of nocturnal melatonin secretion from after 22:00 h to before 22:00 h.

This conclusion is corroborated by the finding that the mean melatonin concentration of the 6-h

profile was increased following light therapy compared with pretreatment. The increase in secretion between 18:00 and 24:00 h may indicate either an earlier onset of nocturnal secretion (Hansen et al., 1987) or increased 24-h secretion. Skwerer et al. (1988) reported that 24-h melatonin secretion was not increased by light therapy. Thus, our results are consistent with an advance in the melatonin rhythm.

Previous studies demonstrated an association between a phase advance in the timing of the melatonin rhythm and clinical improvement (Lewy et al., 1987; Terman et al., 1988; Sack et al., 1990). For example, Sack et al. (1990) noted a l-h advance in melatonin onset and a decrease in depressive symptoms in SAD patients following 1 week of morning light therapy. Rosenthal et al. (1990), using a morning + evening phototherapy protocol in an attempt to avoid a phase shift, noted a phase advance in some patients, all of whom responded positively to light therapy. Lewy et al. (1987) have suggested that a phase advance in the timing of circadian rhythms mediates the antidepressant effect of light.

While our results similarly demonstrate a phase advance in the melatonin rhythm coincident with clinical improvement, they do not support a direct connection between a phase advance in the melatonin rhythm and clinical remission. Melatonin profiles were similar between the group of responders and the group of nonresponders, at both pretreatment and day 7 of phototherapy. Both responders and nonresponders exhibited a light- induced phase advance in melatonin onset, suggesting that an advance in the melatonin rhythm is not sufficient in itself to induce clinical remission. Conceivably, the group of nonresponders may have a variant of seasonal depression that does not respond to light therapy. With present diagnostic tools, however, it was not possible to differentiate these two groups on the basis of symptoms, clinical severity, or age.

Our conclusion of a dissociation between clinical improvement and an advance in circadian timing receives support from several studies. Terman and Schlager (1990) and Allen et al. (1992) noted a similar dissociation in individual case studies. Wirz-Justice et al. (1993) reported evidence against

J. Rice et al. /Psychiatry Research 56 (I995j 221-228 227

the necessity of a light-induced phase advance of the melatonin rhythm for clinical efficacy.

The similar response in melatonin profiles to FS and CW light indicates that a spectral distribution similar to sunlight is not necessary to modulate melatonin secretion. Indeed, previous studies have reported changes in melatonin secretion following exposure to non-FS white light (Lewy et al., 1987) and narrow spectrum light (Brainard et al., 1985). The equal efficacies of FS and CW light to advance melatonin onset and induce clinical remission indicate that both types of light contain the necessary dose and spectral range to elicit these responses.

Our radioimmunoassay for salivary melatonin undoubtedly had some methodological limita- tions. We consistently observed extremely elevated melatonin concentrations in the first three evening samples. This phenomenon has been noted by other researchers (McIntyre et al., 1987; Miles et al., 1989; Nickelsen et al., 1991). Both McIntyre et al. (1987) and Miles et al. (1989) suggest that food contamination may affect the radioimmunoassay system. This suggestion is consistent with our observations since markedly elevated melatonin concentrations occurred only in the samples im- mediately following the evening meal. We also noted somewhat higher melatonin concentrations overall than expected. Generally, salivary melatonin concentrations at midnight are < 30 pg/ml (Miles et al., 1985a, 1985b, 1987a, 1989; Nowak et al., 1987), although higher peak values have been noted (Vakkuri, 1985; McIntyre et al., 1987; Miles et al., 1987b; Nowak, 1988; Laasko et al., 1990; Nickelsen et al., 1991). Determination of absolute values of melatonin in SAD research may not be as important as 24-h rhythmicity and changes in phase position (McIntyre et al., 1987; Laasko et al., 1990).

In conclusion, measurement of melatonin in saliva offers a noninvasive technique for monitoring light-induced changes in circadian rhythmicity in SAD patients. FS and CW light advance the timing of the onset of nocturnal melatonin secretion and increase evening melatonin concentrations. However, a phase advance in the melatonin rhythm is insufficient to induce clinical remission. Future research may determine whether the light-

induced change in melatonin secretion is nonethe- less a necessary step in the physiological mecha- nism underlying the antidepressant effect of light therapy.

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effect of light therapy on salivary melatonin in seasonal affective disorder

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