Effects of phototherapy on electrooculographic ratio in winter seasonal affective disorder

Psychiatry Research, 49:99-107

99

Elsevier

Effects of Phototherapy on Electrooculographic Winter Seasonal Affective Disorder Norio Ozaki, Norman Dan A. Oren Received

October

E. Rosenthal,

9, 1992; revised

version

Ratio

Douglas E. Moul, Paul J. Schwartz,

received

May IO, 1993; accepted

in

and

July 2, 1993.

Abstract. Low electrooculographic (EOG) ratios have been reported in patients with seasonal affective disorder (SAD). This study was undertaken to replicate these results and to consider the effects of light therapy on the EOG in SAD patients. Sixteen outpatients with SAD and 16 age-, sex-, and medicationmatched control subjects had EOG testing before and after 1 week of light therapy during the winter. The EOG ratios in the SAD patients were only marginally lower than those in the normal control subjects. These differences persisted after light therapy. Although the slightly decreased EOG ratios in SAD patients might have resulted from an artifact of test variability, drowsiness, or other confounding factors, the difference between patients and control subjects raises the possibility of retinal abnormality in SAD. Key Words. Light therapy,

depression,

retina, dopamine,

serotonin.

Although the mechanism of action of phototherapy for seasonal affective disorder (SAD) (Rosenthal et al., 1984) is unknown, the antidepressant effects of light in this

condition seem to be mediated through the eyes (Wehr et al., 1987). White or green lights are more effective antidepressants than either red or blue lights (Brainard et al., 1990; Oren et al., 1991), consistent with the known spectral sensitivity of retinal photoreceptors. The above observations raise the questions as to whether eye abnormalities might be of pathogenic importance in SAD. Eye-related abnormalities found previously in SAD patients include low electrooculographic (EOG) ratios (Lam et al., 1991), low electroretinographic b-wave amplitudes in female SAD patients, and high amplitudes in male SAD patients (Lam et al., 1992). Several other studies of ocular function, however, have not differentiated SAD patients from control subjects (Oren et al., 1993). The EOG records eye-movement voltages between electrodes placed near the eye. These voltages reflect the standing potential between the cornea and the back of the eyeball (Arden and Kelsey, 1962). The cornea, lens, and retinal pigment epithelium

At the time that this research was done, Norio Ozaki, M.D., was Visiting Fellow; Norman E. Rosenthal, M.D., was Chief, Section on Environmental Psvchiatry; Douglas E. Maul. M.D.. was Senior Clinical Investigator; Paul J.Schwartz, M.D., was Senior Clinical In&tigator; and Dan A. Oren, M.D., was Senior Clinical Investigator, Clinical Psychobiology Branch, National Institute of Mental Health, Bethesda, MD. (Reprint requests to Dr. N. Ozaki, Clinical Psychobiology Branch, NIMH, Bldg. 10, Rm. 4S-239, 9000 Rockville Pike, Bethesda, MD 20892, USA.) 0165-1781/93/$06.00

@ 1993 Elsevier Scientific

Publishers

Ireland

Ltd.

100 contribute to this potential. The potentials from the cornea and lens do not vary with changes in ambient light, but that of the retinal pigment epithelium is reduced during dark adaptation and increased during light adaptation. Therefore, changes in the EOG reflect light and dark adaptation of the retinal pigment epithelium (Ogden, 1989). The EOG ratio (also called the Arden ratio) is determined by dividing the voltage peak during light adaptation by the lowest voltage found during the period of dark adaptation (Arden et al., 1962). Recently, Lam et al. (1991) reported lower EOG ratios in SAD patients compared with normal control subjects. They suggested that this might reflect a subsensitivity to light and speculated that SAD may be associated with retinal abnormalities in the photoreceptor/retinal pigment epithelium complex. The present study was an attempt to replicate the findings of Lam et al. (1991) and to determine whether light therapy changes EOG ratios in SAD patients and individually matched control subjects.

Methods Subjects. Sixteen patients with SAD (Rosenthal et al., 1984) and 16 individually age-, sex-, and medication-matched control subjects participated in the study. Each group consisted of 11 women and 5 men. The ages of the patients (mean = 40 years, SD = 13, range = 22-70) and control subjects (mean = 40 years, SD = 12, range = 22-70) were identical. All subjects were screened with the Structured Clinical Interview for DSM-III-R (Spitzer et al., 1989). Study entry criteria required that no patient meet DSM-III-R Axis I criteria for a psychiatric diagnosis other than major depressive disorder or bipolar disorder (American Psychiatric Association, 1987). All subjects were also required to be in good health, as judged by laboratory tests and physical examinations, with no evidence of eye disease by history or ocular examination. Eleven patients and 11 age- and sex-matched control subjects were free of medication for at least 5 weeks before and during the study; three patients and their control subjects took estrogen and progesterone; and two patients and their control subjects took estrogen alone. All subjects provided informed consent before undergoing the procedure. Procedures. Four trained raters who blind both to the patients’ treatment status and their phase of participation in the study performed all assessments of mood on the basis of the Structured Interview Guide for the Hamilton Depression Rating Scale (HDRS), Seasonal Affective Disorders version (SIGH-SAD; Williams et al., 1988). The SIGH-SAD is composed of the 21-item HDRS and an eight-item scale of the atypical vegetative symptoms of SAD. The raters had an interrater reliability of 0.96 in their assessments of videotaped interviews of 12 depressed patients. An examiner (N.O.) who was unaware of the subjects’ treatment status measured the EOG in the standard manner originally described by Arden et al. (1962). All subjects were tested between 1 p.m. and 530 p.m. between November 1I and March 20 of two consecutive winters. The EOG was recorded separately and simultaneously from each eye with an EPIC-2000s (LKC Technology, Inc.). A silver-silver chloride disk electrode filled with conducting gel was attached near the lateral and medial canthus of each eye; the ground electrode was attached at the middle of the forehead. The high pass and low pass filter settings were 100 Hz and 0.05 Hz, respectively. The stimulus was provided in a Ganzfeld bowl with built-in red-light-emitting diodes as fixation marks at 15” to either side of the center of the bowl. Ten eye movements were recorded for one measurement at a rate of 1.5 movements/second. The measurements were repeated at l-minute time intervals. The average saccade voltage of 10 eye movements was calculated according to the following steps: (1) remove artifacts by applying a 5-point median filter to the waveform, (2) find the peak-to-trough amplitude of each saccade,

101 (3) discard the largest and smallest amplitude, and (4) average the remaining values. The initial baseline measurement was done using a dim background illumination of 10 foot-lamberts inside the Ganzfeld bowl for 6 minutes following the 15minute adaptation to the dim light condition. The subsequent measurements were taken for 16 minutes in total darkness. Finally, the background light was adjusted to 75 foot-lamberts, and measurements were taken for another 13 minutes. All subjects were studied in two randomly ordered conditions: (1) “off light,” more than 1 week and (2) “on light,” following at least 1 week of light therapy. Subjects in the off-light condition were requested to refrain from exposure to bright light during this condition. Subjects in the on-light condition used a light box (SunBox@) with a 2’ X 2’ emitting surface of light angled at 45’ above and in front of the subject. Subjects were asked to glance directly at the light box once each minute during the treatment period. They sat facing the light box directly so that there was a l-foot distance from their eyes to the center of the box. At this distance, subjects received approximately 10,000 lux. In seven patients and seven matched control subjects, light therapy was administered for 45 minutes each morning between 6:30 and 9 a.m. and each evening between 6:30 and 9 p.m. (“45-min-bid”). In nine patients and nine matched control subjects, light therapy was administered for 60 minutes each morning between 6:30 and 9 a.m. with the same box (“I-hr-qam”). Statistics. Because ratios of variables would not necessarily follow a normal distribution (Moul, 1992) the normality of the distribution of the EOG ratios was examined with the W test (Shapiro and Wilk, 1965). The hypothesis of normality was not rejected at the a = 0.05 level. The data, therefore, were analyzed by repeated measures analysis of variance (ANOVA) with two grouping factors (diagnosis: SAD and controls; and light paradigm: 45-min-bid and I-hr-qam) and two repeated measures (eye: right and left; and light condition: on- and offlight). Pearson correlations were examined between both the HDRS score and the total SIGH-SAD score in the off-light condition and the EOG ratios change (off-light vs. on-light) in SAD patients. Pearson correlations were also examined between the difference both in the HDRS score (off-light vs. on-light) and in total SIGH-SAD score (off-light vs. on-light) and the EOG ratio change in SAD patients.

Results group was large enough to detect a difference of 0.08 and 0.12 in the right and left eye, respectively, between on- and off-light conditions at the a = 0.05 level with power > 0.8 (Bartko et al., 1988). Fig. 1 shows the EOG ratios, and Table 1 presents the mean + SD ratios. ANOVA revealed a significant main effect of difference between diagnosis (F = 4.97; df = 1, 28; p < 0.04). The ANOVA showed no other significant effects. Although the hypothesis of normal distribution was not rejected based on the Wtest, inspection of Fig. 1 suggests a high outlier in the control subjects. When this outlier was excluded and the ANOVA was repeated, there was The study

Table 1. Mean electrooculographic ratios in 16 patients with seasonal affective disorder (SAD) and 16 control subjects under “on-light” and “off-light” conditions SAD patients Right eye Condition

Control subjects

Left eye

Right eye

Left eye

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Off-light

2.24

0.28

2.23

0.28

2.42

0.30

2.46

0.32

On-light

2.18

0.25

2.24

0.25

2.37

0.27

2.37

0.27

102

Fig. 1. Electrooculographic (EOG) ratios for each eye in 16 patients with seasonal affective disorder (SAD) and 16 matched control subjects under “on-light” and “off-light” cdnditibns Right

lYe

OFF-LIQHT

ON-LIQHT

3.5 I

Left OFF-LIGHT

ON-LIGHT

.

.

cantroi*

BY*

SAD P*tl*llt*

controt*

w PathIlt

Horizontal lines indicate mean values, ,which differed significantly between (F = 4.97; df = 1, 28; p < 0.04). but not between the on- and off-light conditions.

SAD patients and control

subjects

only a trend toward significance (F = 4. IS; df = 1, 27; p < 0.06). There were no correlations between both the HDRS score and total SIGH-SAD score in the offlight condition and change in the EOG ratios of each eye. There were no correlations between changes in both the HDRS score and total SIGH-SAD score and the EOG ratios of each eye. Table 2 shows the HDRS scores and the total SIGH-SAD scores. After light treatment, patients showed a significant reduction of both the HDRS score (t = 7.57, df’= 31, p < 0.001) and the total SIGH-SAD score (t = 8.76, cif= 31, p < 0.001). There was no significant difference in percentage reduction between the two therapy paradigms used. Eight out of 16 patients met stringent criteria for recovery (posttreatment HDRS score < 8 and reduction to d 50% of the pretreatment score) (Terman et al., 1989). There was no statistically significant difference in the response rate between the two therapy paradigms (two-tailed Fisher’s exact test, p > 0.3).

103

Table 2. Mean HDRS scores and total SIGH-SAD scores in 16 SAD patients and 16 control subjects under “on-light” and “off-light” conditions SAD patients HDRS Condition Off-light On-liqht

Control subjects

SIGH-SAD

SAGH-SAD

HDRS

Mean

SD

Mean

SD

Mean

SD

Mean

SD

16

7

30

6

1

1

2

2

1

2

2

8

7

12

10

1

Note. SAD = seasonal affective disorder. HDRS = Hamilton Depression Rating Scale. SIGH-SAD Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorders Version.

= Structured

Discussion The results of the present study tended to replicate the findings by Lam et al. (1991) of low EOG ratios in SAD patients. Nonetheless, a substantial overlap in EOG ratios was observed between patients and control subjects, and reanalysis with the high outlier excluded showed only a trend toward significance. Thus, a low EOG ratio cannot be regarded as a biological marker or diagnostic test for SAD, as Lam et al. have also pointed out. Light therapy, even when clinically effective, did not affect the EOG ratios. We did not necessarily match the order of on- and off-light conditions between SAD patients and control subjects. Therefore, the effect of the light conditions on the EOG ratios might have been masked if a carry-over effect was present. It remains unclear whether the EOG difference is of pathogenic significance in SAD or is merely an epiphenomenon of the syndrome. Clearly, the mechanism of light therapy does not depend upon correction of the EOG. Study of the EOG in SAD patients in the summer would aid in defining the relationship of the EOG to the syndrome. The validity of EOG ratios depends on accurate and consistent tracking of the fixation lights over a period of 30 minutes. Riemslag et al. (1990) monitored eye position and EOG simultaneously to determine to what extent the variability of the EOG ratio can be explained by the variability of these eye movements. They found that not only is the variability reduced substantially by correction for the actual eye movements, but the routine procedure underestimates the corrected EOG ratio. The modest significance of the present results in SAD might have been due to the variability of eye movements rather than retinal function. On the basis of a review of the examiner’s notes after the study was completed, most subjects-in particular, SAD patients during the off-light period-reported drowsiness and fatigue during the EOG monitoring. Although there was no significant difference in EOG ratios in SAD patients between the on- and off-light conditions, the patients’ drowsiness might have influenced the accuracy of their eye tracking. They might perhaps have been drowsier than normal control subjects even in the “on-light” condition. Clinically, the EOG ratio gives an estimate of the amplitude of the human light peak (LP), the slow increase in the standing potential of the eye that occurs in response to an increase in illumination. The LP reflects a slow depolarization of the basal membrane of the retinal pigment epithelium coincident with a change in apparent membrane resistance (Griff and Steinberg, 1982; Linsenmeier and

104 Steinberg, 1982). Previous studies have demonstrated that intact retinal pigment epithelium, intact photoreceptors, and inner retinal layers are required for the LP generation (Valeton and Van Norren, 1982; Wioland et al., 1990). The low EOG ratios might therefore suggest a subsensitivity to light in the retinal pigment epithelium, the photoreceptors, or the inner retinal layers. This retinal light subsensitivity is consistent with a hypothesis of deficient photoreceptor renewal (RemC et al., 1990) or the observed abnormally phase-delayed circadian rhythms in SAD (Sack et al., 1990), as Lam et al. (1991) have noted. A possible mechanism for the LP generation may be that light induces hyperpolarization of the photoreceptors and allows the release of a diffusible substance (Gouras and Carr, 1965). It has been suggested that “LP substance” is released by photoreceptors and diffuses to the retinal pigment epithelium, although this process has not been fully elucidated (Gallemore et al., 1988). In the retina, dopamine (DA) and serotonin (5_hydroxytryptamine, 5-HT) have been identified as putative neurotransmitters (Ehinger, 1983; Osborne, 1988; Qu et al., 1989) and candidates for the LP substance. The enzymes involved in the biosynthesis and degradation of DA and 5-HT are present in the retina. Moreover, biochemical and pharmacological characterization of specific receptors for DA and 5-HT suggests that the receptors in the retina are identical to those in the brain. Functionally, DA (Dearry and Burnside, 1989) and 5-HT (Arechiga et al., 1990) modify retinal sensitivity in lower vertebrates. These monoamines can increase the standing potential and depress the LP in a manner consistent with a saturation or desensitization of the mechanism that generates the LP (Dawis and Niemeyer, 1988). Furthermore, the blockade of DA and 5-HT biosynthesis modifies the EOG in the chicken eye (Rudolf et al., 1990). Low EOG ratios might thus be interpreted as a result of either retinal DA (Oren, 1991) or 5-HT abnormalities in SAD patients. Although it is not clear whether these possible retinal monoaminergic abnormalities are associated with brain monoaminergic abnormalities, there have been suggestions that DA and 5-HT functions are altered in SAD. Low plasma prolactin levels and elevated eye blink rate found in SAD patients have been construed as evidence of DA abnormalities (Depue et al., 1988, 1990). On the other hand, such abnormalities are not supported by the results of other studies. Specifically, there was no difference in antidepressant efficacy between levodopa combined with a decarboxylase inhibitor and placebo in SAD patients (Oren et al., 1993) and no difference in eye blink rates between SAD patients and control subjects (Barbato et al., 1993). A variety of studies suggest that brain serotonergic functioning may be abnormal in SAD. Activation of SAD patients by carbohydrate-rich meals could be interpreted as reflecting a serotonergic abnormality (Rosenthal et al., 1989). There is evidence that D-fenfluramine, a 5-HT agonist, has antidepressant effects in SAD patients (O’Rourke et al., 1989). Abnormal behavioral and hormonal responses to infusions of the postsynaptic 5-HT agonist meta-chlorophenylpiperazine (Jacobsen et al., 1989; Joseph-Vanderpool et al., 1993) and low density of 3H-imipramine binding sites in platelets (SzLdoczky et al., 1991) in SAD patients are also compatible with 5-HT abnormalities in this condition. Our EOG data are consistent with both the dopaminergic and serotonergic hypotheses of SAD, although other explanations for our findings, including a Type I error due to disproportional influence of an

105 outlier, methodological considered as well.

artifacts, or competing biological hypotheses,

need to be

Acknowledgments. The authors thank Charlotte Brown, Ph.D., Pamela Madden, Ph.D., Fran Myers, R.N., and Holly Clark, M.S.W., for performing mood ratings. This work was supported in part by a Rotary Foundation grant to Dr. Ozaki.

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