55

Psychiatry Research, 43:55-63 Elsevier

Electroretinography Raymond Received

in Seasonal

W. Lam, Craig

W. Beattie,

Affective

Alan

Buchanan,

Disorder and Joseph

A. Mador

October 15, 1991; revised version received April 8. 1992; accepted June 6, 1992.

Abstract. Retinal mechanisms have been hypothesized in the pathophysiology of seasonal affective disorder (SAD). Electroretinography (ERG) is a noninvasive electrophysiologic test that provides an objective measure of photoreceptor and retinal function. We conducted dark-adapted ERG examinations with a bright white light stimulus in a group of depressed, drug-free patients with seasonal affective disorder (6 men, I8 women) diagnosed by DSM-[II- R criteria, and a group of sex- and age-matched control subjects (6 men, 16 women) during the winter. A significant difference was found between SAD patients and controls, but female SAD patients had lower ERG b-wave amplitudes than female controls, while male SAD patients had higher amplitudes than the matched controls. The ERG b-wave implicit times (times from onset of stimulus to peak of b-wave) were significantly longer in the left eyes of the male control subjects. These data may indicate subtle retinal changes in patients with SAD, but the results must be considered preliminary because of the small number of subjects studied and the large intersubject variability in the ERG procedure. Key Words. Depression,

retina, dopamine,

light.

Seasonal affective disorder (SAD) is a term used to describe a syndrome of recurrent depressive episodes that occur in the fall and winter, with clinical remission or hypomanic episodes in the spring and summer (Rosenthal et al., 1984). The etiology of SAD appears linked to environmental light exposure. The prevalence of SAD increases with latitude and is correlated to the shorter winter photoperiod instead of weather variables (Rosen et al., 1990). SAD patients often describe symptom remission when they travel south. SAD is treated effectively with light therapy (also called phototherapy) that consists of sustained daily exposure to bright light (Rosenthal et al., 1984; Terman et al., 1989). The mechanism of action of light therapy is unknown, but the antidepressant effect is mediated through the eyes instead of the skin (Wehr et al., 1986). These observations have generated interest in light sensitivity and retinal mechanisms in SAD. It is possible that the pathophysiology of SAD may directly or indirectly involve the retina. For example, circadian rhythm disturbances are reported in SAD (Lewy et al., 1988; Avery et al., 1990). Light is a strong zeitgeber

Raymond W. Lam, M.D., is Assistant

Professor, Department of Psychiatry, University of British is Clinical Associate Professor, Department of Ophthalmology, University of British Columbia; Alan Buchanan, M.D., and Joseph A. Mador, M.D., are Clinical Assistant Professors, Department of Psychiatry, University of British Columbia. (Reprint requests to Dr. R.W. Lam, Dept. of Psychiatry, University Hospital, UBC Site, 2255 Wesbrook Mall, Vancouver, BC, Canada V6T 2A I .) Columbia;

Craig

0165-1781/92/$05.00

W. Beattie,

M.D.,

@ 1992 Elsevier Scientific

Publishers

Ireland

Ltd

56 (synchronizer) of circadian rhythms, and the zeitgeber effects of light are mediated through the retina. Etiologic hypotheses of subsensitivity and supersensitivity to light have been proposed for SAD (Reme et al., 1990; Beersma, 1990). We have been studying noninvasive electrophysiologic measures of retinal function in seasonal depression. Electrical signals reflecting activity in the retina originate from both the retina and its supporting tissues. Electroretinography (ERG) measures the electrical responses of the retina to standardized light stimuli during dark or light adaptation (Berson, 1975). ERG parameters include the amplitude of the waveform and the implicit time (time from stimulus onset to peak of waveform). The two most conspicuous waveforms in the ERG are the a- and b-waves. Typically, the b-wave implicit time and b-wave amplitude are used as clinical indexes of ERG activity. When the intensity and chromatic characteristics of the light stimulus are varied, the ERG can assess rod, cone, or mixed rod/cone photoreceptor function to provide an objective measure of retinal sensitivity to light (Berson, 1975). In this study, we compared the dark-adapted ERG using a bright white light stimulus in SAD patients and matched normal control subjects.

Methods Twenty-four depressed SAD patients were assessed with an unstructured clinical interview by psychiatrists who were experienced in the assessment of mood disorders. Inclusion criteria for patients included a DSM-III-R diagnosis of major depressive disorder, recurrent, with a seasonal pattern (American Psychiatric Association, 1987), and a score above 15 on the 21-item Hamilton Rating Scale for Depression (HRSD; Hamilton, 1960). Twenty-two control subjects were recruited by advertisement and were matched to patients by age and sex. The control subjects were interviewed by one of us (R.W.L.) and had neither a personal history nor a family history of mood disorder. Exclusion criteria for all subjects included a history of cataracts or retinal disease, severe myopia, and psychotropic drug use within the previous 4 weeks. Patients and controls were administered the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorders version (SIGH-SAD; Williams et al., 1988) by a psychiatrist. The SIGH-SAD is composed of a 21-item HRSD and an 8-item addendum (Atyp) that rates “atypical” depressive symptoms of hypersomnia, increased appetite, increased eating, weight gain, carbohydrate craving, fatigue, social withdrawal, and reverse diurnal variation (worsening of mood in’afternoon and evening). Interrater reliability of the SIGH-SAD is regularly monitored in the research clinic. All subjects underwent identical ERG protocols administered by technicians who were unaware of the subjects’ diagnoses. ERG examinations were done between October and March, with testing times between 9 a.m. and 3 p.m. All subjects were tested after 30 minutes of dark adaptation. Pupils were dilated using tropicamide 1% and cornea1 anesthesia secured by amethocaine 0.5% drops. Cornea1 gold foil electrodes were placed over the lower lids of the subjects’ eyes. The ground electrode was placed on the forehead. The ERG signal was obtained in response to single flashes of white light that were presented at intervals of 5 seconds in a ganzfeld stimulator with an integrated stimulus energy of I .73 cdsec/ m2. ERG signals were conducted to a Nicolet CA-1000 biological amplification system with a signal bandwidth of l-3000 Hz. Signal averaging was used so that for each subject 4-8 waveforms were averaged for the calculation of ERG parameters. The b-wave amplitude was measured from the trough of the a-wave to the peak of the b-wave, and the b-wave implicit time was measured from the stimulus onset to the peak of the b-wave. Because of the relationship between b-wave amplitude and implicit time, the data were analyzed using multivariate analysis of variance (MANOVA) with diagnosis (SAD, control) and sex (male, female) as between-group factors and eye (right, left) as a repeated factor. If the multivariate Pillais’ tests

57 were significant, post hoc univariate tests were done to determine differences between each dependent variable, Analyses were performed on a microcomputer using the SPSS-PC+ statistical package (SPSS, 1988).

Results Table 1 presents demographic data for the 24 SAD patients and the subjects. Twenty patients had a diagnosis of recurrent unipolar depression women) and four patients were diagnosed as having bipolar disorder, type 3 women) (male/female differences not significant by Fisher’s exact analysis of variance (ANOVA) that controlled for diagnosis and sex significant differences in age. The HRSD and Atyp scores also did significantly between male and female SAD patients.

22 control (5 men, 15 II (1 man, test). An found no not differ

Table 1. Demographic data for patients with seasonal affective disorder (SAD) and controls n

Age

SD

HRSD

SD

ATYP

SD

SAD patients 6

35.3

16.6

16.7

9.0

11.0

7.1

Female

16

36.4

6.7

20.2

4.8

14.5

5.3

Total

24

36.2

10.9

19.3

6.1

13.6

5.8

Male

Controls 6

34.3

10.6

1.5

0.8

1.8

1.7

Female

16

37.4

10.3

1 .o

1.0

1.5

0.4

Total

22

36.5

10.2

1.1

1.0

1.5

1.5

Male

Note. HRSD = Hamilton Rating Scale for Depression, 21 -item version. ATYP = SIGH-SAD Atypical Addendum score, 8-item version.

Fig. I shows a representative ERG waveform for a female SAD patient, and Table the summary ERG data. Table 3 presents the results of the MANOVA. There was a significant diagnosis X sex interaction effect (Pillais = 0.18; df = 2,41; p < 0.02), with the univariate test showing this to be due to amplitude differences (F= 9.43; $f = 1,42;p < 0.005). Fig. 2 illustrates this interaction effect, in which the male SAD patients have higher amplitudes than their matched controls, while the

2 presents

Fig. 1. Two typical electroretinographic with seasonal affective disorder b wave

waveforms from a female patient

58 Table 2. Electroretinographic b-wave data for patients affective disorder (SAD) and controls

Implicit time (msec)

Amplitude (mV) n

Right eye

SD

Left eye

with seasonal

Right eye

SD

Left eye

SD

SD

SAD patients

Male

6

349

71

347

49

44.8

2.0

44.2

1.3

Female

18

293

51

302

56

43.1

2.4

43.1

2.4

Total

24

307

60

313

57

43.5

2.4

43.4

2.2

3.1

Controls 6

275

74

275

83

45.2

2.5

46.7

Female

16

337

55

338

49

42.7

3.3

42.9

3.4

Total

22

320

65

320

64

43.4

3.3

44.0

3.7

Male

Table 3. Overall results from multivariate

analysis of variance (MANOVA)

Multivariate test’ P3

F4

Significance5

Diagnosis

0.02

0.5

NS

Sex

0.13

3.0

NS

Eye

0.05

1.1

NS

Diagnosis X sex

0.18

4.6

Diagnosis X eye

0.21

5.5

0.02

0.5

NS

0.14

3.4

p < 0.05

Effect

Sex

X eye

Diagnosis

X sex

X eye

Univariate tests* F6

Significance7

p < 0.02

9.4

Amp,

p < 0.01

11.2

IT, p < 0.002

6.3

IT, p < 0.02

p < 0.005

1. MANOVA, Pillais test of significance. 2. Analysis of variance. 3. Pillais value. 4. Approximate F, df = 2, 41. 5. NS = nonsignificant. 6.df=l,42. 7. Amp = electroretinographic b-wave amplitude; IT = implicit time

Fig. 2. Electroretinographic b-wave amplitudes for patients affective disorder (n = 24) and controls (n = 22) 500 -

with seasonal

59 female SAD patients have lower amplitudes than the female controls. There were no main effects of sex, diagnosis, or eye on the multivariate tests of significance. Therefore, there were no significant differences in the ERG measures between all females and males, between all SAD patients and controls, or between all right and left eyes. There was, however, also a significant higher order interaction effect of diagnosis X sex X eye (Pillais = 0.14; df = 2,41; p < 0.05), with the univariate F test indicating that this was due to implicit time differences (F = 6.3; df = I, 42; p < 0.02). This interactional effect indicates that there are differences between male and female SAD patients and controls in the right and left eyes. As shown in Fig. 3, the male controls have longer implicit times in their left eyes. This is also reflected in the significant diagnosis X eye interaction (control subjects with longer implicit times in their left eyes). There was no significant sex X eye interaction effect (males and females differing between right and left eyes).

Fig. 3. Electroretinographic b-wave implicit times for patients with seasonal affective disorder (n = 24) and controls (n = 22) 55 c .

.

Discussion This study found small but significant differences between SAD patients and wellmatched normal controls on the b-wave amplitudes and implicit times of the darkadapted ERG, but these changes appeared to be different for men and women. Women with SAD have lower b-wave amplitudes than their matched controls, while men with SAD have higher b-wave amplitudes. This should be considered a preliminary report, however, because the sample size is small and the data show considerable variability, particularly for the men. The ERG has a large intersubject variability, and this may explain why we also found a higher order interactional effect, with a significant difference in the b-wave implicit time of the left eye in male control subjects. Another source of variability in this study comes from the use of foil electrodes instead of standard contact lens electrodes (Marmor et al., 1989). The foil electrodes are more subject to blinking and dislodgement than the contact lens electrodes. However, there were no evident technical problems in testing the SAD patients compared with the controls. In fact, the foil electrodes are much more

60 comfortable and produce less anxiety and apprehension during testing than the contact lens electrodes. A further limitation of this study is that only a bright white light stimulus was used to obtain the ERG, which elicits a mixed rod/cone photoreceptor response. It is possible that retinal changes in SAD are confined specifically to either rod or cone photoreceptors. Varying the chromatic characteristics of the light stimulus to assess each photoreceptor system may reduce some of the variability of the results. In nonseasonal depression, for example, significant differences were found only on the blue stimulus, dark-adapted ERG, suggesting dysfunction in rod photoreceptors (Seggie and Steiner, 1990). It is also possible that these retinal changes are greater when depressed SAD subjects are compared with themselves in the remitted statethe so-called ipsitive changes proposed by Lewy et al. (1987)-than when they are compared with normal subjects. In view of the limitations on the ERG data, interpretations and conclusions must be made with caution. However, other electrophysiologic studies have shown subtle differences in retinal function in SAD. Lam et al. (1991) found lowered electrooculographic (EOG) ratios in 19 SAD patients compared with those in age- and sex-matched controls. This finding suggests abnormalities of the photoreceptorretinal pigment epithelium complex that are consistent with reduced retinal response to light-adapted conditions. Oren et al. (1991) found that 14 SAD patients had a lower threshold for light perception during dark adaptation, suggesting increased sensitivity to light compared with controls, but subsequent studies by the same group were unable to replicate that finding (D.A. Oren, personal communication). Terman et al. (1991), also using a dark-adaptation to light protocol, found evidence of cone photoreceptor changes in SAD. These ERG results in SAD also can be compared with recent ERG studies of nonseasonal depression. Seggie and Steiner (1990) conducted scotopic ERG examinations in 14 unipolar, nonseasonal depressed patients and well-matched controls. The patients had significantly increased b-wave amplitudes and decreased implicit times, which the authors interpreted as consistent with a hypothesis of retinal supersensitivity to light (Steiner et al., 1987). These findings are in contrast to those of the SAD patients in this study. Given the clinical and neurobiological differences (Skwerer et al., 1988; Thase, 1989; Allen et al., 1991), and the differential responsiveness to light therapy (Lam et al., 1989b; Blehar and Lewy 1990) between seasonal and nonseasonal depressions, it is plausible that retinal abnormalities may also differ between these groups. Thus, our data lend support to the concept of SAD as a diagnostic group that is distinct from nonseasonal depression. The b-wave amplitude differences between male and female SAD patients is puzzling. The ERG b-wave amplitude is usually higher in women than in men, possibly due to the shorter length of the eyeball in women (Vainio-Mattila, 1951; Peterson 1968). The SAD patients showed a reversal of this pattern. Other neurobiologic studies have not addressed the issue of sex effects, beyond sex-matching of controls. Clinic samples of SAD reflect a greater proportion of women affected, in ratios of 2:l or greater (Rosenthal et al., 1984; Wirz-Justice et al., 1986; Lam et al., 1989~). No studies have yet definitively examined clinical differences between male

61 and female subjects, or differential response to light therapy. Sex differences should thus be more closely examined in SAD. The physiological significance of the ERG results must also be cautiously interpreted because the physiologic origin of the ERG b-wave is not entirely understood. The cellular origin of the b-wave is in the inner nuclear layer of the retina, where it likely arises from a modified glial cell, the Miiller cell (Brown, 1968). Although the Mi,iller cell is not a neuronal element of the retina, within certain bounds the membrane potential is linearly related to light-induced potassium release from photoreceptors, which in turn is proportional to the intensity of the light stimulus. Thus, the ERG b-wave represents an indirect measure of retinal responsivity to light stimuli. Our results suggest that there may be subtle changes in light sensitivity in SAD, although it is unclear whether these are state- or traitdependent changes. Dopamine is also involved in the retinal response to light. Dopamine is present in amacrine neurons in the retina, and dopamine turnover and synthesis are stimulated by light (reviewed by Iuvone, 1986). Dopaminergic activity likely affects the ERG b-wave (Filip and Balik, 1978; Fornari et al., 1980; Gottlob et al., 1990). Changes in retinal dopamine may play a role in SAD (Oren, 1991) and it is possible that some of the ERG differences seen in this study are mediated by dopamine. In this regard, Depue et al. (1988, 1989, 1990) have evidence that suggests central hypodopaminergic activity in SAD, but only women were included in their studies so that sex differences were not addressed. If dopamine is a mediator of ERG changes, it will be important to control for menstrual status in future ERG studies, since estrogen may affect dopaminergic activity (Raymond et al., 1978). In this study, there were no ERG differences between the premenopausal and the postmenopausal women, but phase of menstrual cycle was not specifically controlled. In summary, these preliminary results suggest that there are ERG changes in SAD patients compared with controls, although the direction of change is different for males and females. Because of the variability in the procedure, these results need to be replicated in larger samples. More specific ERG tests may help determine whether abnormalities exist in rod or cone photoreceptors. It also will be important to determine whether the retinal changes in depressed SAD patients are altered by light therapy or by natural summer remissions. Acknowledgments. A modified version of this report was presented at the 9th Annual Meeting of the West Coast College of Biological Psychiatry, San Diego, CA, April 4-6, 1991. This research was supported in part by the Canadian Psychiatric Research Foundation, the Medical Research Council of Canada, and the Zeldowicz Research Award (to Dr. Lam). The authors thank Arlene Tompkins, PhD, for her assistance in data collection, and Athanasios P. Zis, M.D., for his helpful comments.

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Electroretinography in seasonal affective disorder.

Retinal mechanisms have been hypothesized in the pathophysiology of seasonal affective disorder (SAD). Electroretinography (ERG) is a noninvasive elec...
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