Immunological correlates of seasonal fluctuations in mood and behavior and their relationship to phototherapy

Psychiatry Research, 36:253-264 Elsevier

253

Immunological Correlates of Seasonal Fluctuations in Mood and Behavior and Their Relationship to Phototherapy Siegfried Kasper. Norman E. Rosenthal, Susan Barberi, Abigail Williams, Lawrence Tamarkin, Susan L.B. Rogers, and Stanley R. Pillemer Received June 5, 1990; revised version received October 22, 1990; accepted December 5, 1990. Abstract. Immunological parameters were studied before and after phototherapy, with bright and dim light, in 38 individuals with a range of retrospectively reported seasonal changes in mood and behavior. There was a significant negative correlation between the degree of mood and behavioral difficulties in fall and winter (seasonality) and the total number of circulating natural killer cells. Changes in the numbers of circulating helper T cells correlated significantly with changes in mood following phototherapy. Moreover, mitogen-induced lymphocyte blastogenesis increased significantly after phototherapy, but there was no significant difference between the bright and dim light treatments. The results suggest that cellular immune function is associated with both seasonality and response to phototherapy. Key Words. Immune function, lymphocyte blastogenesis, lymphocyte subtypes, depression, seasonal affective disorders, phototherapy.

Seasonal affective disorder (SAD) is a condition in which depressive symptoms regularly recur in fall and winter (Rosenthal et al., 1984). More recently, an opposite type of seasonal problems - regular summer depressions - has been described (Wehr et al., 1987), but this new syndrome is not the focus of the present report in which SAD refers only to the fall/ winter variant. Prominent depressive symptoms in SAD include hypersomnia, hyperphagia, weight gain, and carbohydrate craving. Several studies have documented the antidepressant properties of phototherapy for treatment of SAD (for review: Rosenthal et al., 1988; Terman et al., 1989). In addition, we have found that even those people with milder, subsyndromal winter problems (subsyndromal SAD) benefit from exposure to bright artificial light in the winter, whereas those without such symptoms appear to derive no benefit (Kasper et

Siegfried Kasper, M.D., Psychiatrist and Neurologist, was in the Clinical Psychobiology Branch, National Institute of Mental Health (NIMH), Bethesda, MD, and is now in the Psychiatric Department of the University of Bonn, Germany. Norman E. Rosenthal, M.D., is Chief, Unit of Outpatient Studies; Abigail Williams, B.A., is Research Asssistant; Lawrence Tamarkin, Ph.D., is Biologist; and Susan L.B. Rogers is Research Nurse, Clinical Psychobiology Branch, NIMH, Bethesda, MD. Susan Barberi, B.A., is Biologist, National Institute of Allergic and Infectious Diseases, Bethesda, MD. Stanley R. Pillemer, M.D., is Medical Officer, Office of Prevention, Epidemiology and Clinical Applications, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD. (Reprint requests to Dr. S. Kasper at his current address: Psychiatric Department of the University of Bonn, D-5300 BonnVenusberg, Sigmund Freud-Strasse 25, Germany.) 0165-17gl/91/$03.50

Q 1991 Elsevier Scientific

Publishers

Ireland

Ltd.

254

al., 1989b). Results of recent epidemiological surveys (Kasper et al., 1989b; Rosen et al., 1990) suggest that a substantial proportion of the general population experiences seasonal changes in mood and behavior. These changes are qualitatively similar to those seen in patients with SAD or its subsyndromal form, though less marked in degree. Although the existence of SAD and its response to phototherapy (light therapy, bright light) are well established, we still do not understand the biological basis of this syndrome or the mechanism of action of phototherapy. Among the many reported biological abnormalities in SAD and biological effects of bright light, Skwerer et al. (1988) found heightened mitogen responses of peripheral blood lymphocytes in SAD patients, which are normalized by effective treatment with bright light. An opposite effect of bright light-namely, an enhanced peripheral blood lymphocyte response to mitogen stimulation-has been reported to occur in normal subjects. Several research groups have also reported abnormal patterns of cellular immune function in nonseasonal depressives (Calabrese et al., 1987; Kronfol et al., 1989; Schleifer et al., 1989). In the present study of 38 people with varying degrees of seasonality, we used exploratory data analysis (Abt, 1987) to evaluate the relationships between cellular immune function (as measured by studies of immune cell populations in the peripheral blood), retrospectively reported seasonal changes in mood and behavior (seasonality), and the effects of bright and dim light therapy.

Methods Subjects. Individuals

were selected from a random sample of the population of Montgomery County, Maryland, which is described in detail elsewhere (Kasper et al., 19896, 1990). In brief, 416 people were recruited through a computer-generated list of telephone numbers (random digit dialing) and interviewed by telephone using the Seasonal Pattern Assessment Questionnaire (SPAQ; Rosenthal et al., 1987). Subjects for the present study were selected from the survey population using the following guidelines: (1) The total survey population was divided into 20 classes according to the magnitude of the season&y score (Kasper et al., 1989b), an index of severity of behavioral changes with the seasons obtained from the SPAQ (from 0 to 18, the latter being the highest score in the sample). We intended to interview two individuals (one for participation in the bright light group and one for participation in the dim light group) from each class to obtain a sample that represented the larger survey population in its degree of seasonality. (2) Persons reporting summer difficulties were excluded because the response of summer seasonal problems to phototherapy is unknown. (3) The age range was set between 30 and 60 years because we did not want age to be a confounding variable. (4) Since we wanted to know the response to phototherapy in the general population, the only basis for exclusion was medical (i.e., we did not want to harm the persons investigated). Each questionable case was discussed by our team and a decision was made on the basis of expert consensus (for further details, see Kasper et al., 1990). On the basis of this selection process, we studied 41 individuals (22 men, 19 women; age range 30-58 years; mean age = 41 .Oyears; SD = 7.1 years) with varying degrees of seasonality, representative of the larger survey population. There were 4 SAD patients and 14 individuals with a subsyndromal SAD. They were interviewed personally and further evaluated by physical examination and laboratory tests to determine that they were in good physical health. We performed the Structured Clinical Interview for DSM-III-R (SCID; Spitzer et al., 1987) to establish the presence or absence of a psychiatric diagnosis, and we also determined whether subjects met criteria for SAD (Rosenthal et al., 1984) or its subsyndromal form (S-SAD;

255

Kasper et al., 1989~). Forty persons completed a phototherapy protocol (1 week of phototherapy with either bright or dim light; 2 hours in the morning between 6 and 9 a.m.) during January and February 1987. Twenty subjects received phototherapy with bright light (2500 lux) and 20 subjects with dim light (300 lux), and each of these subgroups represented the larger survey population in its degree of retrospectively reported fall-winter symptoms, termed “seasonality” (see also Kasper et al., 1989b) in this publication. Individuals were randomized into either the bright or dim light condition. Since we matched individuals for sex, age, seasonality, and diagnosis of SAD and S-SAD, we balanced their distribution according to these characteristics between the two treatment conditions (balanced randomization). The timing of phototherapy and blood sampling was not controlled for the menstrual cycle. The effects of phototherapy on mood and behavior were documented using the 21-item Hamilton Rating Scale for Depression (HRSD; Hamilton, 1967) and the Profile of Mood States (POMS; McNair et al., 1981). In both treatment conditions (bright or dim light), a few subjects (5 women, 1 man) were taking medications and continued to do so throughout the treatment protocol. In the bright light group, one subject was on levothyroxin, 187.5 mg/day; one subject was on triamterene i- hydrochlorothiazide, 50 mg/day, and atenolol, 50 mg/day; and one subject was on ibuprofen, 400 mg/day, and propoxyphenyl, 50 mg/day. In the dim light group, one subject was on theophyllin, 30 mg/day; one subject was on ibuprofen, 400 mg/day; and one subject was on timololmaleate, 20 mg/day, ibuprofen, 400 mg/day, and triamterene + hydrochlorothiazide, 50 mg/day. None of the subjects were acutely ill at the time of the study, but histories of the following illnesses were reported by the above-mentioned subjects who were also taking medications: bright light group: one subject had hypothyroidism (thyroxin replacement), one subject had sarcoid arthritis, and one subject had migraine acompagnee; dim light group: one subject had rheumatoid arthritis (in remission, no medication), one subject had bronchial asthma, and one subject had migraines. In 38 of these patients (19 in the bright light group and 19 in the dim light group), we measured mitogen-induced blastogenesis before and after light treatment. In 25 of those subjects (13 treated with bright light and 12 treated with dim light), we also performed surface marker analysis on peripheral blood samples. We could not perform the latter analysis in all study participants for technical reasons that emerged at the beginning of the laboratory part of the study. Unfortunately, we therefore could not perform the surface marker analysis in individuals with a low seasonality score. Lymphocyte Preparation and Processing. Blood was collected in the afternoon hours (on the day before and on the last day of phototherapy) and then cryopreserved until analyzed at the end of the study. For cell preservation, we collected heparinized whole human blood which was later layered onto Ficol. Peripheral blood mononuclear cells (PBMC) were isolated by centrifugation at 3,000 rpm for 7 min. The PBMC layer was removed, washed with PBS, and centrifuged twice at 1,200 rpm for 10 min, and finally resuspended in 50 ml of medium consisting of RPMI-1640 supplemented with 15% fetal calf serum (FCS), which was added dropwise to the tube. Cells were cryopreserved to -40 “C by reducing the temperature lo per min and stored in liquid nitrogen. At the end of the study, cells were quickly thawed under warm running water and 10 ml of RPMI-1640 containing 15% FCS were then added dropwise. The PBMC were centrifuged at 1,200 rpm for 10 min, washed, and then recentrifuged, and the final pellet of PBMC was resuspended in 10 ml of RPMI-1640 containing 15% FCS. The cells were counted and diluted in medium to obtain a final concentration of viable cells of 5 X 105 cells/ ml. The laboratory work was done without knowledge of clinical characteristics and treatment effects of study participants. Determination of Lymphocyte Subpopulations. Methods for flow cytometric analysis were adapted from those of Ault et al. (1985). Peripheral blood mononuclear cells (PBMC) were suspended in RPMI-1640 at a concentration of 10 X 106/ml. Cells were transferred in 1 X 106/ml aliquots to 12 X 75 mm Falcon tubes (Falcon, Oxnard, CA) and washed twice with Hank’s balanced salt solution (HBSS) without phenol red, containing 1% NaN, and 0.1%

256 bovine serum albumin (BSA) (NIH media unit). Monoclonal antibody was added to the cell pellet, and at the same time human IgG was added to block nonspecific binding through the F, receptor. Cells were incubated on ice for 20 min and washed twice with HBSS. Immunofluorescent staining was performed using fluorescein isothiocyanate (FITC) conjugated monoclonal antibodies: Anti-Leu-2 (CD8+, suppressor/cytotoxic T cells), Anti-Leu-3 (CD4+, helper T cells), Anti-Leu-4 (CD3+, pan T cells), Anti-Leu-l l (CDl6+, natural killer cells), Anti-Leu16 (pan B cells), and Anti-Leu-M3 (monocytes) (Becton Dickinson, Mountain View, CA). Just before analysis, propidium iodide (PI, SIGMA), a fluoresecent DNA binder, was added to identify and exclude dead cells. Cells were then run on a fluorescent activated cell sorter (FACS, Model 440, Becton Dickinson, Mountain View, CA). An argon gas laser (Spectra physics, Piscataway, NJ) set at 488 nm was the light source. A 530/ 30 nm band pass and a 620 nm long pass filter screened the green and red wavelengths, respectively. The forward scatter threshold was set to exclude red cells, platelets, and debris based on size. Data from 15,000 viable cells per sample were collected and analyzed by a PDP 1 I/ 73 computer system (Digital Equipment Corp. Nashua, NH) and displayed on a 4 decade logarithmic scale. Lymphocyte Transformation Test. The lymphocyte transformation test was performed using the method of Maluish and Strong (1986). Lymphocyte cell suspensions were plated in 100 ~1 aliquots in Costar 96-well tissue culture clusters and were incubated for 72 hours with 100 ~1 of medium either with or without mitogens-phytohemagglutinin (PHA) or concanavalin A (Con A). The final concentrations of the mitogens were 0.63, 1.25, 2.5, 5.0, and 10.0 pg/ ml per well. Cells were pulsed with 20 ~1 of 2 Ci/ mmol [3H] thymidine. After 6 hours cells were harvested onto glass fiber filters using a cell harvester (Skatron Inc.; with a 50% ethanol/distilled water solution to lyse the cells). The filters were placed in vials, filled with scintillation fluid, and the incorporated [rH]thymidine was counted in a scintillation counter. The incorporated [rH]thymidine was used to determine theproliferative index. We used triple measurements to calculate the proliferative index and expressed the results as the difference of the disintegrations per min (dpm) of the cultures with and without mitogens (Adpm). Statistical Analysis. In the baseline conditions (before light treatment), lymphocyte subpopulations and mitogen-induced lymphocyte blastogenesis were correlated (Spearman’s rank order correlation test) with psychometric assessment scores (objective rating: HRSD; self-rating: POMS) and with the degree of retrospectively reported fall/winter difficulties (seasonality score as determined by the SPAQ: Kasper et al., 19896). Analysis of variance (ANOVA) with repeated measures was used to evaluate the effect of phototherapy with bright or dim light on lymphocyte subpopulations and mitogen-induced lymphocyte blastogenesis. In the latter case, there were two repeated measures: condition (before vs. after light treatment) and dose (of mitogen); and one grouping factor: group (bright vs. dim light). Subjects’ responses to light, as measured by HRSD and POMS, were correlated with the concentration of lymphocyte subtypes and the level of mitogen-induced lymphocyte blastogenesis at baseline, as well as with the change in these parameters (A value) with phototherapy. Changes of mitogen-induced lymphocyte blastogenesis are expressed as peak mitogen responsiveness (see Table 3), which indicates the highest value after stimulation with various different doses of mitogens (e.g., 0.63, 1.25, 2.5, 5.0, and 10.0 pg/ml). Since the purpose of this study was to describe the relationships of seasonality and phototherapy to a variety of immunological parameters, thereby generating hypotheses rather than testing any specific hypothesis, we have not applied corrections for multiple comparisons. The results therefore need to be interpreted cautiously.

Results Baseline Findings (Before Light Treatment). There was a significant negative correlation between the seasonality score (Kasper et al., 19896) and the number of circulating natural killer (NK) cells (r = -0.53; p = 0.01) (Fig. 1). There was no

257 Fig. 1. Correlation between natural killer cells (% total peripheral blood mononuclear cells) and degree of discomfort with fall/winter (seasonality score) in 25 subjects 24 I r=-.53;p=

0.004

.

20 -

.

.

. .

.

.

15 -

05 0

5

10

15

20

Natural Killer Cells (CD 16) SPA0 = Seasonal Pattern Assessment Questionnaire.

significant correlation between peripheral blood NK cell count and the actual reported degree of depressed mood at the time of blood sampling; nor were there any significant relationships between the seasonality score and the other lymphocyte subpopulations or mitogen stimulation results. Changes With Light Treatment. Clinical. We have described elsewhere the clinical effects of light treatment in the present subjects (Kasper et al., 1990). In summary, we found no significant difference between the bright or dim light conditions for the group as a whole, but the SAD and subsyndromal-SAD subgroups responded significantly better (p < 0.05) to treatment with bright light than to treatment with dim light, as measured by the HRSD total score. Lymphocyte subpopulations. There were no significant changes in any lymphocyte subtypes after either light treatment in the group as a whole or in the SAD and subsyndromal-SAD subgroups (see Table 1). In the subjects who received bright light (n = 13), however, there was a significant positive correlation (r = 0.78, p = 0.001)between change in mood (as measured by the HRSD total score) and change in helper T cells over the course of phototherapy (Fig. 2). In other words, the greater the mood improvement following phototherapy with bright light, the higher was the count of helper T cells after this treatment condition. Among these 13 subjects (7 women and 6 men), there were two SAD patients and six subjects with a subsyndromal form of SAD (S-SAD). Note that all six subjects who had an increase of helper T cells had seasonal difficulties (1 SAD and 5 S-SAD), whereas a decrease in helper T cells was apparent in all nonseasonal (n = 5) and in two seasonal (1 SAD,

258

Table 1. The effect of phototherapy with bright or dim light on lymphocyte subpopulations Lymphocyte subpopulations

Untreated’ (n = 25)

After bright light2 (n = 13)

After dim light2 (n = 12)

T cells, total (CD3+) Helper cells (CD4’) Suppressor cells (CDB+) Natural killer (CDlG+)

77.2 f 7.8 51.6 zt 13.6 23.8 zt 8.0

77.2 dz 7.5 52.4 zt 11.8 23.9 f 8.3

75.6 f 6.1 52.2 It 7.1 23.8 f 9.2

8.7

5.3

C4lC8 ratio

1.1 18.1

Macrophages Note.

7.7

(means f

are expressed as percentages

7.9

3.3

10.3 +

9.0 *

B

2.7+

8.4

5.0

13.6 f 2.6f

20.2

8.2

18.2

peripheral blood mononuclear

1.3 10.5

(PBMC).

1.

data the bright dim light are pooled since were not 2.There were no statistically significant changes after phototherapy with either bright or dim light when compared to the untreated condition. 1 S-SAD) subjects (see Fig. 2). Such a correlation was not found for those receiving dim light treatment, or for any other changes in lymphocyte subpopulations or in mitogen stimulation. Proliferative assays. The lymphoproliferative response to both PHA and Con-A increased after phototherapy with both bright and dim light, but this increase was statistically significant only in the PHA group (ANOVA, condition X dose interaction: F = 2.8, df = 180.5, p = 0.01) (Table 2). Although the mean counts for

Fig. 2. Correlation between changes of depression ratings and changes of helper cells before and after treatment with bright light (n = 13) 20 r = .78; p = 0.001

-lo.i -10

-8

-6

-4

-2

0

2

4

6

8

10

A Helper Cells

A-HDRS = difference between total score on the Hamilton Depression Rating Scale before and after phototherapy with bright light, Positive A-HDRS values reflect clinical improvement. A-Helper cells = difference between count (% total peripheral blood mononuclear cells) of helper cells before and after phototherapy with bright light. Positive values reflect an increase of helper cells.

259 tritiated thymidine uptake were higher in the bright light than in the dim light group (Tables 2 and 3) this effect was not statistically signficant for either of the two mitogens tested. We were unable to interpret lymphoproliferative response results on the subgroup with a history of marked seasonal changes because of the small sample size. Inspection of the data, however, revealed that the mitogen changes following phototherapy (expressed as peak mitogen responsiveness) in this subgroup resembled the changes seen in the population as a whole (see Table 3). We examined additional patient characteristics for their possible relationship with immune parameters but found no significant relationship between immune parameters and gender, age, weight, height, or body-mass index.

Discussion Several studies have documented a relationship between immunological and psychological parameters in depressed subjects (Calabrese et al., 1987; Vartanian and Kolyaskina, 1987; Schleifer et al., 1989). We have previously noted abnormal responses to mitogen stimulation in patients with SAD, which were corrected by exposure to bright artificial light (Skwerer et al., 1988). In the same report, we noted that such light treatment appeared to enhance the response to mitogen stimulation in healthy volunteers. The concordance of the results of our present study with our previous findings in healthy controls may be explained by the fact that the sample consisted of only 10% SAD patients. Furthermore, the present study is, to our knowledge, the first in which cellular immune function was investigated in relation to seasonal fluctuations of mood and behavior (seasonality) in a random sample of the general population. In our heterogeneous sample of individuals with varying degrees of seasonality, we found an inverse relationship between the degree of retrospectively reported seasonality and the number of peripheral blood NK cells. As the peripheral blood NK cell numbers did not change with therapy or mood, but correlated with the severity of retrospectively reported symptoms, low NK cell counts may be a trait marker of SAD or S-SAD. However, this assumption needs to be confirmed in future studies. Kronfol et al. (1989) have also reported a reduced number of NK cells in Previous associations have been described nonseasonally depressed patients. between psychological factors and infectious diseases (Meyer and Haggerty, 1962; Kasl et al., 1979); these associations are relevant in view of the important role that NK cells play in the immune response to infections (Groscurth, 1989). Because NK cells are thought to contribute substantially to the elimination of viral infections (Welsh, 1981) it would be worth investigating whether SAD patients are more prone to viral infections, like influenza, and if so, whether their resistance to these infections could be enhanced by phototherapy. Reduced NK cell counts in those with higher seasonality scores may be related to increased plasma cortisol levels in these subjects. Although increased plasma cortisol levels have been reported in patients with nonseasonal depression (Pfohl et al., 1985) they have not been found in depressed patients with SAD (Skwerer et al., 1988). On the other hand, Joseph-Vanderpool et al. (in press) have found a decreased response

Untreated (n = 38)'

888(94)

1,215(227) 2,358 (788)

1,847 (240)

1,383 (202)

10,152(2,946)

11,197 (2,099)

8,436 (1,822)

0.63

3,789(1,210)

2,810 (455)

6,413 (2,109)

5,743 (1,004)

4,754 (1,051)

11,354 (2,744)

14,208 (2,733)

9,834 (2,203)

25,337(5,809)

21,122(4,574)

15,330(3,889) 2,319 (465)

28,898 (4,652)

18,965 (3,772) 27,198 (4,593)

21,613 (4,078)

5.0

14,223 (2,945)

2.5

20,851 (3,569)

1.25

12,111 (2,737)

13,947(2,201)

9,830(1,957)

22,101 (4,896)

25,296 (3,868)

18,455 (3,289)

10.0

1. Summarizes the data of the untreated condition before bright and dim light. 2. Significantly different from the untreated condition (analysis of variance, condition X dose interaction: F = 2.8, df = 180.5, p = 0.01).

Note.PHA = phytohemagglutinin. Con A = concanavalin A. Proliferation index: Difference of the disintegrations per min (dpm) of the cultures with and without mitogens (A dpm).

Afterdim light(n = 19)

Afterbrightlight(n = 19)

892 (105)

899 (81)

Afterdim light (n = 19j2

Con A

907 (80)

801 (136)

0

Afterbrightlight(n = 19)*

Untreated (n = 38)'

PHA

Groups

Mitogen dose (PHA or Con A) @g/ml)

Table 2. Means (k SEM) of dose-dependent mitogen-induced lymphocyte blastogenesis (proliferation index) in individuals before and after phototherapy with bright or dim light

261 Table 3. Peak mitogen responsiveness1 (means f SEM) before and after phototherapy with bright or dim light in individuals with and without seasonal difficulties Individualswith no seasonal*difficulties Mean f SEM

Number

Individualswith* SAD + S-SAD Mean f SEM

Number

PHA

( 4,651)

Untreated3

21,356 (4,612)

n=21

23,274

After bright light

29,372 (4,413)

n=ll

35,032 ( 5,469)

r-l=

8

After dim light

26,460 (5,532)

n=lO

31 ,172 (11,401)

n=

9

( 2,760) ( 3,217) 13,446 ( 4,560)

n=17

Con A Untreated3

10,087 (2,278)

n = 21

12,312

n=17

After bright light

15,009 (2,620)

n=ll

15,550

n=

8

After dim light

12,618 (2,082)

n=lO

n=

9

Note. SAD = seasonal affective disorder. S-SAD

PHA = phyto-

hemagglutinin. Con

Peak mkgen responsiveness:

the highest with different 2.5, 5.0, lO.Oj~g/ml). 2. No statistically significant differences the 2 groups with (SAD + S-SAD) seasons the bright dim light condition. the data the untreated condition before and light.

with

and cortisol SAD patients. This decrease that be interpreted the hypothalamic-pituitaryadrenal axis in patients. did not, however, measure the subjects from this study. The al. (1987) suggest that elevated plasma cortisol may be basis of reduced cell functioning the reduced levels of NK cells in their depressed were related the NK cells, with retrospectively reported with changes mood following phototherapy. It is possible from such correlational data to infer a causal relationship between these two but such may indeed and would be worth elucidating The changes cell compartment associated mood changes give a hint that immune and mood parameters The increased mitogen stimulation seen in present are reminiscent al. (1988) such mitogen stimulation recell function and also, some degree, the cell subpopulations. Changes in mitogen stimulation responses have also been reported have been reported to be increased and Fox, al., 1980) and with electroconvulsive therapy al., 1985) and al., 1985) and

262

(Eisen et al., 1989). While the effects of antidepressant medications on proliferative responses might be due to direct effects of the drugs on the lymphocytes, it is implausible that light therapy and ECT work by such a direct mechanism. Instead, it would seem that if a causal relationship indeed exists between these latter treatments and peripheral immune function, it is likely to be mediated by signals transmitted from the brain to the periphery. Such signals might be mediated by various molecular species (e.g., neurotransmitters, hormones, and lymphokines). Among different factors influencing the results of our study, a confounding variable might have been our reliance only on the retrospective evaluation of the subjects themselves. It is possible that responses might have been influenced by a set bias, which could be controlled either by a simultaneous interview of collateral sources or in a prospective design. We do not think that the retrospective evaluation of seasonal history influenced our results significantly since there are data indicating a good test-retest reliability of the results obtained with the SPAQ (T.A. Hardin, N.E. Rosenthal, and S. Kasper, unpublished observation). The medications that some patients were taking might conceivably have influenced immune parameters. However, the subjects were taking their medications on a long-term basis and their dosage remained stable throughout the study, which would make them seem an unlikely explanation for the observed changes.

Conclusion This study provides new evidence that light is capable of modulating immune function. The mechanisms of these photo-immune effects remain unclear but, insofar as they occur with visible light directed at the faces of clothed subjects, they are probably mediated via the eyes rather than the skin. As such, they are presumably quite different from the effects of ultraviolet light on the immune system, which have been extensively documented (Morison, 1985) and are presumably mediated via the skin. Visible light may prove to be a valuable tool in exploring mechanisms by which the brain communicates with the immune system. Furthermore, it is not inconceivable that the effects of bright light observed in this study, most notably on number of helper T cells, might even be applied to therapeutic advantage. Acknowledgment. The authors thank John J. Bartko, Ph.D., Pamela Kato and Michael J. Bryant for technical assistance.

for statistical

advice,

and

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