- Email: [email protected]
Phototherapy in nonseasonal depression
BIOl, i~SYCHIATRY
257
Phototherapy in Nonseasonal Depression Arthur Mackert, Hans-Peter Volz, Rolf-Dieter Stieglitz, and B no Miiller-Oerlinghausen
Previous reports have shown that bright light exposure max, benefit patients with seaso~l depression. In the present study, the possible therapeutic effect of bright light in nonseasonal major depressive disorder was examined. Forts,-two depressed patients not receivb~g additional antidepressant medication were exposed to bright white light of 25bO iux or dim red light of 50 hoe over one week for m,o hr daily in the morning. The change in depressive symptoms was assessed by rating scales (Hamilton Depression Rating Scale, CGI) and by self-rating scales (Depression Scale, Complaint List, Visual Analogae Scale). Consistent for all ratings, the decrease in depressive sb.'mptoms after bright white light was only slight and not different from dim red-light exposure. Contrary. to the findings in seasonal affective disorder, phototherapy administered over one week for two hr daily is not effective in nonseasonal major depressive disorder. Introduction Seasonal affective disorder (SAD) is characterized by recumng cycles of depression in the fall and winter with hypomania or euthymia in the spring and summer. Lewy et al (1982) first reported on a patient with seasonal mood cycles, whose winter depression retorted when daylight was lengthened with bright artificial light. Subsequent studies have shown that patients with SAD improve on exposure to bright light of approx~ately 2500 lux in intensity, whereas dim light (300 lux or less) has only a negligible therapeutic effect (Rosenthal et al 1984, 1985; James et al 1985; Wehr et al 1987; Isaacs et al 1988). The antidepressant effect produced by bright artificial light appears within one week, w;th r~lanc~ nc..alh,
There have been only a few investigations to determine whether bright light may also induce remission in patients with nonseasonal depression. Kripke et al (1983a) found a significantly greater effect after a single hour of bright light than after dim light exposure from 5 AM to 6 AM in 12 patients suffering from major depressive disorder. Dietzel et al (1986) reported a significant improvement in mood and sleep of 10 female patients with major depressive disorder after a single day of light therapy of 3 hr duration in the morning and 4 hr in the evening. In contrast, Yerevanian et al (1986) found a beneficial effect of a i- to 2-week phototherapy only in seasonal, but not in nonseasonal depressives, although most of the nonseasonal depressives had concurrently received psychotropic
From the Department of Psychiatry. Free University of Berlin. Germany. Address reprint requests to Dr. A. Mackert. Psychiatrische Klinik und Polildinik der Freien Univers~t Berlin, Eschenallee 3, D-1000 Berlin 19 FRG. Received September 2. 1990; revised February 27, 1991. 1991 Society of Biological Psychiatry
0006-3223/91/$03.50
38
BIOL PSYCHIATRY 1991;~:257~268
A. Mackert et al
agents during light treatment. Kripke et al (1987) reported only a minimal reduction in the symptoms of 14 patients with major depression in response to bright light given for 5 days, either for one ~ ia the morning or for one hr both in the morning and in the evening. In a subsequent study, nonseasonal depressed patients neared with bright light over one week for 3 hr daily in the evening showed an approximate 20% decrease in depression ratings when compared to the group receiving dim light in the stone design, which had not improved (Kripke et al 1989). The available literature on the benefits of phototherapy in nonseasonal depression is rather contradictory. This is mainly attributable to the small number of subjects involved and to differences in the experimental design, in particular to (a) the number of days, (b) the time of day, (c) the daily duration of exposure to light, and (d) the concomitant use or nonuse of antidepressants. The aim of the present study was to evaluate a sufficiently large number of patients and determine whether bright light as opposed to dim light is suitable for clinical treatment of patients suffering from major depression without recurrent fall/winter depression. Preliminary reports of some on these data in a siaaller group of patients were recently published (Mackert et al 1990; Volz et al 1990).
Methods
Subjects From January 1987 to November 1988, 50 inpatients consecutively admitted and meeting Research Diagnostic Criteria (RDC) for major depressive disorder (Spitzer et al 1977) consented to participate in the study. Patients with seasonal depression were excluded according to the criteria of seasonality based on DSM-III-R: three episodes, at least two of which were consecutive, with manifestation within a seasonal 90-day period between the beginning of September and the end of November (the seasonal pattern according to DSM-III-R is restricted to a 60-day window). Because 2 patients had a first manifestation of depressive illness between September and November (see Table 2), a seasonal depression occurring during the further course of illness could not be ruled out. Other exclusion criteria were ophthalmologic disorders, alcohol or drug abuse, brain injury and neurological disorders, and acute suicidal tendencies. Patients with an IQ lower than 90 as measured by a multiple choice vocabulary test (Lehrl 1978) were also not included. Before beginning the study, each patient underwent a medical examination including both routine laboratory analysis and electrocardiogram (l~CCi). unne specimens were obtained to detect the use of illicit drugs. The 50 patients were randomly exposed to either bright white or dim red light. The patients were informed that they were to participate in a study, in which two different kinds of exposure to light would be investigated. They were not told that dim red light was expected to be ineffective. Eight patients discontinued the study either because drug treatment was mandatory on clinical grounds (6 patients), or because urine specimens revealed the use of illicit drugs (2 patients). Of the remaining 42 patients, 36 with major depressive disorder and 6 with bipolar depression, 22 were exposed to bright white light and 20 patients to dim red light. As may be seen from Table 1, there were no statistical differences in age, sex, and initial HDRS-scores between these two subgroups. Based on documentation of previous hospitalizations, reports from psychiatrists, who had treated these patients as outpatients, as well as information from relatives and the patients themselves, a drug history was established for each patient with special regard to prior man-
BIOL.PSY(~I~TRY
Phototherapy in Nonseasonal Depression
259
Table I. Age, Sex, and Initial HDRS of Patients Treated with Bright and Dim Light Patients ~ All patients Gender re_Me
female Age (years) Hamilton Depression Rating Scale (HDRS) before treatment
8 33 54.2 ± 13.2 19.3 ± 4.2
Bright white light (n = 22)
to D ~ red ~ght (n = 20)
5
3
17
17
51.5 ± 14.7 19.5 ± 4.1
57.2 ± II.7 |9.1 -*- 4.2
NS (X ~ tesO NS NS
ifestations and an up-to-date history of medication (see Table 2). Thirteen patients were without antidepressant treatment or had taken the last medication at least six weeks prior to the study, two had been treated with tricyclic antidepressants up to three days before light exposure, and the remaining patients were without medication in ~ last 6 - ! 2 days (see Table 2). The mean wash-out period was 8.7 _+. 3.4 days. Thirteen patients presented with the first manifestation of illness (second manifestation: n = 8, third ~ f e s t a t i o n : n - 11, four or more manifestations: n = 10).
Procedure To minimize therapy-independent changes in psychopathology occuning shortly after admission, phototherapy was given from the 4th to 7th day after patients had been admitted to the hospital. During a seven-day period, the patients were rando~y e x p o ~ to either bright white light of 2500 lux or dim red light of 50 lux from 7:20 AM tO 9:20 AM. The patients were sitting alone in a room otherwise shut off from light. Phototherapy was administered under supervision of the ward staff. To guarantee absolute compliance d u n g treatment, a nurse ascertained at lO-min intervals that the patient was s i n g properly in front of the light box and not sleeping. To exclude additional effects of natural su~ght, especially on clear sunny summer days, patients were requested not to leave the hospital during the course of exposure to light. During the seven days of exposure to fight, patients ~id not receive psycbou'-opic medication except a maximum of ! ~ mg chJ.o.~1_hhyd_~Jte per day, when required. On the day before and after light therapy (days 0 and 8), patients were rated on the 21-item Hamilton Depression Rating scale (HDRS, Hamilton 1967) by an experienced and trained rater, blind to the type of exposure to light. The scale of C ~ c a l Global Impressions [(CGI), NIMH 1970, 1976] was completed by the ward physician, who attended to the patients before and after light therapy, and who was also blind to the treatment condition. Additionally, patients completed self-rating scales including the Depression Scale [(parallel form D-S and D-S') yon Zerssen 1986], the Complaint List (C-L, yon 7_erssen 1986) and a visual analogue scale [(VAS) Ai~en 1969] twice ~ l y at 7 AM and 7 PM. To measure subject expectation of the therapeutic method, we assessed the "subjective initial response" (Priebe 1987), which means the patients' statements after the first exposure to bright white or dim red light. The patients were asked whether they believed they receive the fight treatment. There was no difference in expectation
Age
60 35 57 54 67 04 47 43 43 40 60 3! 38 57 42 42 49 24 46
66
48 63 61
Subject
I 2 3 4 5 6 7 8 9 10 II 12 i3 14 15 16 i7 18 19
20
2! 22 23
m f f
f
m f f f f f m f f m f f f f f f m f f
Sex
II i !
I
| ! l I ii i ! I i ll ! !
I
i I1 ! !1 ! I
Diagnosis*
4/64 2/70 5/62
8/79
9/86 4/78 2/87 6/81 5/70 I/86 3/68 10/74 10/86 4/78 12/86 12/85 9/83 4/87 6/73 10/73 2/80 5/87 2/71
m.i.
I st
I 3 2
3
0 3 0 2 I 2 2 4 0 2 0 I ! 0 2 3 5 0 6
p.m.
N ° of
O.
i !/87 ! 1/87 !/88
9•87
9/86 11/86 12/86 1/87 10/86 2/87 3/87 4/87 10/86 3/87 12/86 9,/86 5/87 4/87 3/87 4/87 ! !/87 5/87 4/87 y y y
y
y y y y y y y y y y y y
n
y y y n y y
day 0
S.d.
y y y
y
y y y y n y y n y y y y y y y y y n y
day 8
Clomipramine ( I I ) L-Tryptophan (8) Oxazepam (9), Dibenzepine (9)
0
Maprotiline ( I I ) 0 Clomipramine (3), Ludiomil (3) 0 0 Dibenzepine (3) 0 0 Triflupromazine (2 !) 0 0 Perazine (6) Maprotiline (I 0) Fluspirilene (9) Dibenzepine (10) Maprotiline (14) 0 Amitriptyline (7) lmipramine (10)
Medication
Response to Bright and Dim Light Exposure
m.r.m,
Table 2. Individual Clinical Characteristics and h e i r
b d
1/88 !/88 ~88
1/88
1/87 ~J87 ~87 2/87 ~J87 3/87 3/87 4:87 5/87 5/87 5/87 5~87 5/87 6/87 7/87 7:87 ! I/87 11/87 !/88
b b d d b d b b b d d d b b b b b b d d d
Time of treatment
Type of light exp.
+
+
+
Responder
IP,.t
~t
>
e~,k
51 64 61 66 60 72 53 72 64 65 77 4! 29 66 57 52 78 41 67
f f f f f f f f m f f m f f f f f f m
I I 1 I i I ! ! | i I I I I I il I I !
5/67 10/80 ~88 6/67 3/87 12/87 4/75 7t87 3/86 5/85 7/83 3/88 3/88 2/75 !/88 8173 2/63 1/88 5/49
2 I 0 13 ! 0 2 0 2 ! i 0 0 2 0 7 2 0 5
7187 5/77 2/88 3/88 1188 12/87 !/88 7•87 2/88 4/88 3/88 3/88 3/88 7/88 !/88 4/88 7/88 !/88 8/88
y y y y y y y y y y y y y y y y y y y
y y y y y y y y y y y y y y y y y y y
*, major depressive disorder = !, bipolar depression = !!. Ist m.i,, first manifestation of illness (month/year). N° of p, m , , number of prior manifestations. O, m r , m , , onsel of most recent manifestation (month/year). S,d., sleep disturbances (HDRS, items 4-6) yes,/no -- y/n. Medication, subs~nce and number of days after' the last intake ( ) preceding light therapy. Type of light exposure, bright light (b) ! dim light (d). Time of treatment (month/year) Responder ! + ), decrease of HDRS-score <~50~ between days 0 and day 8.
24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 Clomipramine (7), Maproliline (7) Imipramine (6). L-Tryptophan (6) 0 Clomipramine (10), Diazepam (16) Ciomipramine (14) Chiordiazepoxid (7). Amitriptyline (7) Lorazepam (9), Perazine (9) Lorazepam (10) Clomipraminc (8) Thioridazme ( ! I)
Oxazepam (8) 0 0 Mianserin (7). Nitrazepam (7) Maprotiline (9)
Tranylcypromine (6), Perazine (6) Lorazepam (16) 0 Clomipramine (6), Amitriptyline (6)
10/88 10/88 10/88
9/88
9/88
3/88 3/88 3/88 3/88 4/88 5/88 5/88 5/88 6/88 6/88 6/88 6:88 6/88 8/88
Ix.) O~ m
-¢
.'7. t -
o~
am° O
f~
Z
3"
262
BiOL PSYCHIATRY
1991;30:2Y/-268
Table 3. Sleep Disturbances According to HDRS--Items 4, 5, a ~ 6 before P h o t ~ ~
Variable
4 (insomnia tally)
Severity Bright white light Dim red light To~
01 + 2 318 317 6 35
$ (~)
6 (~)
0| + 2 219 $15 7 34
01 + 2 4 t7 4 |6 8 33
between the bright-light and dim-light groups (t-test, p = 0.37). ~ e n : ¢ were c o n s i s t e d responders to phototherapy if the HDRS-score had ~ by ~ or more between days 0 and 8. Sleep disturbances and possible changes during exposure to light w ~ evaluated by HDRS-items 4, 5, and 6 (item 4: insorrmia early; item 5: insonmia middle;
item 6: insomnia late). Sleep disturbances were found in 40 patients before ~ o t h e r a p y (see Tables 2 and 3). Circadian serum melatonin and blood serotonin profiles were examined before after light therapy (the results are presented in another paper by Rao et al 1991).
Phototherapy Equipment The sources of the bright white light were 6 tiuorescent 60-watt ~ l spectrum light tubes (so-called True-Lite or Vitalite), supported by a m e n frame with an electronic mechanism to prevent flickering. To ensure a light intensity of 2500 lux at eye level, patients were instructed to be sitting at a distance of 90 cm toward the light tubes. Dim light was induced by the same construction mentioned above, with 12 2-watt bulbs instead of 60watt True-Lite tubes, mounted behind a red transparent film. Potentiometer ~ u l a t i o n allowed a light intensity of 50 lax at eye level.
Statistics The data were assessed by a two-factorial, repeated-measth,'es analysis of variance (ANOVA) (factor 1: groups, factor 2: day of treatment).
Results The data of the analysis of variance are prese~'~ m Table 2. Neither the main eftect "'group", nor the interaction "group x day of treatment" were significant, that is, no significant differences exist between the two groups and no specific benefits regarding the treatment condition. Bright light appears to have a small therapeutic advantage over dim light, as shown by HDRS and D-S in Table 4; however, these effects were not statistically significant. Although we found a significant decrease in ~pressive symptomatology after one week of treatment (main effect "day of treatment"), this reduction was small and could not be regarded as a true clinical improvement. All findings were consisteat for both observer and self-rating scales. Defining responders by a minimum of 50% decrease in the HDRS after one week of treatment, ~here were |our responders in the bright white light group and two responders in the ~im red light group. After termination of light therapy, an additional global
15.3 4. 5.0
19.0 4. 9.6 21.7 4. 8.6 29.3 4. 12.5
58.5 4. 19.9 31,.4 4. 19.9
19.5 - 4.1
25.8 4. 8.9 26. ! 4, 6.6 33.2 4. 9.8
73.6 4. 22.3 67.8 4. 20.4
Hamilton Depression Rating Scale (HDRS) Depression Scale D-S D-S' Complaint List (C-L) Visual Analogue Scale (VAS) 7 AM 7 PM
day 8
day 0
Rating instruments
Bright white light(n = 22)
72.7 4. 21.3 69.6 ----- 18.5
24.4 4- 12.1 24.4 4. 10.0 32.1 4. 13.9
19.1 4. 4.2
day 0
62.8 4. 25.6 59.8 4. 28.2
20.4 "4- 12.4 20.0.4- 10.6 29.6 "4" 17.4
17.3 4. 6.2
day 8
Dim red light (n = 20)
<0.01 <0.01 <0.05
<0.01 <0.01
I 1.4 15.5 4.9
13.5 I 1.2
NS NS NS
NS
0.00 0.45 0.01
0.07 0.75
NS
<0.01
12. I NS
0.29
0.58 0.70
0.74 0.00 0.20
1.95
NS NS
NS NS NS
NS
p
F
p
F
F
p
day of treatment"
"'group x
Interaction Factor 2m"day of trealment"
Analysis of variance
Factor I "'group"
Table 4. Rating Scores ~ f o r e and After Phototl'¢rapy and Results o f Analysis o f Variance
.<
t,J N
o
ga
Z
m.
264
A. Mackett et al
BIOL PSYCHIATRY 1991 ;30:257-268
evaluation of the patients' improvement was made by the ward physician (CGI-2). As it was consistent with the other ratings, no difference was noted between bright white light and dim red light (X2 = 0.19, df = 4, ns). bright light much better just slightly better unchanged rather worse much worse
dim light
3
3
8
8
8 2 !
6 2 I
Of the 40 patients with sleep disturbances, only 3 patients improved with bright light and none on exposure to dim light.
Discussion The results show that phototherapy given over one week for two hr daily may not sufficiently benefit patients with nonseasor-~ depression and that exposure to bright light is not significantly superior to dim light in such patients. This conclusion can be validated by the high agreement in the observer's evaluation and the self-ratings. Although there was a significant decrease in depressive symptoms after phototherapy (HDRS: 4 points on bright light), the clinical improvement was too little to recommend artificial bright light as an optimal therapeutic strategy in nonseasonal major depression, at least in our design. Because we studied phototherapy in inpatients and could, therefore, supervise the light exposure, the modest clinical significance cannot be ascribed to a lack of compliance. Our data are in agreement with the study of Kripke et al (1987), who also found a minimal reduction in depression ratings (HDRS: 3 points in use of bright light) after one hr of bright light administered for 5 days to patients with major depression. Similarly, Yerevanian et al (1986) reported light exposure as beneficial in seasonal, but not in nonseasonal depression. Because only 3 patients with sleep disturbances experienced improvement from bright light, we cannot confirm the findings by Dietzel et al (1986) that phototherapy improves sleep in nonseasonal depression. Several factors must be considered to explain the low effectiveness of bright light in nonseasonal depression.
Timh~g and Duration Phototherapy was given over seven days for two hr daily in the morning. Kripke et al ( 1978, 1983a, 1983b) argued that the timing of light relative to a photosensitive interval is critical for its antidepressant effect, because the circadian rhythm is abnormal in depressed patients. Phototherapy at certain critical times should correct this abnormal rhythm and thereby induce an antidepressive effect (Lewy et al 1982, 1984, 1987a). According to the phase-delayed circadian rhythm in most of the patients with SAD, Lewy et al (1987a) and Terman et al (1987) found bright light more effective when given in the morning than when given in the evening. In other investigations, a clear superiority of bright light in the morning over evening exposure in SAD was not confirmed. Hellekson et al (1986) reported that either morning or evening light has a therapeutic effect, while James et al (1985) even found phototherapy in the evening more effective than placebo.
?hototherapy in Nonseasonal Depression
a ~.~
PSVCHtA~Y
265
Because Wehr et al (1986) (in a study using a skeleton ~hot.operiod tech~;q~) argaed that timing is not the determining tactor in phototherapy, we decided on ligI,,t exposth,'e in the morning for practical reasons, for example, more n ~ e s being availal~le for observing the patients in the morning. To avoid the possibility of partial sleep deprivation, light was given between 7:20 AM and 9:20 AM. Therefore, it cannot ~ r , a ~ out that antidepressant effect of phototherapy in the evening would have been greater in our patient group. Another important question is the optimal duration of light exposure. In SAD, Terman et al (1987) compared treatment over i, 2, and 4 ~ and found that the duration of light exposure influences the outcome. In our study, light was given for one week for about 2 hr daily. In SAD, Wirz-Justize el al (1987) found 2 hr of photothe~py superior to 30 min, whereas Lewy et al (1987b) reported no difference using a similar design. In patients with nonseasonal depression, Kripke et al (1987) found no difference between groups receiving I versus 2 hr of light treatment. Because in most of the n u ~ r o u s studies light was given for 2 hr daily, we conclude that this factor is not critical for the smal~ therapeutic effect in our patient group. Nevertheless, Dietzel et al (1986) showed rapid improvement of sleep parameters and subjective well-being after 6 hr of light e x p o s ~ on one day in 10 patients with major depressive disorder. It is possible that we failed to choose the optimal daily duration of light exposure. Phototherapy of more than 2 hr a day should be applied in future studies. Another possibility is that a single week of phototherapy is too brief, since for example in studies using antidepressants a treatment period of four weeks is common. In previous studies, SAD patients improved markedly after one week of light therapy (Rosenthal et al 1984, 1985; James et al 1985; Hel|ekson et al 1986; Thompson et al 1986; Wirz-Justice et al 1986,1987). There have been too few studies dealing with the optimal duration of treatment in nonseasonal depression. Possibly, in our study, phototherapy was terminated prematurely, and our patient group would have needed more than seven treatment sessions to respond positively to bright light. The initial HDRS score of 19 in our group was comparable to the depression scores of SAD patients, so that the lack of clinical significance cannot be attributed to the severity of depression. In further studies, the design should emulate that of p h ~ a c o l o g i c a l studies with treatment duration of four weeks or longer.
Intensity and Spectrum of Light Light exposure of 2500 lux produced no sufficient clinical improve~nt and showed no differences compared to dim light of 50 lux. This is contrary to previous studies with SAD patients, in which bright light of 2500 lux had alleviated depression and was clearly superior to dim light (Rosenthal et al 1984, 1985; James et al 1985; Wehr et al 1987; lsaacs et al 1988). Neve~heless, Wirz-Justic~ et al (1986) were unable to show any difference between br;ght and dim light in SAD. Interestingly, nearly all of their patients responded markedly to both types of light after an exposure of 5 days, whereas in our study, only four of 22 patients responded to bright white light and two of 20 patients to dim red light according to the response criterion of a minimal 50% decrease in the HDRS. Correspondingly, no difference was found between bfigh', white light and dim red light according to the impression of the ward physician (CGI). It was thought that bright light acts via melatonin in SAD because Lewy et al (1980) showed that n/ghtt~e melatonin production could be suppressed by bright light, but not by room light. Because the therapeutic effect of light occurred after exposure to bright light, and manic-depressive
266
BIOL PSYCHIATRY lggl ;30:287-2f~
A. Mackert et al
patients appear to show a suppressed nocturnal melatonin production twice that of healthy subjects (Lewy et al 1981, 1985), these findings gave rise to the melatonin hypothesis, which says that bright light exposure produces the therapeutic effect by modifying the pattern of nocturnal melatonin secretion in patients with SAD (Rosenthal et al 1986). The light inter~sity of 250 lux employed in our study exceeded the melatonin suppression threshold, so this could not have constituted a limitation for the small therapeutic effect. However, in accordance with our own findings (Rao et al 1991), other investigations have called the antidepressant effect of light via the melatonin system into question (Wehr et al 1986; Kripke et al 1987). Although patients with SAD respond to bright light of 2500 lux, light intensities in excess of 2500 lux may be necessary to achieve remission in nonseasonal depressives. Terman et al (1988) found that for some patients light intensities of 10,000 lux may be superior to conventional bright light of 2500 lux. It was ruled out that the light source itself triggered the modest response because we used Vitalite, a full-spectrum light resembling the spectrum of sunlight, which was successfully used in most studies with SAD patients.
Nonspecific Effects Patients with SAD were usually recruited through newspapers. Thus they may have had a positive attitude toward bright white-light therapy. Accordingly, it cannot he ruled out that the patients' positive response arose ~ a l l y from positive expectations with regard to bright-light therapy. This would expire the lesser number of remissions obtained through dim light, as these patients were presumably aware that only bright light is helpful in SAD. Almost all of our patients had never heard of light therapy before, from which it could be concluded that their expectations were not higher than with regard to conventional antidepressant medication. Possibly, patients with SAD are more receptive to such unspecific effects, thus responding ~tter to phototherapy than our patients with nonseasonal depression. The majority of our patients had recently been withdrawn from psychotropic agents. As many of them may have been experiencing the well-known withdrawal exacerbation that may occur, this group may have had a poorer prognosis than even the average inpatient. The placebo response usually accounts for a 30%--40% decrease in depressive symptoms in pharmacological studies (Klein et al 1980). As the mean decrease in the HDRS sum scores was only 22% after phototherapy, a pure placebo effect c ann_ot he would o~. . . .,-,,e,,~',, . t..,. why *'-:-*'" . . . .ruled . . . . .a.n.t. . .T. h. .l t. .-~,,,,,ption ...... ~,,,~,,t white light was not superior to dim red light. To be able to assess the real effect of phototherapy, the factor "placebo" must be controlled. Dim red light is by no means an optimal placebo, because the distinction between verum and placebo light is obvious to the patient and, therefore, the strict conditions of a double-blind study as applied in pharmacological studies did not exist. Some critical remarks on the mean drug-free period of 8.7 days in our study are needed. The biological half-life of most psychotropics has been assumed to be 24 hr or less. Therefore, these drugs should be eliminated during the drug-free period before light exposure. But it is known that approximately 5%-12% of patients metabolize slowly; so the biological half-Ill,..ff tricyclic antidepressants in these patients can be up to 4-5 times the usual half-life (Garvey et al 1984). Psychotropics stored in fat and muscle tissue may lead to a delayed release after discontinuing medication. It can he assumed that our drugfree period of a mean of 8.7 days may be too short for a complete washout in all patients. On the other hand, it was not possible to keep patients drug-free any longer for ethical
Phototherapy in Nonseasonal Depression
n ~ ~YcmA~Y
267
reasons. Because the drug-free period was relatively sport for both Lhe ~ g h t wMm fight and dim red light groups, this factor cannot be responsible for the low effective~ss of bright white light. To conclude, a one-week period of photc4,her-apy given daily for 2 ~" in the morning is not an effective treatment strategy in patients with w',mseasonai depression. The authors wouMlike to express their gratitude to Mrs. S~ Bracket~ Mrs. I. Voigtfor mmtoemg of patiems; Mrs. C. [.anger for help in statistical anMysis; Mrs. C. Peit2 for ~par~tion of ~ manuscript; ~ ~ . K. Bauer and Mr. S. Bantz for their help in tr~s|ation.
References Aitken RCB ( 1969): Measuring of feelings using visual analogue scales. Proc R S ~ Med 62'.989993. Dietzel M, Saletu B, Lesch OM, Sieghardt W, Sch~er~e M (1986): Light treatment in depressive illness. Eur Neurol (Suppl) 25:93-103. Garvey MI, Tuason VB, Johnson RA, Valentine RH, Cooper ~ (1984): Elevated plasma tricyclic levels with therapeutic doses of imivramine. Am J P~'chiatr?; 141:853-856. Hamilton M (1967): Development of a rating scale for primary depressive illness. Br J Cos Clin Psychol 6:278-296. Hellekson CI, Kline JA, Rosenthal NE (1986): Photot~rapy for seasonM affective disorder in Alaska. Am I Psychiawy 143:i035-1037. Isaacs G, Stainer DS, Sensky TE, Moor S, Tomson C (1988): P h o t ~ r a p y and its mechanisms of action in seasonal affective disorder. 1 Affective Disord 14:13-19. James SP, Wehr TA, Sack DA, Parry BL, Rosenthal NE (1985): Treatment of seasonal affective disorder with light in the evening. Br I Psychiatry 147:424 ~28. Klein DF, Gittelmann R, Quitldn F, Rifkin A ( 1980): Diagnostic andDrug Treatment of Psychiatric Disorders: Adults and Children, 2nd ed. Baltimore: William and Wilkens. Kripke DF, Mullaney DJ, Atldnson M, Wolf S (1978): Circadian rhythm disorders in manicdepressives. Biol Psychiatry 13:335-351. Kripke DF, Risch SC, Janowsky D (1983a): Bright white light ~eviates depression. Psychiatry Res 10:105-112. Kripke DF, Risch SC, Janowsky D ( 1983b): Lighting up depression. Psychop~rmacoIBuH 19:525..a,.,$v.
Kripke DF, Gillin JC, Mullaney DJ, Risch SC, Janowsky DS (1987): Treatment of major depressive disorders by bright white light for 5 days. In Halaris A (ed), Chronobiology and Psychiatric Disorders. Amsterdam: Elsevier, pp 207-218. Kripke DF, Mullaney DJ, Savides TJ, Gillin JC ([989): Phototherapy for non-seasonal major depressive disorder. In Rosenthal NE, Biehar M (eds), Seasonal Affective Disorder and Phototherapy. New York: Raven Press, pp 342-356. Lehr! S (1978): MehrfachwahI-Wortschatz-Test (MWT-B). Straube: Erlangen. Lewy AJ, Wehr TA, Goodwin FK, Newsome DA, Markey SP (I 980): Light suppresses melatonin secretion in humans. Science 210:1267-1269. Lewy AJ, Wehr TA, Goodwin FK, Newsome DA, Rosenthal NE (198 [): Manic-depressive patients may be supersensitive to light. Lancet 1:383-384. Lewy AJ, Kern HA, Rosenthal NE, Wehr TA (1982): Bright artificial fight treatment of a manicdepressive patient with a seasonal mood cycle. Am J Psychiatry 139:[496-1498. Lewy AJ, Sack RL, Singer CL (1984): Assessment and treatment of chronobiologic disorders using
268
BIOLPSYCHIATRY I~1 ;.~:257-2~
A. Macketl et al
plasma melatonin levels and bright light exposure: The clock-gate model and the phase response curve. Psychopharmacoi Bull 20:561-565. Lewy AJ, Nurnberger Jl, Wehr TA, et al (1985): Supersensitivity to light: Possible trait marker for manic-depressive illness. Am J Psychiatr), 142:725-727. Lewy AJ, Sack RL, Miller S, Hoban TM (1987a): Antidepressant and circadian phase-shifting effects of light. Science 235:352-354. Lewy AJ, Sack RL, Singer CM, White DM (1987b): ~ phase shift hypothesis for bright light's therapeutic mechanism of action: Theoretical considerations and experimental evidence. Psychopharmacol Bull 23:349-353. Mackert A, Volz HP, Stieglitz RD, Mtiller-Oeflinghausen B (1990): Effect of bright white light on non-seasonal depressive disorder. Pharmacopsychiatry 23:151-154. National Institute of Mental Health (1970): 1 2 ~ l , Clinical Global Impressions. In Guy W, Bonato RR (eds), Mahdi for the ECDEU Assessment Battery, reved. Cl~vy Chase, MD, pp 12-!-12-6. National Institute of Mental Health (1976): 028 CGI, Clinical Global Impressions. in Guy W (ed), ECDEU Assessment Manual for Ps),chopharmacology, rev ed. Rockville, MD; pp 217-222. Priebe S (1987): Early subjective reactions predicting the outcome of hospital treatment in depressive patients. Acta Po,chiatr Scand 76: ! 34-138. Rao ML, Mtiller-Oerlinghausen B, Mackert A, Volz HP, Franke N, Stieglitz RD (1991): Treatment with artificial light ameliorates depressive symptoms concomitantly with attenuation of blood serotonin but not serum melatonin in patients with non-seasonal affective disorder. Biol Psychiatr), (in press). Rosenthal NE, Sack DA, Gillin JC, et al (1984): Seasonal affective disorder---a prescription of the syndrome and preliminary findings with light t h e ~ y . Arch Gen Psychiatry. 41:72-80. Rosenthal NE, Sack DA, Carpenter CJ, Parry BL, Mendelson WB, Wehr TA (1985): Antidepressant effects of light in seasonal affective disorder. Am J Psychiatry 142:!63-170. Rosenthal NE, Sack DA, Jacobsen FM, et al (1986): Melatonin in seasonal affective disorder and phototherapy. J Neural Trans (Suppl) 2 ! :257-267. Spitzer RL, Endicott J, Robbins R (1977): Research Diagnostic Criteria (RDC)for a Selected Group of Functional Disorders, 3rd ed. New York: Biometrics Research. Terman M, Quitkin FM, Ten'nan JS, Stewart JW, McGrath PJ (1987): The timing of phototherapy: effects on clinical response and the melatonin cycle. Psychopharmacol Bull 23:354-357. Terman M, Terman JS, Schlager D, Quitkin FM (1988): Efficacy of 10,000 lux light therapy. Paper presented at the World Psychiatric Association meetings, Washington DC. Thompson C, lsaacs G, Stainer S, Miles A (1986): Seasonal affective disorder-phototherapy and salivary melatonin. Abstract N°263, 15.CINP in Puerto Rico. Volz HP, Macken A, Stieglitz RD, Miiller-Oerlinghausen B (1990): Effect of bright white light therapy on non-seasonal depressive disorder. Preliminary results. J Affective Disord 19:i5-21. yon Zerssen Dv (1986): Clinical Self-Rating Scales (CSRS) of the Munich psychiatric information system (PSYCHIS Mtinchen). In Sartorius N, Ban TA (eds), Assessment of Depression. Berlin: Springer, pp 270-303. Wehr TA, Jacobsen FM, Sack DA, Arendt J, Tamarkin L, Rosenthal ISlE (1986): Phototherapy of seasonal affective disorder. Arch Gen Psychiatry. 43:870-875. Wehr TA, Skwerer RG, Jacobsen FM, Sack DA.. Rosenthal NE (1987): Eye- vs. skin-phototherapy of seasonal affective disorder. Am J Psychiat 144:753-757. Wirz-Justice A, Bucheli B, Graw P, Kielholz P, Fisch HU, Woggon B (1986): Light treatment of seasonal affective disorder in Switzerland. Acta Psychiatr Scand 74:193-204. Wirz-Justice A, Schmid AC, Graw P, et al (1987): Dose relationships of mo~ing bright white light in seasonal affective disorders (SAD). Experimentia 43:574-576. Yerevanian BI, Anderson JL, Grota LJ, Bray M (1986): Effects of bright incandescent light on seasonal and non-seasonal major depressive disorder. Psychiatr Res 18:355-364.
257
Phototherapy in Nonseasonal Depression Arthur Mackert, Hans-Peter Volz, Rolf-Dieter Stieglitz, and B no Miiller-Oerlinghausen
Previous reports have shown that bright light exposure max, benefit patients with seaso~l depression. In the present study, the possible therapeutic effect of bright light in nonseasonal major depressive disorder was examined. Forts,-two depressed patients not receivb~g additional antidepressant medication were exposed to bright white light of 25bO iux or dim red light of 50 hoe over one week for m,o hr daily in the morning. The change in depressive symptoms was assessed by rating scales (Hamilton Depression Rating Scale, CGI) and by self-rating scales (Depression Scale, Complaint List, Visual Analogae Scale). Consistent for all ratings, the decrease in depressive sb.'mptoms after bright white light was only slight and not different from dim red-light exposure. Contrary. to the findings in seasonal affective disorder, phototherapy administered over one week for two hr daily is not effective in nonseasonal major depressive disorder. Introduction Seasonal affective disorder (SAD) is characterized by recumng cycles of depression in the fall and winter with hypomania or euthymia in the spring and summer. Lewy et al (1982) first reported on a patient with seasonal mood cycles, whose winter depression retorted when daylight was lengthened with bright artificial light. Subsequent studies have shown that patients with SAD improve on exposure to bright light of approx~ately 2500 lux in intensity, whereas dim light (300 lux or less) has only a negligible therapeutic effect (Rosenthal et al 1984, 1985; James et al 1985; Wehr et al 1987; Isaacs et al 1988). The antidepressant effect produced by bright artificial light appears within one week, w;th r~lanc~ nc..alh,
There have been only a few investigations to determine whether bright light may also induce remission in patients with nonseasonal depression. Kripke et al (1983a) found a significantly greater effect after a single hour of bright light than after dim light exposure from 5 AM to 6 AM in 12 patients suffering from major depressive disorder. Dietzel et al (1986) reported a significant improvement in mood and sleep of 10 female patients with major depressive disorder after a single day of light therapy of 3 hr duration in the morning and 4 hr in the evening. In contrast, Yerevanian et al (1986) found a beneficial effect of a i- to 2-week phototherapy only in seasonal, but not in nonseasonal depressives, although most of the nonseasonal depressives had concurrently received psychotropic
From the Department of Psychiatry. Free University of Berlin. Germany. Address reprint requests to Dr. A. Mackert. Psychiatrische Klinik und Polildinik der Freien Univers~t Berlin, Eschenallee 3, D-1000 Berlin 19 FRG. Received September 2. 1990; revised February 27, 1991. 1991 Society of Biological Psychiatry
0006-3223/91/$03.50
38
BIOL PSYCHIATRY 1991;~:257~268
A. Mackert et al
agents during light treatment. Kripke et al (1987) reported only a minimal reduction in the symptoms of 14 patients with major depression in response to bright light given for 5 days, either for one ~ ia the morning or for one hr both in the morning and in the evening. In a subsequent study, nonseasonal depressed patients neared with bright light over one week for 3 hr daily in the evening showed an approximate 20% decrease in depression ratings when compared to the group receiving dim light in the stone design, which had not improved (Kripke et al 1989). The available literature on the benefits of phototherapy in nonseasonal depression is rather contradictory. This is mainly attributable to the small number of subjects involved and to differences in the experimental design, in particular to (a) the number of days, (b) the time of day, (c) the daily duration of exposure to light, and (d) the concomitant use or nonuse of antidepressants. The aim of the present study was to evaluate a sufficiently large number of patients and determine whether bright light as opposed to dim light is suitable for clinical treatment of patients suffering from major depression without recurrent fall/winter depression. Preliminary reports of some on these data in a siaaller group of patients were recently published (Mackert et al 1990; Volz et al 1990).
Methods
Subjects From January 1987 to November 1988, 50 inpatients consecutively admitted and meeting Research Diagnostic Criteria (RDC) for major depressive disorder (Spitzer et al 1977) consented to participate in the study. Patients with seasonal depression were excluded according to the criteria of seasonality based on DSM-III-R: three episodes, at least two of which were consecutive, with manifestation within a seasonal 90-day period between the beginning of September and the end of November (the seasonal pattern according to DSM-III-R is restricted to a 60-day window). Because 2 patients had a first manifestation of depressive illness between September and November (see Table 2), a seasonal depression occurring during the further course of illness could not be ruled out. Other exclusion criteria were ophthalmologic disorders, alcohol or drug abuse, brain injury and neurological disorders, and acute suicidal tendencies. Patients with an IQ lower than 90 as measured by a multiple choice vocabulary test (Lehrl 1978) were also not included. Before beginning the study, each patient underwent a medical examination including both routine laboratory analysis and electrocardiogram (l~CCi). unne specimens were obtained to detect the use of illicit drugs. The 50 patients were randomly exposed to either bright white or dim red light. The patients were informed that they were to participate in a study, in which two different kinds of exposure to light would be investigated. They were not told that dim red light was expected to be ineffective. Eight patients discontinued the study either because drug treatment was mandatory on clinical grounds (6 patients), or because urine specimens revealed the use of illicit drugs (2 patients). Of the remaining 42 patients, 36 with major depressive disorder and 6 with bipolar depression, 22 were exposed to bright white light and 20 patients to dim red light. As may be seen from Table 1, there were no statistical differences in age, sex, and initial HDRS-scores between these two subgroups. Based on documentation of previous hospitalizations, reports from psychiatrists, who had treated these patients as outpatients, as well as information from relatives and the patients themselves, a drug history was established for each patient with special regard to prior man-
BIOL.PSY(~I~TRY
Phototherapy in Nonseasonal Depression
259
Table I. Age, Sex, and Initial HDRS of Patients Treated with Bright and Dim Light Patients ~ All patients Gender re_Me
female Age (years) Hamilton Depression Rating Scale (HDRS) before treatment
8 33 54.2 ± 13.2 19.3 ± 4.2
Bright white light (n = 22)
to D ~ red ~ght (n = 20)
5
3
17
17
51.5 ± 14.7 19.5 ± 4.1
57.2 ± II.7 |9.1 -*- 4.2
NS (X ~ tesO NS NS
ifestations and an up-to-date history of medication (see Table 2). Thirteen patients were without antidepressant treatment or had taken the last medication at least six weeks prior to the study, two had been treated with tricyclic antidepressants up to three days before light exposure, and the remaining patients were without medication in ~ last 6 - ! 2 days (see Table 2). The mean wash-out period was 8.7 _+. 3.4 days. Thirteen patients presented with the first manifestation of illness (second manifestation: n = 8, third ~ f e s t a t i o n : n - 11, four or more manifestations: n = 10).
Procedure To minimize therapy-independent changes in psychopathology occuning shortly after admission, phototherapy was given from the 4th to 7th day after patients had been admitted to the hospital. During a seven-day period, the patients were rando~y e x p o ~ to either bright white light of 2500 lux or dim red light of 50 lux from 7:20 AM tO 9:20 AM. The patients were sitting alone in a room otherwise shut off from light. Phototherapy was administered under supervision of the ward staff. To guarantee absolute compliance d u n g treatment, a nurse ascertained at lO-min intervals that the patient was s i n g properly in front of the light box and not sleeping. To exclude additional effects of natural su~ght, especially on clear sunny summer days, patients were requested not to leave the hospital during the course of exposure to light. During the seven days of exposure to fight, patients ~id not receive psycbou'-opic medication except a maximum of ! ~ mg chJ.o.~1_hhyd_~Jte per day, when required. On the day before and after light therapy (days 0 and 8), patients were rated on the 21-item Hamilton Depression Rating scale (HDRS, Hamilton 1967) by an experienced and trained rater, blind to the type of exposure to light. The scale of C ~ c a l Global Impressions [(CGI), NIMH 1970, 1976] was completed by the ward physician, who attended to the patients before and after light therapy, and who was also blind to the treatment condition. Additionally, patients completed self-rating scales including the Depression Scale [(parallel form D-S and D-S') yon Zerssen 1986], the Complaint List (C-L, yon 7_erssen 1986) and a visual analogue scale [(VAS) Ai~en 1969] twice ~ l y at 7 AM and 7 PM. To measure subject expectation of the therapeutic method, we assessed the "subjective initial response" (Priebe 1987), which means the patients' statements after the first exposure to bright white or dim red light. The patients were asked whether they believed they receive the fight treatment. There was no difference in expectation
Age
60 35 57 54 67 04 47 43 43 40 60 3! 38 57 42 42 49 24 46
66
48 63 61
Subject
I 2 3 4 5 6 7 8 9 10 II 12 i3 14 15 16 i7 18 19
20
2! 22 23
m f f
f
m f f f f f m f f m f f f f f f m f f
Sex
II i !
I
| ! l I ii i ! I i ll ! !
I
i I1 ! !1 ! I
Diagnosis*
4/64 2/70 5/62
8/79
9/86 4/78 2/87 6/81 5/70 I/86 3/68 10/74 10/86 4/78 12/86 12/85 9/83 4/87 6/73 10/73 2/80 5/87 2/71
m.i.
I st
I 3 2
3
0 3 0 2 I 2 2 4 0 2 0 I ! 0 2 3 5 0 6
p.m.
N ° of
O.
i !/87 ! 1/87 !/88
9•87
9/86 11/86 12/86 1/87 10/86 2/87 3/87 4/87 10/86 3/87 12/86 9,/86 5/87 4/87 3/87 4/87 ! !/87 5/87 4/87 y y y
y
y y y y y y y y y y y y
n
y y y n y y
day 0
S.d.
y y y
y
y y y y n y y n y y y y y y y y y n y
day 8
Clomipramine ( I I ) L-Tryptophan (8) Oxazepam (9), Dibenzepine (9)
0
Maprotiline ( I I ) 0 Clomipramine (3), Ludiomil (3) 0 0 Dibenzepine (3) 0 0 Triflupromazine (2 !) 0 0 Perazine (6) Maprotiline (I 0) Fluspirilene (9) Dibenzepine (10) Maprotiline (14) 0 Amitriptyline (7) lmipramine (10)
Medication
Response to Bright and Dim Light Exposure
m.r.m,
Table 2. Individual Clinical Characteristics and h e i r
b d
1/88 !/88 ~88
1/88
1/87 ~J87 ~87 2/87 ~J87 3/87 3/87 4:87 5/87 5/87 5/87 5~87 5/87 6/87 7/87 7:87 ! I/87 11/87 !/88
b b d d b d b b b d d d b b b b b b d d d
Time of treatment
Type of light exp.
+
+
+
Responder
IP,.t
~t
>
e~,k
51 64 61 66 60 72 53 72 64 65 77 4! 29 66 57 52 78 41 67
f f f f f f f f m f f m f f f f f f m
I I 1 I i I ! ! | i I I I I I il I I !
5/67 10/80 ~88 6/67 3/87 12/87 4/75 7t87 3/86 5/85 7/83 3/88 3/88 2/75 !/88 8173 2/63 1/88 5/49
2 I 0 13 ! 0 2 0 2 ! i 0 0 2 0 7 2 0 5
7187 5/77 2/88 3/88 1188 12/87 !/88 7•87 2/88 4/88 3/88 3/88 3/88 7/88 !/88 4/88 7/88 !/88 8/88
y y y y y y y y y y y y y y y y y y y
y y y y y y y y y y y y y y y y y y y
*, major depressive disorder = !, bipolar depression = !!. Ist m.i,, first manifestation of illness (month/year). N° of p, m , , number of prior manifestations. O, m r , m , , onsel of most recent manifestation (month/year). S,d., sleep disturbances (HDRS, items 4-6) yes,/no -- y/n. Medication, subs~nce and number of days after' the last intake ( ) preceding light therapy. Type of light exposure, bright light (b) ! dim light (d). Time of treatment (month/year) Responder ! + ), decrease of HDRS-score <~50~ between days 0 and day 8.
24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 Clomipramine (7), Maproliline (7) Imipramine (6). L-Tryptophan (6) 0 Clomipramine (10), Diazepam (16) Ciomipramine (14) Chiordiazepoxid (7). Amitriptyline (7) Lorazepam (9), Perazine (9) Lorazepam (10) Clomipraminc (8) Thioridazme ( ! I)
Oxazepam (8) 0 0 Mianserin (7). Nitrazepam (7) Maprotiline (9)
Tranylcypromine (6), Perazine (6) Lorazepam (16) 0 Clomipramine (6), Amitriptyline (6)
10/88 10/88 10/88
9/88
9/88
3/88 3/88 3/88 3/88 4/88 5/88 5/88 5/88 6/88 6/88 6/88 6:88 6/88 8/88
Ix.) O~ m
-¢
.'7. t -
o~
am° O
f~
Z
3"
262
BiOL PSYCHIATRY
1991;30:2Y/-268
Table 3. Sleep Disturbances According to HDRS--Items 4, 5, a ~ 6 before P h o t ~ ~
Variable
4 (insomnia tally)
Severity Bright white light Dim red light To~
01 + 2 318 317 6 35
$ (~)
6 (~)
0| + 2 219 $15 7 34
01 + 2 4 t7 4 |6 8 33
between the bright-light and dim-light groups (t-test, p = 0.37). ~ e n : ¢ were c o n s i s t e d responders to phototherapy if the HDRS-score had ~ by ~ or more between days 0 and 8. Sleep disturbances and possible changes during exposure to light w ~ evaluated by HDRS-items 4, 5, and 6 (item 4: insorrmia early; item 5: insonmia middle;
item 6: insomnia late). Sleep disturbances were found in 40 patients before ~ o t h e r a p y (see Tables 2 and 3). Circadian serum melatonin and blood serotonin profiles were examined before after light therapy (the results are presented in another paper by Rao et al 1991).
Phototherapy Equipment The sources of the bright white light were 6 tiuorescent 60-watt ~ l spectrum light tubes (so-called True-Lite or Vitalite), supported by a m e n frame with an electronic mechanism to prevent flickering. To ensure a light intensity of 2500 lux at eye level, patients were instructed to be sitting at a distance of 90 cm toward the light tubes. Dim light was induced by the same construction mentioned above, with 12 2-watt bulbs instead of 60watt True-Lite tubes, mounted behind a red transparent film. Potentiometer ~ u l a t i o n allowed a light intensity of 50 lax at eye level.
Statistics The data were assessed by a two-factorial, repeated-measth,'es analysis of variance (ANOVA) (factor 1: groups, factor 2: day of treatment).
Results The data of the analysis of variance are prese~'~ m Table 2. Neither the main eftect "'group", nor the interaction "group x day of treatment" were significant, that is, no significant differences exist between the two groups and no specific benefits regarding the treatment condition. Bright light appears to have a small therapeutic advantage over dim light, as shown by HDRS and D-S in Table 4; however, these effects were not statistically significant. Although we found a significant decrease in ~pressive symptomatology after one week of treatment (main effect "day of treatment"), this reduction was small and could not be regarded as a true clinical improvement. All findings were consisteat for both observer and self-rating scales. Defining responders by a minimum of 50% decrease in the HDRS after one week of treatment, ~here were |our responders in the bright white light group and two responders in the ~im red light group. After termination of light therapy, an additional global
15.3 4. 5.0
19.0 4. 9.6 21.7 4. 8.6 29.3 4. 12.5
58.5 4. 19.9 31,.4 4. 19.9
19.5 - 4.1
25.8 4. 8.9 26. ! 4, 6.6 33.2 4. 9.8
73.6 4. 22.3 67.8 4. 20.4
Hamilton Depression Rating Scale (HDRS) Depression Scale D-S D-S' Complaint List (C-L) Visual Analogue Scale (VAS) 7 AM 7 PM
day 8
day 0
Rating instruments
Bright white light(n = 22)
72.7 4. 21.3 69.6 ----- 18.5
24.4 4- 12.1 24.4 4. 10.0 32.1 4. 13.9
19.1 4. 4.2
day 0
62.8 4. 25.6 59.8 4. 28.2
20.4 "4- 12.4 20.0.4- 10.6 29.6 "4" 17.4
17.3 4. 6.2
day 8
Dim red light (n = 20)
<0.01 <0.01 <0.05
<0.01 <0.01
I 1.4 15.5 4.9
13.5 I 1.2
NS NS NS
NS
0.00 0.45 0.01
0.07 0.75
NS
<0.01
12. I NS
0.29
0.58 0.70
0.74 0.00 0.20
1.95
NS NS
NS NS NS
NS
p
F
p
F
F
p
day of treatment"
"'group x
Interaction Factor 2m"day of trealment"
Analysis of variance
Factor I "'group"
Table 4. Rating Scores ~ f o r e and After Phototl'¢rapy and Results o f Analysis o f Variance
.<
t,J N
o
ga
Z
m.
264
A. Mackett et al
BIOL PSYCHIATRY 1991 ;30:257-268
evaluation of the patients' improvement was made by the ward physician (CGI-2). As it was consistent with the other ratings, no difference was noted between bright white light and dim red light (X2 = 0.19, df = 4, ns). bright light much better just slightly better unchanged rather worse much worse
dim light
3
3
8
8
8 2 !
6 2 I
Of the 40 patients with sleep disturbances, only 3 patients improved with bright light and none on exposure to dim light.
Discussion The results show that phototherapy given over one week for two hr daily may not sufficiently benefit patients with nonseasor-~ depression and that exposure to bright light is not significantly superior to dim light in such patients. This conclusion can be validated by the high agreement in the observer's evaluation and the self-ratings. Although there was a significant decrease in depressive symptoms after phototherapy (HDRS: 4 points on bright light), the clinical improvement was too little to recommend artificial bright light as an optimal therapeutic strategy in nonseasonal major depression, at least in our design. Because we studied phototherapy in inpatients and could, therefore, supervise the light exposure, the modest clinical significance cannot be ascribed to a lack of compliance. Our data are in agreement with the study of Kripke et al (1987), who also found a minimal reduction in depression ratings (HDRS: 3 points in use of bright light) after one hr of bright light administered for 5 days to patients with major depression. Similarly, Yerevanian et al (1986) reported light exposure as beneficial in seasonal, but not in nonseasonal depression. Because only 3 patients with sleep disturbances experienced improvement from bright light, we cannot confirm the findings by Dietzel et al (1986) that phototherapy improves sleep in nonseasonal depression. Several factors must be considered to explain the low effectiveness of bright light in nonseasonal depression.
Timh~g and Duration Phototherapy was given over seven days for two hr daily in the morning. Kripke et al ( 1978, 1983a, 1983b) argued that the timing of light relative to a photosensitive interval is critical for its antidepressant effect, because the circadian rhythm is abnormal in depressed patients. Phototherapy at certain critical times should correct this abnormal rhythm and thereby induce an antidepressive effect (Lewy et al 1982, 1984, 1987a). According to the phase-delayed circadian rhythm in most of the patients with SAD, Lewy et al (1987a) and Terman et al (1987) found bright light more effective when given in the morning than when given in the evening. In other investigations, a clear superiority of bright light in the morning over evening exposure in SAD was not confirmed. Hellekson et al (1986) reported that either morning or evening light has a therapeutic effect, while James et al (1985) even found phototherapy in the evening more effective than placebo.
?hototherapy in Nonseasonal Depression
a ~.~
PSVCHtA~Y
265
Because Wehr et al (1986) (in a study using a skeleton ~hot.operiod tech~;q~) argaed that timing is not the determining tactor in phototherapy, we decided on ligI,,t exposth,'e in the morning for practical reasons, for example, more n ~ e s being availal~le for observing the patients in the morning. To avoid the possibility of partial sleep deprivation, light was given between 7:20 AM and 9:20 AM. Therefore, it cannot ~ r , a ~ out that antidepressant effect of phototherapy in the evening would have been greater in our patient group. Another important question is the optimal duration of light exposure. In SAD, Terman et al (1987) compared treatment over i, 2, and 4 ~ and found that the duration of light exposure influences the outcome. In our study, light was given for one week for about 2 hr daily. In SAD, Wirz-Justize el al (1987) found 2 hr of photothe~py superior to 30 min, whereas Lewy et al (1987b) reported no difference using a similar design. In patients with nonseasonal depression, Kripke et al (1987) found no difference between groups receiving I versus 2 hr of light treatment. Because in most of the n u ~ r o u s studies light was given for 2 hr daily, we conclude that this factor is not critical for the smal~ therapeutic effect in our patient group. Nevertheless, Dietzel et al (1986) showed rapid improvement of sleep parameters and subjective well-being after 6 hr of light e x p o s ~ on one day in 10 patients with major depressive disorder. It is possible that we failed to choose the optimal daily duration of light exposure. Phototherapy of more than 2 hr a day should be applied in future studies. Another possibility is that a single week of phototherapy is too brief, since for example in studies using antidepressants a treatment period of four weeks is common. In previous studies, SAD patients improved markedly after one week of light therapy (Rosenthal et al 1984, 1985; James et al 1985; Hel|ekson et al 1986; Thompson et al 1986; Wirz-Justice et al 1986,1987). There have been too few studies dealing with the optimal duration of treatment in nonseasonal depression. Possibly, in our study, phototherapy was terminated prematurely, and our patient group would have needed more than seven treatment sessions to respond positively to bright light. The initial HDRS score of 19 in our group was comparable to the depression scores of SAD patients, so that the lack of clinical significance cannot be attributed to the severity of depression. In further studies, the design should emulate that of p h ~ a c o l o g i c a l studies with treatment duration of four weeks or longer.
Intensity and Spectrum of Light Light exposure of 2500 lux produced no sufficient clinical improve~nt and showed no differences compared to dim light of 50 lux. This is contrary to previous studies with SAD patients, in which bright light of 2500 lux had alleviated depression and was clearly superior to dim light (Rosenthal et al 1984, 1985; James et al 1985; Wehr et al 1987; lsaacs et al 1988). Neve~heless, Wirz-Justic~ et al (1986) were unable to show any difference between br;ght and dim light in SAD. Interestingly, nearly all of their patients responded markedly to both types of light after an exposure of 5 days, whereas in our study, only four of 22 patients responded to bright white light and two of 20 patients to dim red light according to the response criterion of a minimal 50% decrease in the HDRS. Correspondingly, no difference was found between bfigh', white light and dim red light according to the impression of the ward physician (CGI). It was thought that bright light acts via melatonin in SAD because Lewy et al (1980) showed that n/ghtt~e melatonin production could be suppressed by bright light, but not by room light. Because the therapeutic effect of light occurred after exposure to bright light, and manic-depressive
266
BIOL PSYCHIATRY lggl ;30:287-2f~
A. Mackert et al
patients appear to show a suppressed nocturnal melatonin production twice that of healthy subjects (Lewy et al 1981, 1985), these findings gave rise to the melatonin hypothesis, which says that bright light exposure produces the therapeutic effect by modifying the pattern of nocturnal melatonin secretion in patients with SAD (Rosenthal et al 1986). The light inter~sity of 250 lux employed in our study exceeded the melatonin suppression threshold, so this could not have constituted a limitation for the small therapeutic effect. However, in accordance with our own findings (Rao et al 1991), other investigations have called the antidepressant effect of light via the melatonin system into question (Wehr et al 1986; Kripke et al 1987). Although patients with SAD respond to bright light of 2500 lux, light intensities in excess of 2500 lux may be necessary to achieve remission in nonseasonal depressives. Terman et al (1988) found that for some patients light intensities of 10,000 lux may be superior to conventional bright light of 2500 lux. It was ruled out that the light source itself triggered the modest response because we used Vitalite, a full-spectrum light resembling the spectrum of sunlight, which was successfully used in most studies with SAD patients.
Nonspecific Effects Patients with SAD were usually recruited through newspapers. Thus they may have had a positive attitude toward bright white-light therapy. Accordingly, it cannot he ruled out that the patients' positive response arose ~ a l l y from positive expectations with regard to bright-light therapy. This would expire the lesser number of remissions obtained through dim light, as these patients were presumably aware that only bright light is helpful in SAD. Almost all of our patients had never heard of light therapy before, from which it could be concluded that their expectations were not higher than with regard to conventional antidepressant medication. Possibly, patients with SAD are more receptive to such unspecific effects, thus responding ~tter to phototherapy than our patients with nonseasonal depression. The majority of our patients had recently been withdrawn from psychotropic agents. As many of them may have been experiencing the well-known withdrawal exacerbation that may occur, this group may have had a poorer prognosis than even the average inpatient. The placebo response usually accounts for a 30%--40% decrease in depressive symptoms in pharmacological studies (Klein et al 1980). As the mean decrease in the HDRS sum scores was only 22% after phototherapy, a pure placebo effect c ann_ot he would o~. . . .,-,,e,,~',, . t..,. why *'-:-*'" . . . .ruled . . . . .a.n.t. . .T. h. .l t. .-~,,,,,ption ...... ~,,,~,,t white light was not superior to dim red light. To be able to assess the real effect of phototherapy, the factor "placebo" must be controlled. Dim red light is by no means an optimal placebo, because the distinction between verum and placebo light is obvious to the patient and, therefore, the strict conditions of a double-blind study as applied in pharmacological studies did not exist. Some critical remarks on the mean drug-free period of 8.7 days in our study are needed. The biological half-life of most psychotropics has been assumed to be 24 hr or less. Therefore, these drugs should be eliminated during the drug-free period before light exposure. But it is known that approximately 5%-12% of patients metabolize slowly; so the biological half-Ill,..ff tricyclic antidepressants in these patients can be up to 4-5 times the usual half-life (Garvey et al 1984). Psychotropics stored in fat and muscle tissue may lead to a delayed release after discontinuing medication. It can he assumed that our drugfree period of a mean of 8.7 days may be too short for a complete washout in all patients. On the other hand, it was not possible to keep patients drug-free any longer for ethical
Phototherapy in Nonseasonal Depression
n ~ ~YcmA~Y
267
reasons. Because the drug-free period was relatively sport for both Lhe ~ g h t wMm fight and dim red light groups, this factor cannot be responsible for the low effective~ss of bright white light. To conclude, a one-week period of photc4,her-apy given daily for 2 ~" in the morning is not an effective treatment strategy in patients with w',mseasonai depression. The authors wouMlike to express their gratitude to Mrs. S~ Bracket~ Mrs. I. Voigtfor mmtoemg of patiems; Mrs. C. [.anger for help in statistical anMysis; Mrs. C. Peit2 for ~par~tion of ~ manuscript; ~ ~ . K. Bauer and Mr. S. Bantz for their help in tr~s|ation.
References Aitken RCB ( 1969): Measuring of feelings using visual analogue scales. Proc R S ~ Med 62'.989993. Dietzel M, Saletu B, Lesch OM, Sieghardt W, Sch~er~e M (1986): Light treatment in depressive illness. Eur Neurol (Suppl) 25:93-103. Garvey MI, Tuason VB, Johnson RA, Valentine RH, Cooper ~ (1984): Elevated plasma tricyclic levels with therapeutic doses of imivramine. Am J P~'chiatr?; 141:853-856. Hamilton M (1967): Development of a rating scale for primary depressive illness. Br J Cos Clin Psychol 6:278-296. Hellekson CI, Kline JA, Rosenthal NE (1986): Photot~rapy for seasonM affective disorder in Alaska. Am I Psychiawy 143:i035-1037. Isaacs G, Stainer DS, Sensky TE, Moor S, Tomson C (1988): P h o t ~ r a p y and its mechanisms of action in seasonal affective disorder. 1 Affective Disord 14:13-19. James SP, Wehr TA, Sack DA, Parry BL, Rosenthal NE (1985): Treatment of seasonal affective disorder with light in the evening. Br I Psychiatry 147:424 ~28. Klein DF, Gittelmann R, Quitldn F, Rifkin A ( 1980): Diagnostic andDrug Treatment of Psychiatric Disorders: Adults and Children, 2nd ed. Baltimore: William and Wilkens. Kripke DF, Mullaney DJ, Atldnson M, Wolf S (1978): Circadian rhythm disorders in manicdepressives. Biol Psychiatry 13:335-351. Kripke DF, Risch SC, Janowsky D (1983a): Bright white light ~eviates depression. Psychiatry Res 10:105-112. Kripke DF, Risch SC, Janowsky D ( 1983b): Lighting up depression. Psychop~rmacoIBuH 19:525..a,.,$v.
Kripke DF, Gillin JC, Mullaney DJ, Risch SC, Janowsky DS (1987): Treatment of major depressive disorders by bright white light for 5 days. In Halaris A (ed), Chronobiology and Psychiatric Disorders. Amsterdam: Elsevier, pp 207-218. Kripke DF, Mullaney DJ, Savides TJ, Gillin JC ([989): Phototherapy for non-seasonal major depressive disorder. In Rosenthal NE, Biehar M (eds), Seasonal Affective Disorder and Phototherapy. New York: Raven Press, pp 342-356. Lehr! S (1978): MehrfachwahI-Wortschatz-Test (MWT-B). Straube: Erlangen. Lewy AJ, Wehr TA, Goodwin FK, Newsome DA, Markey SP (I 980): Light suppresses melatonin secretion in humans. Science 210:1267-1269. Lewy AJ, Wehr TA, Goodwin FK, Newsome DA, Rosenthal NE (198 [): Manic-depressive patients may be supersensitive to light. Lancet 1:383-384. Lewy AJ, Kern HA, Rosenthal NE, Wehr TA (1982): Bright artificial fight treatment of a manicdepressive patient with a seasonal mood cycle. Am J Psychiatry 139:[496-1498. Lewy AJ, Sack RL, Singer CL (1984): Assessment and treatment of chronobiologic disorders using
268
BIOLPSYCHIATRY I~1 ;.~:257-2~
A. Macketl et al
plasma melatonin levels and bright light exposure: The clock-gate model and the phase response curve. Psychopharmacoi Bull 20:561-565. Lewy AJ, Nurnberger Jl, Wehr TA, et al (1985): Supersensitivity to light: Possible trait marker for manic-depressive illness. Am J Psychiatr), 142:725-727. Lewy AJ, Sack RL, Miller S, Hoban TM (1987a): Antidepressant and circadian phase-shifting effects of light. Science 235:352-354. Lewy AJ, Sack RL, Singer CM, White DM (1987b): ~ phase shift hypothesis for bright light's therapeutic mechanism of action: Theoretical considerations and experimental evidence. Psychopharmacol Bull 23:349-353. Mackert A, Volz HP, Stieglitz RD, Mtiller-Oeflinghausen B (1990): Effect of bright white light on non-seasonal depressive disorder. Pharmacopsychiatry 23:151-154. National Institute of Mental Health (1970): 1 2 ~ l , Clinical Global Impressions. In Guy W, Bonato RR (eds), Mahdi for the ECDEU Assessment Battery, reved. Cl~vy Chase, MD, pp 12-!-12-6. National Institute of Mental Health (1976): 028 CGI, Clinical Global Impressions. in Guy W (ed), ECDEU Assessment Manual for Ps),chopharmacology, rev ed. Rockville, MD; pp 217-222. Priebe S (1987): Early subjective reactions predicting the outcome of hospital treatment in depressive patients. Acta Po,chiatr Scand 76: ! 34-138. Rao ML, Mtiller-Oerlinghausen B, Mackert A, Volz HP, Franke N, Stieglitz RD (1991): Treatment with artificial light ameliorates depressive symptoms concomitantly with attenuation of blood serotonin but not serum melatonin in patients with non-seasonal affective disorder. Biol Psychiatr), (in press). Rosenthal NE, Sack DA, Gillin JC, et al (1984): Seasonal affective disorder---a prescription of the syndrome and preliminary findings with light t h e ~ y . Arch Gen Psychiatry. 41:72-80. Rosenthal NE, Sack DA, Carpenter CJ, Parry BL, Mendelson WB, Wehr TA (1985): Antidepressant effects of light in seasonal affective disorder. Am J Psychiatry 142:!63-170. Rosenthal NE, Sack DA, Jacobsen FM, et al (1986): Melatonin in seasonal affective disorder and phototherapy. J Neural Trans (Suppl) 2 ! :257-267. Spitzer RL, Endicott J, Robbins R (1977): Research Diagnostic Criteria (RDC)for a Selected Group of Functional Disorders, 3rd ed. New York: Biometrics Research. Terman M, Quitkin FM, Ten'nan JS, Stewart JW, McGrath PJ (1987): The timing of phototherapy: effects on clinical response and the melatonin cycle. Psychopharmacol Bull 23:354-357. Terman M, Terman JS, Schlager D, Quitkin FM (1988): Efficacy of 10,000 lux light therapy. Paper presented at the World Psychiatric Association meetings, Washington DC. Thompson C, lsaacs G, Stainer S, Miles A (1986): Seasonal affective disorder-phototherapy and salivary melatonin. Abstract N°263, 15.CINP in Puerto Rico. Volz HP, Macken A, Stieglitz RD, Miiller-Oerlinghausen B (1990): Effect of bright white light therapy on non-seasonal depressive disorder. Preliminary results. J Affective Disord 19:i5-21. yon Zerssen Dv (1986): Clinical Self-Rating Scales (CSRS) of the Munich psychiatric information system (PSYCHIS Mtinchen). In Sartorius N, Ban TA (eds), Assessment of Depression. Berlin: Springer, pp 270-303. Wehr TA, Jacobsen FM, Sack DA, Arendt J, Tamarkin L, Rosenthal ISlE (1986): Phototherapy of seasonal affective disorder. Arch Gen Psychiatry. 43:870-875. Wehr TA, Skwerer RG, Jacobsen FM, Sack DA.. Rosenthal NE (1987): Eye- vs. skin-phototherapy of seasonal affective disorder. Am J Psychiat 144:753-757. Wirz-Justice A, Bucheli B, Graw P, Kielholz P, Fisch HU, Woggon B (1986): Light treatment of seasonal affective disorder in Switzerland. Acta Psychiatr Scand 74:193-204. Wirz-Justice A, Schmid AC, Graw P, et al (1987): Dose relationships of mo~ing bright white light in seasonal affective disorders (SAD). Experimentia 43:574-576. Yerevanian BI, Anderson JL, Grota LJ, Bray M (1986): Effects of bright incandescent light on seasonal and non-seasonal major depressive disorder. Psychiatr Res 18:355-364.