THE EFFECTS OF MELATONIN AND BRIGHT LIGHT THERAPY IN SEASONAL AFFECTIVE DISORDER A PLACEBO CONTROLLED STUDY PMJ HAFFMANS, SAP LUCIUS, WA DIJKEN, RBC Department of Research, The Hague, The Netherlands Seasonal affective disorder (SAD) is a subsyndromal diagnosis in bipolar disorder or recurrent major depressive disorder, characterized by the recurrence of depressive episodes, which in most cases start in fall or winter and remit in the following spring or summer [American Psychiatric Association, 1994]. Moreover, most patients suffer from atypical symptoms like hyperphagia, hypersomnia, weight gain, fatigue and carbohydrate craving [Rosenthal et al., 1984]. Several studies reported the effectivity of a treatment with bright light [Terman et al., 1989]. As the treatment synchronises the biological clock and the rhythm of the serum melatonin in particular, chronobiological phase shifting is suggested as a possible explanation for the underlying mechanism of bright light therapy [Lewy et al., 1987; Lewy et al., 1988]. Given in the morning, bright light therapy has an acute suppressive effect on the serum melatonin levels and prolongs the subjective day [Lewy et al., 1980]. As melatonin is involved in the synchronisation of the biological clock as Zeitgeber [Rosenthal et al., 1986; Arendt et al., 1987; Rosenthal et al., 1992; Arendt, 1997], administration of melatonin a.n. could have an effect comparable with bright light therapy [Lewy et al., 1998]. This lead to the hypothesis that melatonin a.n. in combination with morning bright light treatment should have an positive additional effect on the treatment of SAD. In this study, the effects of bright light therapy in combination with oral melatonin a.n. or placebo a.n. are evaluated in patients suffering from seasonal affective disorder. In this double blind placebo controlled study, outpatients diagnosed with a seasonal affective disorder according to DSM-IV (major depressive disorder, recurrent with seasonal pattern; 296.3x), without laboratory abnormalities were asked to participate. After giving a written informed consent the patients filled in the SAD version of the Beck Depression Inventory (BDI) [Beck et al., 1961]. Eligible were patients with a score of at least 21 on the BDI at baseline. Excluded were patients with other axis-I pathology, psychotic or manic features, epilepsy, cataract, glaucoma and eye complaints. In the analysis 16 patients were included. Two patients dropped out due to severe side-effects (nausea, anxiety). All patients participating the study were treated with two consecutive weeks (2x5 days) of bright light therapy (BLT). At 8 a.m. the subjects were exposed to 10.000 lux bright light for 30 min. at a distance of 3050 centimetres. The patients were randomised to either melatonin 2.5 mg a.n. (group 1) or placebo (group 2) with identical capsules taken at 10 p.m. each day. Assessments of the severity of the seasonal affective disorder took place before treatment (baseline) and after one, two and six weeks. The Hamilton Rating Scale for Depression, version for seasonal affective disorders 53

[HRSD-SAD; Hamilton, 1967; Williams et al., 1992], is a self-rating scale in which expresses the severity of the seasonal affective disorder. As in fact the HRSD-SAD is an extended version of the HRSD, the scores on the HRSD and an atypical score were derived from the equivalent items on the HRSD-SAD [Terman et al., 1990]. The SAD version of the Beck Depression Inventory (BDI, Beck et al., 1961; Beck et al., 1979) is a selfrating scale on the severity of the depression in four categories: no depression, mild depression, mild to moderate depression and moderate to severe depression. The SAD version of the BDI is only used as instrument for inclusion. This version includes items concerning atypical depressive symptoms. The Symptom Checklist - 90 items [SCL-90; Arindell et al., 1981], is the Dutch version of the Hopkins Symptom Checklist (HSCL), validated by Arindell and Ettema. The SCL-90 was filled in by the patients at baseline and week six. The effects of the treatment were analysed by MANOVA. To find possible differences between the groups a Hierarchical Cluster Analysis was performed. Differences between the groups were tested for significance by two-tailed t-test. For all statistical tests, p-values ( 0.05 were considered significant. Sixteen patients (7M, 9F, mean age 42.3, S.D.=15) participated in the study. The mean score on the SAD version of the BDI at baseline was 25.0 (S.D.=9.4). The mean total scores on the HRSD-SAD, HRSD, and BDI at baseline and during the treatment are given in table 1. Table 1: Mean scores and SD on the HRSD-SAD (total score), HRSD and BDI (standard version) before and after 1, 2 and 6 weeks and their standard deviations (n=16). (n=16)

baseline

week 1

week 2

week 6

HRSD-SAD HRSD BDI

31.8 (9.7) 16.9 (6.1) 21.3 (8.1)

20.5 (11.9) 10.5 (8.0) 12.7 (9.5)

18.7 (14.2) 10.2 (9.2) 11.3 (10.6)

16.6 (13.6) 09.1 (6.2) 09.8 (9.6)

Multivariate analyses show a significant decrease on the HRSD-SAD (p=.004), the HRSD (p=.010) and the BDI (p=.011) between baseline and one, two and six weeks. The items expressing atypical symptoms show significant decreases (p=.000).The effect on the sumscores is only significant in the period between baseline and the first week in both groups (HRSD-SAD p=.005). Both changes between week one and week two (p=.363) and between week two and week six (p=.188) are not found significant. The same results are found for the scores on the HRSD and the BDI (see figure 1).

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Figure 1: Course of the mean scores on HRSD-SAD, HRSD, and BDI in the total population (n=16). The SCL-90 shows a decreasing trend on every subscale, though only the scale measuring insufficiency in thoughts and acting (see obsessive-compulsive disorder according to Derogatis, 1994) and the depression scale are significant. The mean depression value according to the SCL-90 decreases from mean 40.2 at baseline (S.D.=11.2; classified as severe) to 27.0 in week six (S.D.=8.7; moderate; see table 2). Table 2: Mean percentual decrease (M.P.D.) after six weeks, p-value and significance of the subscales of the SCL-90 of the total population (n=16). (n=16)

M.P.D. (%)

p-value

Sleep (SLA) Hostility (HOS) Agorafobia (AGO) Remaining (OV) Anxiety (ANG) Insufficience (IN) Physical (SOM) Sensitivity (SEN) Depression (DEP) Psychoneuroticism (PSNEUR)

08.9 18.5 14.3 10.7 20.1 24.7 17.5 11.9 27.1 18.9

.709 .343 .401 .429 .206 .035* .162 .523 .027* .144

* p ( 0.05 55

Hierarchical Cluster Analysis was performed to examine if two groups could be determinated, based on the scores of the HRSD-SAD, HRSD and BDI. The groups differentiated significantly on these scales after two and six weeks (p=.000 for all). After breaking the medication code, the two groups appeared to be exactly the two medication conditions. Figure 2 shows the results found in condition 1 (BLT in combination with melatonin) and in condition 2 (BLT in combination with placebo). The range of the percentual decrease of the HRSD-SAD total score during the treatment in condition 1 varied from 12% to -67%. Condition 2 showed percentual decreases in the range from 32% to 100%.

Figure 2: HRSD-SAD score of condition 1 (BLT and melatonin) and condition 2 (BLT and placebo) in the treatment SAD. The aim of the study was to evaluate the additional effects of melatonin to bright light in the treatment of patients with seasonal affective disorder. The results show a significant overall decrease in the severity of depression measured by HRSD-SAD, HRSD, and BDI. Especially in the first week of the treatment a very obvious, significant decrease in the scores on the scales was found. Though not significant, the decreasing trend lasted till the sixth week. Both typical and atypical depressive symptoms decreased during after the treatment. The SCL-90 shows a significant improvement concerning depression and insufficiency in thought and acting. Unexpectedly the condition consisting of patients treated with bright light with the active medication turned out to be the non-responding group. A possible explanation might be that melatonin in addition to BLT results in an overshoot of phase advancing effects. The double phase advancing effects of both BLT and melatonin might be too much and might result in a desynchronisation, with consequently the clinical symptoms. Obviously to combine controlled bright light and melatonin in the management or treatment of SAD is not advantageous. These findings do not support the suggestion of Arendt to combine melatonin treatment and controlled bright light in the management of rhythm disorders [Arendt, 1997]. However, timing of the bright light treatment and melatonin might play a crucial role. In con56

formity with the report of Lewy et al., the patients treated in the melatonin condition, appeared to be very sensitive to the soporific effect of melatonin [Lewy et al., 1998]. Although the patients in the placebo group improved by the phototherapy, a contribution to the effect by the forced structure in daily rhythm (i.e. being present at eight a.m. each day), can not be excluded [Amir et al., 1996]. REFERENCES American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders. 4th edition. Washington: American Psychiatric Association Amir S., and Stewart J. (1996) Resetting of the circadian clock by a conditioned stimulus. Nature, 379: 542-545. Arendt J, Aldhous M, English J, Marks V, Arendt JH, Marks M and Folkard S (1987) Some effects of jet-lag and their alleviation by melatonin. Ergonomics, 30: 13791393 Arendt J (1997): Melatonin. In Schwartz WJ (ed), Sleep science: intergrating basic research and clinical practice, Vol 15. Basel: Karger, pp 196-228. Arrindell W.A., and Ettema J.H.M. (1981) Dimensionele structuur, betrouwbaarheid en validiteit van de Nederlandse bewerking van de Symptom Checklist (SCL-90). Ned. Tijdschr. Psychol., 36: 77-108 Beck AT, Ward CH, Mendelson M, Mock J and Erbaugh J (1961) An inventory for measuring depression. Archives of General Psychiatry, 4: 53-63 Beck A.T., Rush A.J., Shaw B.F., Emery G. (1979) Cognitive therapy of depression. N. Guilford. Derogatis, L. R. (1994) The Symptom Checklist 90-R: Administration, scoring, and procedures manual. (3 ed.). MN: National Computer Systems. Hamilton (1967) Development of a rating scale for primary depressive illness. Br. Journ. Soc. Clin. Psychology, 6: 278-296 Lewy AJ, Wehr TA and Goodwin FK (1980) Light suppresses melatonin secretion in humans. Science, 210: 1267-1269 Lewy AJ, Sack RL, Miller LS, Hoban TM (1987): Antidepressant and circadian phaseshifting effects of light. Science 235:352-354. Lewy AJ, Sack RL, Singer CM, White DM and Hoban TN (1988) Winter depression and phase-shift hypothesis for bright light’s therapeutic effects: history, theory, and experimental evidence. Journal of Biological Rhythms, 3: 121-134 Lewy A.J., Bauer V.K., Cutler N.L. and Sack R.L. (1998) Melatonin treatment of winter depression - a pilot study. Psychiatry Res. 77: 57-61 Meesters Y., and Jansen J.H. (1993) Assessing atypical seasonal affective disorder complaints by means of self-rating. Acta Psychiatrica Scandinavica, 88: 361-363 Rosenthal NE, Sack DA, Gillin JC, Lewy AJ, Goodwin FK, Davenport Y, Mueller PS, Newsom DA and Wehr TA (1984) Seasonal affective disorder: a description of the syndrome and preliminary findings with light therapy. Archives of General Psychiatry, 41: 72-80

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Rosenthal N.E. et al. (1986) Melatonin in seasonal affective disorder and phototherapy. J. of Neural Transm., 21: 257-267 Rosenthal N.E. and Wehr T.A. (1992) Towards understanding the mechanism of action of light in seasonal affective disorder. Pharmacopsychiatry, 25: 56-60 Terman M, Terman JS, Quitkin FM, McGrath PJ, Steward JW, Rafferti B, (1989) Lighttherapy for seasonal affective disorder. A review of efficacy, Neuropsychopharmacology, 2: 1-22 Terman JS, Terman M, Schlager D, Rafferty B, Rosofsky M, Link MJ, Gallin PF, Quitkin FM (1990): Efficacy of brief, intense light exposure for treatment of winter depression. Psychopharmacology Bulletin 26:3-11. Williams JBW, Link MJ, Rosenthal NE, Terman M (1992): Structured guide for the Hamilton Depression Rating Scale, seasonal affective disorders version (SIGH-SAD). New York: New York State Psychiatric Interview.

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