The phase shift hypothesis for the circadian component of winter depression

Abstract

The finding that bright light can suppress melatonin production led to the study of two situations, indeed, models, of light deprivation: totally blind people and winter depressives. The leading hypothesis for winter depression (seasonal affective disorder, or SAD) is the phase shift hypothesis (PSH). The PSH was recently established in a study in which SAD patients were given low-dose melatonin in the afternoon/evening to cause phase advances, or in the morning to cause phase delays, or placebo. The prototypical phase-delayed patient, as well as the smaller subgroup of phase-advanced patients, optimally responded to melatonin given at the correct time. Symptom severity improved as circadian misalignment was corrected. Circadian misalignment is best measured as the time interval between the dim light melatonin onset (DLMO) and mid-sleep. Using the operational definition of the plasma DLMO as the interpolated time when melatonin levels continuously rise above the threshold of 10 pg/mL, the average interval between DLMO and mid-sleep in healthy controls is 6 hours, which is associated with optimal mood in SAD patients.

Figure 1.. Use of bright light and low-dose melatonin to treat circadian phase disorders. Adapted from ref 10: Lewy AJ, Sack RL. The role of melatonin and light in the human circadian system. In: Buijs R, Kalsbeek A, Romijn H, Pennartz C, Mirmiran M, eds. Progress in Brain Research, Vol, 111, Hypothalamic Integration of Circadian Rhythms. Amsterdam: Elsevier; 1996:205-216. Copyright © Elsevier 1996

Figure 2.. The dim light melatonin onset (DLMO) in plasma is operationally defined as the interpolated time when melatonin levels continuously rise above the threshold of either 10 pg/mL or 2 pg/mL (which usually occurs about 1hour earlier). In this figure the DLMO₂ is at about 20:30 and the DLMO10 is about 21:30.

Figure 3.. Schematic diagram of normal phase relationships (rounded to the nearest integer) between sleep phase markers, the 10 pg/mL plasma dim light melatonin onset (DLMO) and the core body temperature minimum derived from historical controls. A DLMO-midsleep phase angle (PAD) difference of 6 h is the hypothesized interval for optimal circadian alignment in SAD (seasonal affective disorder) patients. Sleep times were determined using actigraphy. Adapted from ref 20: Lewy AJ, Lefler BJ, Emens JS, Bauer VK. The circadian basis of winter depression. Proc Natl Acad Sci U S A. 2006:103:74147419. Copyright © National Academy of Sciences 2006

Figure 4.. Pretreatment SIGH-SAD depression score as a function of PAD (the interval between the DLMO and midsleep, as shown in Figure3). (The circled data point from a 36-year-old female SAD subject who was assigned to placebo treatment was the only one that met outlier criteria [z =3.02] and was therefore removed from all subsequent analyses and did not substantially affect any of the above findings [no outliers were detected in any other analyses].) The parabolic curve (minimum =5.88) indicates that PAD accounts for 17% of the variance in SIGH-SAD scores (F [2, 65] =6.43). A significant linear correlation was found for the absolute deviation from the parabolic minimum (r=0.39, R² =0. 15, df =65, P =0.001), confirming the validity of the parabolic curve fit. SAD, seasonal affective disorder; PAD, phase angle difference. Adapted from ref 20: Lewy AJ, Lefler BJ, Emens JS, Bauer VK. The circadian basis of winter depression. Proc Natl Acad Sci U S A. 2006:103:74147419. Copyright © National Academy of Sciences 2006

Figure 5.. Post-treatment SIGH-SAD score as a function of PAD. The parabolic curve (minimum =6. 18) indicates that PAD accounts for 11% of the variance in SIGH-SAD scores [F (2, 65)=3.96] for all subjects and 19% for phase-delayed subjects [F (2,45)=5.19]. Absolute deviations from the parabolic minima (6. 18 and 5.85, respectively) were statistically significant (advanced and delayed subjects: r=0.29, R²=0.09 df=65, P=0.02; delayed subjects: r=0.48, R²=0.23, df=65, P=0.001). SAD, seasonal affective disorder; PAD, phase angle difference Adapted from ref 20: Lewy AJ, Lefler BJ, Emens JS, Bauer VK. The circadian basis of winter depression. Proc Natl Acad Sci USA. 2006: 103:7414-7419. Copyright © National Academy of Sciences 2006

Figure 6.. Post-treatment SIGH-SAD score as a function of PAD in delayed subjects. (The parabolic curve and related statistics for the delayed subjects are provided in Figure 4). The linear correlation between PAD and SIGH-SAD score (diagonal hatched line) did not reach statistical significance, confirming that the parabolic curve in Figure 4 for delayed subjects (R2=0.19, P=0.009) is the better fit for these data. Directional linear correlations for underand overshifters (to the right and left of PAD 6, respectively) were both statistically significant. The parabolic curve for subjects receiving PM melatonin indicates that PAD accounts for 65% of the variance in SIGH-SAD scores (F [2, 8] =7.57; minimum =5.56); the correlation between the absolute deviation from the parabolic minimum was also statistically significant (r=0.75, R²=056, df=8, P=0.001 SAD, seasonal affective disorder; PAD, phase angle difference. Adapted from ref 20: Lewy AJ, Lefler BJ, Emens JS, Bauer VK. The circadian basis of winter depression. Proc Natl Acad Sci U S A. 2006:103:74147419. Copyright © National Academy of Sciences 2006

Figure 7.. Percent change in SIGH-SAD score as a function of net change in absolute deviation toward and away from PAD 6 in PM melatonin treated advanced and delayed subjects. Pretreatment vs posttreatment shifts with respect to PAD 6 account for 35% of the variance. SAD, seasonal affective disorder; PAD, phase angle difference Adapted from ref 20: Lewy AJ, Lefler BJ, Emens JS, Bauer VK. The circadian basis of winter depression. Proc Natl Acad Sci U S A. 2006:103:74147419. Copyright © National Academy of Sciences 2006

Figure 8.. Percent change in (SIGH-SAD) depression score after correct treatment incorrect treatment and placebo, as well as incorrect treatment and placebo combined (correct treatment such as giving PM melatonin to phase-delay SAD patients, etc; see text for details of the composition of these treatment groups). Baseline SIGH-SAD scores for the three treatment groups (correct treatment incorrect treatment and placebo) were 28.9+1.0, 28.8+1.3, and 26.6+1.4, respectively. The Kruskal-WallisHtest (χ²=5.83, df=2, P=0.05) was statistically significant, but not the one-way ANOVA (F =2.96 on [2, 65], P=0.06). By using the Welch two-sample f test to compare differences in the change scores of the correct-treatment group with those of the other groups, correct treatment significantly decreased depression ratings more than the other groups: incorrect (19.1%: t =2.09, df =40.8, P =0.04); placebo (20.9%: t=2. 60, df =34.2, P=0.01); the latter two groups combined (19.9%: t=2.65, df =32.1, P=0.01). Pretreatment to post-treatment percent changes were significant for all groups: correct (t =5.43, df = 16, P<0.001), incorrect (f =2.20, df =26, P=0.04), placebo (t=2.50, df =23, P=0.02), and the latter two groups combined (t =3.25, df =50, P =0.002). Effect sizes (ES) are shown for pretreatment to posttreatment percent change scores for each group; also shown are the more conservative ES for differences in change scores between the correct treatment group and the other groups. (Before phase typing, percent change in the pm treated group was -28.5 + 5.6, and percent change in the am treated group was -15.5 + 8.0, although there were no statistically significant differences between the three treatment groups in percent changes in SIGH-SAD scores [see above]). SAD, seasonal affective disorder Adapted from ref 20: Lewy AJ, Lefler BJ, Emens JS, Bauer VK. The circadian basis of winter depression. Proc Natl Acad Sci U S A. 2006:103:74147419. Copyright © National Academy of Sciences 2006.

Figure 9.. Previously unpublished analyses based on data from the study by Lewy et al, 2006. SIGH-SAD and HAM-D scores of the groups receiving melatonin treatment given at the correct time vs. the incorrect time or placebo are shown by week. Although a two-sample t-test showed significant differences in the SIGHSAD scores of the treatment groups only at week 3 (P=0.04), the response appears to start between week 1and week 2. A two-sample t-test showed significant differences in the HAM-D scores of the two groups beginning at week 2 and increasing at week 3 (P=0.05, P=0.03, respectively), though these differences are also apparent at week 1. Additionally, regressions were run over the SIGH-SAD and HAM-D scores (P =0.04 and P =0.03, respectively) of each individual's weekly assessments, and a twosample t-test confirmed that the slopes of the subjects receiving correctly-timed melatonin were different from those receiving incorrectly-timed melatonin or placebo. SAD, seasonal affective disorder