The circadian basis of winter depression

Abstract

The following test of the circadian phase-shift hypothesis for patients with winter depression (seasonal affective disorder, or SAD) uses low-dose melatonin administration in the morning or afternoon/evening to induce phase delays or phase advances, respectively, without causing sleepiness. Correlations between depression ratings and circadian phase revealed a therapeutic window for optimal alignment of circadian rhythms that also appears to be useful for phase-typing SAD patients for the purpose of administering treatment at the correct time. These analyses also provide estimates of the circadian component of SAD that may apply to the antidepressant mechanism of action of appropriately timed bright light exposure, the treatment of choice. SAD may be the first psychiatric disorder in which a physiological marker correlates with symptom severity before, and in the course of, treatment in the same patients. The findings support the phase-shift hypothesis for SAD, as well as suggest a way to assess the circadian component of other psychiatric, sleep, and chronobiologic disorders.

Conflict of interest statement

Conflict of interest statement: A.J.L. is coinventor on several melatonin use-patents owned by Oregon Health & Science University currently not licensed to any company.

Figures

Fig. 1.

Schematic diagram of normal phase relationships (rounded to the nearest integer) between sleep phase markers, the 10 pg/ml plasma DLMO (10), and the core body temperature minimum (Tmin) (27, 32) derived from historical controls. The present study used the DLMO/midsleep interval PAD of 6 h as the hypothesized therapeutic window for optimal circadian alignment. Sleep times were determined actigraphically. Plasma melatonin levels were obtained under dim light every 30 min in the evening. The operational definition of the DLMO is the interpolated time of continuous rise above the threshold of 10 pg/ml; for example, if the melatonin level at 8 p.m. was 5 pg/ml and at 8:30 p.m. was 15 pg/ml, the DLMO would be 8:15 p.m.

Fig. 2.

Pretreatment SIGH-SAD depression score as a function of PAD (the interval between the DLMO and midsleep). [The circled data point (from a 36-year-old female 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.]

Fig. 3.

Posttreatment 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).

Fig. 4.

Posttreatment SIGH-SAD score as a function of PAD in delayed subjects. (The parabolic curve and related statistics for the delayed subjects are provided in Fig. 3.) The linear correlation between PAD and SIGH-SAD score (diagonal hatched line) did not reach statistical significance, confirming that the parabolic curve in Fig. 3 for delayed subjects (R2 = 0.19, P = 0.009) is the better fit for these data. Directional linear correlations for under- and 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 = 0.56, df = 8, P = 0.01).

Fig. 5.

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.

Fig. 6.

Percent change in (SIGH-SAD) depression score after correct treatment, incorrect treatment, and placebo, as well as incorrect treatment and placebo combined (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–Wallis H test (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 t 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 posttreatment percent changes were significant for all groups: correct (t = 5.43, df = 16, P < 0.001), incorrect (t = 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).]