Winter Depression: Integrating mood, circadian rhythms, and the sleep/wake and light/dark cycles into a bio-psycho-social-environmental model

Abstract

The phase shift hypothesis (PSH) states that most patients with SAD become depressed in the winter because of a delay in circadian rhythms with respect to the sleep/wake cycle: According to the PSH, these patients should preferentially respond to the antidepressant effects of bright light exposure when it is scheduled in the morning so as to provide a corrective phase advance and restore optimum alignment between the circadian rhythms tightly coupled to the endogenous circadian pacemaker and those rhythms that are related to the sleep/wake cycle. Recent support for the PSH has come from studies in which symptom severity was shown to correlate with the degree of circadian misalignment: it appears that a subgroup of patients are phase advanced, not phase delayed; however, the phase-delayed type is predominant in SAD and perhaps in other disorders as well, such as non-seasonal unipolar depression. It is expected that during the next few years the PSH will be tested in these and other conditions, particularly since healthy subjects appear to have more severe symptoms of sub-clinical dysphoria correlating with phase-delayed circadian misalignment; critically important will be the undertaking of treatment trials to investigate the therapeutic efficacy of morning bright light or afternoon/evening low-dose melatonin in these disorders in which symptoms are more severe as the dim light melatonin onset (DLMO) is delayed with respect to the sleep/wake cycle (non-restorative sleep should also be evaluated, as well as bipolar disorder). The possibility that some individuals (and disorders) will be of the phase-advanced type should be considered, taking into account that the correct timing of phase-resetting agents for them will be bright light scheduled in the evening and/or low-dose melatonin taken in the morning. While sleep researchers and clinicians are accustomed to phase-typing patients with circadian-rhythm sleep disorders according to the timing of sleep, phase typing based on the DLMO with respect to the sleep/wake cycle may lead to quite different recommendations for the optimal scheduling of phase-resetting agents, particularly for the above disorders and conditions.

Figure 1

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) derived from historical controls. The present study used the melatonin/mid-sleep interval (phase angle difference, or PAD) of 6 hours as the hypothesized therapeutic window for optimal circadian alignment. Sleep times were determined actigraphically. Plasma melatonin levels were obtained under dim light every 30 minutes in the evening. The operational definition of the melatonin onset 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 melatonin onset would be 8:15 p.m. Adapted from[7], with permission.

Figure 2

Figure 2 (left). Effect of light on melatonin secretion. Each point represents the mean concentration of melatonin (+/− standard error) for six subjects. Figure 2 (right). Effect of different light intensities on melatonin secretion. The averaged values for two subjects are shown. Symbols: (O) 500 lux; (X) 2500 lux; (●) 1500 lux; and (□) asleep in the dark. Melatonin levels were measured by mass spectrometry [13]. These early studies were responsible for an increased awareness of the importance of the light/dark cycle as a zeitgeber (time cue) for human circadian rhythms and for the use of the dim light melatonin onset (DLMO) as a circadian phase marker and of bright light as a circadian phase resetting agent in the treatment of circadian phase disorders, including winter depression (SAD) and the circadian disorders experienced by totally blind people. From [21], with permission.

Figure 3

The optimal times to schedule bright light exposure and low-dose melatonin administration to cause circadian phase shifts are based on their respective phase response curves (PRCs) which are about 12 hours out of phase with each other. The 10 pg/ml plasma (3 pg/ml saliva) melatonin onset marking circadian time (CT) 14, can be used to indicate when advance and delay responses occur, in order to maximize phase shifts. The crossover times are eight hours before (circadian time 6), and four hours after (circadian time 18), the melatonin onset. Also indicated are clock times typical for individuals who awaken at 6 a.m. (0600). Optimally, exogenous melatonin should overlap with either the onset or the offset of the endogenous melatonin profile. High doses (greater than about 5 mg) may be less effective than lower doses, because of spillover onto the wrong zone of the melatonin phase response curve. The crossover times for the light PRC are based on the one published by Czeisler and co-workers [75] in the Johnson Atlas of PRCs [76]; the optimal light times for scheduling light are based on earlier work [26] and the melatonin crossover and optimal scheduling times are based on the melatonin PRC [4939]. Adapted from [62] with permission.

Figure 4

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. 13% has been added to the change in SIGH-SAD score to remove the average placebo response. Pretreatment vs. post-treatment shifts with respect to PAD 6 account for 35% of the variance. Adapted from [7], with permission.