While it was previously thought that circadian rhythms were entrained through light signals coming from the visual system per se, recent studies have identified a novel class of intrinsically light sensitive retinal ganglion cells that send axonal projections to the SCN independently of rod and cone photoreceptors.21 These SCN-projecting cells express newly discovered photopigments such as melanopsin22 and cryptochromes.23 Circadian rhythms have been an important focus for SAD research. Lewy et al proposed a phase shift hypothesis of SAD, suggesting that seasonal

depression occurs when intrinsic circadian rhythms, such Inhibitors,research,lifescience,medical as the melatonin and temperature rhythms, are phase delayed relative to the external clock and/or sleep/wake cycle.24 According to this model, light therapy should exert its therapeutic effect by correcting these phase abnormalities. A further prediction of this hypothesis is that www.selleckchem.com/products/Decitabine.html morning light therapy should be superior to evening light therapy for the larger group of SAD patients who start with a phase delay, based on the Inhibitors,research,lifescience,medical ability of morning light to cause a corrective phase advance. This contrasts the effect of evening light, which would further delay circadian

phase. Regarding the first component of the phase shift hypothesis, Inhibitors,research,lifescience,medical several studies have looked for a phase delay in circadian rhythms in SAD patients relative to controls. While both positive and negative studies have been reported,16,25-32 it could be argued that one or more masking effects may have Inhibitors,research,lifescience,medical limited some of these results. One study that used a stringent constant routine protocol to minimize the problem of masking effects did find circadian phase delays in a small number of hypersomnic patients.33 However, given the intensive nature of the constant routine protocol, dim light melatonin onset (DLMO), which can be measured using salivary samples, is a more practical means of assessing circadian phase in larger samples. Using this methodology, a recent study in 68 SAD patients found that 71% were in fact phase delayed, while 29% were phase advanced, suggesting that the phase advanced subtype might Inhibitors,research,lifescience,medical be more common than previously thought.34

Regarding the question of whether light therapy works by correcting a phase delay in circadian rhythms, two meta-analyses35,36 do support the prediction that morning light, which phase advances circadian rhythms, is more effective than light administered at other times of day. Melatonin given in the evening, a different means of producing a phase advance, much has also been shown to have therapeutic effects in SAD patients, particularly for subjects having a phase delay at baseline.34 Other work has shown that while the ability of light to produce a phase advance contributes to its clinical efficacy, this is not limited to subjects who are phase delayed to start with. Rather, it is the size of the phase advance relative to one’s sleep rhythm that is most important, with the optimal response achieved with light given 8.