Bright light is one of the most powerful time cues for the internal circadlan timing system. Light exposure at specific times of the 24-h period can result in a phase-shift in the endogenous circadlan rhythms of a variety of functions, such as melatonin secretion, body temperature, and sleep propensity.34-36 These tlme-dependent effects of

light were described by phase-response curves (PRCs).13,37 In general, morning bright-light exposure induces a phase advance, whereas evening bright light exposure induces phase delay. Using the entraining properties Inhibitors,research,lifescience,medical of light to synchronize sleep-wake schedule of patients with CRSDs has become an increasingly popular therapy Artificial bright light applied by light devices at the intensities of 2000 to 4000 lux has been successfully used to realign the Orcadian phase of patients with DSPS and ASPS, and some evidence supports its effectiveness in treatment of nonentrained type sleep disorders, Inhibitors,research,lifescience,medical jet lag, shift work, and dementia.38 The American Academy of Sleep Medicine has provided the recommended intensities and time 11mits for phototherapy in the treatment of these disorders.38 Endogenous melatonin secreted by the pineal gland is another potent regulator of the sleep-wake

cycle. It is thought that the nighttime increase in melatonin concentration Inhibitors,research,lifescience,medical reduces body temperature, which promotes the onset of sleep.39 Previous findings have demonstrated that pharmacological preparations of melatonin mimic the effects of endogenous melatonin, which are time-dependent: phase advance Inhibitors,research,lifescience,medical is produced by melatonin admlnistered in the evening, whereas melatonin our administration in the morning induces phase delays.40 Thus, the PRC to melatonin is about 12 h out of phase Inhibitors,research,lifescience,medical with the PRC

to light.41 Administration of melatonin might be a preferable therapeutic strategy for many patients, who find phototherapy too demanding, leading to decreased compliance. The beneficial effects of 0.5 to 5 mg/day melatonin have been demonstrated in several types of CRSDs.42-46 Importantly, treatment with melatonin not only synchronizes the sleep-wake cycle of patients with CRSDs, but also significantly and Entinostat clinically meaningfully improves several dimensions of their daytime functioning.47 Although some recent well-designed studies indicate that even relatively large doses of melatonin (10 mg/day for a month) have no toxlcological effects,48 Its long-term effects remain to be fully researched and resolved. In patients for whom all of these treatment modalities fail to help, a rehabilitative approach is recommended. The patients should be guided to accept that their condition is permanent, and should be encouraged to consider changes in lifestyle that will be congruent with their sleep-wake cycle.