The melatonin PRC was first described using four daily doses of 0.5 mg melatonin in sighted people. It has been by and large replicated by two other research groups.73,74 In sighted people who habitually awaken at 7.00 am, the break points that divide the two intervals of the melatonin PRC occur at 1.00 pm (CT 6) and 1.00 am (CT 18), just as with the light PRC. The phase-advance zone is between 1.00 am and 1.00 pm; the phase-delay zone is between 1.00 am and 1.00 pm. Once again, the phaseadvance Inhibitors,research,lifescience,medical zone of the melatonin PRC extends from CT 6 to CT 18, and the phase-delay zone extends from CT 18 to CT 6. Therefore, once the time of the MO is known, the advance

zone extends from 8 h before the MO until 4 h after the MO. The delay zone extends from 4 h after the MO until 8 h before the MO. Treating SAD patients with melatonin: the importance of creating Inhibitors,research,lifescience,medical “owerfap” Creating “overlap” may be an important principle in optimizing melatonin’s phase-shifting effects. ‘Phis was demonstrated in a pilot study treating SAD patients with melatonin.75 In order to avoid the soporific side effect of sleepiness that occurs in some people, the dose of melatonin is kept to a minimum, so as to reduce the initial spike in melatonin levels following an oral, immediaterelease formulation. However, according

Inhibitors,research,lifescience,medical to the melatonin PRC, the earlier Inhibitors,research,lifescience,medical melatonin is given in the afternoon (at least for the second half of the advance zone), the greater the magnitude of the phase-advance shift. If a low dose is given too early, however, there will be a melatonin-frec interval

between the end of the exogenous pulse and the beginning of the endogenous melatonin profile that occurs about 14 h after waketime in entrained, sighted people. Therefore, a second (or even a third or possibly fourth) small dose of melatonin Inhibitors,research,lifescience,medical is given to create overlap between elevated melatonin levels arising from exogenous and endogenous sources, so that the SCN is exposed to one continuous melatonin signal. Recently, a more definitive test of the PSH for SAD was completed, using three to four small doses of melatonin (0.075-0.1 mg) given every 2 h in the morning or in the afternoon/evening. One hundred patients were studied over four winters. One-third of them did not receive melatonin in any capsule, although all subjects took the same Resminostat number of capsules per day. Subjects were held to consistent bedtimes and waketimes of their choosing. The results supported the PSH. In the most phase-delayed group of patients (those with a DLMO ZT >14.6), there was a OTX015 concentration significant correlation between the amount of phase delay at baseline and the severity of depression ratings. After 3 weeks of treatment, this correlation remained significant, but only if depression severity was analyzed with regard to the absolute difference from the hypothesized “normal.” ZT of 14.