Clinical applications of melatonin in circadian disorders

Figures & data

Figure 1. Schematic diagram depicting neuroanatomic regulation of mammalian melatonin production. Reproduced from reference 18: Vessely LH, Lewy AJ. Melatonin as a hormone and as a marker for circadian phase position in humans. In: Pfaff D, Arnold A, Etgen A, Fahrbach S, Rubin R, eds. Hormones, Brain and Behavior, Vol 5. San Diego, Calif: Elsevier Science; 2002:121-141. Copyright © 2002, Elsevier Science.

Figure 2. Relationship between the endogenous melatonin profile, the melatonin phase response curve (PRC), and the sleep/wake cycle. MO, melatonin onset; BFR, blind free-runner; CT, circadian time. Adapted from reference 41: Lewy AJ, Bauer VK, Hasler BP, Kendall AR, Pires MLN, Sack RL. Capturing the circadian rhythms of free-running blind people with 0.5 mg melatonin. Brain Res. 2001;918:96-100. Copyright © 2001, Elsevier Science BV.

Figure 3. A totally blind subject with free-running circadian rhythms during four trials of oral melatonin administration. Each data point represents an assessment of circadian phase as determined by successive measurements of the time that endogenous plasma melatonin concentrations rose above the 10 pg/mL threshold. Vertical lines represent the timing and duration of exogenous melatonin administration. The slopes of the fitted regression lines indicate circadian period (shown in hours beside the regression lines) during a given treatment. The calculated circadian periods represent mean determinations between days of assessment; fluctuation of circadian period probably occurs as the melatonin dose stimulates different parts of the shifting phase response curve (PRC). a. Baseline free-running circadian rhythm of 24.92 h. b. Administration of 10 mg melatonin for 17 days beginning at CT 20.5 led to a shortened period of 24.34 h without entrainment. c. Administration of 9 to 10 mg of melatonin over 83 days again failed to entrain this subject but shortened circadian period to 24.36 h. d. Administration of 20 mg initially at CT 14.6 shortened the subject's circadian period to 24.58 h after 60 days. e. Administration of 0.5 mg, initially at CT 20.6, caused entrainment (circadian period of 23.98 h) after 47 days. Reproduced from reference 92: Lewy AJ, Emens JS, Sack RL, Hasler BR Bernert RA. Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period. Chronobiol Int. 2002;19:649-658. Copyright © 2002, Marcel Dekker.

Figure 4. Pharmacokinetic data from two different melatonin doses (0.5 and 10 mg) in relation to the endogenous melatonin profile and the melatonin phase response curve (PRC). The 0.5 mg dose and the endogenous melatonin profile are data from the subject in this study. The 10 mg data were from another subject and were not collected beyond 10 h; it is clear that they cause more stimulation of the delay zone of the melatonin PRC than the 0.5 mg dose. By convention, circadian time (CT) 14 is the endogenous melatonin onset (MO). In free-running subjects, the endogenous melatonin profile and the melatonin PRC (which are phase-locked) drift later each day with respect to the sleep/wake cycle. Normal phase is when the MO occurs 2 h before sleep onset (14 h after waketime). Exogenous melatonin causes phase advances when it is given between CT 6 and CT 18 and causes phase delays when it is given between CT 18 and CT 6; however, the concentrations and duration of exogenous melatonin levels as they spill over onto the wrong zone of the melatonin PRC may also affect the phase-shifting effect of exogenous melatonin. Reproduced from reference 92: Lewy AJ, Emens JS, Sack RL, Hasler BP, Bernert RA. Low, but not high, doses of melatonin entrained a free-running blind person with a long circadian period. Chronobiol Int. 2002;19:649-658. Copyright © 2002, Marcel Dekker.

Figure 5. Pretreatment tau predicts phase angle of entrainment (PAE). PAE is the interval (in hours) between the time of the bedtime 10 mg melatonin dose and the entrained melatonin onset (MO) of the endogenous melatonin profile. This figure is an updated version of what has been previously reported, and the tau of one person has been changed to 24.58 h from 24.63 h, correcting an error in the previous report. The horizontal dotted line indicates that entrainment will fail if the phase angle of entrainment is more than 8 h. Reproduced from reference 93: Lewy AJ, Hasler BR Emens JS, Sack RL. Pretreatment circadian period in free-running blind people may predict the phase angle of entrainment to melatonin. Neurosci Lett. 2001;313:158-160. Copyright © 2001, Elsevier Science.

Figure 6. Blue circles represent an assessment of circadian phase as determined by the time that endogenous salivary melatonin concentrations continuously rose above the 0.7 pg/mL threshold. Vertical lines represent the timing and duration (days) of exogenous melatonin administration of 0.05 mg (black line) and 0.025 mg (gray line). All times are presented in Pacific Standard Time (some times have been converted from Daylight Saving Time).

Table I Phase typing for circadian rhythm disorders.