Methods for treating circadian rhythm disorders

Abstract

A method for treating circadian rhythm disorders is described. The method involves the administration of melatonin, melatonin agonists or compounds that stimulate endogenous melatonin production so that the durations of the effective plasma concentrations of melatonin, melatonin agonists or compounds that stimulate endogenous melatonin production overlap with onset or offset of pre-treatment endogenous melatonin production, to provide a circadian-rhythm phase advance or phase delay, respectively. The methods of the invention also provide for concentration and/or duration of the effective plasma concentrations of melatonin, melatonin agonists or compounds that stimulate endogenous melatonin production to be greater in the time interval between about 8 hours before the dim light endogenous melatonin onset (DLMO) to about 4 hours after DLMO than in the time interval from about 4 hours after DLMO to about 8 hours before DLMO to achieve a circadian-rhythm phase advance. The methods of the invention also provide for concentration and/or duration of the effective plasma concentrations of melatonin, melatonin agonists or compounds that stimulate endogenous melatonin production to be greater in the time interval between about 4 hours after DLMO to about 8 hours before DLMO than in the time interval from about 8 hours before DLMO time to about 4 hours after DLMO to achieve a circadian-rhythm phase delay. In addition, the invention provides methods for regulating a human's exposure to light and dark to prevent or enhance, respectively, the human's endogenous production of melatonin. The use of melatonin antagonists, inverse agonists and melatonin inhibitory compounds such as beta-blockers for achieving a circadian-rhythm phase-shifting effect (opposite to that of melatonin administration) are also provided by the invention. The methods of the invention are illustrated by teachings for use of these methods for alleviating a variety of circadian rhythm-related disorders, including jet lag, winter depression, shift work-related desynchronies and sleep phase disorders.

We claim:  
     
         1 . A method for achieving a circadian rhythm phase-delaying effect in a human, the method comprising the step of: 
 administering to the human an amount of melatonin, melatonin agonist or compound that increases endogenous production of melatonin in the human, wherein said administration produces in the human a plasma melatonin or agonist concentration of greater than quiescent melatonin or equivalent agonist levels at a time that does not overlap with onset of endogenous melatonin production in the human, and    wherein when melatonin, melatonin agonist or compound that increases endogenous production of melatonin in the human is administered to produce plasma melatonin or agonist concentration of greater than quiescent melatonin or equivalent agonist levels that overlaps offset of endogenous melatonin production, said greater than quiescent melatonin or equivalent agonist levels rise after the melatonin onset and fall before the next melatonin onset.    
     
     
         2 . The method of  claim 1  wherein melatonin, melatonin agonist or compound that increases endogenous production of melatonin in the human is administered to produce plasma melatonin or agonist concentration of greater than quiescent melatonin or equivalent agonist levels that rise after about CT 18 and fall before about CT 14.  
     
     
         3 . The method of  claim 2  wherein melatonin, melatonin agonist or compound that increases endogenous production of melatonin in the human is administered to produce plasma melatonin or agonist concentration of greater than quiescent melatonin or equivalent agonist levels that rise after about CT 18 and fall before about CT 6.  
     
     
         4 . The method of  claim 2  wherein melatonin, melatonin agonist or compound that increases endogenous production of melatonin in the human is administered to produce plasma melatonin or agonist concentration of greater than quiescent melatonin or equivalent agonist levels that rise after about CT 18 and fall before about CT 1.  
     
     
         5 . A method according to claims  1 ,  2 ,  3  or  4  wherein exogenous melatonin, melatonin agonist or compound that increases endogenous production of melatonin in the human is administered to a human in an immediate-release formulation.  
     
     
         6 . A method according to claims  1 ,  2 ,  3  or  4  wherein exogenous melatonin, melatonin agonist or compound that increases endogenous production of melatonin in the human is administered to a human in a delayed-release formulation  
     
     
         7 . A method according to claims  1 ,  2 ,  3  or  4  wherein exogenous melatonin, melatonin agonist or compound that increases endogenous production of melatonin in the human is administered to a human in a sustained-release formulation.  
     
     
         8 . A method according to claims  1 ,  2 ,  3  or  4  wherein exogenous melatonin, melatonin agonist or compound that increases endogenous production of melatonin in the human is administered to a human in any combination of an immediate-release formulation, a delayed-release formulation or a sustained-release formulation.  
     
     
         9 . A method for achieving a circadian rhythm phase-delaying effect in a human, the method comprising the step of administering to the human an amount of melatonin, melatonin agonist or compound that increases endogenous production of melatonin in the human, wherein said administration produces in the human a plasma melatonin or agonist concentration of greater than quiescent melatonin or equivalent agonist levels during the time interval from about CT 18 to about CT 6 than from the time interval from about CT 6 to about CT 18.  
     
     
         10 . A method according to  claim 9  wherein melatonin, melatonin agonist or compound that increases endogenous production of melatonin in the human is administered after CT 18 and prior to about CT 1.  
     
     
         11 . A method for alleviating a circadian rhythm disorder in a human, the method comprising the step of achieving a circadian phase-delaying effect in the human according to the method of claims  1 ,  2 ,  3  or  4 .  
     
     
         12 . The method of  claim 11  wherein the circadian rhythm disorder is jet lag.  
     
     
         13 . The method of  claim 11  wherein the circadian rhythm disorder is winter depression.  
     
     
         14 . The method of  claim 11  wherein the circadian rhythm disorder is a sleep disorder.  
     
     
         15 . The method of  claim 14  wherein the sleep disorder is schedule-induced.  
     
     
         16 . The method of claims  14  or  15  wherein the sleep disorder is delayed sleep phase syndrome or advanced sleep phase syndrome.  
     
     
         17 . The method of  claim 11  wherein the circadian rhythm disorder is a free-running circadian rhythm disorder.  
     
     
         18 . A method for alleviating a circadian rhythm disorder in a human, the method comprising the step of achieving a circadian phase-delaying effect in the human according to the method of claims  9  or  10 .  
     
     
         19 . The method of  claim 18  wherein the circadian rhythm disorder is jet lag.  
     
     
         20 . The method of  claim 18  wherein the circadian rhythm disorder is winter depression.  
     
     
         21 . The method of  claim 18  wherein the circadian rhythm disorder is a sleep disorder.  
     
     
         22 . The method of  claim 21  wherein the sleep disorder is schedule-induced.  
     
     
         23 . The method of claims  21  or  22  wherein the sleep disorder is delayed sleep phase syndrome or advanced sleep phase syndrome.  
     
     
         24 . The method of  claim 18  wherein the circadian rhythm disorder is a free-running circadian rhythm disorder.