patients with non-24-hour sleep  wake rhythm disorder ( n24swd ) exhibit a sleep pattern that is asynchronous with the external light  dark cycle , typically involving a cycling , relapsing  remitting pattern of sleep disturbances , including nighttime insomnia and daytime sleepiness . here , we report the case of a patient with n24swd comorbid with major depressive disorder , who was successfully treated with a low dose of aripiprazole . a 47-year - old female presented with an 8-year complaint of difficulty falling asleep and waking up in the morning . the patient was diagnosed with major depressive disorder at the age of 35 years and was treated with various antidepressants since that time . at the age of 40 years , the patient s sleep ramelteon 8 mg / d and then melatonin 1 mg / d were administered , but these did not provide effective treatment . in january 2016 , after treatment with aripiprazole 3 mg / d in the morning for 4 weeks , the patient s sleep her sleep  wake cycle remained synchronized when the same dose of aripiprazole was administered for at least 6 months . although the detailed mechanism of action is unclear , aripiprazole may be an appropriate treatment for patients with circadian rhythm sleep  wake disorders . wake disorder ( crswd ) characterized by an inability of the endogenous circadian rhythm to be entrained to the external light n24swd patients typically exhibit an intrinsic rhythm longer than 24 h , and a cycling , relapsing  remitting pattern of sleep disturbances , including nighttime insomnia and daytime sleepiness , arising from internal desynchronization.1,2 interestingly , previous studies reported that mood disorders , including major depressive disorder ( mdd ) and bipolar disorder , are highly comorbid in reported n24swd patients.2,3 these findings suggest that certain pathophysiological relationships may exist between mood disorders and n24swd.4 however , no reports have described effective treatment strategies for mood disorders with crswds . aripiprazole is a second - generation antipsychotic ( sga ) with the unique profile of a dopamine partial agonist . regarding the efficacy of aripiprazole for crswd comorbid with mood disorder , only one delayed sleep wake phase disorder ( dswpd ) case with mdd5 and one complex crswd case with bipolar disorder6 have been reported , with both reports suggesting a phase - modulating effect of aripiprazole . dswpd is another crswd , defined by an abnormally late sleep period compared with conventional or socially desirable times . dswpd has an onset mechanism similar to that of n24swd , and some patients progress from dswpd to n24swd.2 in the current study , we report a case of a sighted n24swd patient with mdd whose sleep written informed consent was obtained from the patient for the publication of this case and accompanying images . a 47-year - old female presented with an 8-year complaint of difficulty falling asleep and waking up in the morning . she visited our hospital ( tokyo women s medical university hospital ) for the first time in august 2004 and was diagnosed with mdd according to diagnostic and statistical manual of mental disorders , fourth edition , text revision ( dsm - iv - tr ) criteria,7 exhibiting depressed mood , markedly diminished interest , and loss of energy . the patient had no history of problems with the use of alcohol and other substances . pharmacological treatment with antidepressants , including paroxetine , milnacipran , fluvoxamine , and duloxetine , was administered alternately . however , her depressive symptoms showed repeated exacerbation , and she was unable to work regularly . after a 3-month period of hospitalization for depression in 2007 , the patient stopped working and exhibited social withdrawal . the patient exhibited depression with moderate severity , as indicated by a clinical global impression - severity scale ( cgi - s)8 score of 4.0 . the moderate depressive state continued from that time . at the age of 40 years ( in 2009 ) , the patient s sleep wake cycle began to extend , independently of changes in depressive symptoms . in december 2014 , she was diagnosed with n24swd using the international classification of sleep disorders , third edition ( icsd-3).9 at that time , she was taking 40 mg / d of duloxetine ( in the morning ) , but no other antidepressants or sedatives / hypnotics . ramelteon 8 mg / d ( at 7 pm ) was administered , and sleep hygiene education was provided , but these treatments did not positively affect circadian dysregulation . in june 2015 , the patient began taking melatonin 1 mg / d ( at 7 pm ) , but this treatment also had no effect . calculated from sleep onset and offset time using sleep diary data between september 2014 and november 2015 , the mean ( standard deviation [ sd ] ) time of the patient s sleep , awake , and sleep  wake cycle were 12.9 ( 5.2 ) , 20.5 ( 7.3 ) , and 33.4 ( 10.2 ) h , respectively . in december 2015 , aripiprazole 3 mg / d ( after morning meal ) was administered , primarily to improve the loss of energy . after treatment for 4 weeks ( in the middle of january 2016 ) , the patient s sleep subsequently , the patient fell asleep between 12 midnight and 3 am and awoke between 8 am and 11 am ( figure 1 ) , similar to her sleep  wake pattern before she was diagnosed with n24swd . although the patient s depressive symptoms , including loss of energy , were not improved by treatment with aripiprazole ( a cgi - s score of 4.0 ) , her sleep  wake cycle remained synchronized on the same dose of aripiprazole for at least 6 months , and the mean ( sd ) time of the patient s sleep , awake and sleep  wake cycle were 9.9 ( 2.1 ) , 14.3 ( 2.7 ) and 24.2 ( 3.0 ) h , respectively ( calculated using sleep diary data between february 2016 and july 2016 ) . to our knowledge , this is the first case report showing an effect of aripiprazole on n24swd comorbid with mdd . in this case , depression preceded the onset of n24swd . thus , the patient s social withdrawal as a result of depressive symptoms may have affected the development of n24swd . in addition , the use of antidepressants may also have altered sleep architecture and/or phase shift . however , the patient s prolonged sleep wake cycle lasted for > 6 years , independently of the severity of depressive symptoms or differences in antidepressants used . moreover , the patient s social withdrawal did not improve after the administration of aripiprazole . additionally , it should be noted that the patient s depressive symptoms did not show any significant improvement , in contrast to the drastic change in sleep therefore , it is unlikely that an augmentation effect of aripiprazole on depression indirectly improved n24swd . rather , our findings suggest that aripiprazole may have directly affected the internal circadian rhythm . therapeutic interventions for n24swd should be targeted at entraining the patient s circadian pacemaker at an appropriate phase relative to the environmental light  dark cycle . morning light therapy has been used in a number of cases with n24swd.1013 as a pharmacological treatment , melatonin , which can induce phase shifts of the human circadian pacemaker , has been used in patients with n24swd . melatonin therapy has been reported to be efficacious for patients with n24swd in open - label studies.1315 the melatonin receptor agonist ramelteon is an alternative treatment option . regarding the efficacy of ramelteon for n24swd , a small case series with two patients has been previously reported.16 it is unclear why melatonin and its synthetic agonist did not improve the sleep  wake cycle in the current case . one possibility is that melatonin and ramelteon may not have been administered at the most appropriate time of day . in the current study , we did not measure melatonin to evaluate dim - light melatonin onset , or deep body temperature , which could have indicated more appropriate timing for taking melatonin or ramelteon . however , unlike idiopathic crswd , crswd comorbid with mood disorders may require a specialized treatment approach that includes the use of lithium17 or aripiprazole . wake rhythm is a clinically important issue . in recent years , as a circadian rhythm adjustment factor other than melatonin , several studies have suggested that dopamine and serotonin regulate the circadian rhythm by coordinating with melatonin secretion.1823 aripiprazole , a partial agonist of dopamine and serotonin , can modulate both dopamine and serotonin through d2 and 5-hydroxytryptamine ( 5-ht)-1a receptors when used at low doses.24,25 in addition , aripiprazole can secondarily increase hypothalamic histamine release , which can promote wakefulness.26 furthermore , treatment with aripiprazole has been reported to increase the level of gsk-3 phosphorylation.27 through the inhibition of gsk-3 , aripiprazole can promote proteasome - mediated degradation of rev - erb and inhibit the transcription of the clock gene bmal1 , which has the potential to shorten the sleep . it would be useful to ascertain whether aripiprazole is effective for non - crswd patients exhibiting difficulty waking up , long sleep duration , or excessive daytime sleepiness . further research with a larger number of cases will be needed to clarify the effects of aripiprazole on n24swd . severe crswd is relatively common , particularly among patients with mood disorders in clinical situations . the current study suggests that aripiprazole may be an appropriate treatment choice for patients with crswds .
backgroundpatients with non-24-hour sleep  wake rhythm disorder ( n24swd ) exhibit a sleep pattern that is asynchronous with the external light  dark cycle , typically involving a cycling , relapsing  remitting pattern of sleep disturbances , including nighttime insomnia and daytime sleepiness . here , we report the case of a patient with n24swd comorbid with major depressive disorder , who was successfully treated with a low dose of aripiprazole.case presentationa 47-year - old female presented with an 8-year complaint of difficulty falling asleep and waking up in the morning . the patient was diagnosed with major depressive disorder at the age of 35 years and was treated with various antidepressants since that time . at the age of 40 years , the patient s sleep  wake cycle began to extend without exacerbation of depressive symptoms . 
 the patient was diagnosed with n24swd at the age of 43 years . 
 ramelteon 8 mg / d and then melatonin 1 mg / d were administered , but these did not provide effective treatment . in january 2016 , after treatment with aripiprazole 3 mg / d in the morning for 4 weeks , the patient s sleep 
 wake cycle became markedly synchronized to the environmental light 
 dark cycle . 
 her sleep  wake cycle remained synchronized when the same dose of aripiprazole was administered for at least 6 months.conclusiontreatment-refractory asynchrony of the sleep 
 wake cycle in an n24swd patient with depression was successfully treated with aripiprazole . 
 although the detailed mechanism of action is unclear , aripiprazole may be an appropriate treatment for patients with circadian rhythm sleep  wake disorders .