Advanced Circadian Phase in Mania and Delayed Circadian Phase in Mixed Mania and Depression Returned to Normal after Treatment of Bipolar Disorder

Abstract

Disturbances in circadian rhythms have been suggested as a possible cause of bipolar disorder (BD). Included in this study were 31 mood episodes of 26 BD patients, and 18 controls. Circadian rhythms of BD were evaluated at admission, at 2-week intervals during hospitalization, and at discharge. All participants wore wrist actigraphs during the studies. Saliva and buccal cells were obtained at 8:00, 11:00, 15:00, 19:00, and 23:00 for two consecutive days. Collected saliva and buccal cells were used for analysis of the cortisol and gene circadian rhythm, respectively. Circadian rhythms had different phases during acute mood episodes of BD compared to recovered states. In 23 acute manic episodes, circadian phases were ~7hour advanced (equivalent to ~17hour delayed). Phases of 21 out of these 23 cases returned to normal by ~7hour delay along with treatment, but two out of 23 cases returned to normal by ~17hour advance. In three cases of mixed manic episodes, the phases were ~6-7hour delayed. For five cases of depressive episodes, circadian rhythms phases were ~4-5hour delayed. After treatment, circadian phases resembled those of healthy controls. Circadian misalignment due to circadian rhythm phase shifts might be a pathophysiological mechanism of BD.

Keywords: Bipolar disorders; Circadian dysregulation; Circadian rhythm; Phase shift.

Fig. 1

The shifting of acrophases of circadian rhythms in bipolar disorder patients. Note that the acrophase is the timing of the peak of the best-fitting sine curve. (a) The acrophase transitions of salivary cortisol circadian rhythms in bipolar patients compared to controls as the circadian peaks shifted in timing. (b) The acrophase transitions of the relative PER1/ARNTL expression circadian rhythms in bipolar patients compared to controls. The outer circular axis indicates the clock time of each acrophase assessment for each patient. Acrophases of circadian rhythms of bipolar patients were observed over the course of hospitalization. Evaluation was performed at acute states (near start of hospitalization), and every two weeks into recovery states (at the end of hospitalization). The arrow presents the direction of change in acrophase of the circadian rhythm from the acute state to the recovery state of each patient. If the duration of hospitalization was no longer than 2 weeks, there were only initial and final assessments, so the acrophase arc is an arrow that has a solid circle at the time of the first acute acrophase assessment and the head of the arrow pointing to the recovery acrophase. If the duration of hospitalization was longer than 2 weeks, there were sometimes intermediate and final assessments, with acrophases illustrated as two or three arrow heads along the arc. Red and orange arrows indicate the shifting of acrophase of circadian rhythms in manic episodes, green arrows indicate that of mixed episodes, and blue arrows indicate that of depressive episodes. The gray sector indicates the range of acrophases for the healthy controls. The radius of each arc was arbitrarily chosen to contrast the different groups of participants, and does not represent the amplitudes of the circadian rhythms.

Fig. 2

Mean biochemical circadian rhythms in healthy controls (N = 18). (a) Circadian rhythms of salivary cortisol in healthy controls. (b) Circadian rhythms of relative PER1/ARNTL expression levels in healthy controls. Black dots indicate mean ± SEM, curved black lines indicate the fitted sine curves of mean values, and broken red lines indicate the timing of the acrophases of each circadian rhythm.

Fig. 3

Mean biochemical circadian rhythms in manic episodes (majority, N = 21 episodes). (a) Circadian rhythms of salivary cortisol in manic episodes (majority). (b) Circadian rhythms of relative PER1/ARNTL expression levels in manic episodes (majority). Black dots indicate mean ± SEM, curved black lines indicate the fitted sine curves of mean values, and broken red lines indicate acrophases of each circadian rhythms.

Fig. 4

Mean biochemical circadian rhythms in manic episodes (minority, N = 2 episodes). (a) Circadian rhythms of salivary cortisol in manic episodes (minority). (b) Circadian rhythms of relative PER1/ARNTL expression levels in manic episodes (minority). Black dots indicate mean ± SEM, curved black lines indicate the fitted sine curves of mean values, and broken red lines indicate acrophases of each circadian rhythms.

Fig. 5

Mean biochemical circadian rhythms in mixed manic episodes (N = 3 episodes). (a) Circadian rhythms of salivary cortisol in mixed manic episodes. (b) Circadian rhythms of relative PER1/ARNTL expression levels in mixed manic episodes. Black dots indicate mean ± SEM, curved black lines indicate the fitted sine curves of mean values, and broken red lines indicate acrophases of each circadian rhythms.

Fig. 6

Mean biochemical circadian rhythms in depressive episodes (N = 5 episodes). (a) Circadian rhythms of salivary cortisol in depressive episodes. (b) Circadian rhythms of relative PER1/ARNTL expression levels in depressive episodes. Black dots indicate mean ± SEM, curved black lines indicate the fitted sine curves of mean values, and broken red lines indicate acrophases of each circadian rhythms.

Fig. 7

Hypothesis on circadian rhythm shift model of bipolar disorder. Circadian phase orientations had distinct abnormalities in acute manic episodes versus mixed episodes versus depressive episodes. The phase disturbances resolved through advance or delay to recover the normal phase orientation after treatment.